Clinical trial NCT03301636
Conditions: Melanoma
Keywords: Melanoma, Metastaic Melanoma
Sponsor: NewLink Genetics Corporation
Start date: 2017-12-08; Completion date: 2019-11-04
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an adaptive clinical trial that includes a dose escalation phase followed by a randomized controlled Phase 3 trial. The purpose of the dose escalation phase is to establish the Phase 3 dose of indoximod in combination with pembrolizumab or nivolumab in subjects with unresectable or metastatic melanoma and evaluate PK. Subsequently the efficacy, safety and tolerability of indoximod plus pembrolizumab or nivolumab versus placebo plus pembrolizumab or nivolumab will be studied in subjects with unresectable or metastatic melanoma in the Phase 3 portion of the trial.

The phase 3 study will not proceed per Sponsor decision.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Pembrolizumab intervention 2: Nivolumab intervention 3: Indoximod
Intervention descriptions: intervention 1: Pembrolizumab will be administered intravenously every 3 weeks starting on day 1. intervention 2: Nivolumab will be administered intravenously every 2 weeks starting on day 1. intervention 3: Indoximod will be administered orally every 12 hours starting at Day 1

Protocol documents:
Prot_000.pdf: 
 
CONFIDENTIAL NOT FOR DISTRIBUTION  
(see confidentiality statement page 3) 
 
 
PROTOCOL NUMBER: NLG2107 
TITLE: A Phase 2/3 (Adaptive Design) Study of the 
Concomitant Administration of Indoximod or 
Placebo plus Pembrolizumab or Nivolumab in 
Adult Patients with Unresectable Stage III or Stage 
IV Malignant Melanoma 
 STUDY PHASE: 2/3 
INVESTIGATIONAL 
PRODUCT: 
 
INDOXIMOD  
IND # 
 
CLINICALTRIALS.GOV# 
 
SPONSOR: 
NCT03301636 
 
NewLink Genetics Corporation 
2503 South Loop Drive, Suite 5100 
Ames, IA 50010 
STUDY DIRECTOR: 
 
 
 
SAFETY MEDICAL 
MONITOR: 
Eugene Kennedy, MD 
Chief Medical Officer 
NewLink Genetics Corporation 
 
Eugene Kennedy, MD 
Chief Medical Officer 
NewLink Genetics Corporation 
PROTOCOL REVISION: 
VERSION DATE: 
 
Version 4.0 Global 
27-AUG-2018 
 




CONFIDENTIAL 
 
NLG2107 Version 4.0 
 
3 
CONFIDENTIALITY STATEMENT 
 
This document contains confidential information that is proprietary to NewLink Genetics 
Corporation (NewLink). You may only disclose the contents to study personnel under your 
supervision who need to know the contents for the purpose of conducting a clinical study, in 
addition to your IRB or other Committees for evaluation of the investigational drug as appropriate 
under the following condition: the contents of this document must remain confidential and may 
not be disclosed to any other person or entity without prior written permission from NewLink. 
This will not apply to disclosure that is required by governmental regulations or laws; however, 
you must promptly notify NewLink of any such disclosure. Any supplemental information that 
may be added or appended to this document is also confidential and proprietary to NewLink and 
must be treated in the same manner. 
 
 
 
 


CONFIDENTIAL 
 
NLG2107 Version 4.0 
 
4 
INVESTIGATOR ACKNOWLEDGEMENT 
I have received and read the Investigator’s Brochure for indoximod and this protocol NLG2107, 
including all appendices, and agree to make all reasonable efforts to adhere to the protocol. I agree 
to conduct the study in compliance with all applicable US FDA regulations (including 21 CFR 
Parts 312, 50 and 54), ICH Good Clinical Practice (GCP), and any locally applicable regulations. I 
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol. 
I agree that, prior to the commencement of this study, I must obtain all required Institutional 
approvals including Independent Ethics Committee/ Institutional Review Board associated with 
the clinical facility where the study will be conducted for this protocol and the informed consent 
document.  
I will provide all study personnel under my supervision with copies of this protocol, the indoximod 
Investigator’s Brochure, and access to all study-related information provided by the Sponsor and 
designated CRA. I will discuss this study-related information with my staff to ensure that they are 
fully informed about the investigational product and the protocol. 
I agree to provide all Subjects with a signed and dated copy of the informed consent document, as 
required by FDA regulations and ICH GCP. I further agree to report to NewLink Genetics any 
adverse events in accordance with the terms of this protocol, as per the applicable regulations from 
US FDA regulation 21 CFR 312.64 where applicable. 
  
  
 
 
 
 
 
 
Principal Investigator Printed Name 
 
Site Number 
  
 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 


CONFIDENTIAL 
 
NLG2107 Version 4.0 
 
5 
Protocol Amendment Summary of Changes Table 
  
DOCUMENT HISTORY 
Document 
Date 
Amendment Version 4.0 
27-AUG-2018 
Amendment Version 3.0 Global 
30-MAR-2018 
Amendment Version 2.0 Global (2.1 UK Specific) 
28-DEC-2017 
Amendment Version 2.0 
07-NOV-2017 
Amendment Version 1.1 
18-SEP-2017 
Original Protocol (Version 1.0) 
21-AUG-2017 
 
Amendment V4.0, 27-AUG-2018 
 
Overall Rationale for the Amendment: 
1. To modify the protocol to reflect only the phase 2 dose escalation portion of the study is 
proceeding.  The double-blind phase 3 portion will no longer be implemented.  
2. To allow the transition of current subjects on the Phase 2 dose level 1 (600mg) 
indoximod dose cohort to transition from the indoximod HCl F1 tablets over to the 
indoximod HCl F2 tablets. 
3. To make minor edits and administrative changes 
 
Summary of Revisions 
 
1. Cover page and running head: Updated protocol version # and date 
2. Minor administrative edits throughout 
3. Added the statement “With protocol Version 4: The phase 3 study will not proceed.” to 
all applicable sections: 
a. Sections 1.1 and 1.2, 1.3.3, 1.3.4, and 1.3.5 
b. Section 2.1 
c. Section 3 
d. Sections 4.1, 4.2.2, 4.3, and 4.4.2 
e. Section 6, 6.1.1, 6.3.1, 6.3.2, 6.3.3, and 6.11 
f. Section 7.2.7, 7.2.8, and 7.7.2 
g. Section 8.1, 8.2.1, 8.4.1, 8.5.1, and 8.5.2.2 
4. In Section 2.1 Study Rationale, added “The sponsor has decided not to pursue the Phase 3 
portion of the trial given the recent announcement of the negative Phase 3 trial results 
observed in melanoma patients with another IDO inhibitor currently in development.  At 
this time, further development of indoximod in melanoma is pending additional data from 
smaller scale trials.” 
5. In Section 6.1.1, clarified that with protocol Version 4, subjects on the Phase 2 dose level 
1 (600mg) will be transitioned over to the indoximod HCl F2 tablets after re-consent. 
6. In Section 6.7, added information regarding NewLink Genetics’ expanded access 
program. 
 


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NLG2107 Version 4.0 
 
6 
Table of Contents 
1. 
PROTOCOL SUMMARY ................................................................................................... 9 
1.1. 
Synopsis .......................................................................................................................................................... 9 
1.2. 
Study Schema............................................................................................................................................... 11 
1.3. 
Schedule of Activities (SoA) ........................................................................................................................ 13 
1.3.1. 
Phase 2 Schedule A: Pembrolizumab Q3 weeks plus Indoximod Q12 hours until toxicity/ progression. 13 
1.3.2. 
Phase 2 Schedule B:  Nivolumab Q2 weeks plus Indoximod Q12 hours until toxicity/ progression. ...... 15 
1.3.3. 
Phase 3 Schedule A: Pembrolizumab Q3 weeks plus Indoximod/Placebo Q12 hours until toxicity/ 
progression. - With protocol Version 4: The phase 3 study will not proceed. ........................................................ 17 
1.3.4. 
Phase 3 Schedule B:  Nivolumab Q2 weeks plus Indoximod/Placebo Q12 hours until toxicity/ 
progression.  - With protocol Version 4: The phase 3 study will not proceed. ....................................................... 19 
1.3.5. 
Phase 3 Schedule C:  Nivolumab Q4 weeks plus Indoximod/Placebo Q12 hours until toxicity/ 
progression. - With protocol Version 4: The phase 3 study will not proceed. ........................................................ 21 
2. 
INTRODUCTION............................................................................................................... 23 
2.1. 
Study Rationale ........................................................................................................................................... 23 
2.2. 
Background .................................................................................................................................................. 24 
2.2.1. 
Systemic Therapy for Metastatic Malignant Melanoma ........................................................................... 25 
2.2.2. 
PD-1 Checkpoint Inhibition for Melanoma ............................................................................................... 26 
2.2.3. 
 ...................................................................... 26 
2.2.4. 
 ................................................................ 27 
2.3. 
Benefit/Risk Assessment ............................................................................................................................. 28 
3. 
OBJECTIVES AND ENDPOINTS ................................................................................... 29 
4. 
STUDY DESIGN ................................................................................................................. 31 
4.1. 
Overall Design ............................................................................................................................................. 31 
4.2. 
Scientific Rationale for Study Design ........................................................................................................ 32 
4.2.1. 
Phase 2 Portion ......................................................................................................................................... 33 
4.2.2. 
Phase 3 Portion - With protocol Version 4: The phase 3 study will not proceed. .................................... 37 
4.3. 
Justification for Dose................................................................................................................................... 38 
4.4. 
End of Study Definition .............................................................................................................................. 38 
4.4.1. 
End of Treatment/Off Study ..................................................................................................................... 38 
4.4.2. 
End of Study ............................................................................................................................................. 38 
5. 
STUDY POPULATION ..................................................................................................... 39 
5.1. 
Inclusion Criteria ........................................................................................................................................ 39 
5.2. 
Exclusion Criteria ....................................................................................................................................... 41 
5.3. 
Lifestyle Considerations .............................................................................................................................. 42 
5.3.1. 
Meals and Dietary Restrictions ................................................................................................................. 42 
5.3.2. 
Photosensitivity ........................................................................................................................................ 42 
5.4. 
Screen Failures ............................................................................................................................................ 42 
6. 
STUDY INTERVENTION ................................................................................................. 44 
6.1. 
Study Intervention(s) Administered .......................................................................................................... 45 
6.1.1. 
Indoximod ................................................................................................................................................ 45 
6.1.2. 
Indoximod Administration ....................................................................................................................... 46 
6.1.3. 
Nivolumab (Opdivo®) ............................................................................................................................. 46 
6.1.4. 
Pembrolizumab (Keytruda®) ................................................................................................................... 47 
6.1.5. 
Immune Checkpoint Inhibitor (Pembrolizumab/Nivolumab) Administration ........................................... 47 
6.2. 
Preparation/Handling/Storage/Accountability ......................................................................................... 47 


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6.3. 
Measures to Minimize Bias: Randomization and Blinding ..................................................................... 48 
6.3.1. 
Randomization with use of IVRS/IWRS - With protocol Version 4: The phase 3 study will not proceed. . 
 
 .................................................................................................................................................................. 48 
6.3.2. 
Breaking the Blind (IVRS/IWRS) - With protocol Version 4: The phase 3 study will not proceed. ....... 48 
6.3.3. 
Unintentional / Accidental Unblinding - With protocol Version 4: The phase 3 study will not proceed. 48 
6.4. 
Study Intervention Compliance ................................................................................................................. 49 
6.5. 
Concomitant Therapy ................................................................................................................................. 49 
6.5.1. 
Live Vaccines ........................................................................................................................................... 49 
6.5.2. 
CYP inhibitors/inducers ........................................................................................................................... 49 
6.5.3. 
Anticancer Therapy .................................................................................................................................. 49 
6.5.4. 
Steroid Therapy ........................................................................................................................................ 50 
6.5.5. 
Monoamine oxidase inhibitors and Serotonin Syndrome (SS) ................................................................. 50 
6.6. 
Dose Modification ........................................................................................................................................ 50 
6.6.1. 
Pembrolizumab Dosing Modifications ..................................................................................................... 51 
6.6.2. 
Nivolumab Dosing Modifications ............................................................................................................ 51 
6.6.3. 
Treatment of Checkpoint Inhibitor Related Infusion Reaction ................................................................. 51 
6.6.4. 
Management of Adverse Events of Interest (Immune Related Adverse Events) ...................................... 51 
6.6.5. 
Rules for Stopping and Restarting Indoximod ......................................................................................... 52 
6.7. 
Intervention after the End of the Study..................................................................................................... 53 
6.8. 
Discontinuation of Study Intervention ...................................................................................................... 53 
6.9. 
Participant Discontinuation/Withdrawal from the Study ....................................................................... 54 
6.10. 
Lost to Follow Up ........................................................................................................................................ 55 
6.11. 
Discontinuation of Entire Study ................................................................................................................. 55 
7. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................. 56 
7.1. 
Screening and baseline examination .......................................................................................................... 56 
7.2. 
Treatment period ......................................................................................................................................... 57 
7.2.1. 
Physical Examination ............................................................................................................................... 57 
7.2.2. 
Vital signs ................................................................................................................................................. 57 
7.2.3. 
Height and weight ..................................................................................................................................... 57 
7.2.4. 
Performance status .................................................................................................................................... 57 
7.2.5. 
Laboratory evaluations ............................................................................................................................. 58 
7.2.6. 
Pregnancy and assessments of fertility ..................................................................................................... 59 
7.2.7. 
 ...................................................................................................................................... 59 
7.2.8. 
Electrocardiogram (ECG) ......................................................................................................................... 59 
7.2.9. 
End of treatment and premature withdrawal visit ..................................................................................... 59 
7.2.10. 
Follow-Up after End of Treatment ...................................................................................................... 60 
7.3. 
Efficacy Assessments ................................................................................................................................... 60 
7.3.1. 
Tumor Assessments .................................................................................................................................. 60 
7.3.2. 
Response Measurements ........................................................................................................................... 62 
7.4. 
Safety Assessments ...................................................................................................................................... 63 
7.5. 
Adverse Events and Serious Adverse Events ............................................................................................ 64 
7.5.1. 
AE Definition ........................................................................................................................................... 64 
7.5.2. 
Definition of SAE ..................................................................................................................................... 65 
7.5.3. 
AE and SAE Recording ............................................................................................................................ 67 
7.5.4. 
Assessment of Severity ............................................................................................................................. 67 
7.5.5. 
Assessment of Causality ........................................................................................................................... 67 


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7.5.6. 
Follow Up of AEs and SAEs .................................................................................................................... 68 
7.5.7. 
Reporting of SAEs .................................................................................................................................... 68 
7.5.8. 
Exposure to Study Drug During Pregnancy ............................................................................................. 69 
7.6. 
Treatment of Overdose ............................................................................................................................... 69 
7.7. 
Pharmacokinetics ........................................................................................................................................ 69 
7.7.1. 
 
 
 
.  .................................................................................................................................................................. 71 
7.8. 
Biomarkers ................................................................................................................................................... 72 
8. 
STATISTICAL CONSIDERATIONS .............................................................................. 72 
8.1. 
Statistical Hypotheses.................................................................................................................................. 72 
8.2. 
Sample Size Determination ......................................................................................................................... 73 
8.2.1. 
Sample Size Considerations - With protocol Version 4: The phase 3 study will not proceed. ................. 73 
8.3. 
Populations for Analyses ............................................................................................................................. 76 
8.4. 
Statistical Analyses ...................................................................................................................................... 77 
8.4.1. 
Efficacy Analyses ..................................................................................................................................... 77 
8.4.2. 
Safety Analyses ........................................................................................................................................ 77 
8.4.3. 
Other Analyses ......................................................................................................................................... 80 
8.5. 
Interim Analyses .......................................................................................................................................... 80 
8.5.1. 
Interim Analysis Plan - With protocol Version 4: The phase 3 study will not proceed. ........................... 80 
8.5.2. 
Independent Data Safety Monitoring Committee (DSMC) ...................................................................... 82 
8.6. 
Changes in the Conduct of the Study or Planned Analyses ..................................................................... 83 
9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 84 
9.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................................................ 84 
9.2. 
Appendix 2: Clinical Laboratory Tests ..................................................................................................... 88 
9.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting .................................................................................................................................................................... 89 
9.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ................................. 90 
9.5. 
Appendix 5: ECOG Performance Status................................................................................................... 92 
9.6. 
Appendix 6: NYHA Functional Classification .......................................................................................... 93 
9.7. 
Appendix 7: RECIST 1.1 Guideline ........................................................................................................... 94 
9.8. 
Appendix 8: List of Abbreviations ............................................................................................................. 95 
10. 
REFERENCES ................................................................................................................ 96 
 




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10 
time of analysis will be censored based on the last recorded date 
on which the patient was known to be alive. 
Secondary Endpoints:  
Objective response rate: The first tumor assessment test will be 
conducted at 9 weeks (+/- 1 week) followed by assessments every 
9 weeks (+/- 1 week) for duration of study participation. Defined 
as the proportion of subjects who have best response as complete 
response or partial response based on RECIST 1.1. 
 
Safety and tolerability:  
As assessed by percentage of subjects with adverse events, 
through up to 30 days after end of treatment and 
 
As assessed by percentage of subjects with changes in laboratory 
parameters, through up to 30 days after end of treatment. 
Number of Participants:  
Phase 2 
12-18 subjects (depending on dose escalation) – 3 to 6 per dose level 
Phase 3 
600 subjects (With protocol Version 4: The phase 3 study will not 
proceed.) 
 
Treatment and Study Duration: 
The maximum treatment duration for individual patients will be 24 months of treatment. 
The duration of the overall study is projected to be 34 months (from first patient first visit to last 
patient last visit). 
 


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11 
1.2. 
Study Schema 
 
Phase 2 
Table below summarizes dose levels of indoximod and pembrolizumab or nivolumab for the 
Phase 2 study.  The Phase 2 study will be completed in the United States and therefore the fixed 
doses of pembrolizumab and nivolumab will be used as provided below.  
 
Dose Level 
Indoximod (oral) Pembrolizumab Dose (IV) 
Nivolumab Dose (IV) 
1 
600 mg Q12 hours 
200 mg IV Q3 weeks 
240 mg IV Q2 weeks 
2 
1200 mg Q12 hours 
200 mg IV Q3 weeks 
240 mg IV Q2 weeks 
3 
1800 mg Q12 hours 
200 mg IV Q3 weeks 
240 mg IV Q2 weeks 
Dosing regimen: Dosing cycles will be 21 days in length during combination immunotherapy 
(indoximod plus pembrolizumab) and will be 14 days in length during combination 
immunotherapy (indoximod plus nivolumab). Pembrolizumab will be dosed on the 1st day of each 
21-day cycle.  Nivolumab will be dosed on the 1st day of each 14-day cycle. Indoximod will be 
given as a single dose on Cycle 1 Day 1 and then blood for 
testing will be collected at 
designated timepoints for the next 3 days.  Indoximod will then be dosed twice daily on all days 
of each cycle. 
 
