Clinical trial NCT02052648
Conditions: Glioblastoma Multiforme Glioma Gliosarcoma Malignant Brain Tumor
Keywords: glioblastoma multiforme glioma gliosarcoma malignant brain tumor
Sponsor: NewLink Genetics Corporation
Start date: 2014-03-01; Completion date: 2019-06-20
Enrollment: 160 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study, investigators will conduct a phase I/II trial in recurrent (temozolomide resistant) glioma patients. The overall goal of this study is to provide a foundation for future studies with indoximod tested in newly diagnosed glioblastoma patients with radiation and temozolomide, or in combination with vaccine therapies.

Detailed description:
The aim of this study is to identify the safety profile and the recommended dose for phase 2 study of the combination of indoximod (portion 1, phase 1b study). Investigators will then evaluate the tolerability and the preliminary activity in patients with recurrent GBM in three different situations:

* Combination of indoximod and temozolomide (bevacizumab-naive patients)
* Combination of indoximod and temozolomide in patients currently receiving or having received and failed bevacizumab.
* Combination of indoximod and temozolomide with stereotactic radiation. Ancillary studies will be conducted to assess the correlation between intra-tumoral IDO expression or serum biomarkers (immune monitoring) and treatment efficacy.

If the current study shows an acceptable safety profile and suggests preliminary evidence of activity, this will provide the justification for subsequent randomized phase 2 studies in refractory glioblastoma multiforme (GBM).

Arms: arm 1: Phase 1B patients will receive Indoximod given in escalating doses. Initial dosing will be 600 mg BID by mouth with escalation planned to 1200 mg BID by mouth. The medication should be taken twice daily for 28 days each cycle.

Temozolomide will also be given by mouth at 150 mg/m\^2 x 5 days at all dosing levels of indoximod. Each cycle is 28 days. Patients will continue until they experience disease progression or toxicity. arm 2: Bevacizumab naïve phase II patients who will receive indoximod with temozolomide. Indoximod will be dosed at 1200mg BID. Temozolomide will be dosed at 150 mg/m2 and may be escalated up to 200 mg/m2. arm 3: Phase II patients who will receive indoximod with temozolomide and bevacizumab who have previously been treated with bevacizumab.

Indoximod will be dosed at 1200mg BID. Temozolomide will be dosed at 150 mg/m2 and may be escalated up to 200 mg/m2. Bevacizumab will be dosed at 10mg/kg. arm 4: Phase II patients who will receive indoximod with temozolomide and stereotactic radiosurgery. Indoximod will be dosed at 1200mg BID. Temozolomide will be dosed at 150 mg/m2 and may be escalated up to 200 mg/m2. Single fraction SRS dose will be 16 or 20 Gy depending on target volume. The total 5-fraction SRT dose will be 27.5 Gy.
Interventions: intervention 1: Indoximod intervention 2: Temozolomide intervention 3: Bevacizumab intervention 4: Stereotactic Radiation
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 
STATEMENT OF CONFIDENTIALITY 
The confidential information in the following document is provided to you as an investigator, potential 
investigator, or consultant, for review by you, your staff, and applicable institutional review board(s). It is 
understood that the information will not be used, divulged, or published without the written consent of 
NewLink Genetics Corporation, except to the extent necessary to obtain informed consent from those persons 
to whom study medication may be administered. 
 
 
 
Clinical Trial Protocol 
NLG-2102 
A Phase 1/2 Study of the Combination of Indoximod and Temozolomide 
for Adult Patients with Temozolomide-Refractory Primary 
Malignant Brain Tumors 
 
IND #: 
Clinicaltrials.gov #: NCT02052648 
 
Version 3 Dated: 08/27/2015 
Replaces Version 2 Dated 06/30/2014 
 
 
Study Sponsor: 
NewLink Genetics Corporation 
Iowa State University Research Park 
2503 South Loop Drive, Suite 5100 
Ames, Iowa, USA 50010 
 
 
Investigational Agent: 
Indoximod (1-methyl-D-tryptophan, D-1MT) 
 
 
 


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Contact Infoi’mafiou 
Sponsoi’ 
 
 
 
Clinical & Medical 
Affairs/MedicRI monitor 
 
 
 
 
 
 
Clinical Trial 
Management 
 
 
 
 
 
 
 
IHlmiinotliel’R } 
Shipment 
 
 
 
 
 
Clinical Reseai ch 
Samples 
 
 
 
 
NewLiiA Genetics Corpoi’ation 
Iowa State University Research Park 
2503 South Loop Drive. Suite 5100 
Aines, Iowa 10010 
 
Eugene Kennedy, M.D., FACS 
Vice Resident, Clilucal and Medical Affahs 
NewLuA Genetics Corporation 
2303 South Loop Drive. Seite 5100 
Aines. Iowa 50010 
 
Lucinda Teiuumt, RN. MS 
Diiectoi’ of Clinical Affahs 
NewLink Genetics Corpoiation 
2503 South Loop Diive, Suite 5100 
Amies. Iowa 50010 
 
 
Supply Chain 
NewLink Genetics Coipoiation 
2503 South Loop Diive, Suite 5100 
Anies. Iowa 50010 
 
 
 
Jeniufer Stevens 
Clinical linmtuiology Research Associate III 
NewLink Genetics Corpoiation 
2503 South Loop Diive, Suite 5100 
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Lead Institution: 
Georgia Regents University (GRU) Cancer Center: 
Neuro-Oncology Program, Immune Therapy Program, Experimental 
Therapeutics Program, Pediatric Oncology Program, Departments of 
Neurosurgery and Radiation Oncology 
 
Investigators: 
Primary Investigator: Frank Mott, MD (1) 
 
Co-Investigators: Theodore S. Johnson, MD, PhD (2) 
Cole A. Giller, M.D, PhD (3) 
John Vender M.D (3) 
Feng-Ming Kong M.D, PhD (4) 
Jin JianYue PHD (4) 
Cargill H. Alleyne M.D (3) 
 
 
Laboratory Co-Investigator: David H. Munn, MD 
 
Senior Statistician: Ramses F Sadek, PhD(1) 
 
 
(1): Division of Hematology/ Oncology, GRU Cancer Center. 
(2): Division of Pediatric Oncology, GRU Cancer Center.  
(3): Department of Neurosurgery, Georgia Regent University. 
(4): Department of Radiation Oncology, GRU Cancer Center. 
 
Principal Investigators and Participating Sites 
 
Multiple institutions throughout the United States will be conducting this study. For a full list of 
participating institutions please refer to the Clinicaltrials.gov website listing for this study 
(NCT02052648). 


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PROTOCOL SYNOPSIS 
 
Title: 
A Phase 1/2 Study of the Combination of Indoximod and 
Temozolomide for Adult Patients with Temozolomide-Refractory 
Primary Malignant Brain Tumors 
 
Primary Objective: 
Phase 1 
To determine the recommended phase 2 doses of indoximod and 
temozolomide in combination for treatment of progressive high- 
grade glioma (including glioblastoma multiforme) or gliosarcoma 
 
Phase 2 
To evaluate efficacy as measured by six-month progression-free 
survival (PFS) of indoximod plus temozolomide (with or without 
bevacizumab or stereotactic radiation therapy SRS) in patients with 
progressive glioblastoma multiforme (GBM) 
 
Population: 
Adult patients (16 years and older) with histologically proven 
intracranial glioblastoma or gliosarcoma (phase 2) or any high-grade 
glioma (phase 1). There must be imaging confirmation of tumor 
progression or regrowth. Patients must have completed a course of 
radiation therapy and at least 2 adjuvant cycles of temozolomide (phase 
2). 
Sample Size: 
 
Phase 1: 
12-18 subjects (depending on dose escalation) 
 
Phase 2: 
Up to 132 subjects 
Cohort 2a: 68 subjects who will receive indoximod with 
temozolomide (for those that are naïve to bevacizumab) 
Cohort 2b: 24 subjects who will receive indoximod with 
temozolomide and bevacizumab in patients currently receiving or 
having previously received and failed bevacizumab 
Cohort 2c: 40 subjects who will receive indoximod with 
temozolomide and stereotactic radiosurgery 
 
Investigational Drug: 
Indoximod (1-methyl-D-tryptophan, D-1MT) 
 
Dosage/Treatment: 
 
Phase 1: 
Table below summarizes dose levels of indoximod and 
temozolomide for the Phase 1 portion of the study. 
 
Dose Level 
Indoximod DOSE (oral) 
Temozolomide Dose (oral) 
1 
600 mg BID x 28 days 
150 mg/m2 x 5 days 
2 
1000 mg BID x 28 days 
150 mg/m2 x 5 days 
3 
1200 mg BID x 28 days 
150 mg/m2 x 5 days 


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This protocol will be conducted in the adult population and children age 16 years or older. A 
companion study for a pediatric population (brain tumors) will be opened after the completion of 
the Phase 1 portion of this study. 
 
 
 
 
Phase 2: 
During Phase 2 portion of study, Indoximod will be administered 
at RP2D. The dose of indoximod will be determined in the phase 1 
portion of the trial. 
 
Patients will be separated into three different cohorts, based on their 
prior therapy (bevacizumab-naïve or bevacizumab-failure) and 
current potential indication for stereotactic re-irradiation. 
Cohort 2a: Indoximod with temozolomide (for patients naïve to 
bevacizumab) 
Cohort 2b: Indoximod with temozolomide and bevacizumab (for 
patients currently receiving or having previously received and 
failed bevacizumab) 
Cohort 2c: Indoximod with temozolomide and stereotactic 
radiosurgery 
 


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Table of Contents 
1.0 
OBJECTIVES ....................................................................................................................9 
1.1 
Primary Objectives ...................................................................................................9 
1.2 
Secondary Objectives .............................................................................................. 9 
2.0 
BACKGROUND ................................................................................................................9 
2.1 
Introduction ..............................................................................................................9 
2.2 
Indoximod (1-Methyl-D-tryptophan, NSC- 
IND# 
IND# 
IND# ......................................................................................................................10 
2.3 
Temozolomide (Temodar®) ...................................................................................11 
2.4 
Recurrent glioblastoma ..........................................................................................11 
3.0 
RATIONAL FOR COMBINING INDOXIMOD AND TEMOZOLOMIDE ............12 
4.0 
PATIENT SELECTION AND ELIGIBILITY .............................................................13 
4.1 
Inclusion Criteria ...................................................................................................13 
4.2 
Exclusion Criteria ..................................................................................................15 
4.3 
Inclusion of Women and Minorities ......................................................................16 
4.4 
Baseline Tests ........................................................................................................16 
5.0 
REGISTRATION PROCEDURES ................................................................................17 
5.1 
Registration Process ...............................................................................................17 
6.0 
TREATMENT PLAN ......................................................................................................17 
6.1 
Experimental Design Synopsis ..............................................................................17 
6.2 
Phase 1b Treatment Plan (Portion 1) .....................................................................18 
6.3 
Phase 2 Treatment Plan (Cohort 2) ........................................................................21 
6.4 
Study Agent Administration and Pharmacokinetic considerations .......................21 
6.5 
Indoximod Administration .....................................................................................22 
6.6 
Temozolomide (Temodar®) Administration ..........................................................22 
6.7 
Administration of Radiation (SRS or SRT) ...........................................................22 
6.8 
General Concomitant Medication and Supportive Care Guidelines ......................23 
6.9 
Duration of Therapy ...............................................................................................23 
6.10 
End of Treatment and Premature Withdrawal Visit ..............................................23 
6.11 
Duration of Follow-up .......................................................................................... 24 
6.12 
Criteria for Removal from Study Therapy .............................................................24 
7.0 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................24 
7.1 
Temozolomide (Temodar®) ...................................................................................24 
7.2 
Indoximod ..............................................................................................................26 
7.3 
Bevacizumab: .........................................................................................................26 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................27 


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11.0 
12.0 
8.1 
Most Common Adverse Events ............................................................................ 27 
8.1.1 
Adverse Events for Indoximod ............................................................ 27 
8.1.2 
Adverse Event List(s) for Teinozoloniide. ............................................ 27 
8.2 
Adverse Event Reporting. ..................................................................................... 28 
8.3 
Roritine  Adverse Event Repoi4inp ............................................................................ 30 
8.4 
Reporting  Reqiiii’einents  for Baseline Adverse Events. ........................................... 30 
8.5 
Adverse Event Case Report Form. ....................................................................... 30 
8.6 
Pregnancy. ............................................................................................................ 30 
PHARMACEUTICAL INFORMATION. ................................................................... 31 
9.1 
Indoximod (l-methyl-D-hyptophan, IND # 78060/78189, NSC-721782) 
phariiiaceiitical infoiuiation .................................................................................. 31 
9.2 
Teriiozoloinide (Teniodar&) ................................................................................. 32 
 
 
STUDY CALENDAR ..................................................................................................... 36 
MEASL REMEhT OF EFFECT ................................................................................... 38 
12.1 
Criteria  for Evaluation  of Therapy Effectiveness ..................................................... 38 
12.2 
Response Criteria ....................................................................................................... 38 
12.3 
Special circiunstances ........................................................................................... 35 
12.4 
Evaluation of Best Overall Response.................................................................... 40 
12.ñ 
Confilxna†oiy Measurement/Dui’ation of Response ................................................. 41 
12.6 
Response Review .................................................................................................. 41 
13.0 
DATA REPORTING  / REGULATORY REQUIREMENTS ........................................... 42 
13.1 
Regulatory Compliance/Good Clinical Practices ................................................ 42 
13.2 
Regiilatoiy Dociuiientotion. .................................................................................. 42 
13.3 
Institutional  Review Board (IRB) ......................................................................... 43 
13.4 
Informed Consent. ................................................................................................ 43 
13.5 
Administrative Requirements ............................................................................... 43 
13.6 
Hiiriian Subjects Pi’otection. ..................................................................................... 45 
14.0 
STATISTICAL 8IETHODS........................................................................................ 46 
14.1 
General statistical considerations. ..................................................................... 46 


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14.2 
Sample Size ............................................................................................................47 
14.3 
STATISTICAL ANALYSIS ................................................................................ 47 
14.4 
Treatment Randomization and Blinding ................................................................49 
14.5 
Study Populations and analysis datasets ................................................................49 
14.6 
Study Endpoints .....................................................................................................50 
14.6.1 
Safety Endpoints ...................................................................................50 
14.6.2 
Efficacy Endpoints ................................................................................50 
14.7 
INTERIM ANALYSIS ..........................................................................................50 
15.0 
APPENDICES ..................................................................................................................53 


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1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
Phase 1b component: To determine the recommended phase 2 doses of indoximod and 
temozolomide in combination for treatment of progressive high-grade glioma (including 
glioblastoma multiforme) or gliosarcoma 
 
Phase 2 component: To evaluate efficacy as measured by six-month progression-free survival 
(PFS) of indoximod plus temozolomide (with or without bevacizumab or stereotactic radiation 
therapy SRS) in patients with progressive glioblastoma multiforme (GBM) 
 
1.2 
Secondary Objectives 
 
Phase 1b: 
1. 
To determine the adverse event profile and identify regimen-limiting toxicities (RLT) 
of indoximod plus temozolomide in combination therapy 
2. 
To test the hypothesis that the addition of indoximod will not reduce the overall dose 
of temozolomide delivered or delay the timing of administration, compared to historical 
controls 
3. 
To determine the pharmacokinetic profile of indoximod in the setting of this treatment 
regimen. 
 
Phase 2: 
1. 
To determine efficacy as measured by objective response rate (ORR), overall survival, 
safety, and tolerability of indoximod plus temozolomide in patients with progressive 
GBM 
2. 
To determine ORR, safety, and tolerability of indoximod plus temozolomide and 
bevacizumab in GBM patients whose disease progressed during therapy with a 
bevacizumab-based regimen 
3. 
To determine ORR, safety, and tolerability of indoximod plus temozolomide and 
stereotactic radiosurgery (SRS) in GBM patients who may reasonably benefit from 
tumor debulking. 
 
2.0 
BACKGROUND 
 
2.1 
Introduction 
 
Glioblastoma is a diffusely infiltrating tumor that spreads microscopically throughout the brain. 
Therefore, all local therapies, such as surgery and radiation, are inherently palliative. Long-term 
disease control requires therapies targeting tumor cells throughout the brain, such as chemotherapy 
and small molecule pathway inhibitors. 


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The present standaid of core for newly diagnosed plioblastoino involves inoxiniN surgical 
resection followed by concun’ent radiotherapy with telnozolomide, on orolly available DNA 
alkylatinp agent followed by at least 6 months of adjiivant temozolomide. 
 
Several clinical tiials foi recurrent plioblastoina tested the efficacy of different strategies that 
include EGFR inhibitors, the PDGFR/KIT inhibitor, the PDGFR and VEGFR inhibitor, and the 
lnTOR inhibitor CCI-779 (telnsuolimus) as suigle apents. Despite initial enthiisiosln, treatment of 
recurrent glioblastoma with these single pathway inhibitors has penei’ally been disappointing. 
without response or survival 1’ates superior 10 traditional cheniothei‘apies. Combination studies 
with telnozolomide are ongoing. 
 
A data set froln the North American Brain Tumor Consortiiun pooled data froln multiple phase 2 
clinical trials for 1’eciuxent/progressive plioblastonm. all of which were consideied negative. This 
lneta-analysis denionstiated an overall 6-month pi’ogiession-free survival rate of 15% foi’ patients 
with recurrent/piogiessive glioblastoina treated with small molecule inhibitors as sinple ogentsl . 
Thus, novel therapies are needed in this disease. 
Recently, bevacizuinab has been approved os a standard thelapy foi ieciuient GBM based on 
single arm oi iandoinized phase 2 sttidies. Cun’ent clinical practice varies, tailored to individiml 
patients, so not all patients receive bevacizuinab. In the ciurent study, patients who me akeady 
receiving bevaciziunab and hove progressed on theiapy will not stop bevacizuiuob. 
 
Key cellular and molecular immune system mediators in the context of bi‘ain tumors have been 
identified end include TGF-§, cytotoxic T cells, T1’egs, CTLA-4, PD- I and IDO. New and 
promising inununotheropeiitic drugs as well as conibinotoriol strategies that focus on the 
simultaneous inhibition of inununosuppi’essive checkpoints, both in innnune and brain tulnor cells: 
will open new avenues fo1 the ti’eatment of hiph grade glio s. 
 
In this study, we will conduct o phose 1/2 trial in recurrent (teinozoloinide resistant) glionia 
patients. The overall poal of this study is to provide a foimdation for fittue sttidies with indoximod 
tested in newly diagnosed glioblostoma patients with iadiotion and telnozolomide, or in 
combination with vaccine theiapies. 
 
2.2 
Indoximod l-Methyl-D-tryptophan, hSC
 
 
IND 
 
 
Indoximod was developed to inhibit the indoleomine 2, 3 dioxygenase (IDO) enzymatic pathway, 
which is important in the natural ie ilotion of immune responses. This potent immune 
suppi’essive mechanism hos been implicated in preserving tissue allografts, most dramatically in 
preventing T cell-mediated iejection of pateioally-derived fetal silo-antigens in pregnancy 2. IDO 
also repulotes iininime responses in infection, autoiininime syndromes, and malignant states 
(reviewed in ref 3)3. Indoximod inhibits the IDO pathway end inipi’oves onti-tiunor T cell 
responses,  slowing  the  m’owth  of  tuino’i s4 ’.  This  IDO-pathway  inhibitor  wcs  subsequently 
developed for clinical rise via NCI’s RAID program md is currently on the list of priority agents 
for continued development by the Concer Therapy Evaluation Program (CTEP) 6. Initial work 
showed that the D-enantiomer was more effective in shrinking hunols than either the L- 


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enantiomer or the racemic mixture. Indoximod has very good oral bioavailability and favorable 
pharmacokinetics with twice daily dosing. In addition, the drug was well tolerated in preclinical 
animal studies. 
 
Phase 1 trials of indoximod (IND#78060 and #78189) have been conducted and enrolled 65 
patients with various solid malignancies, including breast, colon, melanoma, sarcoma, pancreatic, 
and lung cancer. The maximum dose of indoximod administered was 2000 mg PO BID given for 
28 day cycles. No maximum tolerated dose was established because the drug demonstrated good 
tolerability. Five patients achieved prolonged stabilization of their disease (longer than six 
months), and other patients experienced mixed responses during the trial. No objective responses 
were achieved by patients on the study. Three patients, who had been previously treated with 
experimental immunotherapy, experienced autoimmune hypophysitis when started at the lowest 
dose level of indoximod. Subsequently, similar patients were excluded from the study, and no 
additional cases of hypophysitis were documented. Correlative studies showed elevations in 
serum C-reactive protein levels and tumor-specific autoantibodies. In conclusion, indoximod was 
well tolerated, showed biological activity, and had modest anti-tumor activity as monotherapy. 
 
2.3 
Temozolomide (Temodar®) 
 
Temozolomide, an oral alkylating agent with good penetration of the central nervous system, has 
been evaluated in patients with glial malignancies. Initial studies evaluated the efficacy of 
temozolomide in patients with recurrent glioblastoma and anaplastic glioma. A large, randomized 
phase 2 study by Yung and colleagues7 treated patients with recurrent glioblastoma with either 
temozolomide (200 mg/m2 days 1-5 of a 28-day cycle) or procarbazine (150 mg/m2 28 day- on, 
28-day off schedule). The study demonstrated only a modest objective response rate for both 
regimens (approximately 5%), but a superior 6-month progression-free survival rate for 
temozolomide (21% vs. 9%) was found. 
 
In a phase 3 trial performed by the EORTC and the NCIC, patients with newly diagnosed 
glioblastoma were randomized to receive either radiation therapy alone or concurrent radiation and 
temozolomide followed by 6 months of adjuvant temozolomide8. The study demonstrated a 
statistically significant improvement in median survival for the combination treatment arm (12.1 
vs. 14.6 months) as well as a significant increase in 2-year survival (10% vs. 26%). This chemo- 
radiation regimen has been widely accepted as the new standard of care for patients with newly 
diagnosed glioblastoma. However, Temozolomide has demonstrated limited efficacy in recurrent 
glioma patients who previously have received adjuvant therapy with temozolomide9. 
 
2.4 
Recurrent glioblastoma 
 
The standard of care for recurrent glioblastoma multiforme (GBM) has not been clearly 
established. GBMs are highly vascularized brain tumors and growth has been shown to be 
angiogenesis dependent, thus stimulating interest in developing antiangiogenic therapeutic 
strategies. 


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Antiangiogenic agents are one of the most promising novel agents in development for GBM but 
to date have not substantially changed overall survival. The development of targeted therapy based 
on tumor vascular blockade led to the approval of bevacizumab for recurrent or progressive 
glioblastoma, since it was proven that this offers a new opportunity for patients suffering from this 
malignancy. Bevacizumab is a recombinant antivascular monoclonal antibody binding to 
circulating Vascular Endothelial Growth Factor (VEGF) preventing this cytokine from reaching 
its receptors (VEGFR1 and VEGFR2) on endothelium. This results in an inhibition of endothelial 
cell proliferation and vessel sprouting. In addition to its role as a regulator of angiogenesis, VEGF 
has been found to mediate immunosuppression. VEGF impairs maturation of dendritic cells, 
resulting in diminished antigen-presenting function, but also suppresses T cell function through a 
number of proposed mechanisms10. In vivo, inhibition of VEGF after the administration of 
bevacizumab with adoptive cell transfer results in a significant infiltration of T cells, presumably 
due to normalization of tumor vasculature, as well as significant tumor growth inhibition11. 
 
Recent intriguing data have been obtained by vaccinating patients with the epidermal growth factor 
receptor variant III (EGFRvIII) peptide, reproducing a specific epitope arising because of large 
deletion of the EGFR gene. 
 
Survival in patients with recurrent GBM is poor regardless of which treatment strategy is 
employed. Median progression free survival is 2.5 months in adults with bevacizumab-refractory 
GBM12. The ongoing effort to identify effective strategies for the treatment of recurrent GBM 
includes combination strategies with agents that target complementary or redundant pathways. 
Incorporation of novel trial designs that permit simultaneous evaluation of several agent 
combinations and allow for rapid discontinuation of ineffective regimens can accelerate the 
clinical evaluation of such candidate regimens. 
 
3.0 
RATIONAL FOR COMBINING INDOXIMOD AND TEMOZOLOMIDE 
 
Chemotherapy and immunotherapy can have additive or synergistic effects. A number of current 
trials combine early-phase immunomodulatory agents with standard chemotherapy regimens. 
Indoximod is a potent and selective inhibitor of IDO in phase 1/2 development in solid tumors. 
Temozolomide is FDA approved for the treatment of front line and recurrent glioblastoma and 
forms the basis for the combination therapies in GBM. Development of a well-tolerated and active 
combination of these two drugs has the potential for further improvement in the treatment of 
refractory GBM. Substantial preclinical data support using this combination. 
 
Indoximod (1-Methyl-D-Tryptophan) synergizes with a number of different chemotherapy drugs 
in multiple tumor models4, 5. Recent animal studies conducted at GRU Cancer Center in Dr. 
Theodore Johnson’s laboratory suggest a survival benefit in mice with glial tumors using either D- 
1MT or DL-1MT in combination with a standard treatment platform of alkylator chemotherapy 
(cyclophosphamide or temozolomide) plus radiation. These studies also suggest enhanced 
inflammatory effects (intratumoral complement activation) when 1MT is added to chemotherapy 
(temozolomide) or chemo-radiation treatments. In addition, widespread target IDO expression has 
been documented in both the glioma tumor cells and in surrounding host astrocytes using this 
model13. In other studies, a low-dose metronomic TMZ regimen reduced the number of circulating 
Tregs in vivo14. 


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IDO as a therapeutic target in glioblastoma: 
IDO is expressed by tumor cells in a large proportion (50-90%) of primary glioblastoma biopsy 
samples15 (and unpublished data, Johnson and Munn). In human glioma patients, IDO expression 
appears to be an independent prognostic factor, as its upregulation is associated with poor 
prognosis16. In addition, Wainwright et al have recently used an in vivo mouse glioma model 
(GL261) to demonstrate the critical role of IDO in promoting GBM survival and progression16. In 
this study they also showed the importance of IDO in recruiting regulatory T cells into brains of 
tumor-bearing mice16. Thus, in this preclinical model, the IDO-pathway appears to play a pivotal 
role in suppressing T cell responses against glial tumors and promoting their progression. 
 