Phase 3 - With protocol Version 4: The phase 3 study will not proceed. 
Once a dose for indoximod in combination with pembrolizumab/nivolumab is established in 
Phase 2, an additional 600 patients will be enrolled in a two-arm, randomized, double-blind, 
placebo-controlled, fixed-dose Phase 3 study. Treatment will be initiated using standard of care 
(SOC) immune checkpoint inhibition consisting of pembrolizumab or nivolumab in combination 
with indoximod or placebo.  
 
Three possible treatment schedules are available depending on the checkpoint inhibitor and 
frequency of administration that is chosen by the study physician. 
 
Schedule 
Checkpoint Inhibitor* 
Indoximod/Placebo 
A 
Pembrolizumab IV every 3 weeks 
Given orally every 12 hours 
B 
Nivolumab IV every 2 weeks 
Given orally every 12 hours 
C 
Nivolumab IV every 4 weeks 
Given orally every 12 hours 
 
*Dose to be as per package insert/approved label in country of treatment 
 
 
 


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RANDOMIZATION SCHEMA - With protocol Version 4: The phase 3 study will not 
proceed. 
 
Randomization stratified by: 
• Choice of checkpoint inhibitor (pembrolizumab vs nivolumab) 
• Prior BRAF inhibitor treatment 
• Stage at randomization (Stage III/M1a/M1b vs M1c/M1d) 
Criteria for M1 status: 
M1a – Metastases to skin, subcutaneous, or distant lymph nodes (M1a, M1a(0), and M1a(1)) 
M1b – Metastases to lung (M1b, M1b(0), and M1b(1)) 
M1c – Metastases to all other visceral sites (non-central nervous system) sites (M1c, M1c(0), and 
M1c(1)) 
M1d – Distant metastasis to central nervous system (M1d, M1d(0), and M1d(1)) 
 
 
 
 
 
 
 
 
 
*Standard-of-care dosing of pembrolizumab or nivolumab per country 
 
Note: On study treatment must be initiated within 5 days after randomization. 
 
1:1 Randomization 
 
PD-1 checkpoint inhibitor* 
+ indoximod orally every 12 hours 
 
PD-1 checkpoint inhibitor* 
+ placebo orally every 12 hours 


























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25 
may be curable with current therapy; but stage IV metastatic disease (or relapsed/recurrent disease) 
is highly refractory to therapy. Thus, experimental clinical trials provide an accepted treatment 
option for metastatic or relapsed/refractory melanoma. 
 
In Europe, melanoma is the sixth and seventh most common malignancy in men and women, 
respectively [8]. The median age at diagnosis is 59 years. The incidence of melanoma varies 
between different European countries but the estimated incidence was about 39.6 cases /100,000 
men and 42.5 cases /100,000 women in 2012. In Europe in 2012, the mortality rate was 
approximately 8.8 cases/100,000 in males and 6.9 cases/100.000 in females [8]. The outcome of 
melanoma depends on the stage at presentation [2].  
  
Most patients (84%) with melanoma initially present with stage I or II (localized) disease; 8% have 
stage III (regional) disease; and 4% have stage IV disease (distant metastases) [28]. Of the patients 
who present with localized melanoma, however, up to 12% will eventually develop distant 
metastases [14, 18, 42]. The survival rate for patients with stage IV melanoma is low; from 2001 
to 2007, 85% of patients with distant metastases were not expected to survive 5 years [28]. The 
median survival of patients with stage IV disease is less than 1 year [48, 1]. 
 
Current treatments for metastatic melanoma include systemic therapy, surgery and radiotherapy. 
Spontaneous regression of melanoma has been reported with an incidence of less than 1%. 
Complete resection of isolated metastases to one anatomic site (lung, gastrointestinal tract, bone 
or brain) may occasionally achieve long term survival. Systemic treatment may consist of 
chemotherapy, and/or immunotherapy. Palliative radiotherapy is indicated for symptomatic relief 
of metastases to brain, bones and viscera.  
 
2.2.1. 
Systemic Therapy for Metastatic Malignant Melanoma 
 
Current standard of care – overview. 
Current standard of care for metastatic and unresectable melanoma per the NCCN guidelines [29] 
is to select the appropriate first line systemic therapy based on the individual characteristics of 
each patient.  
 
First line options are: 
Immunotherapy: Anti–programmed death 1 (anti-PD-1) antibodies guidelines [29]: 
• Pembrolizumab (Keytruda®) 
• Nivolumab (Opdivo®) 
 
Targeted therapy if BRAF V600 positive mutation: preferred if clinically needed for early 
response 
Combination therapy BRAF/MEK inhibition provided by either: 
• Dabrafenib/ trametinib  
• Vemurafenib/cobimetinib  
 
Combination therapy with nivolumab (anti-PD1) combined with ipilimumab (CTLA-4) therapy 
produces a better objective response rate (ORR) and median progression-free survival time (PFS), 
than either monotherapy but with significantly higher risk of severe toxicity [38]. Whilst this 


















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34 
Definition of a regimen-limiting toxicity: During dose-escalation, RLTs will be defined as any 
of the following events determined by the Investigator to be possibly related to treatment 
irrespective of outcome: 
• Any Grade 3 or higher (≥ Grade 3) non-hematologic AE that is not clearly related to the 
disease or unrelated intercurrent illness. Fatigue, nausea or vomiting are not RLTs unless 
it precludes administration of the immunotherapy checkpoint standard of care backbone 
therapy (pembrolizumab or nivolumab). Grade 3 elevation in bilirubin, AST, ALT, alkaline 
phosphatase or creatinine will be considered RLT only if resolution to ≤ Grade 2 requires 
more than 21 days. Permanent discontinuation of treatment for elevation in bilirubin, AST, 
ALT, alkaline phosphatase or creatinine is required if parameters for permanent 
discontinuation are met per Prescribing Information for pembrolizumab or nivolumab.  
• Hematological toxicities to include: 
• Grade 4 thrombocytopenia or neutropenia lasting more than 5 days 
• Grade 3 or 4 thrombocytopenia with clinical significant bleeding (i.e., requires 
hospitalization, transfusion of blood products, or other urgent intervention) 
• Grade 3 febrile neutropenia lasting more than 5 days 
• Grade 4 anemia not explained by underlying disease or some other concomitant 
disorder 
• A Grade 3 or greater immune-related severe adverse event that meets the accepted 
criteria for permanent discontinuation of pembrolizumab/nivolumab, as specified under 
the stopping- rules in Section 6.6, is considered a RLT. 
• Any other adverse event possibly related to treatment causing a delay of more than 21 
days. 
 
Note, however, that less severe immune-related toxicity (Grade 2 or greater but not meeting the 
criteria for permanent discontinuation of pembrolizumab/nivolumab), which resolves to Grade 1 
or better with steroid therapy, is not considered a RLT. These toxicities are managed with a delay 
of dosing and administration of corticosteroids (orally or intravenously) until the event improved 
to Grade 1 or lower. However, if, after this management, the event does not improve to Grade 1 
or better, then nivolumab/pembrolizumab and indoximod will be discontinued permanently, and 
the event considered as a RLT. 
 
Otherwise qualifying toxicities that can clearly be attributable to causes other than study treatment, 
such as disease progression or unrelated intercurrent illness, should be excluded as a RLT. 
 
For purposes of the dose escalation in this trial, determination of toxicity for dose escalation 
purposes will be made after the third patient of any cohort has completed the first 28 days of 
combination immunotherapy. 
 
AEs not known and expected from pembrolizumab/nivolumab and not seen in previous 
indoximod trials will be considered regimen toxicities initially. Any Grade 3 or higher 
regimen toxicity mandates a conference call within 3 business days between investigators 
and sponsor to discuss attribution and response. 
 




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36 
• if none of the three patients or 1 or less of the 6 patients in the dose level 3 (1800 mg PO 
every 12 hours) experiences a RLT, dose level 3 will be declared the recommended Phase 
3 dose (RP3D), 
. 
• If two or more patients at a particular dose level experience RLTs and the next lower dose 
has had only 3 patients enrolled, dosing will be de-escalated to the next lower dose and 3 
additional patients will be enrolled so that at least 6 patients have been treated with the 
dose intended as the RP3D dose. 
• In summary, the dose escalation continues until at least two patients among a cohort of six 
patients experience RLT (i.e., ≥ 33% of patients with a RLT at that dose level). The MTD 
informing the recommended dose for the phase 3 from a safety point of view is defined as 
the dose level just below this toxic dose level. 
 
If increase in mean drug exposure after a single dose (AUC (0-inf)) or after multiple Q12 hour doses 
(AUC0-12) from one dose cohort to another is less than 50% of the expected dose-proportional 
increase, then enrollment into the next higher dose cohort may be cancelled subject to Sponsor 
decision following input from the DSMC.  In that case, if the last dose cohort tested included only 
3 patients and a decision is made to cancel enrollment into the next dose cohort based 
 
, 3 more patients will be added to the last dose cohort to test for MTD. 
 
The MTD will be considered the largest dose level at which at most 1 out of 6 patients experiences 
a RLT. If the MTD is not reached at level 3, then no further dose-escalation will be allowed, based 
on the information 
 currently available on indoximod. 
 
Delayed Toxicities: It is possible that some adverse events that would qualify as RLTs during the 
initial evaluation period may not emerge until many months on therapy with indoximod (hence, 
after escalation has already occurred to the next dose step).  Any such late adverse event that may 
still be considered an RLT, the DSMC, study investigators, treating physician, and Sponsor will 
consult to determine if the adverse event qualifies as an RLT.  If it does, it will be dealt with as 
above. However, any patients who were already enrolled at the higher dose will be reduced to the 
dose that triggered the RLT. These patients will continue treatment at the lower dose, but will not 
be evaluable for definition of the RLT (because they received mixed dosing). 
 
4.2.1.2. 
Restarting Pembrolizumab or Nivolumab and Indoximod During Dose 
Escalation  
 
For immunotherapy, certain autoimmune AEs are an expected consequence of successful immune 
stimulation, and may even correlate with tumor response. 
 
In the Phase 1 trials of indoximod, administration of indoximod to patients who previously 
received ipilimumab caused isolated recall hypophysitis. This was managed safely, and all patients 
were successfully re-started on indoximod without other additional toxicity, and were treated for 
>6 months with stable disease. Therefore, it could be stated that the underlying hypothesis of this 
combination therapy is to treat toxicity, manage that toxicity, and then prolong the state of immune 
activation with indoximod, which is previously demonstrated to be less toxic, well tolerated, and 
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Thus, patients with an “on-target”, expected immune-related adverse event, which does not rise to 
the level of permanent discontinuation criteria for pembrolizumab or nivolumab (as defined in 
Section 6.6) and which resolves (to Grade 1 or better) with corticosteroids, may be re-started on 
pembrolizumab or nivolumab and indoximod (same dose) if they meet all of the restarting criteria 
described in Section 6.6. 
 
Isolated hypophysitis, in the absence of other regimen-limiting toxicity, is an expected (on-target) 
toxicity of the combination. It is scored as a RLT for purposes of dose-escalation, but isolated 
hypophysitis will be managed by stopping all study medication, treating with corticosteroids and 
hormone replacement (thyroid and cortisol) until clinically stable, and then (at the judgment of the 
treating investigator) restarting pembrolizumab or nivolumab and indoximod at the same dose if 
clinically stable. This approach was well tolerated in the Phase 1 trial of single-agent indoximod 
by patients who experienced recall hypophysitis. Patients with hypophysitis will remain on 
hormone replacement as long as needed. 
 
Monitoring of RLTs: Monitoring of adverse events will continue until any ongoing event is 
resolved or stabilized. A data safety monitoring committee will provide independent oversight of 
safety and the risk–benefit ratio. 
 
4.2.2. 
Phase 3 Portion - With protocol Version 4: The phase 3 study will not proceed. 
 
Patients will not be enrolled in the Phase 3 portion until all patients in the dose-escalation 
component have completed the RLT determining portion of the Phase 2 aspect of the trial, and the 
recommended Phase 3 dose determined. The independent DSMC and representatives of the 
Sponsor will meet by teleconference to review all toxicity data from the dose-escalation 
component. When all agree on the safety and appropriateness of the indoximod-established Phase 
3 dose, then the Phase 3 portion will begin. Once this has occurred, a letter with the results of this 
teleconference discussion will be sent out providing the established Phase 3 dose and stating 
enrollment into Phase 3 can proceed.  
 
Once a dose for indoximod in combination with pembrolizumab or nivolumab is established in 
Phase 2, an additional 600 patients will be enrolled in a two-arm, randomized double-blind, 
placebo-controlled, fixed-dose Phase 3 study.  
 
The established dose of indoximod (or placebo) will be administered concomitantly with 
pembrolizumab or nivolumab. If pembrolizumab/nivolumab must be stopped due to unacceptable 
pembrolizumab- or nivolumab-related toxicity, then indoximod will also be stopped.  See Section 
6.6 for details. In the case of disease progression or unacceptable toxicity, patients discontinued 
from the study treatment will be followed-up for survival.  
 
The intention in this study is to evaluate the benefit of adding indoximod to the regimen of immune 
checkpoint inhibition. If a subject experiences an immune checkpoint inhibitor-related adverse 
event that requires withdrawal of the checkpoint inhibitor, the subject should also discontinue 
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4.3. 
Justification for Dose 
 
The starting dose of indoximod used in the Phase 2 dose escalation aspect of the protocol is based 
upon the safety data generated in greater than 700 study subjects to date. Indoximod has been dose 
escalated to doses as high as 2000 mg Q12 hr. The largest quantity of safety data has been 
generated at a dose of 1200 mg Q12 hr. No DLT/RLTs have been experienced with indoximod to 
date. Preclinical models in non-human primates indicate that the new formulation of indoximod 
can result in 30-50% increase in drug exposure levels. The starting dose of 600 mg was chosen as 
the dose that would provide an initial exposure range within a safety margin previously explored 
by the 1200 mg Q12 hr capsule formulation even if the current tablet formulation increased 
exposure in humans by as much as 100% compared to the previous capsule formulation. The dose 
will then be escalated according to standard 3+3 escalation rules. The Phase 3 dose will be set 
based upon data generated in Phase 2, along with review of safety 
 data from 
supporting studies including investigations in AML and healthy volunteers. - With protocol 
Version 4: The phase 3 study will not proceed. 
4.4. 
End of Study Definition 
4.4.1. 
End of Treatment/Off Study 
 
End of Treatment:  Subjects who discontinue treatment for any reason (progressive disease or 
other) and continue on follow-up and/or survival checks. Subjects that withdraw consent for 
treatment can still be followed for progressive disease and/or survival. The reason for 
discontinuation of treatment must be documented.  For subjects who withdraw consent, every 
attempt will be made to determine the reason.  Subjects that discontinue for reasons other than 
progressive disease should continue tumor assessments.  
 
All subjects must have an End of Treatment Evaluation regardless of the reason for treatment 
discontinuation.  At the time of the End of Treatment Evaluation Visit, the procedures outlined in 
Section 7.2.9 should be performed. 
 
Off Study: Subjects will be considered off study at the time of death or withdrawal of full consent 
or the study ends. These subjects will not participate in follow-up or survival checks. 
 
4.4.2. 
End of Study 
 
With protocol Version 4: The phase 3 study will not proceed.  
 
The end of study is defined as the date of the last visit of the last participant in the Phase 2 portion 
of the study.  
 




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9. Serum Creatinine ≤ 1.5 x ULN, or creatinine clearance (Ccr) > 60 mL/min based on the 
Cockcroft-Gault equation. 
10. Total bilirubin, amylase and lipase ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, 
total bilirubin ≤ 3 x ULN, with direct bilirubin ≤ 1.5 x ULN) 
11. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≤ 3 x ULN, (in 
subjects with liver metastases, < 5 x ULN) 
12. Serum Albumin ≥ 3 g/dL 
13. Patients must have normal pituitary function as determined by investigator clinical 
judgment. 
14. HIV positive patients who are stable on antiretroviral medication (ART). Patients stable on 
ART are deﬁned as those who have received ART for at least 1 year with no adverse drug 
reactions requiring regular monitoring, no current illnesses or pregnancy, a good 
understanding of lifelong adherence, and evidence of treatment success. Treatment success 
is deﬁned as two consecutive undetectable viral load measures or, in the absence of viral 
load monitoring, rising CD4 counts or CD4 counts above 200 cells/mm3 and an objective 
adherence measure. 
15. Patients with known brain metastases will only be eligible after definitive treatment of 
brain metastases with SBRT or surgery provided that the brain lesions are stable (without 
evidence of progression by imaging for at least 4 weeks before the first dose of study 
treatment), subject is neurologically stable and has had no persistent side effects / 
complications from the treatment,  have no evidence of new or enlarging brain metastases 
confirmed by repeat imaging, and have not required steroids for at least 14 days before 
study treatment.  
16. If female of childbearing potential, must have a negative urine or serum pregnancy test 
within 72 hours prior to receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. If 
female of childbearing potential, must be willing to use an adequate method of 
contraception as outlined in Appendix 4, for the course of the study through minimum of 
4 months (for those who receive pembrolizumab) and a minimum of 5 months (for those 
who receive nivolumab) after the last dose of study medication. Note: Abstinence is 
acceptable if this is the usual lifestyle and preferred contraception for the subject.  
17. If male of childbearing potential, must agree to use an adequate method of contraception 
as outlined in Appendix 4, and not to donate sperm starting with the first dose of study 
therapy through minimum of 4 months (for those who receive pembrolizumab) and a 
minimum of 5 months (for those who receive nivolumab) after the last dose of study 
therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
18. Ability to ingest oral medications 
19. Ability to understand and the willingness to sign a written informed consent document. 
 
 
 
 
 


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5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. Has Ocular Melanoma 
2. Has received prior systemic treatment for unresectable or metastatic melanoma (except 
BRAF directed therapy as noted in inclusion criteria #3).  
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
IDO1 inhibitor or any other antibody or drug specifically targeting checkpoint pathways 
other than anti-CTLA-4 which is permitted in the adjuvant setting.  
4. Has received prior adjuvant therapy, monoclonal antibody or an investigational agent or 
device within 4 weeks or 5 half-lives (whichever is longer) before study Day 1 or not 
recovered (Grade 1 or at baseline) from AEs due to previously administered agents. 
Exception to this rule would be use of bisphosphonates, which is not excluded. 
5. Has received prior radiotherapy within 2 weeks of therapy. Subjects must have recovered 
from all radiation-related toxicities, not require corticosteroids, and not have had radiation 
pneumonitis. A 1-week washout is permitted for palliative radiation (2 weeks of RT) to 
non-CNS disease. 
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days before the first dose of study treatment. 
7. Has known active, uncontrolled brain or CNS metastases and/or carcinomatous meningitis.  
8. History or presence of an abnormal electrocardiogram (ECG) that, in the investigator’s 
opinion, is clinically meaningful.  Screening QTc interval > 480 msec is excluded 
(corrected by Fredericia or Bazett formula).  In the event that a single QTc is > 480 msecs, 
the subject may enroll if the average QTc for the 3 ECGs is < 480 msecs. 
9. Has clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months from first dose of study drug administration, New York Heart 
Association Class III or IV congestion heart failure (see Appendix 6), and arrhythmia 
requiring therapy.  Medically controlled arrhythmia would be permitted. 
10. Has history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to pembrolizumab, nivolumab or tryptophan-containing substances.  
11. Is pregnant or breast-feeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through minimum of 
4 months (for those who receive pembrolizumab) and a minimum of 5 months (for those 
who receive nivolumab) after the last dose of study treatment. 
12. Patients who have active, chronic, or on active treatment for Hep B or Hep C are excluded.  
13. Any other cancer, unless the patient has been disease-free for ≥ 5 years (except treated and 
cured basal-cell or squamous-cell skin cancer, superficial bladder cancer, or treated 
carcinoma in situ of the cervix, breast, or bladder and treated localized prostate cancer with 
undetectable PSA for 2 years). 
14. Patients with laboratory evidence of pancreatitis are excluded. 
15. Has presence of a gastrointestinal condition that may affect drug absorption. 
16. Patients with an active autoimmune disease that has required systemic treatment in past 2 
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs).  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 




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enrolled/randomized. Those who are not eligible for enrollment/randomization or dosing will be 
considered as screening failures.  Data for screen failure reason, eligibility criteria, and 
demography will be captured in the eCRF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This space has intentionally been left blank. 




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Note: Dosing of pembrolizumab and nivolumab will be per approved label in the country the 
patient is treated in.  For example, in the U.S., pembrolizumab will be administered at 200 mg per 
dose and nivolumab will be administered at 240 mg per dose (per package inserts).  For rest of 
world (ROW), pembrolizumab will be administered at 2 mg/kg and nivolumab will be 
administered at 3 mg/kg per dose unless the appropriate health authorities approve an alternate 
dosing regimen. In that case, the approved dosing regimen will be followed.  
6.1. 
Study Intervention(s) Administered 
 
Indoximod 
Oral 
600-1800 mg 
Q12 hours 
Nivolumab 
Intravenous 240 mg, 480 mg, or 3 mg/kg (as 
per package insert/approved label 
in country of treatment) 
Q2 or Q4 weeks 
Pembrolizumab 
Intravenous 200 mg or 2 mg/kg (as per 
package insert/approved label in 
country of treatment) 
Q3 weeks 
 
6.1.1. 
Indoximod  
 
Chemical Name: 
(R)-2-amino-3-(1-methyl-1H-indol-3-yl) propanoic acid 
hydrochloride;  
1-methyl-D-tryptophan hydrochloride 
 
Other Names: 
indoximod, Indoximod Hydrochloride (HCl); 1-methyl-D-
tryptophan HCl; D-1MT HCl 
 
Classification:  
 
Immunomodulatory 
 
Molecular Formula:  
C12H15ClN2O2    M.W.: 254.71 g/mol 
 
Approximate Solubility: 
Highly soluble in water and simulated gastric fluids (SGFs). 
 
Mode of Action: 
 
Inhibition of IDO pathway activity. 
 
How Supplied:        
Indoximod is supplied by NewLink Genetics as Indoximod HCl 
(F1) 600 mg tablets (used for Phase 2 dose level 1) or Indoximod HCl 
(F2) 600 mg tablets (used for Phase 2 dose levels 2 and 3 and Phase 
3).  With protocol Version 4, subjects on Phase 2 dose level 1 will 
be transitioned over to the indoximod HCl F2 tablets after re-
consent. The phase 3 portion of this study will not proceed. 
 
The Indoximod HCl (F1) tablets contain indoximod HCl drug 
substance and the inactive ingredients microcrystalline cellulose, 


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sodium 
croscarmellose, 
magnesium 
stearate, 
hydroxypropyl 
methylcellulose (HPMC), colloidal silicon dioxide, and the film 
coating Opadry® 02A280001 white, which contains HPMC and 
titanium dioxide. 
 
The Indoximod HCl (F2) tablets contain indoximod HCl drug 
substance and the inactive ingredients microcrystalline cellulose, 
sodium 
croscarmellose, 
magnesium 
stearate, 
hydroxypropyl 
methylcellulose (HPMC), colloidal silicon dioxide, and the film 
coating Opadry® II 85F18422 White, which contains polyvinyl 
alcohol, titanium dioxide, polyethylene glycol/macrogol, and talc. 
 
The 600 mg film-coated tablets are white to off white hard tablets 
debossed with “IDX” on one side and bisected by a score on the 
other side. 
 
Storage:         
 
Stored at controlled room temperature (59 - 77°F / 15 - 25°C) 
 
Stability:       
Shelf-life surveillance of the intact bottles is on-going.  
 
Route of Administration:      Oral 
 
 
6.1.2. 
Indoximod Administration 
 
The indoximod tablets are 600 mg each. The number of tablets will be determined by the dose and 
should be taken in the morning and evening. No food should be taken for at least 2 hours before 
and at least 1 hour after administration of the morning and evening doses. The medication should 
be taken twice daily (Q12 hours) in a continuous fashion. Patients should be told to swallow whole 
tablets without breaking, splitting or chewing with a full glass of water. Antacids are also not 
allowed to be taken for at least 1 hour before and 1 hour after administration of the indoximod.  
No specific pre-medications are required. 
 
6.1.3. 
Nivolumab (Opdivo®) 
 
Please refer to the current Prescribing Information and/or Summary of Product Characteristics for 
nivolumab (Opdivo) for details on mechanism of action, 
 risks, and management 
of adverse events. Links are provided for reference. 
 
https://packageinserts.bms.com/pi/pi opdivo.pdf 
 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003985/WC500189765.pdf  
 
 


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6.1.4. 
Pembrolizumab (Keytruda®) 
 
Please refer to the current Prescribing Information and/or Summary of Product Characteristics for 
pembrolizumab (Keytruda) for details on mechanism of action, 
 risks, and 
management of adverse events. Links are provided for reference. 
 
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf  
 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
Product Information/human/003820/WC500190990.pdf  
 
6.1.5. 
Immune Checkpoint Inhibitor (Pembrolizumab/Nivolumab) Administration 
 
The study is designed to evaluate the addition of indoximod, to standard of care checkpoint 
immunotherapy, pembrolizumab or nivolumab. The administration of these agents 
(pembrolizumab/nivolumab) should be done at the direction of the treating physician according to 
the physician’s usual standard of care practices. 
 
Management of risk for autoimmune side effects: 
• Tissue-specific inflammatory events (known as immune related adverse events or 
reactions) can be associated with indoximod and immune checkpoint inhibition treatment. 
• Careful laboratory and symptom monitoring for pituitary dysfunction and pancreatitis is 
warranted based on the prior experience with patients treated with indoximod and 
ipilimumab. 
• Careful monitoring for other potential inflammatory symptoms (including enterocolitis, 
skin reaction, hepatic toxicity, pneumonitis, nephritis, and uveitis) will be also performed. 
• Management of immune-related adverse events from immune checkpoint inhibition and 
indoximod will include administration of corticosteroids (orally or intravenously), a delay 
in a scheduled dose, or discontinuation of therapy. Assigned doses will be delayed in case 
of immune-related adverse event of Grade 2 or higher until the event improves to Grade 
1 or lower. Immune checkpoint inhibition will be restarted at this point and continue every 
3 weeks per protocol. 
• For corticosteroid-refractory side effects, TNF-blocking agents (e.g. infliximab) or other 
immunosuppressive medications (e.g. mycophenolate mofetil) will be administered. 
• Details of algorithmic management will be as described in the respective package inserts 
and Investigators should follow all prescribing information therein. 
6.2. 
Preparation/Handling/Storage/Accountability 
 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 


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accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e. receipt, reconciliation, and final disposition records). 
4. Details for the preparation, handling, storage, and accountability are provided in the 
NLG2107 Pharmacy Manual. Further guidance and information for the final disposition of 
unused study interventions are also provided in the NLG2107 Pharmacy Manual.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization with use of IVRS/IWRS - With protocol Version 4: The phase 3 
study will not proceed. 
 
The Phase 3 portion of the study will randomize 600 patients with a 1:1 ratio into two arms: 
indoximod plus pembrolizumab/nivolumab and placebo plus pembrolizumab/nivolumab.  The 
randomization will be stratified by the choice of checkpoint inhibitor (physician’s choice of 
pembrolizumab or nivolumab), M1 stage at time of randomization (StageIII/M1a/b vs M1c/d), and 
prior BRAF inhibitor treatment of the malignant melanoma. 
 
All participants will be centrally assigned to randomized study intervention using an Interactive 
Voice/Web Response System (IVRS/IWRS). Before the study is initiated, the telephone number 
and call-in directions for the IVRS and/or the log in information & directions for the IWRS will 
be provided to each site. 
 
Study intervention will be dispensed at the study visits summarized in SoA.  
6.3.2. 
Breaking the Blind (IVRS/IWRS) - With protocol Version 4: The phase 3 study 
will not proceed. 
 
The IVRS/IWRS will be programmed with blind-breaking instructions. All effort must be made 
to maintain the double-blind.  In case of an emergency, the investigator has the sole responsibility 
for determining if unblinding of a participant’s treatment assignment is warranted. Participant 
safety must always be the first consideration in making such a determination. If the investigator 
decides that unblinding is warranted, the investigator should make every effort to contact the 
sponsor prior to unblinding a participant’s treatment assignment unless this could delay emergency 
treatment of the participant. If a participant’s treatment assignment is unblinded, the sponsor must 
be notified within 24 hours after breaking the blind. The date and reason that the blind was broken 
must be recorded in the source documentation and case report form, as applicable.   
6.3.3. 
Unintentional / Accidental Unblinding - With protocol Version 4: The phase 3 
study will not proceed. 
The term unintentional or accidental unblinding refers to occurrences in which personnel from the 
CRO, Investigator Sites, or the Sponsor are unblinded to treatment allocation when they should 
remain blinded. The incident was not planned and was not due to involvement in a planned 


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unblinding event or an emergency unblinding scenario. Accidental unblinding typically occurs 
when a study plan or process was not followed or the handling of unblinded information (or 
investigational product) deviates from defined standards resulting in a breakdown of the firewall 
between the blinded and unblinded team members. 
In the case of an accidental unblinding at the site level, sites must contact their CRA (clinical 
monitor).  The CRA will escalate to the Project Leader and Sponsor so that an investigation can 
occur. The site will be requested to complete documentation providing the date and reason for 
unblinding and the names and titles of the unblinded personnel. Documentation of the occurrence 
will be kept in the subject’s source documents and the Investigator Site Files.  
6.4. 
Study Intervention Compliance 
 
Subjects must be compliant with study treatment.  Non-compliance is defined as missing 
treatments or study visits for non-medical reasons or complying with indoximod/placebo 
administration below an 85% threshold on two sequential study visits. 
6.5. 
Concomitant Therapy 
 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the participant is receiving at the time of enrollment or receives during 
the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
 
The Medical Monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. In general, the use of any concomitant medication/therapies deemed necessary for the 
care of the patient is permitted, except as specifically prohibited. 
6.5.1. 
Live Vaccines 
 
The administration of any live, attenuated vaccines are prohibited during the study and for three 
months after the last dose of study therapy. 
6.5.2. 
CYP inhibitors/inducers 
 
The administration of strong inhibitors/inducers of CYP3A4 including clarithromycin, 
telithromycin, nefazodone, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, 
saquinavir, tipranavir, phenytoin, rifampin, phenobarbital; inhibitors/inducers of CYP2D6 
including bupropion, fluoxetine, paroxetine, quinidine, rifampin; and inhibitors/inducers of 
CYP2C9 including amiodarone, rifampin, phenobarbital is prohibited in this study.  
6.5.3. 
Anticancer Therapy 
 
Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) other than the study 
treatment(s) must not be given to patients while the patient is on the study. If such agents are 


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required for a patient, then the patient must be withdrawn from the study. Exceptions may be made 
for limited interventions (radiation therapy or surgery) intended to palliate a specific medical 
problem (i.e. cord compression or bowel obstruction) on an individual basis. These cases should 
be discussed with the Medical Monitor. 
 
Subjects are allowed to receive palliative radiotherapy and/or the use of bisphosphonates for 
painful bone lesions. 
6.5.4. 
Steroid Therapy 
 
Systemic corticosteroid use will not be permitted on this study with the exception of treating 
immune-mediated AEs or adrenal insufficiency.  Systemic corticosteroid use for exacerbation of 
chronic conditions (such as asthma, COPD, rash) is allowed as long as dosing does not exceed 10 
mg daily of prednisone equivalent. 
6.5.5. 
Monoamine oxidase inhibitors and Serotonin Syndrome (SS) 
 
As IDO inhibitors affect tryptophan metabolism, which could lead to an accumulation of serotonin, 
monoamine oxidase inhibitors are prohibited during study treatment.  Investigators and patients 
should be made aware of this risk and the symptoms of serotonin syndrome. 
 
Signs and symptoms include: 
• 
Agitation or restlessness 
• 
Confusion 
• 
Rapid heart rate and high blood pressure 
• 
Dilated pupils 
• 
Loss of muscle coordination or twitching muscles 
• 
Muscle rigidity 
• 
Heavy sweating 
• 
Diarrhea 
• 
Headache 
• 
Shivering 
• 
Goose bumps 
 
Severe serotonin syndrome can be life-threatening. Signs and symptoms include: 
• 
High fever 
• 
Seizures 
• 
Irregular heartbeat 
• 
Unconsciousness 
6.6. 
Dose Modification 
 
Dosing delays and/or modification of the following agents should be performed consistent with 
standard of care practice by the treating physician within the guidelines provided in the respective 
package inserts/Prescribing Information and/or Summary of Product Characteristics. 
 


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6.6.1. 
Pembrolizumab Dosing Modifications 
 
Please refer to the current Prescribing Information and/or Summary of Product Characteristics for 
pembrolizumab (Keytruda) for details on management of adverse events and dosing modifications. 
Links are provided for reference. 
 
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf  
 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
Product Information/human/003820/WC500190990.pdf 
 
Note: If pembrolizumab is held and/or permanently discontinued, indoximod is also held and/or 
permanently discontinued. 
 
6.6.2. 
Nivolumab Dosing Modifications 
 
Please refer to the current Prescribing Information and/or Summary of Product Characteristics for 
nivolumab (Opdivo) for details on management of adverse events and dosing modifications. Links 
are provided for reference. 
 
https://packageinserts.bms.com/pi/pi opdivo.pdf  
 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003985/WC500189765.pdf 
 
Note: If nivolumab is held and/or permanently discontinued, indoximod is also held and/or 
permanently discontinued. 
 
6.6.3. 
Treatment of Checkpoint Inhibitor Related Infusion Reaction 
 
Infusion reactions should be graded according to CTCAE version 4.03 Allergic reaction/ 
hypersensitivity criteria. 
 
Severe infusion reaction requires permanent discontinuation for further treatment. 
 
Appropriate medical therapy including fluids, epinephrine, corticosteroids, IV antihistamines, 
bronchodilators, and oxygen should be available for use in the treatment of such reactions. In each 
case of an infusion reaction, the investigator should institute treatment measures according to the 
best available medical practice.  
 
6.6.4. 
Management of Adverse Events of Interest (Immune Related Adverse Events) 
 
The most common toxicities that occur with indoximod are fatigue, nausea, vomiting and 
headache. These can be managed with general supportive care. When severe (Grade 3 or greater) 
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Indoximod can result in the same immune-mediated adverse reactions as the checkpoint inhibitors, 
nivolumab and pembrolizumab. At this time, attribution of these events is difficult to determine 
until more data are available. The underlying principle of determining toxicity in this treatment 
combination is determination if new, unique, toxicities arise or if the well described toxicities 
associated with PD-1 checkpoint inhibition occur at a meaningfully increased rate. When these 
toxicities occur, the management guidelines described in the respective package 
inserts/Prescribing Information and/or Summary of Product Characteristics (SmPCs) for 
nivolumab/pembrolizumab should be followed.   
 
In general, assessment and management of any immune-mediated adverse events should follow 
the following algorithm unless specifically stated otherwise in the Prescribing Information and/or 
Summary of Product Characteristics (SmPCs). 
 
Grade 
Assessment and Management 
Grade 1 
Asymptomatic; Diagnostic changes only; Continue nivo/pembro and indoximod 
 
Grade 2 
Mild to moderate symptoms; Grade 2 diagnostic abnormalities. Hold nivo/pembro and 
indoximod treatment.  Provide supportive care. 
IV Steroid Dose: Methylprednisolone 0.5-1.0 mg/kg/day or equivalent until stable 
 
If improving: Transition to oral steroid at start of taper. 
Dose suggested: 60 mg prednisone daily x 2 weeks 
Taper over 4 weeks or more to reduce recurrence of symptoms. May consider re-initiation of 
nivo/pembro and indoximod 
 
If progressing: Treat as Grade 3-4 
Hospitalization if indicated. Multidisciplinary evaluation of toxicity 
 
Grade 3/4 
Discontinue nivo/pembro and indoximod (not in case of hypothyroidism)  
Hospitalization if indicated 
Increase dose of Methylprednisolone 2.0-4.0 mg/kg/day or equivalent until stable 
 
Refractory to 
steroid 
treatment 
If no improvement or progression, additional immunosuppressant treatment may be needed 
• 
Infliximab 5 mg/kg (except if contraindicated) 
• 
Mycophenolate mofetil 1 gram twice daily 
• 
Cyclosporine or intravenous immunoglobulin (IVIG) 
 
 
6.6.5. 
Rules for Stopping and Restarting Indoximod  
 
The half-lives of immune checkpoint inhibitors are long (>15 days), and the toxicity may be 
cumulative. In contrast, the half-life of indoximod is much shorter (~8 hrs), and discontinuation of 
indoximod results in a prompt reduction in drug levels. Indoximod is a reversible inhibitor of the 
IDO pathway. In multiple indoximod Phase 1 and 2 trials, patients did not show cumulative 
toxicity over many months of therapy. 
 