Immunologic effect of stereotactic radiation: 
Hypofractionated stereotactic radiation plus concomitant TMZ followed by TMZ is a feasible 
treatment option associated with potential survival benefits and low risk of complications in 
selected patients with recurrent malignant glioma. The potential advantages of combined chemo- 
radiation schedules in patients with recurrent malignant gliomas is currently under evaluation. 
Recent reports of stereotactic radiation in combination with immune-modulatory drug ipilimumab 
(anti-CTLA-4) describe systemic tumor regression following local irradiation of single lesions17, 
18. This effect is consistent with an immune-activating effect of stereotactic radiosurgery, which 
has been predicted from preclinical models. 
 
Study rationale: 
The aim of this study is to identify the safety profile and the recommended dose for phase 2 study 
of the combination of indoximod (portion 1, phase 1b study). We will then evaluate the tolerability 
and the preliminary activity in patients with recurrent GBM in three different situations: 
• 
Combination of indoximod and temozolomide (bevacizumab-naïve patients) 
• 
Combination of indoximod and temozolomide in patients currently receiving or having 
received and failed bevacizumab 
• 
Combination of indoximod and temozolomide with stereotactic radiation. 
Ancillary studies will be conducted to assess the correlation between intra-tumoral IDO expression 
or serum biomarkers (immune monitoring) and treatment efficacy. 
If the current study shows an acceptable safety profile and suggests preliminary evidence of 
activity, this will provide the justification for subsequent randomized phase 2 studies in refractory 
GBM. 
This study conducted in adults will be expanded to include pediatric patients in a linked companion 
protocol that will be initiated after the completion of the phase 1 portion in adults. 
 
 
4.0 
PATIENT SELECTION AND ELIGIBILITY 
 
4.1 
Inclusion Criteria 
 
• Histologically proven intracranial glioblastoma multiforme (WHO grade IV glioma) or 
gliosarcoma. In addition, the Phase 1b cohort will include patients with progressive WHO 


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grade III glioma. There must be imaging confirmation (with and without gadolinium 
contrast) of tumor progression or regrowth. 
 
• Patients will be eligible if the original histology was lower grade glioma and a subsequent 
diagnosis of glioblastoma or gliosarcoma is made. 
 
• Unequivocal radiographic evidence for tumor progression by MRI. It is understood that 
some patients may be resected prior to enrolling onto protocol. 
 
• Patients must have completed a course of radiation therapy and at least 2 adjuvant cycles 
of temozolomide for the phase 2 component. 
 
• Patients enrolling onto Cohort 2b who have been taken off bevacizumab must have had at 
least a 28 day washout from any previous administration of bevacizumab. It is preferred 
that patients who fail bevacizumab prior to trial entry remain on bevacizumab in the trial. 
 
• Prior temozolomide is not required for the phase 1 component; prior radiation is required 
for the phase 1 arm. It is suggested (but not required) that patients be at least 3 months post 
radiation to reduce the chances of pseudoprogression. 
 
• Patients must be on a steroid dose < 2 mg of dexamethasone daily (or equivalent), and this 
dose must not have increased for at least 14 days prior to obtaining the enrollment. 
 
• ECOG performance status <1 or Karnofsky >70% (Appendix A). 
 
• Age > 16 years 
 
• Normal organ functions, which includes adequate: 
Bone marrow function as defined by the following laboratory values: 
• Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L 
• Platelets ≥ 100 x 109/L 
• Hemoglobin ≥ 9.0 g/dL 
 
• Renal function (creatinine level within normal institutional limit, or creatinine clearance 
>60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal). 
 
• Liver function (AST/ALT <2.5 X institutional upper limit of normal, Total bilirubin ≤ 1.5 
times ULN, INR within 1.5 times ULN (or if receiving anticoagulant therapy an INR of ≤ 
3.0 is allowed with concomitant increase in PT or an aPTT ≤ 2.5 × control). 
 
• Must be 28 days from the administration of any investigational agent or prior cytotoxic 
therapy with the following exceptions: 
o Must be 14 days from administration of non-cytotoxic agents (e.g., bevacizumab 
(except COHORT 2b), interferon, tamoxifen, thalidomide, cis-retinoic acid, tyrosine 
kinase inhibitor, etc.). 


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• Patients with prior therapy that included interstitial brachytherapy, Gliadel wafer, or 
stereotactic radiosurgery must have confirmation of progressive disease, rather than 
radiation necrosis, by PET scanning, Thallium scanning, MRI spectroscopy, or surgical 
documentation. 
 
• The effects of indoximod on the developing human fetus are unknown. 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 two forms of contraception (hormonal 
and barrier method of birth control or abstinence) prior to study entry and for the duration 
of study participation. Use of contraception or abstinence should continue for a minimum 
of 1 month after completion of the study. Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she should discontinue the study drug and 
inform her treating physician immediately. Also men should be discouraged from fathering 
children while on treatment. 
 
 
4.2 
Exclusion Criteria 
 
• Prior invasive malignancy that is not low-grade glioma, high-grade glioma, glioblastoma, 
or gliosarcoma (except non-melanomatous skin cancer or carcinoma in situ of the cervix) 
unless the patient has been disease free and off therapy for that disease for a minimum of 
3 years. 
 
• Patients on the phase 2 portion of the study may not have more than 2 prior regimens for 
recurrent disease for glioblastoma/gliosarcoma. Patients on the phase 1 portion of the study 
may not have had more than 3 prior regimens. 
 
• Active systemic infection requiring treatment, including any HIV infection or 
toxoplasmosis. 
 
• Systemic corticosteroid therapy > 2 mg of dexamethasone daily (or equivalent) at study 
enrollment. 
 
• Patients with baseline QTc interval of >470 msec at study entry and patients with 
congenital long QT syndrome. 
 
• Patients with significantly altered mental status that would prohibit the understanding or 
rendering of informed consent and compliance with the requirements of this protocol must 
have a legally authorized representative (LAR) willing to participate and support the 
patient throughout the trial. Such situations will be handled as discussed in Appendix C. 
Affected patients without a LAR are excluded from participation. 
 
• Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality 
that may increase the risk associated with study participation or study drug administration, 


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or may interfere with the interpretation of study results, and in the judgment of the 
investigator would make the patient inappropriate for entry into this study. 
 
• Active or history of autoimmune disease 
 
• Pregnant women are excluded from this study, where pregnancy is confirmed by a positive 
serum hCG laboratory test (> 5 mIU/mL); breastfeeding should be discontinued. 
 
• Patients with known autoimmune thyroid disease or positive anti-TPO antibodies (anti- 
Thyroid Peroxidase) at time of screening. 
 
4.3 
Inclusion of Women and Minorities 
 
No exclusion is made on the basis of sex, race or ethnic background. 
 
4.4 
Baseline Tests 
 
• Baseline and Eligibility Tests will include (See Section 11.0, Table 5 for details) 
 
• Pre-Study Tests to be completed within 14 days prior to proposed treatment start include: 
 
• Baseline MRI performed within 14 days prior to initiating therapy 
 
• Upon approval of the Version 3 protocol amendment, 12 consecutive patients will 
receive Baseline ECG (also to be repeated at 3 hours after first (cycle 1, day 1) 
indoximod dose administration, again on Cycle 2, Day 1 after morning indoximod dose 
administration, as clinically indicated, and at the end of therapy). 
 
• Pre-Study Tests to be completed within 7 days prior to proposed treatment start include: 
 
• Baseline history and complete physical examination (to include height and weight) 
within 7 days prior to initiating therapy. 
 
• Serum chemistries including BUN, creatinine, albumin, and glucose; electrolytes 
including sodium, potassium, and calcium; INR; liver function tests including total 
bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase to be done within 7 
days prior to initiating therapy. 
 
• HCG pregnancy test (serum or urine) to be done within 7 days prior to first treatment 
for all women with child-bearing potential 
 
• LH, FSH and ACTH to be drawn at baseline and then monthly while on active 
treatment. Full endocrine analysis will be done if clinical suspicion and/or MRI data is 
suggestive of pituitary inflammation. 


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• 
TSH, T3 and Free T4 to be drawn ct baseline and then monthly while on octive 
treatment. If abnormal. complete anti-TPO antibodies (anti-Th ’Oid Peroxidase). If 
abnormal. iuonitoi clinically for thyroid dysfunction and supplement with thyioid 
hoonones as needed. 
 
• 
CBC with platelets and 5-part differential (to include neutrophils, lymphocytes, 
eosinophils, bosophils, end inonocytes) to be done within 7 days prior to initiating 
theiapy. 
 
• 
Blood (appi’oxiinotely 4 inL) for lneosiuement of 
obtained on lust day of treatment prioi to drup aAninistrotion) 
ct baseline (con be 
 
 
5.0 
REGISTRATION PROCEDL’RES 
 
5.1 
Registration Process 
 
All patients lnust be registered on s0idy before begiiming therapy. 
All subjects must have a: (1) sigaed Informed Consent Docimient md, (2) a completed 
Eligibility Checklist Form befoi’e iepisti’ation on the study. To iepistei o subject for this 
protocol, an autho1’ized physician or their designee must FAX or EMAIL the subject 
infoixuotion to the NewLink Genetics Registiation Office or the site’s desipnoted CRA between 
the hours of 8:30 A.M. and 5:00 P.M. Centi’al Standaid  Time. Monday  thi’ough  Friday. 
(FAX: (515) 296-3556; EMAIL: PotientRepisti’ations@1inkp.coin). No evening, weekend or 
holiday iegistrations will be peimitted. Once eligibility is confused, NewLink will FAX or 
EMAIL a confirmation of iegistration to the site. 
 
A file of copies of all leports, laboiatoiy sttidies end other pertinent infornmtion docimienting 
the subject’s eligibility fo1 sttidy will be maintained in the Clinical Research Office of NewLink 
Genetics Corpoiation. 
 
6.0 
TREATMENT PLAN 
6.1 
Experimental Design Synopsis 
 
The sttidy is designed as a prospective Phase lb/2 trial of the combination of indoximod and 
temozolomide in odult patients with progressive glioblastolna iniiltifoime (WHO grade IV glionia) 
or pliosoicolno. In addition, the Phase lb cohort will include patients with progressive WHO grode 
plioiuo. There must be imaging confMxuation of tumor progression or regiowth aftei’ completing 
a standard coiuse of radiation theiapy and at least 2 adjuvant cycles of temozolomide. 
The triol will be performed in two cohol4s: 
 
Cohort 1 
hase lb 


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Patients will be followed both clinically and radiopraphically every 8 weeks fo1 evidence of tiunor 
progression. Post-treatment scans will be colnpoi’ed to the baseline MRI scan and iesponses will 
be assessed based using RANO ciiteiia (see Section 12.2.1). 
 
Safety will be evaliuited by following the giudelines piovided in the National Cancel Instittite 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) Veision 4.03. 
 
6.2 
Phase lb Treatment Plan (Portion 1) 
 
Cohort 2 
hase 2 


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The standard i’epimen with temozoloinide is one of the backbone regimens into which new agents 
will be integrated for patients with GBM. To establish the safety and the RP2D of the new agent 
indoximod in combination with teiuozolomide, it is necessary to determine the attiibiition of all 
toxicities. Howevel, when telnozolomide is administered as standard regimen, it is associated with 
sipnificont toxicities that may confound efforts to define the tiue toxicity of new agents added to 
this backbone. The danper is thot the high iate of toxicity of the backbone iepimen will iesult in 
an unacceptably high rate of rejecting oll dose levels of new ogents. It has been recommended in 
these situations thot a ‘yiapiuotic” approach be adopted foi determining dose limiting toxicities. 
In this approach only grade 3 and 4 toxicities thot are attributable to the test apent and iesult in the 
delay of the adininisti’ation of the backbone iepimen temozoloinide will be considered as iepinien 
limiting. Thus for purposes of the dose escNation in this trim definition of Regimen Limiting 
Toxicities will be defined as the following toxicities occiurinp divine the first cycle (28 days) of 
the treatment (which includes the combination of teiuozoloniide with indoximod) 
 
O Any m’ade 4 non-heiuotologica1 toxicity thot is treatment-ielated with the exception of 
alopecia, nausea and vomiting or lyiuphopenia. 
 
O Any grade 3 non hernatolopical toxicity that is treatment related that results in delay of 
backbone regimen (teinozoloinide) by greatei than 4 weeks. 
 
O Giade 4 thronibocytopenio (<25,000/ inin3) attributable to indoximod that results in delay of 
backbone chemotheiapy for greater than 4 weeks 
 
O  Gi’ade 4 (<500/ nun3) neutropenia lasting lnore than 7days, or Giade 3 (<l000/ nun’) febrile 
neiiti’openio. 
 