The rules for holding and restarting indoximod will follow the same rules described for the 
checkpoint inhibitors pembrolizumab/nivolumab as described in the applicable package 
insert/Prescribing Information and/or Summary of Product Characteristics (SmPCs). 
 


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Follow the below recommendations for indoximod in addition to the recommendations outlined 
for the checkpoint inhibitor.  Indoximod is only to be restarted in conjunction with the checkpoint 
inhibitor (pembrolizumab/nivolumab): 
• When the AE is resolved to < Grade 1 and the patient is stable and is off steroids, the 
patient may re-start indoximod at the same dose, if, in the judgment of the treating 
physician, restarting indoximod is not contraindicated for that patient. 
• Patients must re-start indoximod within 12 weeks of their last dose or go off treatment.  
• Patients with isolated hypophysitis or pituitary dysfunction who are stable on hormone 
replacement (thyroid and cortisol) are eligible to restart indoximod, as long as the 
endocrine dysfunction is stable on replacement therapy. These patients will remain on 
hormone replacement as long as necessary. 
• No patient should be re-started on indoximod if, in the judgment of the treating 
investigator, this would be clinically contraindicated (e.g., due to the severity of the 
antecedent toxicity, or to the patient’s medical condition). 
 
In general, indoximod was very well tolerated in previous Phase 1 and 2 trials and seldom required 
any dose reductions. If a dose reduction is deemed necessary due to persistent grade 3-4 nausea 
due to the number or size of the tablets, one dose reduction by 600 mg per dose (1800mg BID to 
1200mg BID as example) is permitted. Indoximod will not be restarted at full dose after a dose 
reduction. If this dose reduction is not tolerated then discontinuation of the study treatment is 
required. 
6.7. 
Intervention after the End of the Study 
 
The Sponsor will offer post-trial access to indoximod free of charge to eligible patients in 
accordance with the NewLink Genetics Expanded Access Policy, as outlined on the NewLink 
website, http://www.newlinkgenetics.com/about-us/expanded-access/.    
 
6.8. 
Discontinuation of Study Intervention  
 
Eligible subjects who are enrolled into the study may be discontinued from study treatment and 
followed up per protocol if any of the following occur: 
• Confirmed radiographic or clinical progression of disease. However, patients may continue 
treatment beyond progression if they are deriving clinical benefit, are clinically stable, and 
meet the following criteria: 
• Absence of clinically significant signs and symptoms indicating disease progression. 
• No decline in ECOG performance status. 
• Absence of rapid progression of disease. 
• Absence of progressive tumor critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
While patients will be classified for statistical analysis as “progressed” upon first radiologic 
confirmation of tumor, such patients could continue study drug treatment. Patients who are 
allowed to continue study treatment beyond progression must be re-consented as they may 
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• Any adverse event requiring permanent discontinuation of treatment as per the 
Prescribing Information and/or Summary of Product Characteristics.   
• Intercurrent illness that prevents further administration of treatment 
• Withdrawal of consent 
• Lack of compliance or excessive deviations with study schedule in agreement with the 
Medical Monitor 
• Have the inability to be compliant with study treatment in opinion of investigator defined 
as missing treatments or study visits for non-medical reasons or complying with oral study 
drug administration below an 85% threshold on two sequential study visits. 
• Lost to follow-up (after repeated attempts for >30 days have been made to contact the 
subject including letters sent by registered mail to the subject and designated alternate 
contact) 
• Subject becomes pregnant or starts breast-feeding 
• Sponsor discontinuation of study 
• Investigator’s decision (in consultation with the Medical Monitor and subject for general 
or specific changes in the subject's medical condition and/or intercurrent illness that may 
render the subject unacceptable for further treatment. The reason for removal must be 
documented in the case report form [eCRF]). 
 
*NOTE: Subjects discontinued from study treatment will be followed-up per protocol (e.g., EOT 
visit, continue tumor evaluation by RECIST 1.1 if they discontinue from treatment for reasons 
other than progression) unless subject withdraws consent from all follow-up. 
 
Patients who discontinue study treatment will be followed for survival status until they are lost to 
follow up or death whichever occurs first.  
6.9. 
Participant Discontinuation/Withdrawal from the Study 
 
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
• A participant may withdraw from receiving treatment but continue to participate in follow-
up activities.  
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request in writing, destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
• See SoA for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed. 


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6.10. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
 
6.11. 
Discontinuation of Entire Study  
 
This study may be discontinued for any of the following reasons: 
• The study is completed per protocol. 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping 
• Determination of futility 
• The Sponsor may terminate the study electively or if required by regulatory decision.   
One interim safety analysis is planned after approximately 60 subjects have been treated in the 
Phase 3 portion of the study. The results of this analysis may lead to termination of the study. Any 
time during the study, the data safety monitoring committee (DSMC) may recommend (and the 
Sponsor agrees) to discontinue the study.  Please see Section 8.5.2 for details regarding the interim 
safety analysis and DSMC. - With protocol Version 4: The phase 3 study will not proceed. 
If the study is terminated prematurely, the sponsor will notify the investigators, IRB and Ethics 
Committees, and regulatory authorities of the decision and the reason for terminating the study.  
 


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7. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions 
are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to record 
details of all participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the SoA. 
 
7.1. 
Screening and baseline examination 
 
Informed consent must be signed before any screening procedures. The investigator is obliged to 
give the patient thorough information about the study and the study related assessments, and the 
patient should be given ample time to consider his/her participation. The investigator must not start 
any study related procedure before ICF is signed and dated by both patient (and impartial witness, 
if applicable) and investigator. 
 
Screening includes obtaining written informed consent, a physical exam, demography, medical 
history/current medical conditions, current concomitant medications/therapies, disease history and 
extent of disease, and prior anticancer therapies. 
 
Patient demographics and other baseline characteristics 
The following patient demographic, baseline characteristics, and assessments will be collected 
within 28 days prior to initiating therapy unless otherwise specified: 
• General demography 
• Medical history/current medical conditions (including prior and concomitant 
medications) 
• Physical examination, weight and height 
• Vital signs including sitting blood pressure/pulse and heart rate, respiratory rate and 
temperature 
• ECOG performance status 
• CBC w/diff, platelets - to be done within 7 days prior to initiating therapy. 
• Serum chemistry (sodium, potassium, magnesium, calcium, chloride, glucose, blood urea 
nitrogen (BUN), creatinine, total protein, alkaline phosphatase, albumin, total bilirubin, 
aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase 
(ALT), 
lactate 
dehydrogenase (LDH), phosphorus) – to be done within 7 days prior to initiating therapy.  


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Liver function tests must be completed or repeated within 3 days prior to immune 
checkpoint inhibitor administration per package insert.  
• INR, PT, PTT 
• Amylase, lipase 
• LH, FSH 
• Free T4, TSH, ACTH 
• Urinalysis 
• ECG (in triplicate) 
• AE evaluation 
• Radiologic Tumor measurements (CT/MRI of brain, chest, abdomen) 
• Pregnancy test (urine or serum) – to be done within 72 hours prior to first treatment for 
all women with child-bearing potential 
 
7.2. 
Treatment period 
 
Patients will be asked to visit the clinic every two to four weeks depending on the checkpoint 
inhibitor and schedule they will receive.  Treatment will continue until any off treatment criteria 
as outlined in Sections 6.6 and 6.8 are met.  
 
The schedule of on-treatment assessments/activities (SoA) can be found in Section 1.3. 
 
7.2.1. 
Physical Examination 
 
A complete physical examination includes a major review of body systems (general appearance, 
skin, neck including thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities and neurological examination).  
 
7.2.2. 
Vital signs 
 
Body temperature, sitting pulse rate, respiratory rate and sitting blood pressure will be measured. 
 
7.2.3. 
Height and weight 
 
Height in centimeters will be measured at baseline and body weight to the nearest 0.1 kilogram 
will be measured. 
 
7.2.4. 
Performance status 
 
The performance status will be assessed according to: 
• ECOG (Oken et al. 1982) performance status scale. 
 
 
 


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7.2.5. 
Laboratory evaluations  
7.2.5.1. 
Hematology 
 
Hematology tests are to be performed by the local laboratory according to the Visit Schedule 
outlined in Section 1.3. The Hematology panel includes red blood cells (RBC), hemoglobin, 
hematocrit, platelet count, total white blood cells (WBC) count, and a WBC differential including 
neutrophils, lymphocytes, monocytes, eosinophils and basophils. 
 
7.2.5.2. 
Clinical Chemistry 
 
Clinical chemistry tests are to be performed by the local laboratory according to the Visit Schedule 
outlined in Section 1.3. The Clinical chemistry panel includes sodium, potassium, magnesium, 
calcium, chloride, glucose, blood urea nitrogen (BUN), creatinine, total protein, alkaline 
phosphatase, albumin, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), lactate dehydrogenase (LDH), phosphorus.  
 
Note: LFTs (ALT, AST, and T. bilirubin) must be performed within 3 days prior to each 
immune checkpoint inhibitor dosing visit. The results of these tests must be reviewed by the 
principal investigator (or designee) prior to dosing. 
 
7.2.5.3. 
Endocrine  
 
Free T4, thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH) levels are 
to be performed by the local laboratory according to the Visit Schedule outlined in Section 1.3. 
 
7.2.5.4. 
Pituitary 
 
Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels are to be performed by 
the local laboratory according to the Visit Schedule outlined in Section 1.3. 
 
7.2.5.5. 
Coagulation 
 
Coagulation testing will be measured with international normalized ratio (INR), pro-thrombin time 
(PT) and Partial Thromboplastin Time (PTT) by the local laboratory according to the Visit 
Schedule outlined in Section 1.3. 
 
7.2.5.6. 
Pancreas Function 
Amylase and lipase levels are to be performed by the local laboratory according to the Visit 
Schedule outlined in Section 1.3. 
7.2.5.7. 
Urinalysis 
 
Urinalysis can include dipstick analysis and will be performed at screening visit and at the end of 
treatment visit. Additional urinalysis can be done during study if clinically indicated. 
 




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• CBC with differential and platelets. 
• Serum chemistries. 
• INR, PT, PTT 
• Urinalysis. 
• ECG (in triplicate) 
• Pregnancy test (for women of child-bearing potential) 
• Concomitant medications and adverse events assessed at end of treatment. 
 
7.2.10. 
Follow-Up after End of Treatment 
 
After the End of Treatment Visit, a follow-up visit will be conducted after 3 months to assess 
safety and tolerability and will include the following: 
• Update medical history including current cancer therapy receiving every 3 months. 
• Physical examination including ECOG performance status, vital signs, weight, and a 
review of body systems every 3 months. 
• CBC with differential and platelets per SOC practices. 
• Serum chemistries per SOC practices. 
• Imaging every 9 weeks until progression. Imaging per SOC practices after progression. 
• Review of cancer-related treatments and adverse event assessments. 
 
Patients will be followed for survival. Follow-up visits will continue for 2 years as per Section 1.2 
(and as stated above). For those surviving longer than 2 years, follow-up can be performed using 
telephone contact, correspondence with treating physicians, and death records as necessary to 
update vital status at least every 6 months until death or lost to follow-up or the study ends. Further 
therapy will be at the discretion of the treating physician. 
7.3. 
Efficacy Assessments  
 
Tumor response and progression will be determined by blinded independent central review using 
RECIST 1.1 criteria (see Appendix 7).  An Imaging Manual will be provided to the clinical sites 
for details on submission of imaging data. 
7.3.1. 
Tumor Assessments 
 
At baseline, CT/MRI of brain, chest, and abdomen will be performed to assess disease status.  
Scans of additional locations may be necessary depending on known or suspected disease sites.  
 
The first tumor assessment test after baseline will be conducted at 9 weeks (+/- 1 week) followed 
by assessments every 9 weeks (+/- 1 week) for duration of study participation. Whenever possible, 
clinical evaluation of superficial lesions should not be used as the sole form of measurement. 
However, when necessary, color photograph with metric caliper is acceptable. 
 
The tumor assessment (TA) performed during screening will be used as a baseline for efficacy 
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• CT/MRI of the brain is required during screening to determine eligibility.  If no brain 
lesions at time of randomization, then subsequent brain scans are not required unless 
clinically indicated.  
• CT/MRI imaging of the chest and abdomen is required at Screening and at each TA, 
regardless of the location of known metastases. In addition, CT/MRI scans must be obtained 
of anatomic regions not covered by the chest and abdomen scans in subjects where there is 
clinical suspicion of deep soft tissue metastases (e.g., lesions in the thigh). Such additional 
CT/MRIs will be required at Screening when deep soft tissue disease is known/suspected 
and must be consistently repeated at all TAs if a deep soft tissue lesion is identified during 
Screening. The same imaging modality must be used for all TAs, unless contraindicated. 
 
Imaging-based evaluation is preferred to clinical examination. Helical (spiral) CT scans of the chest 
and abdomen are preferred. If not available, MRI can be used; however, a measurable lesion must 
not have the longest diameter smaller than 20 mm by MRI (10 mm on spiral CT). IV contrast 
should be used for all CT scans; if IV contrast is contraindicated, oral contrast maybe used, or MRI 
should be used at the Screening exam and at all TA time points. Subjects who develop contrast 
allergy after study enrollment must be followed by MRI for subsequent tumor measurements. 
 
To be considered measurable lesions, tumor lesions must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size 
of: 
• 10 mm by CT scan and MRI (CT scan/MRI slice thickness no greater than 5 mm; see 
RECIST 1.1 Guidelines,  Appendix II on imaging guidance). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable). 
• Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm.  It is not recommended to double the slice 
thickness/interval for measurable lymph nodes). At baseline and in follow-up, only the 
short axis will be measured and followed.  
 
Sections should be contiguous, similarly sized and consistent from visit-to-visit. Chest x-rays and 
ultrasound are not acceptable methods to measure disease. Response and progression of disease 
must be documented by CT or MRI similar to the methods used at Screening. 
 
If bone lesions are identified at any time during the study, additional imaging studies of the 
lesion(s) must be performed to confirm the malignant nature of the new findings on the bone scan. 
If an abnormal bone scan is observed at any time point throughout the study, a repeat bone scan 
must be performed prior to the confirmation of a CR (e.g., the remaining metastatic lesions must 
have resolved. In case of new lesions such as pleural effusion, cytology must be performed to 
identify and confirm malignancy. Skin and soft tissue lesions will be captured as non-measurable 
lesions through physical examination only. 
 
Any subject who develops an objective tumor response (CR or PR) or progression (PD) is 
required to undergo confirmatory scans between 4 and 6 weeks from the prior scan in order 
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Subjects who are discontinued from study treatment for reasons other than disease progression will 
continue to have tumor evaluation by RECIST 1.1 until another anti-cancer treatment is started, 
progression of disease, death, loss to follow up or withdrawal of consent, whichever comes first.  
7.3.2. 
Response Measurements 
 
RECIST 1.1 criteria 
To assess tumor response by RECIST 1.1, provided as Appendix 7: RECIST 1.1 Guideline, all 
tumors present at the Baseline Determination are documented. Lesions are classified into 
measurable and non-measurable, as defined by RECIST 1.1. From the measurable lesions, no more 
than 5 target lesions should be identified, and no more than 2 target lesions per organ. The sum of 
diameters for target lesions (longest diameters for non-nodal lesions and short-axis diameters for 
lymph nodes) is recorded and followed across future visits. All malignant lesions not selected as 
target lesions are documented and followed qualitatively as non-target lesions. At each follow-up 
visit, target and non-target lesion response is assessed as follows: 
• Evaluation of Target lesions – criteria to be used to determine objective tumor response for 
target lesions 
o Complete Response (CR): disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
o Partial Response (PR): at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
o Progressive Disease (PD): at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. Note: the appearance 
of one or more new lesions is also considered progression 
o Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum diameters while on 
study. 
o Not Evaluable (NE): no imaging or measurement is performed at a particular time 
point, or only a subset of lesion measurements are made at an assessment. 
• Evaluation of non-target lesions: 
o Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (short axis 
<10 mm). 
o Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
o Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
Note: appearance of one or more new lesions is also considered progression  
 
At each visit, scans are also assessed for the presence of new lesions. 
 
Overall response is determined by the combination of target lesion response, non-target lesion 
response, and the status of new lesions, as shown in the following table: 




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also be identified by physical examination and review of laboratory results. The Investigator or 
designee will record all pertinent information on the appropriate AE reporting page of the subject’s 
eCRF whether or not they are considered causally related to the study interventions. 
 
The Investigator should attempt to establish a diagnosis of the AE based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
verbatim term rather than individual signs/symptoms.  
 
For every AE, the Investigator must document the following: 
• Diagnosis or description of event 
• Onset date 
• Assessment of the severity 
• Assessment of the causal relationship separately for pembrolizumab/nivolumab, 
indoximod 
• Assessment of seriousness of the event (i.e. whether it is an SAE) 
• Method of treatment taken for the AE 
• Action taken related to each study drug (pembrolizumab, nivolumab, indoximod) include 
the following: dose interruption, dose delay, dose reduction, or study drug discontinuation 
• Outcome of event and end date; all SAEs must be followed until resolution, subject death 
or until the SAE is deemed stable or irreversible 
• Phase 2 during RLT window (first 28 days of treatment): any event which meets the criteria 
as a RLT will be noted as such on the eCRF. 
7.5. 
Adverse Events and Serious Adverse Events 
7.5.1. 
AE Definition 
 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
 
For this clinical study, AEs will be captured with the start of treatment (treatment-emergent adverse 
events) and not at the time of informed consent.  
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, not related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
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b. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred 
or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline 
is not considered an AE. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition. Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
c. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
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7.5.3. 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related 
to the event. 
• 
The investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
Sponsor. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to Sponsor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
7.5.4. 
Assessment of Severity 
 
The severity of each AE will be graded by the Investigator according to the current version of the 
NCI CTCAE (v4.03). The criteria can be found at http://ctep.cancer.gov/reporting/ctc.html.  
 
For AEs not listed in the NCI-CTCAE, the following similar grading system should be used: 
• Grade 1 Mild AE 
• Grade 2 Moderate AE 
• Grade 3 Severe AE 
• Grade 4 Life-threatening or disabling AE 
• Grade 5 Death related to AE 
 
Severity, which is a description of the intensity of manifestation of the AE, is distinct from 
seriousness, which implies a subject outcome or AE-required treatment measure associated with a 
threat to life or functionality. An AE assessed as Grade 4 based on the NCI CTCAE grades may 
or may not be assessed as serious based on the seriousness criteria. 
 
The severity rating must be recorded on the appropriate AE reporting page of the subject’s eCRF. 
7.5.5. 
Assessment of Causality 
 The Investigator will assess the relationship between the investigational product and the AE by 
answering ‘yes’ or ‘no’ to the question: ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the investigational product?’ If it is deemed that there is a 
reasonable causal relationship between the AE and investigational product, it is to be considered 
as “related”.  
• 
The investigator is obligated to assess the relationship between each study intervention 
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• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor. 
• 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
7.5.6. 
Follow Up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated SAE data to Sponsor within 24 hours of receipt of 
the information. 
7.5.7. 
Reporting of SAEs  
• 
Investigators must immediately report to the Sponsor any serious adverse events whether or 
not they are considered related to the investigational agent(s)/intervention.  
• 
The SAE must initially be reported within 24 hours of learning of the SAE, followed by a 
complete SAE report within 3 calendar days of the initial 24-hour report. 
• 
Refer to the Study Manual for copies of the forms and instructions for reporting to the Sponsor.  
• 
Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and are considered related to the investigational drug 
require reporting on the same timelines as noted above. 










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In the analysis of the first co-primary endpoint, PFS, a log-rank test will be used to test for a 
difference in the time to PFS between treatment groups.  
 
In the analysis of the second co-primary endpoint, OS, a log-rank test will be used to test for a 
difference in the time to OS between treatment groups.  
 
The null hypothesis will be rejected in favor of the alternative hypothesis if either of the co-
primaries is significant at the 2-sided p-value for the treatment group difference from the above 
corresponding primary analysis is less than 0.025. 
 
Separate Kaplan-Meier (KM) plots for PFS and for OS time will be presented for each treatment 
group. 
 
The above primary analysis and KM plots will be based on the Intent-to-Treat (ITT) population. 
In a further sensitivity analysis, the primary analysis will be repeated using the Per-Protocol Set 
(PPS). 
8.2. 
Sample Size Determination  
8.2.1. 
Sample Size Considerations - With protocol Version 4: The phase 3 study will 
not proceed. 
Each of the co-primaries, PFS and OS, will be allocated 0.025 2-sided.  
This trial will compare PFS and OS for the combination indoximod and pembrolizumab/ 
nivolumab versus pembrolizumab/nivolumab alone.  
It is assumed that the comparators, nivolumab and pembrolizumab will perform similarly. 
For PFS, pembrolizumab alone PFS survival was acquired from the survival curves from Keynote 
066.  PFS survival information for the combination, indoximod and pembrolizumab, was available 
from interim results of the single-arm trial NLG2103.  
Data were plotted from available pembrolizumab trials and indoximod interim data and time-
dependent failure rates were extracted from these plots and were used in the sample size 
calculations. 
There are several limitations that affect the calculations.  
For checkpoint inhibitors, T. T. Chen (JNCI J Natl Cancer Inst (2015) 107(9)) notes that delayed 
treatment effects as well as a “floor” are common.  
The term “floor” refers to the situation in which the survival curves, rather than following a 
constant risk model (exponential), exhibit a risk which decreases over time, approaching a 
horizontal asymptote with some percentage of patients remaining essentially risk-free for the 
remainder of the trial. T.T. Chen refers to this a “cure rate model”.  
For the PFS, the data beyond month 10 in these sources is extremely limited. So it remains an open 
question as to whether a floor exists for pembrolizumab, and if so, what that floor is (i.e., what 
proportion of patients will remain event free for the remainder of the trial.  For sample size 


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calculations, it is necessary to make assumptions for the curve beyond 10 months. A number of 
trial configurations were investigated.  The final power calculations were based on the following 
assumptions:  
(i) 
From months 11 through 15, the survival curves continue to decline at the same 
rate as observed during months 3-10, and 
(ii) 
after month 15, the curves are essentially horizontal, i.e., no further events are 
observed.   
For OS, although a cure rate might exist, the survival curves for Keynote 006 do not show this, so 
there was no cure rate assumption for OS. 
For each of the co-primary endpoints, the final analysis will be event-driven. Based on a variety 
of considerations for the two co-primary endpoints, a sample size of 600 patients was selected.  
The number of events to trigger an analysis for PFS is 415 and for OS the trigger is 325 events.  
Hazard ratios are 0.69 for PFS and 0.67 for OS.   
Power calculations for both PFS and OS were based on the following assumptions: 
1. N = 600 patients across approximately 125 clinical trial sites (projecting 4-5 subjects per 
site with a maximum enrollment per site of 45 subjects (7.5% of total) allowed) 
2. Randomization 1:1. 
3. Enrollment: 15 months 
4. Expected trial length to achieve number of events: 30 months PFS, 60 months OS. 
5. Significance Level for each co-primary endpoint: 0.025 2-sided 
6. Loss: 1% per year 
7. Length of delayed treatment effect: 2 months PFS, 1 month OS 
8. The effect of interim analyses were not taken into account here, but will be assessed later: 
The assumed failure rates for PFS are 
Table 1 Assumed Conditional Failure Rates (annual) For PFS 
Month 
Indoximod Combination 
Pembrolizumab 
0-2 
.55797 
.55797 
2-3 
.65701 
.97922 
3-4 
.8685 
.84671 
4-6 
.65674 
.58204 
6-15 
.47474 
.62154 
15+ 
.001 
.001 
The assumption that there are no events beyond month 15 leads to an approximate cure rate for 
PFS of about 37% for the combination arm, 25% for the pembrolizumab alone arm. For PFS, the 
observed difference between the two observed survival curves determined the treatment effect. 
The assumed failure rates for OS are: 


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Table 2 Assumed Conditional Failure rates (annual) For OS 
 
Conditional Annual Failure Rate 
Months 
Pembrolizumab 
Indoximod Combination 
1 
.3846 
.3846 
2-3 
.3846 
.2692 
4-9 
.3200 
.2240 
10+ 
.1600 
.1120 
For OS, the treatment effect after the delay was assumed to be 30%. 
The power under these assumptions is about  
• 91.2% for PFS, 
• 85.9% for OS. 
Power calculations were based on the method of Lakatos (1988), which is implemented in PASS 
15. 
For PFS (Table 1), the time dependent rates for the control group were obtained from Robert C et 
al. (Robert, Caroline, et al. "Pembrolizumab versus ipilimumab in advanced melanoma." New 
England Journal of Medicine 372.26 (2015): 2521-2532) – the Keynote 006 trial, Figure 1. The 
time dependent rates for the combination arm were based on NewLink clinical trial NLG2103. For 
OS (Table 2), the time-dependent failure rates for the control group were also obtained from 
Keynote 006, Figure 2.   
Figure 1 PFS curves from Keynote 006 (Robert et al NEJM) 
 
 




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8.4. 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
8.4.1. 
Efficacy Analyses 
Phase 3 Efficacy Endpoints - With protocol Version 4: The phase 3 study will not proceed. 
Endpoint 
Statistical Analysis Methods 
Primary 
The co-primary efficacy endpoints below will be analyzed using ITT and the 
PPS:  
1. Progression-free survival (PFS) time which is defined as time from date of 
randomization until the earliest date of disease progression per RECIST 1.1, 
or death from any cause, whichever comes first. Patients who have neither 
progressed nor died will be censored at the last tumor assessment date for 
the endpoint PFS and will be assessed per RECIST 1.1.  
2. OS is defined as the time from the date of randomization until death from 
any cause. Any patient not known to have died at the time of analysis will 
be censored based on the last recorded date on which the patient was known 
to be alive. 
The primary analysis for both PFS and OS will be stratified by checkpoint 
inhibitor treatment (pembrolizumab or nivolumab).  
Secondary 
The following secondary efficacy endpoint will be analyzed using ITT and the 
PPS: 
• Objective response rate (ORR): The first tumor assessment test will be 
conducted at 9 weeks followed by assessments every 9 weeks for duration 
of study participation. Defined as patients who have a best response as 
complete or partial response based on RECIST 1.1. 
An overall false-positive rate of 5% level for the above key secondary efficacy 
endpoint will be maintained, in that no significance of the key secondary endpoint 
will be claimed unless either of the co-primary statistical analyses is significant 
at the 2.5% level. We will compare response rates in the study groups using the 
stratified Miettinen and Nurminen method (1985). 
8.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population.  
The safety and tolerability of the pembrolizumab/nivolumab plus indoximod combination will be 
determined by reported AEs, SAEs, RLTs, physical examination findings, vital sign 
measurements, 12-lead ECG readings, clinical laboratory evaluations, and treatment 
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For each safety parameter, the last assessment made before the first dose of the indoximod for each 
period will be used as the baseline for all analyses of that safety parameter. 
8.4.2.1. 
Regimen-limiting Toxicities 
RLTs will be reported as AEs and summarized separately by schedule and cohort for the Safety 
Analysis Population.  
8.4.2.2. 
Adverse Events 
 
All subjects will be assessed regularly for the occurrence of AEs from the time of first dose of the 
indoximod until 30 days after the last dose, initiation of new systemic anticancer therapy, or death, 
whichever comes first.  
 
The incidence of treatment-emergent AEs (TEAEs) will be summarized and tabulated using the 
Medical Dictionary for Regulatory Terms (MedDRA) by System Organ Class (SOC) and Preferred 
Term (PT). An AE occurring during the treatment period will be considered a TEAE if it was not 
present before the first dose of indoximod or if it was present before the first dose of indoximod but 
increased in severity during the treatment period. If more than one AE is reported before the first 
dose of indoximod and is coded to the same PT, the AE with the greatest severity will be used as 
the benchmark for comparison with the AEs that were also coded to that PT and that occurred 
during the treatment period. An AE that occurs more than 30 days after the last dose of 
indoximod will not be counted as a TEAE, unless recommended by the Medical Monitor or 
Investigator. 
 
All AEs captured in the database will be included in by-subject data listings including those that 
are not treatment-emergent (ie, were reported between the time the ICF was signed until the date 
of the first indoximod dose). Only TEAEs will be summarized in tables. 
 
TEAEs will be coded using the most current version of MedDRA available at the time of study 
start and data will be summarized for each indoximod dose level within a schedule by System 
Organ Class (SOC) and preferred term for the Safety Population.  The number and percent of 
subjects reporting each TEAE will be summarized, as well as the number of TEAEs.  A subject 
with 2 or more TEAEs within the same level of summarization (ie, SOC or preferred term) will be 
counted only once in that level using the most severe event or most related (for the relationship to 
study medication table). Percentages will be based upon the number of subjects in the Safety 
Population within each indoximod dose level within a schedule. 
 
Additional summary tables will be generated for grade 3 or higher TEAEs, TEAEs considered 
related to indoximod, TEAEs by severity and relationship, deaths, DLTs, SAEs, and TEAES 
leading to treatment discontinuation. 
 
A by-subject AE data listing, including verbatim term, SOC, preferred term, treatment, severity, 
outcome, and relationship to treatment, will be provided.  Separate listings will be generated for 
deaths, DLTs, SAEs and AEs leading to treatment discontinuation. 


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8.4.2.3. 
Clinical Laboratory Parameters 
 
For chemistry, coagulation and hematology parameters, laboratory measurements including actual 
values at the visit and their changes from baseline during the treatment period, will be summarized. 
In addition, the maximum and minimum post-treatment values will be presented. 
 
Shift tables from baseline to the worst post-baseline category during the treatment period will be 
provided for chemistry parameters and hematology parameters. The possible categories in shift 
tables could include “normal” and “abnormal” based on normal ranges, along with clinical 
significance information if applicable. Both scheduled and unscheduled post baseline values 
during the treatment period will be considered.  
 
All clinical laboratory data will be listed by subject. Values outside the normal ranges will be 
flagged and toxicity grades will be displayed for relevant parameters. 
8.4.2.4. 
Vital Signs 
Vital signs will be summarized by indoximod dose level within a schedule using descriptive 
statistics (mean, standard deviation, median, minimum, and maximum) and presented for each 
timepoint, including change from baseline, for the Safety Analysis Population.  Clinically 
significant post-baseline vital sign findings will be reported as AEs.  A by-subject data listing of 
all vital sign data will be generated.  
8.4.2.5. 
Electrocardiograms 
 
Heart rate, RR interval, PR interval, QT interval, and QTcB and/or QTcF interval will 
be summarized by indoximod dose level within a schedule using descriptive statistics (mean, 
standard deviation, median, minimum, and maximum) and presented for each timepoint, including 
change from baseline, for the Safety Analysis Population.  The mean of triplicate values at the 
screening visit will be used to calculate the baseline value. 
 
Clinically significant post-baseline ECG findings will be reported as AEs.  A by-subject data 
listing of all ECG data will be generated. 
 
The number and percentage of subjects with elevated QTc values (> 450 msec, > 480 msec, and > 
500 msec) at baseline and end of treatment will be presented. In addition, the number and 
percentage of subjects with QTc values that increase by > 30 msec and > 60 msec from baseline 
to end of treatment will be presented. 
 
A shift table from baseline to the worst post-baseline values during the treatment period will be 
provided for QTcF and QTcB intervals. The following categories will be used: ≤ 450 msec, > 450 
and ≤ 480 msec, > 480 and ≤ 500 msec, and > 500 msec. 
8.4.2.6. 
Physical Examinations 
Detailed information on the physical examinations will be listed by subject. Clinically significant 
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Figure 3 Accrual of Events over Calendar Time Based on Time-Dependent Event Rates 
Expected for PFS and for OS. 
 
 
 
ii. 
Group-Sequential Design Issues. 
With the co-primary endpoints of PFS and OS, issues arise. In particular, PFS events will accrue 
much more quickly than OS events. 
 
By design, the alpha was allocated equally to each of the co-primary endpoints. Even if there was 
no interim analysis, the PFS events are projected to reach the designated total for the final analysis 
at about month 30.  
 
In order to maintain maximum power for the final PFS analysis, while meeting the demand for an 
interim analysis for efficacy, a Lan-DeMets spending function will be designed to test the interim, 
spending about 0.001/2 of the .05/2 alpha allocated to the PFS co-primary. This single interim for 
PFS efficacy would have to take place when about half the total 491 PFS events occur. Referencing 
Figure 3, this would occur at about 13 months. Allowing 3 months for full determination of PFS 
status through month 13 leads to an expected interim meeting at about 16 months. OS will not be 
examined for efficacy at this interim. The PFS interim for mid-course correction is expected to 
take place at the same meeting. 
 
Using similar rationale, the single interim for OS efficacy would take place at about month 22; 
half of the designated maximum OS event should occur at about 21 months, and for OS data, the 
data should be ready of the meeting in about 1 month. At that meeting, both mid-course correction 
for OS and early termination for efficacy would be considered. An additional consideration is that 


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increasing sample size for OS when early trial termination for superior efficacy of PFS is likely 
could be counterproductive. 
 
Developing group-sequential spending functions to meet these demands when hazards and 
hazard ratios are time-dependent is complex, and is still underway. 
 
The Statistical Analysis Plan will describe the planned interim analyses in greater detail. 
 
The interim analyses will be conducted by an independent statistician and analyzed by the 
independent DSMC.  The DSMC will take all appropriate measures to avoid accidental transfer of 
unblinded data or analysis results to the Sponsor or other blinded parties.  The DSMC is charged 
with providing recommendations to the Sponsor based on their review.  
8.5.2. 
Independent Data Safety Monitoring Committee (DSMC) 
 
This study will be overseen by an independent Data Safety Monitoring Committee (DSMC) which 
will operate according to FDA Guidance for Clinical Trial Sponsors: Establishment and Operation 
of Clinical Trial Data Monitoring Committees – OMB Control No. 0910-0581) and the Committee 
for Medicinal Products for Human Use (CHMP) Guideline on Data Monitoring Committees – 
EMEA/CHMP/EWP/5872/03). The DSMC will be independent and will follow an agreed Charter 
and will give recommendations on continuation of the study.  They may suggest changes to study 
conduct and will review data against pre-agreed stopping rules.   
8.5.2.1. 
DSMC Composition 
 
The DSMC is comprised of four voting members, a non-voting member (ad-hoc clinical expert), 
a statistician and a secretary to the DSMC.   
8.5.2.2. 
DSMC Operations 
 
During the dose escalation Phase 2, the DSMC will review 
 safety data. They 
will review other data as the need arises, in agreement with the Sponsor and as detailed in minutes 
of DSMC meetings and, as necessary, in an amended Charter. The DSMC will review data towards 
or at the end of each dose cohort and/or at other times as the need arises and will provide 
recommendations on study conduct, including on progression to the next cohort based on pre-
agreed definitions of Regimen Limiting Toxicity (RLT) and Maximum Tolerated Dose (MTD). 
They will also give a recommendation on the dose for the Phase 3 part of the trial, based on these 
and other factors as become apparent during the dose escalation phase. 
 
With protocol Version 4: The phase 3 study will not proceed. 
During the Phase 3 part of the trial, the DSMC will review accrual information and safety data 
such as listings and natures of adverse events as well as other data as the need arises in agreement 
with the Sponsor and as detailed in minutes of DSMC meetings and, as necessary, in an amended 
Charter. The DSMC will review the safety of the study drugs and procedures on a quarterly basis, 
or at other times as the need arises, while any subject is still receiving study drug. 
 


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In Phase 3, an interim safety analysis will be performed by the DSMC when 60 subjects have been 
treated with at least one cycle of therapy.  The DSMC will conduct a thorough safety review of 
unblinded safety data. Reports of the adverse events and treatment related toxicity will be 
generated. 
The 
safety 
and 
tolerability 
of 
the 
combination 
of 
indoximod 
with 
pembrolizumab/nivolumab will be assessed by evaluating the proportion of patients experiencing 
Grade 3 or higher non-hematologic AEs, death due to any cause, and SAEs for each arm of the 
randomized portion of the study. If the cumulative incidence of treatment related Grade 3 or higher 
AEs, deaths, other SAEs or frequency of relapsed or refractory disease in the indoximod arm 
exceeds the control arm by >25%, study accrual will be held until complete analysis of the data is 
preformed and no definitive toxicity pattern is identified. 
 
8.6. 
Changes in the Conduct of the Study or Planned Analyses 
 
Any changes from the analyses planned in the protocol will be documented in the SAP which will 
be finalized prior to database lock.  Any changes in the analyses performed after the SAP has been 
finalized will be documented in the Clinical Study Report (CSR). 
 