O Delay in starting second cycle by more than 2 weeks due to toxicity attributable to test agent 
indoximod 
 
 
AEs not known and expected from ternozolornide and not seen in phase 1 indoximod will be 
considered regimen toxicities initially. Any grade 3 or higher regimen toxicity mandates a 
conference call next business day between investigators anil sponsor to discuss attribution 
and response. 
 
In the presence of clinical neuro-deterioration, a brain MRI will be performed to evaluate 
the presence of tumor progression versus tumor necrosis (and brain edema). If the diagnosis 
remains questionable, MR Spectroscopy will be performed, as usually recommended. 
 
If temozolomide is discontinued due to toxicity, patients may continue to receive indoximod 
alone. 


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The different dose-levels are defined in Table 1. 
 
Each cycle is 28 days. Pharmacokinetic study will be performed for each patient in phase 1 portion 
after a single dose of indoximod. Patients will continue until they experience disease progression 
or toxicity. 
 
Table1. Dose levels (Phase 1 portion). 
 
Patients will be assigned in cohorts of three. 
 
Dose escalation will occur according to the following schema: 
 
Number of Patients with RLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enroll next three patients at the next higher 
dose level. 
≥2 out of 3 
Dose escalation will be stopped. Next lower 
dose will be declared MTD. If only three 
patients were enrolled at lower dose level, an 
additional three patients will be enrolled. 
1 out of 3 
3 more patients are enrolled at this dose. 
• If 0 of 3 of these experience a RLT, 
escalate to next level 
• If 1 or more of these experience RLT, 
dose escalation is stopped and next 
lower dose is declared MTD 
 
MTD will be declared to be the highest dose at which ≤ 1 out of 6 patients experiences a RLT. 
MTD in this context is considered a function of indoximod in this combination and not a MTD for 
indoximod in any other context / combination. 
 
The period for determination of dose-limiting toxicities will be the initial 28 days of treatment. 
The recommended phase 2 dose will include an assessment of toxicities that occur at later time 
points. 
 
The initial dose of indoximod will be 600 mg BID. If a RLT is reported at Dose Level 1, a lower 
dose may be added after consultation between the Investigators, Medical Monitor and Sponsor, 
depending on the cumulative safety data. The protocol will be amended at that time accordingly. 


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6.3 
Phase 2 Treatment Plan (Cohort 2) 
Indoximoil with temozolomide (cohort 2a): 
This group of patients will receive fixed doses of indoximod and temozoloinide deteonined in the 
phase I port, based on toleiability. 
 
Indoximod with temozolomide and bevacizumab or previous bevacizumab (Cohort 2b): 
 
This group of patients who are currently on bevacizuinab (the usiml dose for plioblastonia 10 
Ing/kg every 2 weeks) and have become bevacizuinab-refractory will be continued on 
bevacizumob (some dose) along with fixed dose of indoximod end temozolomide. Patients who 
are not ciuTently being tieated with bevacizuinob, having demonstrated progression on 
bevocizumab end been taken off bevacinunab by theu treating physician will be treated as in 
cohort 2a but accounted for as to analysis of results in Cohort 2b. In this cohoi4, stei’eotoctic 
radiation (oi i’e-radiation) will not be allowed. 
 
Indoximod with temozolomide and stereotactic radiosurgery (Cohort 2c): 
 
Patients who are suitable fo1 re-iadiotion with steieotoctic iadiosiugeiy (SRS) or hypofiactionated 
stereotactic i’adiotion treatment (SRT) will be enrolled in Cohort 2e. SRS or SRT will be combined 
with fixed doses of indoximod and telnozolomide deteixuined in phase 1. SRS and SRT will be 
adnunistei’ed 2 weeks after the initiation of indoxñnod end teniozolomide. The dose and volume 
of radiation will be described in detail in section 6.7. 
 
Cycle length and duration: 
Eoch cycle is 28 days. Patients will continue imtil they experience disease piogiession oi toxicity 
(as defined in Section 6.7). 
 
6.4 
Study Agent Administration and Pharmacokinetic considerations 
 
Treatment will be administered on an outpatient basis. 
 
All patients in the phose 1 poi4ion of the trial will have pharmacokinetics performed on day 1 of 
the first cycle. Patients will be adniinisteied o sinple dose of indoximod at the appropriate dose 
level. They will also take their lust dose of temozoloinide as well as the fu’st dose of prophylactic 
Bactrini end anti-elnetic in the morning of day I with the indoximod. Phainmcokinetics for 
indoximod will be evaluated ovei the next 48 horns md patients will begin twice daily indoximod 
on day 3. Patients will resume telnozolomide on the evening of day 3 and complete the remaining 
four doses of the lust cycle of temozoloinide on days 3-6. The cycle will refrain 28 days in length. 


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Reported adveise events and potential risks are described in Section 7.1. A ]31’O]31’iate dose 
lnodificotions are described in Section 7. No investigationol oi’ commercial agents or therapies 
othei than those desci ibed below may be adininisteied with the intent to treat the patient’s 
malignancy. 
 
 
6.5 
Indoximod Administration 
 
 
 
6.7 
Administration of Radiation (SRS or SRT) 
 
SRS oi SRT will be adininistrated for Cohol4 2c patients 2 weeks aftel the initiation of indoximod 
and temozoloinide. The use of single fraction SRS o1 5 fractions of SRT will depend on the ttunor 
voliune. Sinple fraction SRS will be given to patients with the target volimie of less than 4 cc, 
while 5-fiaction SRT will be given to patients with the tarpet voliune loi ge than 4 cc. 
 
Foi single fiaction SRS, piescription dose will be 16 Gy when the toiget volume is loiger then 1.5 
cc. The presciiption dose con go up to 20 Gy when the torget volume is less than 1.5 cc. 
 
Foi 5-fiaction SRT, the presciiption dose will be genei’ally 5.5 Gy/fiaction with a totol dose of 
27.5 Gy. The prescription  dose may be reduced if the critical no 
1 stluc0ne constiains connot 
be met. 
 
The tai get voliune is defined as the contrast enhanced lesion in MRI. A margin of 0-2 min lnay be 
added to the planning tnget volume (PTV). The piescription dose should be cover at least 95% of 
the toiget volume. The presciiption isodose line could be os low as 50%. The FLAIR enhanced 
area in the FLAIR MRI may be defined os the sub-toiget volimie and a dose of 70-80% of 
prescription dose niay be given to this sub-tarpet voliune. 
 
The constiaints of the ciitical stiuc0nes mainly includes the optical apparatus and the bi’ain stem. 
Foi single-fraction SRS, Moxiiniun dose of the optical apparatus (0.03 cc of the voliune) should 
receive less than 8 Gy, the maximimi dose of the brain stem (0.03 cc of the voliune) should be less 


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than 12 Gy. For 5-fraction SRT, the maximum dose of the optical apparatus (0.03 cc of the volume) 
should receive less than 15 Gy total dose, and the maximum dose of the brain stem (0.03 cc of the 
volume) should be less than 23 Gy. 
 
Any FDA cleared external beam radiation delivery system, including conventional linear 
accelerators, cyberknife, tomotherapy, or gamma knife may be used for the treatment delivery. 
 
6.8 
General Concomitant Medication and Supportive Care Guidelines 
 
All standard of care anti-emetics, anti-diarrheals, antibiotics or hematopoietic growth-factors are 
permitted if clinically indicated. Patients on temozolomide should be treated per standard 
institutional practices for pneumocystis carinii (PCP) prophylaxis. 
 
6.9 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 
 
• Disease progression. 
• Intercurrent illness that prevents further administration of treatment. 
• Unacceptable adverse event(s). 
• Patient decides to withdraw from the study 
• Patient 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 
treatments below an 85% threshold on two sequential study visits 
• General or specific changes in the patient's condition that render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
At the discretion of the treating physician, if it is thought to be the best possible course of treatment, 
subjects may be able to stay on indoximod alone after temozolomide/bevacizumab treatment if 
they do not go on to other treatment regimens. 
 
6.10 
End of Treatment and Premature Withdrawal Visit 
 
Once a participant discontinues study therapy for any reason, the participant will be asked to return 
to the clinic within 30 days for the assessments listed below. 
 
• Update medical history including prior and concomitant medications. 
• Physical examination including vital signs, height, and weight, and a review of body 
systems. 
• ECOG performance status 
• CBC with differential and platelets. 
• Serum chemistries. 
• ECG 
• 
. 
• Concurrent medications and adverse events assessed at end of treatment. 


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6.11 
Duration of Follow-up 
 
After the End of Treatment Visit, Follow up visits will be conducted every 3 months for 2 years, 
to include the following: 
 
• Update medical history including current cancer therapy receiving every 3 months. 
• Physical examination including vital signs, height, and weight, and a review of body 
systems every 3 months. 
• CBC with differential and platelets per SOC practices. 
• Serum chemistries per SOC practices. 
• Serum kynurenine and tryptophan levels every 6 months. 
 
Patients will be followed for survival and possible long-term toxicity from this treatment. Follow- 
up visits will continue for 2 years as per Section 11 (and as stated above). For those surviving 
longer than 2 years, follow-up will 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. Further therapy will be at the discretion of the treating physician. 
 
 
6.12 
Criteria for Removal from Study Therapy 
 
Patients will be removed from study therapy when any of the criteria listed in Section 6.9 applies. 
If rapid life-threatening disease progression happens, or unacceptable adverse event(s) occur, or 
patient decides to discontinue the study, or patient becomes pregnant or starts breast-feeding, the 
patient will be removed from the study therapy. The reason for study removal and the date the 
patient was removed must be documented on the Case Report Form. 
 
7.0 
DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 
Temozolomide (Temodar®) 
 
First Cycle: Temozolomide will be started at a dose of 150 mg/m2/day. Patients that had already 
been on temozolomide pre-study at a dose of 100 mg/m2/day due to temozolomide toxicity (i.e., 
neutropenia, thrombocytopenia, etc.) can start the study at 100 mg/m2/day at the discretion of the 
treating physician. 
 
Second Cycle: If patients tolerate the first cycle of combination therapy without any temozolomide 
related toxicities, the patient may be dose escalated up to 200 mg/m2/day at the discretion of the 
treating physician. The dose of temozolomide will be modified according to: (1) non-hematologic 
AE during the preceding treatment cycle, as well as (2) the worst ANC and platelet counts. 
Recalculation of BSA and temozolomide doses is required if the patient has a 10% or greater 
weight change (+/-) from baseline or from the last weight used to calculate BSA and drug doses. 


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Delay: On day 1 of each cycle (within the prior 72 hours), ANC 1.5 x 109/L, platelet count 100 x 
109/L and all grade 3 or 4 non-hematologic AEs (except for alopecia, nausea, and vomiting) must 
have resolved (to grade 1). 
 
If AEs persists, treatment should be delayed by 1 week for up to 4 consecutive weeks. If, after 4 
weeks of delay, all AEs have still not resolved: then any further treatment with temozolomide 
should be stopped. 
 
Dose Reductions: If, during the first cycle, all non-hematologic AEs observed were grade 2 (except 
alopecia, nausea and vomiting) and with platelets > 100 x 109/L and ANC > 1.5 x109/L: then the 
temozolomide dose should remain the same. 
 
Dose reductions: If any non-hematologic AE observed was grade > 2 (except alopecia, nausea and 
vomiting) and/or if platelets < 50 x 109/L and/or ANC < 1 x 109/L, then the dose should be reduced 
by one dose level (table 2). Patients who require more than two dose reductions will have treatment 
stopped. 
 
If any treatment-related non-hematologic AE observed was grade 4 (except alopecia, nausea and 
vomiting) then temozolomide treatment should be stopped. 
 
Subsequent cycles: Any dose reductions of temozolomide will be determined according to: (1) 
non-hematologic AE during the preceding treatment cycle, as well as (2) the lowest ANC and 
platelets observed. No dose escalation should be attempted. The same dose reductions as for the 
second cycle should be applied. Important: If the dose was reduced or delayed for AEs, there will 
be no dose escalation in subsequent treatment cycles. 
 
Table 2.Dose Adjustment Table 
Dose level 
Dose mg/m2 
Remarks 
-2 
100 
Reduction if prior AE 
-1 
125 
Reduction if prior AE 
0 
150 
Starting dose for cycle 1 
 
Table 3: Worst Treatment-Related Hematologic AE During the Previous Cycle 


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Table 4. Summary of Dose Modifications or Discontinuation for Temozolomide-Related Adverse 
Events 
 
 
7.2 
Indoximod 
 
In general, indoximod was very well tolerated in previous phase 1 trials and seldom required any 
dose reductions. If a dose reduction is deemed necessary due to intolerance from taking the 
required number of pills or grade 3-4 nausea, one dose reduction by 200 mg 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. 
 
7.3 
Bevacizumab: 
 
In cohort 2b, the dose of bevacizumab will be 10 mg/kg every 2 weeks 


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Per the drug insert of bevacizumab, there are no recommended dose reductions. 
Bevacizumab will be temporarily suspended for: 
• At least 4 weeks prior to elective surgery. 
• Severe hypertension not controlled with medical management. 
• Severe infusion reactions. 
 
Bevacizumab will be discontinued for the following: 
 
• Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the 
gastrointestinal tract, intra-abdominal abscess) 
• Wound dehiscence and wound healing complications requiring medical intervention. 
• Serious hemorrhage (i.e., requiring medical intervention) 
• Severe arterial thromboembolic events. 
 
At the discretion of the treating physician if it is thought to be the best possible course of treatment, 
subjects may be able to stay on temozolomide plus indoximod or indoximod alone after 
temozolomide/bevacizumab treatment if they do not go on to other treatment regimens. 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following 
list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine 
whether the event requires expedited reporting in addition to routine reporting. 
 
8.1 
Most Common Adverse Events 
 
8.1.1 
Adverse Events for Indoximod 
 
The most common adverse reactions (> 10% incidence) are: fatigue, nausea, anorexia, anemia, 
diarrhea, lymphopenia, neutropenia, abdominal pain, shortness of breath, rash, vomiting, 
constipation, thrombocytopenia, headache, and alopecia. 
 
The most common Grade 3 to 4 hematologic laboratory abnormalities that have developed during 
treatment with indoximod are: thrombocytopenia, neutropenia, leukopenia, and lymphopenia. 
 
 
8.1.2 
Adverse Event List(s) for Temozolomide 
 
• The most common adverse reactions (≥10% incidence) are: alopecia, fatigue, nausea, 
vomiting, headache, constipation, anorexia, convulsions, rash, hemiparesis, diarrhea, 
asthenia, fever, dizziness, coordination abnormal, viral infection, amnesia, and insomnia. 


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• The most common Grade 3 to 4 hematologic laboratory abnormalities (≥ 10% incidence) 
that have developed during treatment with temozolomide are: lymphopenia, 
thrombocytopenia, neutropenia, and leukopenia. 
 
• Allergic reactions have also been reported. 
 
8.2 
Adverse Event Reporting 
 
Subject data accrued on this study will be reported in accordance with Code of Federal Regulations 
Title 21 (21CFR) 312.32. 
 
This study will utilize the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 for grading all adverse events. 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.03. A copy 
of the CTCAE version 4.03 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
The Site P.I. will notify the IRB and NewLink Genetics (Study Sponsor) who in turn will notify 
the FDA and other regulatory agencies of all serious adverse events as required by law or 
regulation. All participating investigators will be notified of IND Safety Reports by Investigator 
Alerts sent through email. Serious Adverse Event (AE) Reporting by investigators will be done as 
outlined below. 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study. Intercurrent illnesses or injuries should be regarded as 
adverse events. Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Related/Attribution to the use of the drug: There is a reasonable possibility (more likely than not) 
that the experience may have been caused by the investigational drug. 
 
Attribution Categories: 
Unrelated 
The AE is clearly NOT related to the intervention. 
Unlikely 
The AE is doubtfully related to the intervention. 
Possible 
The AE may be related to the intervention. 
Probable 
The AE is likely related to the intervention. 
Definite 
The AE is clearly related to the intervention. 
 
A serious adverse event is any AE that is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 


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• a congenital anomaly or birth defect 
• an important medical event 
 
Reporting Requirements for Serious Adverse Events (21CFRPart312) 
 
Investigators MUST immediately report to the sponsor ANY serious adverse events within 
24 hours of learning of the SAE, whether or not they are considered related to the 
investigational agent(s)/intervention (21CFR312.64) 
 
An adverse events is considered SERIOUS if it results in ANY of the following outcomes: 
1. Death 
2. A life-threatening adverse event 
3. An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for > 24 hours 
4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
5. A congenital anomaly/birth defect 
6. Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA21CFR312.32; 
ICHE2A and ICHE6). 
 
 
SAE reporting timelines are defined as: 
o “24 Hour; 5 Calendar Days” – The SAE must initially be reported within 24 hours of 
learning of the SAE, followed by a complete SAE report within 5 calendar days of the 
initial 24 hour report. 
 
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. 
 
Deaths clearly due to progressive disease should NOT be reported expeditiously but rather should 
be reported via routine reporting (death report). 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in this 
protocol. Any condition responsible for surgery should be documented as an adverse event if the 
condition meets the criteria for and adverse event. 
 
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 


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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. 
 
SAE Reporting Form and Content: For those events that meet the criteria for serious as listed 
above, please complete a Serious Adverse Event Reporting Form. This form will be provided by 
NewLink Genetics. Please send to NewLink Genetics within the time frames listed above. Please 
FAX to (515) 296-3556 or EMAIL to SAE_Reporting@linkp.com. Please call (515) 598-2935 
with any reporting questions. You may also contact and send this form to the CRA designated for 
your site. 
 
8.3 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. AEs reported through 
expedited SAE reports must also be reported in routine study data submissions (CRFs). 
 
8.4 
Reporting Requirements for Baseline Adverse Events 
 
A pertinent positive finding identified on baseline assessment is to be documented as a Baseline 
Adverse Event using CTCAE terminology and grade on the provided Baseline CRF. An expedited 
AE report is not required if a patient is entered on to the study with a pre-existing condition (e.g., 
elevated laboratory value, diarrhea). The baseline AE must be re-assessed throughout the trial and 
reported if it fulfills expedited AE reporting guidelines. 
1) 
If the pre-existing condition worsens in severity, the investigator must reassess the event 
to determine if an expedited report is required. 
2) 
If the AE resolved and then recurs, the investigator must re-assess the event to determine 
if an expedited report is required. 
3) 
No modification in grading is to be made to account for abnormalities existing at 
baseline. 
 
8.5 
Adverse Event Case Report Form 
 
All adverse events (regardless of grade and attribution) observed while on study and for 30 days 
after last dose of treatment, must be recorded on the adverse event case report form. After 30 days 
from last dose of treatment, only adverse events that are attributed to the study drug/combination 
(possible, probable, or definite) are required to be recorded on the adverse event forms. 
 
8.6 
Pregnancy 
 
The teratogenic potential of indoximod is unknown. During the course of the study, all women of 
childbearing potential who are participants and all spouses of participants must be instructed to 
contact the Principal Investigator immediately if pregnancy is suspected. Pregnancy in a 
participant or partner of a participant who is receiving treatment will be reported following 


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procedui’es for a SAE (olthoiiph it will not be coded as a SAE). The event will be i’ecorded in the 
pregnancy CRF. If pregnancy is suspected in a participant or partnei of a participant prioi’ to study 
drup administiation, the sttidy drug will be withheld until the b-hCG test result is available. If 
pregnancy is confirmed. the patient will not ieceive study drug and will be withdrawn fiom the 
stridy. If pregnancy is suspected while the patient is ieceiving sttidy drug, the study tip will be 
immediately withheld until the result of a §-hCG test result is available. If pi’epnmcy is confirmed, 
the patient will be permanently discontinued from the study in an appropriate manner. Protocol- 
required procediues foi study discontiniwtion will be performed imless contiaindicated by 
pregnancy (e.p., x-iay studies). Other appropriate follow-up procedures should be conside1’ed, if 
indicated. In addition, the Principal Investipatoi will repoit pregnancy-related follow-up 
information, including perinotol and neonatal outcomes to the IRB. Infants will be monitored for 
a nuniniuni of eight weeks. 
 
 
 
 
 
 
 
 
 
 
 
How supplied: Indoximod is supplied by NewLink Genetics os 200 Ing capsules. The capsules 
contain the inactive ingredients lactose nionohydiate, microcrystalline cellulose, sodiimi 
croscoiniellose, colloidal silicon dioxide, and nmgnesiiun stearate. The capsules are packaged 175 
capsules/bottle in white opoque HDPE bottles. 
 
The 200 nip capsules are white opaque hard gelatin capsules. 
 
Storage: Stored at contiolled ioom teiupeiattue (59-77°F). 
 
Stability: Shelf-life surveillance of the intoct bottles is on-goinp. Initial lots have been stable at 48 
months. 
 
Route of Administration: Oral 


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Agent Ordering and Agent Accountability: Indoximod is supplied and shipped by NewLink 
Genetics Corporation to the study site. Each shipment is accompanied by a Clinical Investigational 
Material Shipment Receipt Form. Upon receipt, at the clinical site, the product is stored in the 
clinical site’s Investigational Pharmacy or designated area. 
 
As required by FDA regulations for all drug storage, procurement and usage are carefully 
monitored and documented. The Principal Investigator will oversee this process and delegate 
responsibility as needed to conduct the trial under Good Clinical Practices. A careful inventory is 
maintained at each of the clinical sites. 
 
9.2 
Temozolomide (Temodar®) 
 
Please refer to the package insert for comprehensive information. 
 
Formulation Other Names: Methazolastone; Temozolomide is supplied in white opaque, 
preservative-free, two-piece, hard gelatin capsules of the following p.o. dosage strengths: 5 mg, 
20 mg, 100 mg, 140 mg, 180 mg, and 250 mg. Dose is rounded to the nearest 5 mg based on 
surface area. Each capsule contains drug substance in combination with lactose, anhydrous NF, 
colloidal silicon dioxide NF, sodium starch glycolate NF, tartaric acid NF, and stearic acid NF. 
The capsule shells contain gelatin NF, titanium dioxide USP, and sodium lautyl sulfate NF. 
 
Mode of Action: Alkylating agent of imidazotetrazinone class. 
 
Storage and Stability: The capsules are packaged in amber glass bottles and should be stored at 
25°C. Temperature excursions between 15 and 30°C are permissible. Refer to the commercially 
labeled bottles for expiration dating. 
 
Pharmacokinetics: Temozolomide is rapidly and completely absorbed after oral administration; 
peak plasma concentrations occur in 1 hour. Food reduces the rate and extent of temozolomide 
absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, 
and Tmax increased 2-fold (from 1.1 to 2.25 hours) when temozolomide was administered after a 
modified high-fat breakfast. 
 
Temozolomide is rapidly eliminated with a mean elimination half-life of 1.8 hours and exhibits 
linear kinetics over the therapeutic dosing range. Temozolomide has a mean apparent volume of 
distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean 
percent bound of drug-related total radioactivity is 15%. 
 
Metabolism and Elimination: Temozolomide is spontaneously hydrolyzed at physiologic pH to 
the active species, 3-methyl- (triazen-1-yl) imidazole-4-carboxamide (MTIC) and to 
temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide 
(AIC), which is known to be an intermediate in purine and nucleic acid biosynthesis and to 
methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes 
play only a minor role in the metabolism of temozolomide and MTIC. 
 
Relative to the AUC of temozolomide, the exposure to MTIC and ACI is 2.4% and 23%, 


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respectively. About 38% of the administered teniozolonude tots radioactive dose is iecovered 
over 7 days; 37.7% in urine and 0.8% in feces. The majority of the 1’ecoveiy of radioactivity in 
urine is os unchanged temozoloinide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), 
and unidentified polai metabolites(s) (170/»). Oveiall clearance of teinozoloinide is about 5.5 
L/In/m2. 
 
10.0 
CORRELATIYE/SPECIAL STLWIES 
 
The following sttidies will be performed as part of this study 
• 
Phaonacokinetics 
• 
Assessment of prinwiy ttmioi biopsy/resection samples (foixuolin-fixed, paiaffin-embedded) 
stained for: (1) IDO and TDO expression 
• 
Evaluation of blood for bioinoikers of IDO activity (kyniuenine and tiyptophan). before and 
after initiation of therapy 
• 
Evaluation of seoun for C-reactive protein ct diagnosis end duiinp thelapy 
• 
Banking of blood for fittue studies 
10. 
 