If any amendments to this protocol are necessary, the Sponsor will propose them in writing to the 
Investigator. Any amendments proposed by the Investigator will be reviewed and approved by the 
Sponsor prior to submission for IRB review and implementation. No protocol amendment may be 
implemented (with the exceptions noted below) before it has been submitted to the Regulatory 
Agency and approved by the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC). In addition, the Investigator signature page must be signed and submitted to the Sponsor. 
 
If the protocol is amended to eliminate or reduce the risk to subjects, the amendment may be 
implemented before IRB/IEC review and approval. However, the IRB/IEC must be informed in 
writing of such an amendment, and approval must be obtained within reasonable time limits. 
 
Protocol deviations brought to the attention of the Sponsor after their occurrence will only be 
recognized and assessed for ethical, medical, scientific, and regulatory implications and for impact 
on the subject’s participation in the study, and will be documented. Such deviations cannot be 
waived. 
 
Protocol violations (which are deviations that have a major impact on the subject’s rights, safety, 
or well-being or the integrity and authenticity of the study data) can never be waived. 
 
 


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9. 
Supporting Documentation and Operational Considerations 
9.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
 
Ethical Considerations 
This study will be performed in accordance with the protocol, the Declaration of Helsinki, the ICH 
Harmonized Tripartite Guideline for GCP, and all applicable local regulatory requirements. The 
study will be conducted in full compliance with FDA guidelines for GCP and in accordance with 
the ethical principles that have their origins in the Declaration of Helsinki and 21 CFR §312.120. 
 
Institutional Review Board  
It is the responsibility of the Investigator to obtain the approval of the Independent Ethics 
Committee (IEC) / Institutional Review Board (IRB) before the start of the study. A copy of the 
approval letter will be supplied to the Sponsor, along with a roster of IEC / IRB members. During 
the course of the study, the Investigator or designee will provide timely and accurate reports to the 
IEC / IRB on the progress of the study at appropriate intervals (not to exceed 1 year) and at the 
completion of the study. Investigator or designee will notify the IEC / IRB of serious AEs (SAEs) 
or other important safety findings. The study protocol, informed consent form (ICF), information 
sheet advertisements (if any), and amendments (if any) will be approved by the IRB at each study 
center in conformance CFR, Title 21, Part 56.  
 
Subject Information and Consent 
Before the start of any study-related procedures are undertaken, the Investigator or designee must 
obtain written, informed consent from each study in accordance with US federal regulations (21 
CFR §50) and the ICH document “Guidance for Industry – E6 Good Clinical Practice: 
Consolidated Guidance”. Informed consent will be obtained by discussing with the subject the 
purpose of the study, the risks and benefits, the study procedures, and any other information 
relevant to the subject. 
 
The Investigator or designee must explain to the subject that for purposes of evaluating the study 
results, that subject’s private health information obtained during the study may be shared with the 
Sponsor, regulatory agencies, and IECs / IRBs, before enrolling that subject into the study. It is 
the Investigator’s (or designee’s) responsibility to obtain permission to use private health 
information per the Health Information Portability and Accountability Act (HIPAA) from each 
subject, or if appropriate, the subject’s legal representative. 
 
The subject or his/her legal representative will document his/her informed consent by signing the 
current version of the written, IRB-approved ICF in the presence of a witness. The person who 
conducted the informed consent discussion with the subject and/or subject’s legal representative 
must also sign the ICF. The subject is given a fully executed copy of the ICF bearing all appropriate 
signatures, and the original must be maintained in the clinical master files at the site. 
 


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The Investigator, or designee, is responsible for the content of the ICF, but the original and any 
updated versions must be approved by the Sponsor prior to submission to the IRB/IEC. The ICF 
should also include any additional information required by local laws relating to institutional 
review. All active Subjects participating on the protocol must be re-consented each time the ICF 
is updated and re-approved by the IRB/IEC. 
 
Study Management and Investigator Obligations 
 
Investigator and Clinical Sites 
The PI at each study center (clinical site) is the individual responsible for ensuring that the 
investigation is conducted according to the signed Investigator’s statement, the protocol, and ICH 
GCP guidelines at his/her site. 
 
The PI at each clinical site will be responsible for the management of the study, which will include 
but not be limited to oversight of other designated study Investigators and study staff conducting 
any activities related to the study, maintenance of the study file and subject records, 
correspondence with the IRB, and completion of the electronic case report forms (eCRFs).  
 
Data Monitoring 
Before the first subject is dosed in the study, a Sponsor representative will meet with the 
Investigator and clinical site study staff to review the procedures for conducting the study and to 
train the staff on recording the data on the eCRFs using the electronic data capture (EDC) 
system.  The Sponsor representative will periodically monitor the progress of the study by 
conducting on–site visits.  The Sponsor representative will also be able to review query statuses 
remotely, which may warrant more frequent communication with the Investigators and clinical 
site study staff.   
 
The Investigator will make available to the Sponsor representative the source documents, the 
signed consent forms, all other study-related documents, and the computer that accesses the 
eCRFs.  The Investigator or designee will be responsible for reviewing eCRFs, resolving data 
queries generated by the Sponsor via the system, providing missing or corrected data, approving 
all changes to the data, and endorsing the subject data within the EDC system.  This approval 
method will include applying an electronic signature, a uniquely assigned username and a 
password that together will represent a traditional handwritten signature. 
 
Data Recording and Documentation 
Data collection will involve the use of the Sponsor electronic data capture (EDC) system, to which 
only authorized personnel will have access. In addition to periodic monitoring occurring within 
the system by Sponsor personnel, programmatic edit checks will be used to review the data for 
completeness, logic, and adherence to study protocol. As a result of this monitoring and these 
checks, queries may be issued electronically to the clinical study center and answered 
electronically by that study center. The identifying information (assigned username, date, and 
time) for both the originator of the query (if created during the monitoring process) and the 
originator of the data change (if applicable), as well as the Investigator’s approval of all changes 
performed on his or her Subjects’ data, will be collected. 
 


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All data collected in the context of this study will be stored and evaluated according to regulatory 
requirements and applicable guidance for electronic records. Data will be stored and evaluated in 
such a way as to guarantee subject confidentiality in accordance with the legal stipulations 
applying to confidentiality of data. Study records (e.g., copies of eCRFs, regulatory documents, 
etc.) will be retained at the study center, along with adequate source documentation, according to 
FDA and ICH requirements. All study records must be available for inspection by the Sponsor, its 
authorized representatives, and FDA officials. 
 
Retention and Review of Records 
The PI must maintain the documentation relating to this study. If the Sponsor, the FDA, or another 
regulatory authority wishes to review any documentation relating to the study, the PI must permit 
access to such records. 
 
The PI must retain a copy of all records that support the eCRFs for this study (e.g., ICFs, clinical 
laboratory reports, source documents, indoximod dispensing records) for a period of at least 15 
years after study completion unless local regulations or study center policies require a longer 
retention period or otherwise notified in writing by the Sponsor.  
 
If the PI retires, relocates, or for other reasons withdraws from the responsibility of keeping the 
study records, custody must be transferred to a suitable alternate custodian employee of the study 
center or to a suitably qualified and responsible third party. The Sponsor must be notified in writing 
of the name and address of the new custodian before such transfer is made.  
 
No study records shall be destroyed without notifying and giving the Sponsor the opportunity to 
arrange long-term storage for such study records or to authorize in writing the destruction of 
records after the required retention period. 
 
Subject Confidentiality 
All subject records will only be identifiable by a unique subject identification number. Subjects’ 
names or identifying information other than the data as specified for the eCRF collection are not 
to be transmitted to the Sponsor. The PI will keep a master subject list on which the subject number 
and full name, address, and telephone number of each subject are listed. 
Study Sponsorship 
The Sponsor for this study is: 
 
NEWLINK GENETICS CORPORATION  
  
The Sponsor Study Director and contact person is: 
Eugene Kennedy, MD 
Chief Medical Officer 
NewLink Genetics Corporation 
Email: gkennedy@linkp.com  
  
NewLink Genetics Corporation 


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2503 South Loop Drive, Suite 5100 
Ames, IA 50003 
Telephone: 515-296-5555 
Facsimile: 515-296-3556 
www.linkp.com 
  
Study Audits and Inspections 
The study may be evaluated by the Sponsor and/or designees and government inspectors who must 
be allowed access to eCRFs, source documents, and other study files. Sponsor audit reports will 
be kept confidential. The Investigator should promptly notify Sponsor of any audits scheduled by 
any regulatory authorities, and promptly forward copies of audit reports. 
 
Study Termination 
The Sponsor reserves the right to terminate the study in its entirety or at a specific study center at 
any time. 
 
Reporting and Publication 
All data generated in this study will be the property of the Sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study. 
 
Publication of the results by the Investigators will be subject to the signed contractual agreement 
between the PI and the Sponsor 
 
 


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9.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in the table below will be performed by the local laboratories. 
• Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Protocol-Required Clinical Laboratory Assessments 
Lab Test 
Parameters 
Timing 
Chemistry 
Sodium, potassium, magnesium, calcium, chloride, glucose, 
blood urea nitrogen (BUN), creatinine, total protein, alkaline 
phosphatase, albumin, total bilirubin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), 
lactate dehydrogenase (LDH), phosphorus.  
• Pre-study 
• Weekly during Cycle 1 
and then Day 1 of each 
subsequent Cycle 
• EOT Visit 
• Per SOC during follow-
up  
Hematology 
Total white blood cell count (WBC), WBC differential to 
include neutrophils, lymphocytes, monocytes, basophils, and 
eosinophils, red blood cell count (RBC), hemoglobin level, 
hematocrit level, platelet count.   
• Pre-study 
• Weekly during Cycle 1 
and then Day 1 of each 
subsequent Cycle 
• EOT Visit 
• Per SOC during follow-
up  
Coagulation 
Prothrombin time (PT), partial thromboplastin time (PTT), 
and international normalized ratio (INR) 
• Pre-study 
• EOT Visit 
Urinalysis  
Specific gravity, pH, protein, glucose, ketones, bilirubin, 
and blood. 
• Pre-study 
• As clinically indicated 
during treatment 
• EOT Visit 
Pregnancy 
test* 
Urine pregnancy test or Serum β–hCG as confirmation of 
positive urine test 
*only for women of child-bearing potential 
• Pre-study 
• Every 3 – 4 weeks 
depending on PD-1 
Schedule 
• EOT Visit 
Pituitary  
Luteinizing hormone (LH) and follicle stimulating hormone 
(FSH) 
• Pre-study 
• Day 1 of each Cycle 
 
Endocrine 
Free T4, thyroid-stimulating hormone (TSH), and 
adrenocorticotropic hormone (ACTH) levels. 
• Pre-study 
• Day 1 of each Cycle 
 
Pancreatic 
Amylase and lipase enzymes 
• Pre-study 
• Day 1 of each Cycle 
 
 
Investigators must document their review of each laboratory safety report. 
 
 




CONFIDENTIAL 
NLG2107 Version 4.0 
 
 
90 
9.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
  
Contraception Guidance: 
Male and Female participants 
Male and female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in the 
following table. 
 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• Oral  
• Intravaginal  
• Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study intervention, 
which may reduce the efficacy of the contraceptive method. In this case, two highly effective 
methods of contraception should be utilized during the treatment period and for at least 120-
150 days (4-5 months) after the last dose of study intervention  


CONFIDENTIAL 
NLG2107 Version 4.0 
 
 
91 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
The Investigator must report any pregnancy (including the pregnancy of a male subject’s partner), 
even if no AE has occurred, on a Pregnancy Report Form within 24 hours of the Investigator 
becoming aware of the pregnancy. See the Study Manual for a copy of the form and instructions 
on how to submit this information to the Sponsor.  
Female Subjects who become pregnant while on the study will be immediately discontinued from 
study treatment, and complete the End-of-Treatment visit at 30 days post-last dose follow-up 
period, reporting all AEs including any related to the pregnancy. In addition, the Investigator will 
make every attempt to confirm the outcome of the pregnancy and report this on a follow-up 
Pregnancy Report form.   
Based on their actions, both pembrolizumab and nivolumab can cause fetal harm when 
administered to pregnant women. For this reason and because indoximod may affect maternal 
immune tolerance of the fetus, sexually active women of child-bearing potential must agree to use 
effective contraception prior to study entry and for the duration of study treatment and for a 
minimum of 4 months (for those who receive pembrolizumab) and a minimum of 5 months (for 
those who receive nivolumab) after completion of study treatment. 
 
 






CONFIDENTIAL 
Protocol NLG2107 Version 4.0 
 
 
94 
 
9.7. 
Appendix 7: RECIST 1.1 Guideline  
 
The publication with the RECIST v.1.1 criteria can be accessed at: 
  
 




CONFIDENTIAL 
Protocol NLG2107 Version 4.0 
 
 
96 
10. 
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G.S., Arditi, M., Shimada, K., Duhadaway, J.B., et al. (2012). Opposing biological 
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tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain 
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Borgognoni,L. (2010). Indoleamine 2,3-dioxygenase+ cells correspond to the BDCA2+ 
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Candeloro, P., Belladonna, M.L., Bianchi, R., Fioretti, M.C., and Puccetti, P. (2002). 
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Mellor, A.L., Prendergast, G.C., and Munn, D.H. (2007). Inhibition of IDO in dendritic 


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Cancer Res. 67, 792- 801. 
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15. Larkin J, Hodi FS, Wolchok JD. (2015). Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. N Engl J Med. 373 (13): 1270-1. 
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immunosuppression in melanoma sentinel nodes. Clin. Cancer Res. 11, 107-112. 
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18. McCarthy WH, Shaw HM, Thompson JF, Milton GW. Time and frequency of recurrence 
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Iwashima, M., and Munn, D.H. (2003). Cutting Edge: Induced indoleamine 2,3 
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21. Mezrich, J.D., Fechner, J.H., Zhang, X., Johnson, B.P., Burlingham, W.J., and Bradfield, 
C.A. (2010). An interaction between kynurenine and the aryl hydrocarbon receptor can 
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(2005). Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the 
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A.L. (2005). GCN2 kinase in T cells mediates proliferative arrest and anergy induction in 
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dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J. Clin. 
Invest. 114, 280-290. 
27. Munn, D.H., Zhou, M., Attwood, J.T., Bondarev, I., Conway, S.J., Marshall, B., Brown, 
C., and Mellor, A.L. (1998). Prevention of allogeneic fetal rejection by tryptophan 
catabolism. Science 281, 1191-1193. 
28. National Cancer Institute SEER stat fact sheets: Melanoma of the skin. Available at: 
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https://www.nccn.org/professionals/physician gls/f guidelines.asp  
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excision for primary cutaneous malignant melanoma. Ann Surg. 1983;198:65–69.  
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nodal pathogenic driver of lung cancer and metastasis development. Cancer discovery 2, 
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SAP_001.pdf: 
Statistical Analysis Plan 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03 
INC Research © LLC 
Page 1 of 47
Sponsor Name: 
NewLink Genetics Corporation 
Protocol Number and Title: 
NLG2107 
A Phase 2/3 (Adaptive Design) Study of the 
Concomitant Administration of Indoximod or 
Placebo plus Pembrolizumab or Nivolumab in 
Adult Patients with Unresectable Stage III or 
Stage IV Malignant Melanoma 
Protocol Version and Date: 
Version 1.0 21-Aug-2017 
Version 1.1 18-Sep-2017 
Version 2.0 08-Nov-2017 
Version 3.0 30-Mar-2018 
Version 4.0 27-Aug-2018 
Syneos Health (Formerly 
INC Research) Project 
Code: 
1010280 
Author: 
SAP Version: 
  V1.0 for Phase 2 
SAP Version Date: 
04-Dec-2019
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to NewLink Genetics 
Corporation. Acceptance of this document constitutes agreement by the recipient that no 
information contained herein will be published or disclosed without prior written authorization 
from an official of NewLink Genetics Corporation.  However, this document may be disclosed to 
appropriate Institutional Review Board and Ethics Committees or duly authorized representatives 
of a national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, Syneos Health 
(formerly INC Research) should be notified promptly. 
NCT03301636 






Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 4 of 47 
TABLE OF CONTENTS 
 GLOSSARY OF ABBREVIATIONS ...................................................... 8 
 PURPOSE ............................................................................... 10 
 
Responsibilities ...................................................................................... 10 
 
Timings of Analyses ................................................................................. 10 
 STUDY OBJECTIVES .................................................................. 11 
 
Primary Objective ................................................................................... 11 
 
Exploratory Objective .............................................................................. 11 
 
Brief Description..................................................................................... 11 
 
Subject Selection .................................................................................... 12 
 
Sample Size Determination ........................................................................ 12 
 
Treatment Assignment and Blinding ............................................................. 12 
 
Administration of Study Medication ............................................................. 13 
 
Indoximod Administration .................................................................... 13 
 
Immune Checkpoint Inhibitor (Pembrolizumab/ Nivolumab) Administration ........ 13 
 
Study Procedures and Flowchart ................................................................. 13 
 ENDPOINTS ............................................................................ 14 
 
Efficacy Endpoints ................................................................................... 14 
 
 
 
Safety Endpoints ..................................................................................... 14 
 ANALYSIS SETS ........................................................................ 15 
 
Enrolled Set - Phase 2 .............................................................................. 15 
 
Safety Analysis Set (SAF) - Phase 2 .............................................................. 15 
 
 ................................................. 15 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 5 of 47 
 GENERAL ASPECTS FOR STATISTICAL ANALYSIS ............................... 16 
 
General Methods ..................................................................................... 16 
 
Key Definitions ....................................................................................... 16 
 
Baseline ......................................................................................... 16 
 
Change from Baseline ......................................................................... 16 
 
Duration of Treatment (Weeks) ............................................................. 17 
 
Treatment-emergent Adverse Event (TEAE) ............................................ 17 
 
Missing Data .......................................................................................... 17 
 
Visit Windows ........................................................................................ 18 
 DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION .. 19 
 
Subject Disposition and Withdrawals ............................................................ 19 
 
Demographic and Other Baseline Characteristics ............................................ 19 
 
Demographic Characteristics ............................................................... 19 
 
Disease Characteristics ....................................................................... 19 
 
Medical History ...................................................................................... 20 
 
Medical History ................................................................................. 20 
 
Prior Anticancer Radiotherapy ............................................................. 20 
 
Prior Anticancer Surgery .................................................................... 20 
 
Prior Anticancer Medication ................................................................. 20 
 
Medication and Procedure ......................................................................... 20 
 
Prior and Concomitant Medication .......................................................... 20 
 
On-Study Therapeutic Procedure ............................................................ 20 
 EFFICACY .............................................................................. 21 
 
Tumor Assessments ................................................................................. 21 
 
Response Evaluations ............................................................................... 21 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 6 of 47 
 
 
 SAFETY ................................................................................. 27 
 Extent of Exposure and Compliance ............................................................. 27 
 Dose Limiting Toxicities (DLT) .................................................................... 27 
 Adverse Events ....................................................................................... 27 
 Laboratory Evaluations ............................................................................. 29 
 Vital Signs ............................................................................................. 29 
 12-Lead Electrocardiogram (ECG) ................................................................ 29 
 Physical Examination ............................................................................... 30 
 Eastern Cooperative Oncology Group (ECOG) Performance Status ....................... 30 
 Colletion of Tumor Tissue ......................................................................... 31 
 CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ............................ 32 
 REFERENCE LIST ...................................................................... 33 
 PROGRAMMING CONSIDERATIONS ................................................. 34 
 General Considerations ............................................................................ 34 
 Table, Listing, and Figure Format ............................................................... 34 
 
General .......................................................................................... 34 
 
Headers .......................................................................................... 34 
 
Display Titles ................................................................................... 35 
 
Column Headers ................................................................................ 35 
 
Body of the Data Display ..................................................................... 35 
 
Footnotes ....................................................................................... 36 
 QUALITY CONTROL .................................................................. 37 
 INDEX OF TABLES .................................................................... 38 
 INDEX OF FIGURES ................................................................... 40 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 7 of 47 
 INDEX OF LISTINGS ................................................................... 41 
 MOCK-UPS ............................................................................. 43 
 APPENDIX .............................................................................. 44 
 
 
 
 






Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 10 of 47 
 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures of the Phase 2 portion of the study which will be produced, 
and the statistical methodologies that will be used, are complete and appropriate to 
allow valid conclusions regarding the study objectives.   
 