 
 
 
 
 
 
 
 
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11.0 
STUDY CALENDAR 
 
Baseline evaluations including lobolatory exaiiiinations, and history and physical exam conducted 
within 7 days prior to initiation of piotocol therapy. Baseline MRI and ECG must be performed 
within 14 days prior to the start of therapy. In the event that the patient’s condition is detei ioratinp, 
laboiatory evaluations should be repented within 48 horus piior to initiation of the next cycle of 
theiapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: Albumin. alkaline phosphatase. total bilirubin. blCarbDnate. BUN. calcium. chloride, creatinine, glucose, phosphonis. 
potassium, total protein. SGOT [AST]. SGPT [ALT], sodium. 
*history and physical exam will be performed by physician aud''or niidlevel proiJdei Dr designated fellDU. 
** Will be done within 7 deys before the staid of the study drop. 
*** The endocrine tests should be drawn around 7 a m. due to the natural circadiaii fluctuations of ACTH 
 
PK Time Points (Single Dose of Indoximod) — Cvcle 1 of PhRse 1 
D.BY 
Time Point 
D.44’ 
Time Point 
Day 1 
Pre- a.m. dose 
Day 1 
6 hours s/p a.m. dose 
Day 1 
15 minutes s/p a.m. dose 
Day 1 
8 hnurs s/p a.m. dose 
30 minutes s/p a.in. dose 
Day 1 
12 horns s/p a.m. dose 
60 minutes s/p a.in. dose 
Day2 
24 hours s/p Day 1 s.m. dose 
120 minutes s/p a.in. dose 
Day3 
48 horns s/p Day l a.m. dose 
4 hoitrs s/p a.m. dose 
e mven 
e 1, see section 6 
Stud calendar for hase 1 com orient  escalation hase 
Cycle I 
Wk 2 
Cycle 2 and subsequent cycles 
FoBow- 
Therapy 
Pre Study 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
2 yea s 
Infomied consent 
Verify elipibzlity criteria 
Medical History* 
Concurrent medication 
Vital signs 
Physical exam* 
Perfomiaiice Status 
CBC’D** 
SOC 
C-Reactire Protein 
TSH, T3, T4 (and anti- 
TPO antiboAes if 
LH. FSH, ACTH*** 
Pregnancy test for wolnen 
of childbeai ing 
al** 
Patient will be asked about contraceptive every time beiiip eraluated by study 
staff (Prouder. RN) if they are iii childbearing age. 
Blood fo1 fiitui e testiii 
MRI 
Indoxnnod 
leinozoloinide 
DLT Assessment 
MRI will be re  eated ev 
8 weeks. 
SOC 


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Stud calendar for 
hase 2 com orient. 
Cycle I 
Ple- 
in 2 
 
 
Cycle 2 and subsequent cycles 
 
 
 
Therapy 
 
 
Informed consent 
Verify eligibzlity critei ia 
Medical History * 
Concurrent medication 
Vital signs 
sical exam* 
Perfomiaiice status 
 
CBCD** 
 
C-Reactive Protein 
TSH. T3, T4 (and anti-TPO 
antiboAes if needed 
LH. FSH. ACTH*** 
 
Pregnancy test for women 
of childbealinp potential** 
 
Blood fo1 fiitui e testing 
Indoxuiiod  + Temozolomide 
Indoxnnod + Temozolouiide 
+ Bevacizimiab 
 
Indoxuiiod + Temozolomide 
+ SRT 
MRI 
Vital States Check 
Slid 
Day  1 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient null be asked about coirtraceptive erery time belnp eralimted 
by soidy staff (R ovidei. RN) if they ale Mr childbearing age 
 
 
 
 
 
 
SRT 
 
MRI wd1 be re  eated es e 
8 w'eeks o1 eve 2 c cles. 
 
years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6ino for 1  ears 
*Hzstolj and physical exam will be perfomied by physician anAol midlevel pioiuder or designated fellow. 
** \*i1l be done within 7 days before the start of the study dms. 
*** The eiidocruie tests should be drawn around 7 a m. due to the natural circadian fliictriations of ACTH 
E: ECG to be completed pre-study and 1 hour after fast indominod dose on the first 9 subjects enrolled in Phase 2. 
Upon approval of the 4"elsioii 3 plotocol auienAneut. 12 consecutive patients will Ieceive Baseline ECG (also to be 
repeated at 3 horns after lust indoximod dose administration (Cycle 1. Day 1), agani on Cycle 2. Day 1 after inoriuiip 
indommod dose administration. as clinically Indicated. and at the end of therapy). 
A: Albumin. alkaline phosphatase. total bilirubin, bicarbonate, BUN. calcivnm chloride, creatinine, glucose, 
phosphorus. potassiimi. total protein SGOT [AST], SGPT [ALT], so‹1iuin. 
B: Bevacizimiab 
T: Teinozolomide 
Indomlnod 
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12.0 
MEASUREMENT OF EFFECT 
 
In addition to a baseline scan, patients should be re-evaluated every 8 weeks (or every 2 cycles) 
after starting study treatment until response is noted. 
 
12.1 
Criteria for Evaluation of Therapy Effectiveness 
 
Tumor response and regrowth can frequently be difficult to measure directly. Serial neurological 
exams and MRI scans may provide a guide to the actual course. Time interval to progression will 
be measured from registration until deterioration is documented by the individual investigator 
using these guides. 
• Overall survival will be measured from the start of GBM treatment on protocol until death. 
• Progression-free survival will be measured from the start of GBM treatment on protocol 
until the first occurrence of progression on protocol or death. 
• The quality of survival will be measured by neurological functional classification and 
performance status. 
• Toxicities will be measured using the CTCAE criteria, version 4.03 
 
12.2 
Response Criteria 
 
For this study we will be utilizing the RANO criteria (See Table 7): 
 
Complete Response 
Complete response requires all of the following: complete disappearance of all T1 gadolinium 
enhancing measurable and nonmeasurable disease sustained for at least 8 weeks; no new lesions; 
stable or improved nonenhancing (T2/FLAIR) lesions; and patient must be off corticosteroids or 
on physiologic replacement doses only, and stable or improved clinically. In the absence of a 
confirming scan at least 8 weeks after first indication of an objective response is noted, this 
response will be considered only stable disease. 
 
Partial Response 
Partial response requires all of the following: > 50% decrease, compared with baseline, in the sum 
of products of perpendicular diameters of all measurable T1 gadolinium enhancing lesions 
sustained for at least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable or 
improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared 
with baseline scan; and patient must be on a corticosteroid dose not greater than the dose at time 
of baseline scan and is stable or improved clinically. In the absence of a confirming scan at least 8 
weeks after first indication of an objective response is noted, this response will be considered only 
stable disease. 
 
Stable Disease 
Stable disease occurs if the patient does not qualify for complete response, partial response, or 
progression (see next section) and requires the following: stable nonenhancing (T2/FLAIR) lesions 
on same or lower dose of corticosteroids compared with baseline scan and clinically stable status. 
In the event that the corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression on neuroimaging, and subsequent follow-up imaging shows 
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considered to show stable disease will be the scan obtained when the corticosteroid dose was 
equivalent to the baseline dose. 
 
Progression 
Progression is defined by any of the following: >25% increase in sum of the products of 
perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or 
increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on 
stable or increasing doses of corticosteroids compared with baseline scan or best response after 
initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear 
progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other 
causes apart from the tumor, or to decrease in corticosteroid dose. Failure to return for evaluation 
as a result of death or deteriorating condition should also be considered as progression. 
 
The apparent increases in tumor burden that sometimes precede responses (pseudo-progression) 
in patients receiving immune therapy may reflect either continued tumor growth until a sufficient 
immune response develops or transient immune-cell infiltrate with or without edema (Wolchok 
CCR 2009). In the absence of overt clinical deterioration, patients with apparent radiographic 
disease progression in the first two months of therapy will be re-scanned 8 weeks later to evaluate 
progression, as long as they remain clinically stable (Taal et al, Cancer 113:405-410, 2008). In 
addition, a brain Magnetic Resonance Spectroscopy (MRS) may be performed (per investigator’s 
decision) to differentiate tumor progression versus tumor necrosis/inflammation. 
 
Nonmeasurable enhancing lesion increased to measurable enhancing disease 
Patients with non-measurable enhancing disease whose lesions have significantly increased in size 
and become measurable (minimal bidirectional diameter of > 10 mm and visible on at least two 
axial slices that are preferably, at most, 5 mm apart with 0-mm skip) will also be considered to 
have experienced progression. Ideally, the change should be significant (>5 mm increase in 
maximal diameter or >25% increase in sum of the products of perpendicular diameters of 
enhancing lesions). In general, if there is doubt about whether the lesion has progressed, continued 
treatment and close follow-up evaluation will help clarify whether there is true progression. 
 
12.3 
Special circumstances 
Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Non-target lesions include measurable lesions that exceed the maximum 
numbers per organ or total of all involved organs as well as non-measurable lesions. Measurements 
of these lesions are not required, but the presence or absence of each should be noted throughout 
follow-up. 
 
Steroid dose: 
Increase in corticosteroid dose alone, in the absence of clinical deterioration related to tumor, will 
not be used as a determinant of progression. Patients with stable imaging studies whose 
corticosteroid dose was increased for reasons other than clinical deterioration related to tumor do 
not qualify for stable disease or progression. They should be observed closely. If their 
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disease; if further clinical deterioration related to tumor becomes apparent, they will be considered 
to have progression. The date of progression should be the first time point at which corticosteroid 
increase was necessary. 
 
Clinical deterioration 
Determination of clinical deterioration is left to the discretion of the treating physician, it is 
recommended that a decline in the KPS from 100 or 90 to 70 or less, a decline in KPS of at least 
20 from 80 or less, or a decline in KPS from any baseline to 50 or less, for at least 7 days, be 
considered neurologic deterioration unless attributable to comorbid events or changes in 
corticosteroid dose. Similarly, a decline in the Eastern Cooperative Oncology Group and WHO 
performance scores from 0 or 1 to 2 or 2 to 3 would be considered neurologic deterioration. 
 
Uncertainty regarding progression 
The patient may continue on treatment and remain under close observation (e.g., evaluated at 4- 
week intervals). If subsequent evaluations suggest that the patient is in fact experiencing 
progression, then the date of progression should be the time point at which this issue was first 
raised. 
 
Multifocal Tumors 
 
Progressive disease is defined as > 25% increase in the sum of products of perpendicular 
diameters of all measurable lesions compared with the smallest tumor measurements after 
initiation of therapy. The appearance of a new lesion or unequivocal progression of nontarget 
lesions will also be considered progression. 
 
Partial response is defined as >50% decrease, compared with baseline, in the sum of products of 
perpendicular diameters of all measurable lesions sustained for at least 4 weeks with stable or 
decreasing corticosteroid doses. 
 
Table 7: Summary of RANO criteria 
 
 
12.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria (see table 8 and section 12.2). 


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Table 8: Summary of evaluation of best overall response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression, 
even after discontinuation of treatment. In some circumstances it may be difficult to distinguish 
residual disease from normal tissue. 
12.5 
Confirmatory Measurement/Duration of Response 
Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed four weeks after the criteria for response are first met. In the 
case of SD, follow-up measurements must have met the SD criteria at least once after study entry 
and at a minimum interval of eight weeks (see section 12.2). 
 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started. 
 
12.6 
Response Review 
 
Patients with measurable disease will be assessed by standard criteria. The purpose of tumor 
measurements will be to assess benefit to the patients from treatment and to determine 
appropriateness for continuing on study. For the purposes of this study, patients should be re- 
evaluated according to the study guidelines and undergo imaging studies as highlighted in the 
study calendar. Following documentation of an objective response, confirmatory scans will also 
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Time to progression: The time between the first day of treatment to the day of disease progression 
as described in section 12.2. 
 
13.0 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Regulatory Compliance/Good Clinical Practices 
 
This study will be conducted in accordance with the following regulations and guidelines, to 
include but not limited to: 
• Declaration of Helsinki (October 2000) 
• Current ICH Guideline for Good Clinical Practice 
• 21 CFR 50: Protection of Human Subjects 
• 21 CFR 54: Financial Disclosure by Clinical Investigators 
• 21 CFR 56: Institutional Review Boards 
• 21 CFR 312: Investigational New Drug Application 
 
13.2 
Regulatory Documentation 
 
Prior to study start-up, investigators will submit the following documents to NewLink Genetics 
Corporation, as outlined in the Essential Documents Section 8.0 of the ICH Guidelines for Good 
Clinical Practice to include but not limited to: 
 
• Signed Confidentiality Agreement 
• Signed Clinical Trial Agreement, if applicable 
• Up-to-date signed and dated Curriculum vitae and copies of medical licenses for Principal 
and one sub/co-investigator with CVs for all investigators to be submitted promptly 
• Financial Disclosure form for Principal and one sub/co-investigator with financial 
disclosure forms for all investigators to be submitted promptly 
• FDA Form 1572 
• IRB approval to conduct the study: IRB-approved informed consent form, 
• Name and address of the IRB with the statement that it is organized and operates according 
to GCP and the applicable laws and regulations 
• IRB membership roster 
• Local laboratory certifications, its name and address 
• Local laboratory normal ranges (a dated copy for tests to be performed during the study). 
• Financial agreement, if applicable. 
• Signed and dated Investigator Agreement page of the final protocol and amendments, where 
applicable. 


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13.3 
Institutional Review Board (IRB) 
 
This Trial will be undertaken only after full approval of the protocol and addenda has been obtained 
from a local IRB and a copy of this approval has been received by the sponsor. The IRB must be 
informed of all subsequent protocol amendments issued by the sponsor. Reports on and reviews 
of, the trial and its progress will be submitted to the IRB by the investigator at intervals set force 
in its guidelines. 
 
13.4 
Informed Consent 
 
Each subject must give written consent and sign other locally required documents after the nature 
of the study has been fully explained. The informed consent form must be signed prior to 
performance of any study-related activity with the exception of baseline imaging (if already 
obtained within 14 days prior to starting study treatment) and baseline lab studies (if already 
obtained within 7 days prior to starting study treatment). The informed consent form that is used 
must be approved both by the sponsor and by the reviewing IRB. The Informed Consent should 
be in accordance of the Declaration of Helsinki, current International Conference on 
Harmonization (ICH) and Good Clinical Practices (GCP) guidelines. 
13.5 
Administrative Requirements 
Protocol modifications 
The investigator will not modify this protocol without obtaining permission from the sponsor. All 
protocol amendments must be issued by the sponsor, signed and dated by the investigator, and 
should not be implemented without prior IRB approval, except where necessary to eliminate 
immediate hazards to the subjects or when the change(s) involves only logistical or administrative 
aspects of the trial (e.g., change in monitor(s), change of telephone number(s). 
 
In situations requiring a modification, the investigator or other physician in attendance will contact 
the medical monitor by fax or telephone (see Contact Information page). This contact must be 
made prior to implementing any departure from protocol. Contact with the sponsor must be made 
as soon as possible in order to outline an appropriate course of action. 
 