RESPONSIBILITIES 
Syneos Health (formerly INC Research) will perform the statistical analyses and are 
responsible for the production and quality control of tables, listings, and figures (TLFs) 
of the Phase 2 portion, except for the exploratory endpoints (i.e. concentration-QT 
analysis). Based on protocol Version 4, the phase 3 study will not proceed, so the 
analysis of the Phase 3 portion will not be performed. 
 
TIMINGS OF ANALYSES 
The primary analysis of safety, tolerability 
 is planned after all Phase 2 subjects 
complete the final study visit or terminate early from the study in Phase 2 portion of 
the study. 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 11 of 47 
 
STUDY OBJECTIVES 
 
PRIMARY OBJECTIVE  
The primary objective (Phase 2) is to establish the Phase 3 dose of indoximod in 
combination with immune checkpoint inhibition pembrolizumab or nivolumab in adult 
patients with unresectable stage III or stage IV malignant melanoma-an open label 
evaluation of 
 safety and tolerability of the combined treatment. With protocol 
Version 4, the phase 3 study will not proceed. 
 
EXPLORATORY OBJECTIVE  
The exploratory objective (Phase 2) is to assess the QT prolongation potential of 
indoximod. Full detail of the concentration-QT analysis will be provided in a separate 
SAP.  
 
BRIEF DESCRIPTION 
The Phase 2 portion of this study is an open-label, dose-escalation study to establish the 
Phase 3 dose of indoximod given in combination with pembrolizumab or nivolumab, 
assessing the 
 safety, and tolerability of indoximod plus pembrolizumab or nivolumab 
(combination therapy) in adult patients with unresectable stage III or stage IV malignant 
melanoma.  
The goal of the Phase 2 trial is to find the maximum dose of indoximod that does not 
induce a regimen-limiting toxicity (RLT) in more than 1/6 of patients treated 
concurrently with pembrolizumab or nivolumab, and the dose below RLT that achieves 
maximum exposure levels. Three doses of indoximod (600, 1200, and 1800 mg) will be 
tested. 
 
 
 
 
 
The dose escalation will follow a linear increase sequence as defined below to define a 
maximum tolerated dose (MTD): 
 
Up to 6 patients will be dosed at dose level 1 (600 mg Q12 hr) for at least 28 
days (through Cycle 1). 
 
If none of the first 3 patients or only 1 or less of the 6 patients in the dose level 
1 (600 mg PO every 12 hours) experiences a RLT, the dose escalation continues 
to the dose level 2 (1200 mg PO every 12 hours). 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 12 of 47 
 
Up to 6 patients will then be treated at dose level 2. 
 
If none of the 3 patients or only 1 or less of the 6 patients in the dose level 2 
(1200 mg PO every 12 hours) experiences a RLT, the dose escalation continues to 
the dose level 3 (1800 mg PO every 12 hours). 
 
Up to 6 patients will then be treated at dose level 3. 
 
If none of the 3 patients or 1 or less of the 6 patients in the dose level 3 (1800 
mg PO every 12 hours) experiences a RLT, dose level 3 will be declared the 
recommended Phase 3 dose (RP3D), 
. 
 
If 2 or more patients at a particular dose level experience RLTs and the next 
lower dose has only 3 patients enrolled, dosing will be de-escalated to the next 
lower dose and 3 additional patients will be enrolled so that at least 6 patients 
have been treated with the dose intended as the RP3D dose. 
 
SUBJECT SELECTION 
Male or female adult patients with unresectable stage III or IV advanced melanoma who 
meet all eligibility criteria will be selected. The detailed inclusion/exclusion criteria 
can be found in the study protocol Sections 5.1 and 5.2. 
 
SAMPLE SIZE DETERMINATION 
The Phase 2 sample size will be 12-18 subjects (depending on dose escalation) – 3 to 6 
subjects per dose level. 
 
TREATMENT ASSIGNMENT AND BLINDING 
The Phase 2 is an open-label study and has no randomization/ blinding.  
The table below summarizes dose levels of indoximod and pembrolizumab or nivolumab 
for the Phase 2 study. The Phase 2 portion of this study will be conducted only in the 
United States and therefore will follow the below dose levels. 
Table 1. Dose Levels of the Phase 2 Portion 
Dose Level 
Indoximod (oral) Pembrolizumab Dose (IV) 
Nivolumab Dose (IV) 
1 
600 mg Q12 hours 
200 mg IV Q3 weeks 
240 mg IV Q2 weeks 
2 
1200 mg Q12 hours 
200 mg IV Q3 weeks 
240 mg IV Q2 weeks 
3 
1800 mg Q12 hours 
200 mg IV Q3 weeks 
240 mg IV Q2 weeks 
Dosing regimen: Dosing cycles will be 21 days in length during combination 
immunotherapy involving pembrolizumab and will be 14 days in length during 


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combination immunotherapy involving nivolumab. Pembrolizumab will be dosed on Day 
1 of each 21-day cycle. Nivolumab will be dosed on Day 1 of each 14-day cycle. During 
Cycle 1, subjects will take the first dose of indoximod on Day 1 and not take another 
dose until Day 4; from Cycle 2, indoximod will be dosed twice daily on all days of each 
cycle. 
 
ADMINISTRATION OF STUDY MEDICATION 
 Indoximod Administration 
The indoximod tablets are 600 mg each. The number of tablets will be determined by 
the dose and should be taken in the morning and evening. No food should be taken for 
at least 2 hours before and at least 1 hour after administration of the morning and 
evening doses. The study medication should be taken twice daily (Q12 hours) in a 
continuous fashion.  
 Immune Checkpoint Inhibitor (Pembrolizumab/ Nivolumab) 
Administration 
The study is designed to evaluate the addition of indoximod, to standard of care 
checkpoint immunotherapy, pembrolizumab or nivolumab. The administration of these 
agents (pembrolizumab/nivolumab) should be done at the direction of the treating 
physician according to the physician’s usual standard of care practices. 
 
STUDY PROCEDURES AND FLOWCHART 
The schedule of activities for Phase 2 can be found in Appendix 1. 


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ENDPOINTS 
 
EFFICACY ENDPOINTS 
The Phase 2 efficacy endpoints include results of the tumor assessments and response 
evaluations by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The 
efficacy data will be listed but not summarized. 
 
 
 
 
. 
 
SAFETY ENDPOINTS  
For Phase 2, the safety and tolerability of the pembrolizumab/nivolumab plus 
indoximod combination will be determined by reported AEs, serious AEs (SAEs), RLTs, 
physical examination findings, vital sign measurements, 12-lead electrocardiogram 
(ECG) readings, clinical laboratory evaluations, and treatment discontinuation due to 
toxicity.  
 


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ANALYSIS SETS 
 
ENROLLED SET - PHASE 2 
The Enrolled Set will include all subjects who are enrolled into the Phase 2 portion of 
the study and provide informed consent. 
 
 
SAFETY ANALYSIS SET (SAF) - PHASE 2 
The Safety Analysis Set (SAF) – Phase 2 will include all subjects who receive at least 1 
dose of any study treatment (indoximod, pembrolizumab, or nivolumab) during the 
Phase 2 portion of the study. This SAF will be used for all safety analysis. Subjects will 
be analyzed according to the treatment actually taken. 
 
 
 
 
 
. 
 


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GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
 
GENERAL METHODS 
All relevant subject data for Phase 2 portion of the study will be included in listings. All 
subjects entered into the database will be included in subject data listings. The listings 
will be generally sorted by the dose level and then Subject ID, unless specified 
otherwise.  
All applicable data will be summarized by dose level and overall for the Phase 2 portion, 
unless specified otherwise. In addition, data will be summarized by visit and/or time-
point where appropriate. Unscheduled or repeat assessments will not be included in 
summary tables, but will be included in listings. 
Continuous variables will be summarized using the number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum. The same number of 
decimal places as in the raw data will be presented when reporting the minimum and 
maximum, 1 more decimal place than in the raw data will be presented when reporting 
the mean and median, and 2 more decimal places than in the raw data will be 
presented when reporting the SD.  
Descriptive statistics for categorical/qualitative data will include frequency counts and 
percentages. The total number of subjects in the dose level (N) for a given population 
will be used as the denominator for percent calculations, unless stated otherwise in the 
table shell. All percentages will be presented with 1 decimal point, unless specified 
otherwise. Percentages equal to 100 will be presented as 100% and percentages will not 
be presented for zero frequencies.  
All analyses and summaries will be produced using SAS® Version 9.3 (or higher). 
 
KEY DEFINITIONS 
 Baseline 
Baseline is defined as the last non-missing assessment before the first dose of any study 
treatment in Phase 2, unless specified otherwise. 
 Change from Baseline 
Change from baseline will be calculated for the post-baseline assessment as: 
Change from baseline = post-baseline value – baseline value 


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 Duration of Treatment (Weeks) 
Duration of treatment is defined as the time from the date of the first dose to the date 
of last dose of any study treatment (indoximod, pembrolizumab, or nivolumab) in Phase 
2. This will be calculated as (date of last dose – date of first dose +1)/7. 
 Treatment-emergent Adverse Event (TEAE) 
A TEAE is an AE that occurs or increases in severity after administration of the first dose 
of indoximod and through 30 days after the last dose of indoximod in Phase 2. 
 
 
MISSING DATA 
For the purposes of assessing treatment emergence for AEs or classifying medications 
into prior/concomitant, the following algorithms will be used for partially missing dates. 
For start dates of events: 
 
The day and month are missing: if the subject started receiving indoximod in the 
reported year, the first dose date of indoximod will be used as the start date; 
otherwise ‘1 January’ will be used as the start date. 
 
The day is missing: if the subject started receiving indoximod in the reported 
month and year, the first dose date of indoximod will be used as the start date; 
otherwise, the first day of the reported month and year will be used as the start 
date. 
For stop dates of events: 
 
The day and month are missing: if the final visit is in the reported year, the date 
of final visit will be used as the stop date; otherwise, ’31 December’ will be used 
as the stop date. 
 
The day is missing: if the final visit is in the reported month and year, the date 
of final visit will be used as the stop date; otherwise, the end of the reported 
month and year will be used as the stop date. 
If an AE has the start date completely missing and the stop date on/after the first dose 
date of indoximod, this AE will be considered as treatment emergent. 
If a medication has the stop date completely missing, this medication will be considered 
as ongoing and concomitant. 
 


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VISIT WINDOWS 
The visits recorded in database will be used for all analyses, except for End of 
Treatment (ET) visit. For subjects who early discontinue from study treatment, the ET 
visit will be mapped to the closest scheduled visit based on the following algorithms. 
Phase 2 Schedule  
Target Scheduled 
Visit  
Mapping Window, inclusive 
Schedule A (Indoximod + 
Pembrolizumab) 
Last Cycle x Day 1 
From (date of Cycle x Day 1) to (date 
of Cycle x Day 1 + 3 days) 
 
Last Cycle x Day 8 
From (date of Cycle x Day 1 + 4 days) 
to (date of Cycle x Day 1 + 10 days) 
 
Last Cycle x Day 15 
After (date of Cycle x Day 1 + 11)  
Schedule B (Indoximod + 
Nivolumab)  
Last Cycle x Day 1 
From (date of Cycle x Day 1) to (date 
of Cycle x Day 1 + 3 days) 
 
Last Cycle x Day 8 
After (date of Cycle x Day 1 + 4 days)  
 
 


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DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
 
SUBJECT DISPOSITION AND WITHDRAWALS 
For subject study status, the number and percentage of subjects for each of the 
following categories will be presented for the Phase 2 portion of the study. 
 
Subjects in Enrolled Set – Phase 2 (the number only) 
 
Subjects in SAF – Phase 2 
 
Subjects in 
– Phase 2 
 
Subjects who completed the Phase 2 study 
 
Subjects who discontinued the Phase 2 study treatment by primary reason of 
discontinuation. 
 
Subjects who discontinued the Phase 2 study by primary reason of 
discontinuation. 
For all categories of subjects, percentages will be calculated using the number of 
subjects from Enrolled Set – Phase 2 unless otherwise specified.  
The data for subject disposition, protocol deviation, eligibility, and whether a subject is 
included in the analysis sets will be listed. 
 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Descriptive statistics will be summarized for the demographic characteristics and 
disease characteristics based on the SAF – Phase 2. Listings will also be presented for 
the demographic characteristics and disease characteristics, respectively. 
 Demographic Characteristics 
The following variables will be summarized: age (years), gender, race, height (cm), and 
weight (kg). 
 Disease Characteristics  
The following variables will be summarized: BRAF mutation status, number of disease 
sites, T Stage, N stage, M stage, and stage at Screening. 


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MEDICAL HISTORY 
 Medical History 
Medical history abnormalities will be coded to Medical Dictionary for Regulatory 
Activities (MedDRA®) terms. The version used will be specified in the data display 
footnote. Medical history will only be listed but not summarized. 
 Prior Anticancer Radiotherapy 
A listing will be provided for the prior anticancer radiotherapy. 
 Prior Anticancer Surgery 
A listing will be provided for the prior anticancer surgery. 
 Prior Anticancer Medication 
A listing will be provided for the prior anticancer medication. 
 
MEDICATION AND PROCEDURE 
 Prior and Concomitant Medication 
Medications will be recorded on the electronic case report form (eCRF), and will be 
coded using the World Health Organization Drug Dictionary (WHO DD).  
Prior medications will be any medications that started and stopped prior to the first 
dose of indoximod. Concomitant medications will be any medications that started or 
continued after the first dose of indoximod. 
Prior and concomitant medications will be tabulated and summarized by dose level. 
Medications will be sorted alphabetically by ATC term and then preferred term within 
ATC term. 
Prior and concomitant medications will be listed in the same table; a column will be 
included in the listing to indicate if the medication is prior or concomitant. 
 
On-Study Therapeutic Procedure 
A listing will be provided for the on-study therapeutic procedures. 


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EFFICACY 
 
TUMOR ASSESSMENTS 
Tumor assessments will be performed for target lesions, non-target lesions, and new 
lesions at baseline and every 9 weeks (± 1 week) after baseline. 
The tumor measurement data and radiological assessment data will be listed.  
 
RESPONSE EVALUATIONS 
Tumor response will be assessed by RECIST 1.1 criteria at each tumor assessment time 
point, which includes the overall response, and individual assessment of target lesions, 
non-target lesions, and new lesions.  
The tumor response data will be listed. 


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Table 3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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SAFETY 
SAF - Phase 2 will be used for all safety analysis of the Phase 2 portion of the study. 
 
EXTENT OF EXPOSURE AND COMPLIANCE 
Exposure of the study treatments (indoximod, pembrolizumab, and nivolumab) will be 
summarized by dose level and overall for the Phase 2 portion of the study. The 
following variables will be summarized: 
 
Maximum number of cycles started 
 
Number of subjects who started the maximum cycle of 1, 2, 3, 4, and so on  
 
Duration of treatment (weeks), defined as Section 6.2.3 
The following variables will be summarized separately for each study treatment 
(indoximod, pembrolizumab, and nivolumab) by dose level and overall for the Phase 2 
portion of the study. 
 
Number of administrations (for pembrolizumab and nivolumab) or tablets taken 
(for indoximod) per subject 
 
The total dose (mg) received per subject 
 
Number of subjects with dose interruption/delay 
 
Number of subjects with dose modification (for pembrolizumab and nivolumab 
only) 
 
Number of subjects with compliance percentage of <85% on 2 sequential cycles 
(for indoximod only)  
The listings of study treatment exposure and administration will be provided.   
 
DOSE LIMITING TOXICITIES (DLT) 
The DLTs will be reported as AEs and summarized separately by dose level and overall 
for Phase 2.  In addition, the DLTs will be listed. 
 
ADVERSE EVENTS 
The AEs will be coded to system organ class (SOC) and preferred term (PT) using the 
MedDRA dictionary. The version used will be specified in the data display footnote. 


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The National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-
CTCAE) will be used to assess the severity of AEs.  If severity is missing, the event will 
be listed as missing severity but summarized as a CTCAE Grade 3.  
The relationship of each AE to each study treatment (indoximod, pembrolizumab, and 
nivolumab) will be classified as related or unrelated. If relationship is missing, the event 
will be listed as missing relationship but summarized as related.  
Summaries will focus on the TEAEs, defined in Section 6.2.4. The TEAEs will be 
summarized by dose level and overall for Phase 2. The number and percent of subjects 
reporting each TEAE will be summarized, as well as the number of TEAEs (if applicable). 
A subject with 2 or more TEAEs within the same level of summarization (i.e., SOC or PT) 
will be counted only once in that level using the most severe event or most related 
event. 
Summaries presenting the frequency of AEs by SOC and PT will be sorted by descending 
frequency of SOC for the ‘Total’ column and then, within a SOC, by descending 
frequency of PT for the ‘Total’ column. 
The following summary tables will be provided: 
 
An overall summary of the frequency of subjects reporting all TEAEs, serious 
TEAEs, TEAEs with CTCAE Grade 3 or higher, indoximod-related TEAEs, TEAEs 
leading to indoximod discontinuation, and TEAEs with fatal outcome.   
 