Record Retention 
In compliance with the ICH/GCP guidelines the investigator/institution will maintain all CRFs and 
all source documents that support the data collected from each patient, and all trial documents as 
specified in Essential documents for the Conduct of a Clinical Trial and as specified by the 
applicable regulatory requirement(s). 
 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents. Essential documents must be retained until at least two years after the last 
approval of a marketing application in an ICH region or at least two years have elapsed since the 
formal discontinuation of clinical development of the investigational product. 
 
These documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform 
the investigator/institution as to when these documents no longer need to be retained. 


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Case Report Forms (CRF) 
CRFs are provided for each patient. Data must be entered onto CRFs in English. All forms must 
be filled out in black ball-point pen. CRFs must be signed by the investigator where indicated. 
 
All CRF corrections are to be made by the investigator or other authorized study center personnel 
as instructed on the CRF title page. The investigator must authorize changes to the recorded safety 
and efficacy data. 
 
The Case Report Forms (CRF) will be designed for the capture of all relevant clinical data for this 
study. The CRFs are to be completed as soon as possible after the subject’s visit, so that they 
always reflect the latest observations on the subjects participating in the trial. All finalized data 
will be reviewed and authorized by the Investigator. Copies of CRF data will be retained by the 
site and Sponsor in accordance with FDA regulations. 
 
Monitoring 
All clinical and standard laboratory data specified in this study will be collected and recorded by 
the nurse coordinator under the supervisions of the Principal Investigator and physician co- 
investigator 
 
NewLink Genetics (sponsor) will perform on-site monitoring visits as outlined in the Monitoring 
Plan for this clinical trial. The dates of the visits will be recorded by the monitor in a trial center 
monitor visit log to be kept at the site. The first routine monitoring visit will usually be made 
approximately 4 weeks after enrollment has begun at that site. At these visits the monitor will 
verify the data entered onto the CRFs with the hospital or clinic records (source documents). 
 
At a minimum, source documentation must be available to substantiate patient eligibility and 
participation, proper informed consent procedures, adherence to protocol procedures, record of 
safety and efficacy parameters, adequate reporting and follow-up of adverse events, administration 
of concomitant medication, drug receipt/dispensing/return records, study medication 
administration information, and date of completion and reason. 
 
Specific items required as source documents will be reviewed with the investigator prior to the 
study. Findings from this review of CRFs and source documents will be outlined in a Site Visit 
Report and discussed with the investigator. The sponsor expects that, during monitoring visits, the 
investigator (and as appropriate the study coordinator) will be available, the source documents will 
be available, and a suitable environment will be provided for review of study-related documents. 
 
Safety Monitoring 
The NewLink Genetics Medical Monitor and Safety Department will review accrual information 
and safety data such as listings and nature of adverse events. Individual SAEs are monitored by 
the Safety Department and Medical Monitor as they are received. All aggregate safety data is 
reviewed at least quarterly by the Safety Department and Medical Monitor. 
 
This study will use a Data Safety Monitoring Committee (DSMC) during phase 2. The DSMC 
will meet quarterly. 


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Use of Information and Publication 
All information on indoximod, NewLink operations, patent application, manufacturing process 
and basic scientific data supplied by the sponsor to the investigator and not previously published 
is considered confidential and remains the sole property of NewLink Genetics. The investigator 
agrees to use this information only to accomplish this study and will not use it for other purposes 
without the sponsor’s written consent. The investigator understands that the information 
developed in the clinical study will be used by NewLink in connection with the continued 
development of indoximod and thus may be disclosed as required to other clinical investigators or 
government regulatory agencies. To permit the information derived from the clinical studies to be 
used, the investigator is obligated to provide the sponsor with all data obtained in the study. 
 
Any publication or other public presentation of results from this study requires prior review of 
NewLink Genetics. Draft abstracts, manuscripts and materials for presentation at scientific 
meetings should be provided to the sponsor as outlined in the clinical trial agreement. 
13.6 
Human Subjects Protection 
Rationale for subject selection 
Advanced glioblastomas affect men and women from all racial/ethnic groups. Subjects from all 
racial/ethnic groups are eligible for this study if they meet the eligibility criteria. We will make 
an attempt at enrolling representative proportions of minorities on this study. 
Efforts will be made to extend accrual to a representative population, but in this phase 1/2 study, 
a balance must be struck between subject safety considerations and limitations on the number of 
individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the need 
to explore gender and ethnic aspects of clinical research on the other hand. 
Participation of Children 
A study to evaluate the efficacy of indoximod in children (< 16 years of age) is planned once part 
1 of this study is completed. 
Evaluation of Benefits and Risks 
Advanced glioblastomas have a very poor overall prognosis. After failing currently available 
regimens, the chance of cure is rare if at all. The benefits of this approach are theoretical and it is 
hoped that the inhibition of IDO will lead to an effective anti-tumor immune response. By 
generating an immune response against the subject's tumor, their overall survival might be 
improved. 
Given the safety demonstrated by indoximod in several clinical studies, and the poor prognosis of 
this patient population, it is believed that the possible benefits from improved survival probability 
far outweigh the risk to the patient. The information obtained in this study may be extremely 
valuable in the treatment of malignancies in the future. The chance of this experimental treatment 
to provide clinical benefit is unknown. All possible benefits and risks will be carefully explained 
to all subjects and the Informed Consent Document will be signed by the subject prior to entrance 
into the protocol. 
There are no new anticipated severe adverse side effects to the treatment approach technique 
employed in this study. Theoretical risks may include the induction of unanticipated autoimmune 
disease and/or liver, kidney, lung, heart and CNS damage and/or coagulopathy and bleeding as a 
result of excessive activation of the complement system. Expected risks and discomforts to the 


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subjects are minimal and will be those of needle sticks for phlebotomy. Subjects will be treated as 
deemed medically appropriate for any immediate or delayed adverse event related to the treatment. 
Blood and tissue specimens collected in the course of this research project may be banked and 
used in the future to investigate new scientific questions related to this study. 
Consent and Assent Processes and Documents 
All subjects will be thoroughly screened prior to admission onto this study. During this time, the 
subject, along with family members, will be presented with a detailed description of the protocol 
treatment. The specific requirements, objectives, advantages and disadvantages will be presented. 
The Informed Consent document is given to the subject (and parent(s) / guardian if patient < 18 
years of age) and they are asked to review it and ask questions prior to agreeing to participate in 
this protocol. The subject will be reassured that participation on this trial is entirely voluntary and 
that they can withdraw or decide against treatment at any time without adverse consequences. The 
Principal Investigator or their designee is responsible for completing the consent process and a 
copy of the completed Consent Document is offered to the subject. 
Recruitment Strategy 
Patients, their physicians or family members may contact the clinical sites directly. Information 
about the clinical trial can be obtained at clinicaltrials.gov. Given the number of patients with 
glioblastoma and the limited therapy available, we believe enrollment for this trial will be 
completed in less than 1 year. 
Patient Confidentiality 
Strict patient confidentiality is standard policy at clinical research sites. Standard practices will be 
followed. 
 
14.0 
STATISTICAL METHODS 
 
14.1 
General statistical considerations 
 
This is an open-label phase 1b/2 clinical trial of indoximod with temozolomide. Descriptive 
statistics will be presented for primary and secondary endpoints employed to analyze the data. 
Summary statistics for continuous variables will include the mean, standard deviation, median, 
and range (minimum/maximum); categorical variables will be presented as frequency counts and 
percentages; and time-to-event variables will be summarized by Kaplan-Meier medians and 
survival plots. Data listings will be created to support each table and to present all data. 
The data will be tabulated and analyzed with respect to patient enrollment and disposition, 
demographic and baseline characteristics, prior and concomitant medications, efficacy and safety 
measures on a per cohort basis for phase 2, and on a per dose level for phase 1. The efficacy 
analysis will be conducted on the Efficacy Evaluable Population and safety analysis will be 
performed on the Safety Population as described in section 14.5. 
Maximum tolerable dose for indoximod with temozolomide will be estimated based on the data 
by using a formal statistical inference procedure based on the percentage of RLT per dose. RP2D 
will then be determined based on the estimated MTD, which should not exceed 1/6 of RLT. 
In the phase 2 trial, the observed 6-month progression free survival (PFS), overall survival, overall 
response rate, duration of response, toxicity and tolerability will be summarized and compared 
with those reported in the literatures for standard-of-care treatment. PFS and OS will be calculated 
starting at the initiation of indoximod. Historical control was chosen in place of active control for 


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low incidence of the malignant brain tumor. Chi-squared test or Fisher Exact test when appreciate, 
will be used to compare the observed 6-month PFS rate, ORR between the experiment group and 
the historical control. The detected overall survival and duration of response will be compared 
with previous published counter parts via log-rank test, separately. 
The correlation of risk factors pertinent to patients’ outcome or response will be assessed in an 
exploratory fashion when sample size allows. 
14.2 
Sample Size 
Phase 1 
Up to 18 evaluable patients with high-grade glioma will be enrolled in the trial. The actual number 
of patients will depend on the RLT and MDT as described in in Section 6.2. 
 
Phase 2 
 
The sample size will be based on the primary end point of 6-month PFS. PFS will be calculated 
starting at the initiation of indoximod therapy. A modified Fleming procedure by A’Hern (2001) 
for single stage phase-II clinical trial will be used and implemented by PASS12 software (NCSS, 
LLC). The sample sizes for cohorts 2a, 2b, and 2c are based the following information of standard 
of care (SOC) and experimental combination therapy (ECT) of percent of patients with 6-month 
progression free survival: 
Cohort 2a: 0.25 for SOC vs. 0.44 for ECT (22) 
Cohort 2b: 0.42 for SOC vs. 0.65 for ECT (23) 
Cohort 2c: 0.40 for SOC vs. 0.58 for ECT (24) 
 
Due to differences in expected rates of enrollment between the phase 2 cohorts (Cohort 2a being 
expected to enroll more readily) as well as the desire to more accurately inform a potential 
randomized trial focusing on the patients eligible for inclusion in Cohort 2a, the statistical 
stringency for Cohort 2a will be higher than that for 2b and 2c. 
 
The minimum required sample sizes estimated are 68, 24, and 40 for cohort 2a, 2b, and 2c, 
respectively. 
 
The sample size for each cohort is estimated to provide 90% power at significance level 2.5% for 
Cohort 2a and 80% power at significance level 10% for Cohorts 2b and 2c. 
 
14.3 
STATISTICAL ANALYSIS 
Phase 1b portion 
➢ Primary endpoint: 
The recommended phase 2 dose will be based on dose escalation method provided in section 
6.2, Table 1. 
 
➢ Secondary endpoints: 
• The adverse events will be listed along with identification of the regimen-limiting 
toxicities (RLT) of indoximod plus temozolomide in combination therapy 


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• The overall dose of temozolomide delivered and timing of administration will be 
compared to historical control using T-test. 
 
Phase 2 portion 
 
➢ Primary endpoint 
 
The primary endpoint is defined as the rate of 6-month progression free survival (PFS) starting at 
the initiation of indoximod among all participants. The study has three cohorts of patients (2a, 2b, 
and 2c). 
 
The following definitions of the parameters apply to all the cohorts: 
P0 = the maximum proportion of the 6-month PFS under SOC. 
P1 = the minimum response proportion of PFS under the new Combination Therapy. 
If the number of responses ≥ R+1, P0 is rejected 
If the number of responses ≤ R, P1 is rejected. 
 
Table 9 summarizes the sample size and stopping rules for cohort 2a, 2b and 2c. 
 
Cohort 
P0 
P1 
Alpha 
Power 
Cut-off 
R+1 
N 
2a 
0.25 
0.44 
0.025 
0.90 
25 
68 
2b 
0.42 
0.65 
0.10 
0.80 
14 
24 
2c 
0.40 
0.58 
0.10 
0.80 
21 
40 
 
 
Cohort 2a: 
A total of up to sixty-eight (68) evaluable patients with intracranial glioblastoma or gliosarcoma and 
not currently on bevacizumab will be enrolled into cohort 2a of phase 2. By the end of the 6-months 
follow up period, a decision will be made if the proportion of patients with PFS, P, is ≤ 0.25 or ≥ 0.44. 
If the number of patients with PFS is 25 or more, the hypothesis that P ≤ 0.25 is rejected with a target 
error rate of 0.025. If the number of patients with PFS is 10 or less, the hypothesis that P ≥ 0.44 is 
rejected with a target error rate of 0.10 (beta =1-power). 
 
Cohort 2B: 
A total of up to twenty-four (24) patients with previous bevacizumab treatment will be enrolled 
into cohort 2b and receive bevacizumab in addition to indoximod with temozolomide. If a patient 
has been taken off bevacizumab after progressing on bevacizumab prior to entry into the study, 
the patient will be considered with Cohort 2b but may receive temozolomide / study drug alone. 
By the end of the 6-months follow up period, a decision will be made if the proportion of patients 
with PFS, P, is ≤ 0.42 or ≥ 0.65. If the number of patients with PFS is 14 or more, the hypothesis 
that P ≤ 0.42 is rejected with a target error rate of 0.10. If the number of patients with PFS is 13 or 
less, the hypothesis that P ≥ 0.65 is rejected with a target error rate of 0.20 (beta =1-power). 
 