TEAEs by SOC and PT 
 
Serious TEAEs by SOC and PT 
 
TEAEs with CTCAE Grade 3 or higher by SOC and PT 
 
Indoximod-related TEAEs by SOC and PT 
 
TEAEs leading to indoximod discontinuation by SOC and PT 
 
TEAEs with fatal outcome by SOC and PT 
 
TEAEs by SOC and PT, and by maximum CTCAE grade  
 
TEAEs by SOC and PT, and by maximum relationship to indoximod  
 
TEAEs by SOC and PT, and by maximum relationship to pembrolizumab  
 
TEAEs by SOC and PT, and by maximum relationship to nivolumab  


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All AEs will be listed by dose level and then subject number of Phase 2. Separate listings 
will be produced for serious TEAEs, TEAEs leading to indoximod discontinuation, and 
TEAEs with fatal outcome. In addition, the listing of all deaths (regardless of cause) will 
be provided. 
 
LABORATORY EVALUATIONS 
The following laboratory tests will be performed locally to evaluate the safety profile: 
clinical chemistry (including endocrine, pituitary, and pancreas function tests), 
hematology (including coagulation), urinalysis, and pregnancy.  
For each laboratory parameter, the actual values and changes from baseline (if 
applicable) will be summarized and the frequency of subjects with clinically significant 
abnormal laboratory values will be tabulated for baseline and each scheduled post-
baseline visit, by dose level and overall for Phase 2. In addition, the maximum and 
minimum post-baseline values will be summarized, if applicable. 
Shift tables (‘Normal’, ‘Abnormal, Not Clinically Significant’, and ‘Abnormal, Clinically 
Significant’) from baseline to the worst post-baseline category during treatment period 
will be provided for the clinical chemistry and hematology parameters. Both scheduled 
and unscheduled post-baseline values during treatment period will be considered.  
All laboratory data will be listed by subject. Values outside the normal ranges will be 
flagged and toxicity grades will be displayed for relevant parameters. Pregnancy test 
results will only be listed. 
 
VITAL SIGNS  
The vital sign measurements include blood pressure (systolic and diastolic), pulse rate, 
respiration rate, and body temperature. 
For each vital sign parameter, the actual values and changes from baseline (if 
applicable) will be summarized for baseline and each scheduled post-baseline visit by 
dose level and overall for Phase 2. 
All vital signs measurements will be listed. 
 
12-LEAD ELECTROCARDIOGRAM (ECG)  
12-lead ECG measurements will be performed in triplicate at the scheduled time points, 
including the heart rate, RR interval, PR interval, QT interval, QTcB and/or QTcF 
interval. ECG overall interpretation will also be collected on the eCRF. 
For summary purposes, the mean of the available repeat measurements at a scheduled 
time point will be used for each continuous parameter; the worst case of interpretation 


Statistical Analysis Plan (Phase 2) 
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categories (‘Normal’, ‘Abnormal, Not Clinically Significant’, and ‘Abnormal, Clinically 
Significant’) at a scheduled time point will be used.  
For each continuous parameter, the actual values and changes from baseline (if 
applicable) will be summarized for baseline and each scheduled post-baseline time 
point by dose level and overall for Phase 2. 
The number (percentage) of subjects with elevated QTc values (‘>450 msec’, ‘>480 
msec’, and ‘>500 msec’) at baseline and end of treatment will be presented; the 
number (percentage) of subjects with QTc values which increase by >30 msec and >60 
msec from baseline to end of treatment will be presented, by dose level and overall for 
Phase 2. 
A shift table from baseline to the maximum post-baseline values during the treatment 
period will be provided for QTcF and QTcB intervals, based on the categories (‘≤450 
msec’, ‘>450 and ≤480 msec’, ‘>480 and ≤500 msec’, and ‘>500 msec’). 
For ECG overall interpretation, the number (percentage) of subjects with individual 
categories (‘Normal’, ‘Abnormal, Not Clinically Significant’, and ‘Abnormal, Clinically 
Significant’) will be summarized for baseline and each scheduled post-baseline time 
point by dose level and overall for Phase 2. 
All ECG measurements and overall interpretation results will be listed. 
 
PHYSICAL EXAMINATION 
A complete physical examination includes a major review of body systems (general 
appearance, skin, neck including thyroid, eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities and neurological examination). 
Clinically significant physical examination findings will be reported on medical history or 
AE eCRFs. 
The date of physical examinations will be listed. 
 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
STATUS 
The ECOG performance status will be based on 6-grade scale (e.g. 0=normal activity; 
5=dead). 
The number (percentage) of subjects with individual categories of ECOG performance 
status will be summarized for baseline and each scheduled post-baseline visit by dose 
level and overall for Phase 2.  
All ECOG performance status data will be listed. 


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CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
Although mentioned in Protocol Section 7.7.1.2, the PK and immunogenicity analysis of 
Permbrolizumab/Nivolumab are excluded from the final analysis. 


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REFERENCE LIST 
1. Gough K, Hutchinson M, Keene O, Byrom B, Ellis S, Lacey L, McKellar J. 
Assessment of Dose Proportionality: Report from the Statisticians in The 
Pharmaceutical Industry/Pharmacokinetics UK joint working party. Drug Inf J. 
1995; 29:1039-1048. 
2. Hummel J, McKendrick S, Brindley C and French, R. Exploratory assessment of 
dose proportionality: review of current approaches and proposal for a practical 
criterion. Pharmaceut. Statist. 2009; 8: 38-49. 
 


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PROGRAMMING CONSIDERATIONS 
 
GENERAL CONSIDERATIONS 
 
One SAS program can create several outputs.  
 
One output file can contain several outputs.  
 
Output files will be delivered in Word format (.rtf). 
 
Numbering of TLFs will follow International Conference on Harmonization (ICH) E3 
guidance.  
 
TABLE, LISTING, AND FIGURE FORMAT 
 General 
 
All TLFs will be produced in landscape format, unless otherwise specified. 
 
All TLFs will be produced using the Courier New font, size 8.  
 
The data displays for all TLFs will have a minimum 1-inch blank margin on all 4 
sides. 
 
Headers and footers for figures will be in Courier New font, size 8. 
 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. 
 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
 Headers 
 
All output should have the following header at the top left of each page: 
NewLink Genetics Corporation Protocol NLG2107      
          
Draft/Final Run 
 
All output should have Page n of N at the top or bottom right corner of each page. 
The TLFs should be internally paginated in relation to the total length (i.e., the 
page number should appear sequentially as page n of N, where N is the total number 
of pages in the table). 
 
The date output was generated should appear along with the program name as a 
footer on each page. 


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 Display Titles 
 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
The title is centered. The analysis set should be identified on the line immediately 
following the title. The title and table designation are single spaced. A solid line 
spanning the margins will separate the display titles from the column headers. There 
will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(XX Analysis Set) 
 Column Headers 
 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
 
Analysis set sizes will be presented for each study group in the column heading as 
(N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
 Body of the Data Display 
13.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified;  
• 
numbers containing fractional portions are decimal aligned. 
13.2.5.2. Table Conventions 
 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity Rating 
N 
mild 
0 
moderate 
8 
severe 
3 
 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 


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 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value should be less than 0.0001 then present as <0.0001. If the p-value is returned 
as >0.999 then present as >0.999. 
13.2.5.3. Listing Conventions 
 
Listings will be sorted for presentation in order of study groups, subject number, 
visit/collection day, and visit/collection time. 
 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
13.2.5.4. Figure Conventions 
 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint values will be displayed on the Y-axis. 
 Footnotes 
 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
 
Footnotes should always begin with “Note:” if it is an informational footnote, or 
with 1, 2, 3, etc. if it is a reference footnote. Each new footnote should start on a 
new line where possible. 
 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source. 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 37 of 47 
 
QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data sets, summary 
tables, data listings, figures or statistical analyses. Syneos Health (formerly INC 
Research) Standard Operating Procedures (SOPs) 03.010 and 03.013 provide an overview 
of the development of such SAS programs. 
Syneos Health (formerly INC Research) SOP 03.009 describes the quality control 
procedures that are performed for all SAS programs and output. Quality control is 
defined here as the operational techniques and activities undertaken to verify that the 
SAS programs produce the output by checking for their logic, efficiency and commenting 
and by review of the produced output. 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 38 of 47 
 
INDEX OF TABLES 
The following tables will be produced (table numbers and titles may be different in the 
final versions): 
Header 
Table Number 
Name 
Analysis Set 
14. 
 
Tables and Figures Referred to but not Included in the Text 
 
14.1 
 
Demographic Data Summary Tables 
 
14.1.1 
 
Subject Disposition 
 
 
14.1.1.1 
Summary of Subject Disposition 
Enrolled Set – 
Phase 2 
14.1.2 
 
Demographic and Baseline Characteristics 
 
 
14.1.2.1 
Summary of Demographic Characteristics 
SAF – Phase 2  
 
14.1.2.2 
Summary of Disease Characteristics 
SAF – Phase 2 
14.1.3 
 
Medications 
 
 
14.1.3.1 
Prior Medications 
SAF – Phase 2 
 
14.1.3.2 
Concomitant Medications 
SAF – Phase 2 
14.1.4 
 
Treatment Compliance 
 
 
14.1.4.1 
Summary of Maximum Cycles Started and Duration of Treatment 
SAF – Phase 2 
 
14.1.4.2 
Summary of Exposure for Indoximod 
SAF – Phase 2 
 
14.1.4.3 
Summary of Exposure for Pembrolizumab 
SAF – Phase 2 
 
14.1.4.4 
Summary of Exposure for Nivolumab 
SAF – Phase 2 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
14.3 
 
Safety Data Summary Tables 
 
14.3.1 
 
Adverse Events 
 
 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
SAF – Phase 2 
 
14.3.1.2 
Incidence of Dose Limiting Toxicities 
SAF – Phase 2 
 
14.3.1.3 
Incidence of Treatment-Emergent Adverse Events 
SAF – Phase 2 
 
14.3.1.4 
Incidence of Serious Treatment-Emergent Adverse Events  
SAF – Phase 2 
 
14.3.1.5 
Incidence of Treatment-Emergent Adverse Events with CTCAE Grade 3 
or Higher  
SAF – Phase 2 
 
14.3.1.6 
Incidence of Indoximod-related Treatment-Emergent Adverse Events  
SAF – Phase 2 
 
14.3.1.7 
Incidence of Treatment-Emergent Adverse Events Leading to 
Indoximod Discontinuation  
SAF – Phase 2 
 
14.3.1.8 
Incidence of Treatment-Emergent Adverse Events with Fatal Outcome 
SAF – Phase 2 
 
14.3.1.9 
Incidence of Treatment-Emergent Adverse Events by Maximum CTCAE 
Grade  
SAF – Phase 2 
 
14.3.1.10 
Incidence of Treatment-Emergent Adverse Events by Maximum 
Relationship to Indoximod 
SAF – Phase 2 
 
14.3.1.11 
Incidence of Treatment-Emergent Adverse Events by Maximum 
Relationship to Pembrolizumab 
SAF – Phase 2 
 
14.3.1.12 
Incidence of Treatment-Emergent Adverse Events by Maximum 
Relationship to Nivolumab 
SAF – Phase 2 
14.3.4 
 
Laboratory Data 
SAF – Phase 2 
14.3.4.1.1 
 
Clinical Chemistry 
SAF – Phase 2 
 
14.3.4.1.1.1 
Summary of Clinical Chemistry  
SAF – Phase 2 
 
14.3.4.1.1.2 
Proportions of Subjects with Clinically Significant Clinical Chemistry 
SAF – Phase 2 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 39 of 47 
Header 
Table Number 
Name 
Analysis Set 
Values  
 
14.3.4.1.1.3 
Shift Table of Clinical Chemistry  
SAF – Phase 2 
14.3.4.1.2 
 
Hematology  
 
 
14.3.4.1.2.1 
Summary of Hematology 
SAF – Phase 2 
 
14.3.4.1.2.2 
Proportions of Subjects with Clinically Significant Hematology Values  
SAF – Phase 2 
 
14.3.4.1.2.3 
Shift Table of Hematology 
SAF – Phase 2 
14.3.4.1.3 
 
Urinalysis 
 
 
14.3.4.1.3.1.1 
Summary of Urinalysis (Continuous)  
SAF – Phase 2 
 
14.3.4.1.3.1.2 
Summary of Urinalysis (Categorical)  
SAF – Phase 2 
 
14.3.4.1.3.2 
Proportions of Subjects with Clinically Significant Urinalysis Values  
SAF – Phase 2 
14.3.4.2 
 
Vital Signs  
 
 
14.3.4.2.1 
Summary of Vital Signs 
SAF – Phase 2 
14.3.4.3 
 
Electrocardiogram (ECG) 
 
 
14.3.4.3.1 
Summary of Electrocardiogram (ECG) 
SAF – Phase 2 
 
14.3.4.3.2 
Proportions of Subjects with Elevated QTcF and QTcB Values 
SAF – Phase 2 
 
14.3.4.3.3 
Shift Table of QTcF and QTcB Intervals 
SAF – Phase 2 
 
14.3.4.3.4 
Summary of Electrocardiogram (ECG) Overall Interpretation 
SAF – Phase 2 
14.3.4.4 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
 
14.3.4.4.1 
Summary of Eastern Cooperative Oncology Group (ECOG) Performance 
Status 
SAF – Phase 2 
If ICH standard sections are removed from the report or additional sections added, the 
highest level section number (14) may change. Templates are provided in Attachment 1. 
 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 40 of 47 
 
INDEX OF FIGURES 
The following figures will be produced (figure numbers and titles may be different in 
the final versions): 
Header 
Figure 
Number 
Name 
Analysis Set 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Templates can be found in Attachment 2. 
 
 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 41 of 47 
 
INDEX OF LISTINGS 
Data collected in the database will be listed. Numbering of listings may be adjusted to 
accommodate split listings or listings that are omitted due to no records. 
Header 
Listing 
Number 
Name 
Analysis Set 
16.2 
 
Subject Data Listings 
 
16.2.1 
 
Subject Disposition 
 
 
16.2.1.1 
Subject Disposition  
Enrolled Set - Phase 2 
16.2.2 
 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations  
Enrolled Set - Phase 2 
16.2.3 
 
Patients excluded from the Analysis 
 
 
16.2.3.1 
Eligibility 
Enrolled Set - Phase 2 
 
16.2.3.2 
Analysis Sets 
Enrolled Set - Phase 2  
16.2.4 
 
Demographic Data 
 
 
16.2.4.1 
Demographic Characteristics  
Enrolled Set - Phase 2 
 
16.2.4.2 
Disease Characteristics 
Enrolled Set - Phase 2 
 
16.2.4.3 
Medical History 
Enrolled Set - Phase 2 
 
16.2.4.4 
Prior Anticancer Radiotherapy  
Enrolled Set - Phase 2 
 
16.2.4.5 
Prior Anticancer Surgery  
Enrolled Set - Phase 2 
 
16.2.4.6 
Prior Anticancer Medication  
Enrolled Set - Phase 2 
 
16.2.4.7 
Prior and Concomitant Medication  
Enrolled Set - Phase 2 
 
16.2.4.8 
On-Study Therapeutic Procedure 
Enrolled Set - Phase 2 
16.2.5 
 
Compliance Data  
 
 
16.2.5.1 
Exposure of Study Treatment 
Enrolled Set - Phase 2 
 
16.2.5.2 
Study Treatment Administration – Indoximod 
Enrolled Set - Phase 2 
 
16.2.5.3 
Study Treatment Administration – Pembrolizumab or Nivolumab 
Enrolled Set - Phase 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16.2.6 
 
Individual Efficacy Response Data 
 
 
16.2.6.1.1 
Tumor Assessment - Target Lesions 
Enrolled Set - Phase 2 
 
16.2.6.1.2 
Tumor Assessment - Non-Target Lesions and New Lesions 
Enrolled Set - Phase 2 
 
16.2.6.2 
Tumor Response Evaluation by RECIST 1.1 
Enrolled Set - Phase 2 
 
16.2.6.3 
Radiological Assessment 
Enrolled Set - Phase 2 
16.2.7 
 
Adverse Event Listings 
 
 
16.2.7.1 
Adverse Events 
Enrolled Set - Phase 2 
 
16.2.7.2 
Dose Limiting Toxicities  
Enrolled Set - Phase 2 
 
16.2.7.3 
Serious Treatment-Emergent Adverse Events 
Enrolled Set - Phase 2 
 
16.2.7.4 
Treatment-Emergent Adverse Events Leading to Indoximod 
Discontinuation 
Enrolled Set - Phase 2 
 
16.2.7.5 
Treatment-Emergent Adverse Events with Fatal Outcome 
Enrolled Set - Phase 2 
 
16.2.7.6 
Death (Regardless of Cause) 
Enrolled Set - Phase 2 
16.2.8 
 
Listing of Individual Laboratory Measurements by Patient 
 
 
16.2.8.1.1 
Clinical Chemistry 
Enrolled Set - Phase 2 
 
16.2.8.1.2 
Hematology 
Enrolled Set - Phase 2 
 
16.2.8.1.3 
Urinalysis 
Enrolled Set - Phase 2 
 
16.2.8.1.4 
Pregnancy Test 
Enrolled Set - Phase 2 
 
16.2.8.2.1 
Vital Signs 
Enrolled Set - Phase 2 
 
16.2.8.2.2 
Electrocardiogram (ECG)  
Enrolled Set - Phase 2  
 
16.2.8.2.3 
Physical Examination  
Enrolled Set - Phase 2 
 
16.2.8.2.4 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Enrolled Set - Phase 2 
 
16.2.8.2.5 
Tumor Tissue Collection  
Enrolled Set - Phase 2 
Templates of the listings are provided in Attachment 3. These templates show what 
information will be contained in the listings but the actual layout (e.g. order of 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 42 of 47 
columns, additional columns) may change to reflect what is actually received. Listings 
may be split into multiple listings if there are too many data points to fit on one page. 
Numbering of listings may be adjusted to accommodate split listings, listings that are 
added and/or listings that are omitted due to no records. If ICH standard sections are 
removed from the report or additional sections added, the highest level section number 
(16) may change. 
 
 


Statistical Analysis Plan (Phase 2) 
NewLink Genetics Corporation Protocol NLG2107 
Version 1.0 
Syneos Health (Formerly INC Research) 1010280 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 43 of 47 
 
MOCK-UPS 
Attachment 1: Planned Table Shells 
Attachment 2: Planned Figure Shells 
Attachment 3: Planned Listing Shells