Cohort 2C: 
A total of up to forty (40) patients with current potential indication for stereotactic re-irradiation 
will be enrolled into cohort 2c and be treated with indoximod with temozolomide and stereotactic 


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radiosurgery. By the end of the 6-months follow up period, a decision will be made if the 
proportion of patients with PFS, P, is ≤ 0.40 or ≥ 0.58. If the number of patients with PFS is 21 or 
more, the hypothesis that P ≤ 0.40 is rejected with a target error rate of 0.10. If the number of 
patients with PFS is 20 or less, the hypothesis that P ≥ 0.58 is rejected with a target error rate of 
0.20 (beta =1-power). 
 
➢ Secondary endpoints: 
• The Overall Response Rate (ORR), overall survival, and tolerability of indoximod plus 
temozolomide will be evaluated for patients with progressive GBM using methods listed 
in the section 14.1. 
 
• The Overall Response Rate (ORR) and tolerability of indoximod plus temozolomide and 
bevacizumab will be evaluated, for patients with GBM, whose disease progressed during 
therapy with a bevacizumab-based regimen, using methods listed in the section 14.1. 
 
• The Overall Response Rate (ORR) and tolerability of indoximod plus temozolomide and 
stereotactic radiotherapy will be evaluated, for patients with GBM patients who may 
reasonably benefit from tumor debulking, using methods listed in the section 14.1. 
 
14.4 
Treatment Randomization and Blinding 
 
This is an open-label; single arm, phase 1/2 study; thus, randomization and blinding are not part 
of the study design. 
14.5 
Study Populations and analysis datasets 
The definitions of study populations are as follows: 
1) Enrolled (Intent-to-Treat): This population will comprise all patients who were enrolled in 
the study whether or not the study drug was administered. 
2) Safety: This population will comprise all patients who receive at least one infusion of 
indoximod and temozolomide. This population will be analyzed for safety. 
3) Efficacy Evaluable - This population will comprise all patients who receive at least one dose 
of study drugs, indoximod with temozolomide, and either undergo at least one post-baseline 
assessment or die before any evaluation. For sensitivity, analyses the efficacy endpoints may 
be repeated in subsets of this population. 
No adult group (except patients with cognitive impairment) is being excluded from 
participation. Patients of both genders, from all racial and ethnic groups are eligible for this 
study. There is no information suggesting differences in absorption, metabolism, or 
disposition or disease response to the study drug among racial or ethnic groups or between 
the genders. Efforts will be made to extend the accrual to a representative population, but, in 
a study accruing small numbers of patients such as this one, the enrollment diversity may not 
be optimal. 
Pediatric patients (<16 years of age) are excluded from evaluation in this study for safety 
considerations. 


 
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14.6 
Study Endpoints 
 
14.6.1 
Safety Endpoints 
Safety analyses will be peifoisted using the safety population os defined in Section 14.5. 
• 
All adverse events (AE’s) will be presented in incidence tables coded by MedDRA 
Pi’eferred Teim (PT), Body System Class (SOC). and NCICTC. Additionally, separate AE 
incidence tables. coded by MedDRA PT end NCICTC, will be presented by: 1) toxicity 
grade (severity) groded by the CTCAE and 2) ielotionship to indoximod with 
teiuozolomide treatment as deteimined by the Investigator (tieatinent related end treatment 
emergent adverse events). 
• 
All selious adverse events, discontinuations due to adverse event, o1 deaths occurring after 
the lust administration of sttidy drug imtil 4 weeks following termination from the triol will 
be siiininarized on a pe1-patient basis. 
• 
Fo1 laboratory tests, siuninary tables describing the fieqiiency with which laboratory 
parameters are outside the normal i’anpe (ct baseline and at any time post-baseline) will be 
displayed. Complete listings of all laboratory data will be provided end values with 
CTCAE Giade > 3 will be identified with flags. A list of all nolxuol laboratory ranges will 
also be plovided. 
• 
Vitol sigas (blood pressure, pulse, temperature) over time will be siunniarized usinp 
descriptive statistics md data listings. 
• 
Percent of patients experiencing dose modifications, inteiniptions, and/or premattu’e 
discontiniiations fiom stridy tip. 
 
 
 
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REFERENCES 
 
1. 
Wong, E.T. et al. Outcomes and prognostic factors in recurrent glioma patients enrolled 
onto phase II clinical trials. J Clin Oncol 17, 2572-2578 (1999). 
2. 
Munn, D.H. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. 
Science 281, 1191-1193 (1998). 
3. 
Johnson, T.S. & Munn, D.H. Host indoleamine 2,3-dioxygenase: contribution to systemic 
acquired tumor tolerance. Immunol Invest 41, 765-797 (2012). 
4. 
Hou, D.Y. et al. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by 
stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 
67, 792-801 (2007). 
5. 
Muller, A.J., DuHadaway, J.B., Donover, P.S., Sutanto-Ward, E. & Prendergast, G.C. 
Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer 
suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11, 312-319 (2005). 
6. 
Cheever, M.A. Twelve immunotherapy drugs that could cure cancers. Immunol Rev 222, 
357-368 (2008). 
7. 
Yung, W.K. et al. A phase II study of temozolomide vs. procarbazine in patients with 
glioblastoma multiforme at first relapse. Br J Cancer 83, 588-593 (2000). 
8. 
Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for 
glioblastoma. N Engl J Med 352, 987-996 (2005). 
9. 
Franceschi, E. et al. Salvage temozolomide for prior temozolomide responders. Cancer 
104, 2473-2476 (2005). 
10. 
Johnson, B.F., Clay, T.M., Hobeika, A.C., Lyerly, H.K. & Morse, M.A. Vascular 
endothelial growth factor and immunosuppression in cancer: current knowledge and 
potential for new therapy. Expert Opin Biol Ther 7, 449-460 (2007). 
11. 
Shrimali, R.K. et al. Antiangiogenic agents can increase lymphocyte infiltration into 
tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 
70, 6171-6180 (2010). 
12. 
Chamberlain, M.C. Role for cytotoxic chemotherapy in patients with recurrent 
glioblastoma progressing on bevacizumab: a retrospective case series. Expert Rev 
Neurother 12, 929-936 (2012). 
13. 
Johnson, T.S., Munn, D.H. & Maria, B.L. Modulation of tumor tolerance in primary 
central nervous system malignancies. Clin Dev Immunol 2012, 1-14 (2012). 
14. 
Banissi, C., Ghiringhelli, F., Chen, L. & Carpentier, A.F. Treg depletion with a low-dose 
metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother 
58, 1627-1634 (2009). 
15. 
Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on 
tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9, 1269-1274 (2003). 
16. 
Wainwright, D.A. et al. IDO Expression in Brain Tumors Increases the Recruitment of 
Regulatory T Cells and Negatively Impacts Survival. Clin Cancer Res 18, 1-12 (2012). 
17. 
Hiniker, S.M., Chen, D.S. & Knox, S.J. Abscopal effect in a patient with melanoma. N 
Engl J Med 366, 2035; author reply 2035-2036 (2012). 
18. 
Postow, M.A. et al. Immunologic correlates of the abscopal effect in a patient with 
melanoma. N Engl J Med 366, 925-931 (2012). 
19. 
A'Hern, R. P, 'Sample size tables for exact single-stage phase II designs.' Statistics in 
Medicine, 20; 859-866 (2001). 
20. 
Fleming, T. R., 'One-sample multiple testing procedure for Phase II clinical trials.' 


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Biometrics, 38,143-151 (1982). 
21. 
Storer B.E., Design and Analysis of Clinical Trials, Biometrics. 45(3); 925-937 
(1989) 
22. 
Perry et. al J Clin Oncol. 2010 Apr 20;28(12):2051-7 
23. 
Friedman et al. J Clin Oncol. 2009 Oct 1;27(28):4733-40 
24. 
Kong et al. Cancer. 2008;112(9):2046. 


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15.0 
APPENDICES 
 


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Appendix B: Study Medication Diary 
Study Medication Diary 
Subject Initials:  
 
Subject #: NLG2102 -    
 
Cycle:  
 
Cycle Start Date:  
/  
/  
 
Subjects planned daily dose:  
mg 
# of capsules dispensed:  
by:  
on  
/  
/   
 
# of capsules returned:  
to:  
 
on  
/  
/   
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each Cycle. 
2. 
You will take  
capsules each 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. Take the capsules whole with a full glass of water. 
3. 
Record the date, the number of capsules you took, and when you took them. 
4. 
If you have any comments or notice any side effects, please record them in the Comments column. 
5. 
Please bring your medication bottle and this form to your physician at each return visit. 
Date 
Day # 
#Capsules 
AM Dose 
(time 
HH:MM) 
#Capsules 
PM Dose 
(time 
HH:MM) 
Comments 
Subject Initials (Signed by Subject):  
Date:  
/  
/ _   
 
To be completed by site staff upon return of study medication diary: 
Total Number of Capsules taken this cycle:  
Percent of Compliance: 
 
Comments on capsules taken, capsules not taken as planned, capsules lost, or other discrepancies:   
 
Signature of Study Nurse or Study Designee: 
  
Date:  
/  
/    
 


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Appendix C: Neuro-Oncology Consent Process 
Neuro-Oncology Consent Process 
Our program offers clinical trials for patients with brain tumors at different stages of disease. We 
offer clinical trials to patients who are newly diagnosed with a brain tumor, as well as patients who 
had disease progression or recurrent brain tumors. We believe that these clinical trials are a good 
option for patients with incurable cancer and strive to offer a clinical trial as a treatment option for 
each of our patients. Furthermore, many patients with recurrent disease have no FDA approved 
effective therapies available, so the opportunity to participate in a clinical trial for these patients 
provides an important therapeutic option. Typically, the majority of brain tumor patients with 
sufficiently good performance status to participate in clinical trials will have the cognitive capacity 
to understand and provide consent to participate in a clinical trial and sign the appropriate consent 
documents. However, some patients are capable of understanding and providing consent, yet they 
have a neurologic deficit as a result of disease or treatment that causes the inability to write or sign 
their name to a document. Occasionally, there are patients who are not capable of providing 
consent independently due to cognitive impairment or communication deficits related to disease 
or treatment that they have received for their disease. Our process for obtaining consent is as 
follows: 
 
1. Patients with a brain tumor with full cognitive and physical ability will independently 
provide consent with a signature of the consent documents following the entire consent 
process. 
2. Patients with a brain tumor with full cognitive ability, but neurologic impairment who 
cannot provide a signature, will provide full consent verbally using the consent document, 
make a mark if they can, and then have a witness sign the consent attesting that the patient 
consented willingly after a full consent process. A family member can act as a witness in 
this situation or anyone outside of the study team can witness this process. A witness 
signature block will be included in the consent document. 
3.  If the investigator has determined that the patient has significant cognitive impairment and 
cannot independently provide consent, an LAR will be required. Verbal assent will be 
obtained, but written assent may not be possible depending on the level of physical and/or 
cognitive impairment. If written assent is possible, the participant will provide assent by 
signing the full consent document along with an LAR. The LAR will be informed of their 
obligation as a surrogate decision maker to determine the patient’s wishes or what is in the 
best interest of the patient. The entire consent process will be well documented in the 
research records and include the Investigator’s assessment of the participant’s ability to 
provide consent independently or the need for an LAR. 
 
The investigators will assess each patient and determine if the patient is competent to 
independently consent to a clinical trial based on their ability to express understanding of the 
information presented regarding the treatment options and expression of their desire to participate 
in the clinical trial. In some cases, use of a patient advocate or neuro-cognitive testing may be 
included in the process to help determine if patient is able to give consent themselves or if the LAR 


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is more appropriate. In situations in which patients’ ability to give consent themselves is not clear, 
the LAR process will be utilized. The investigator’s assessment will be documented in the consent 
documentation notes that are kept in the research chart along with the original consent forms. (See 
attached). 
 
Justification for Including Cognitively Impaired Individuals 
 
Our target population is patients with brain tumors. Not all patients who have brain tumors are 
cognitively impaired. However, for those individuals who are cognitively impaired, we would like 
to offer them the same opportunity to participate in our clinical trials and to do it in a way that is 
consistent with the regulations for obtaining consent in human subjects. Exclusion of cognitively 
impaired patients would be discriminatory, and as described above, many of these patients have 
no proven effective therapies available, so participation in a clinical trial is the best opportunity 
they have for treatment with potentially effective novel therapies. 
 
Greater than Minimal Risk/Risk and Benefit 
 
The clinical trials that are being conducted for the treatment of primary brain tumors are more than 
minimal risk trials. Participation in a clinical trial for an incurable brain tumor offers the prospect 
of direct benefit to an individual. 
 
Cognitively impaired individuals may be at greater risk for non-compliance on a clinical trial and 
may not be able to completely report adverse events or side-effects of treatment. All cognitively 
impaired individuals must have a LAR who acts as a caregiver to ensure compliance, including 
drug administration and reporting of toxicities in some cases. The benefit for including these 
patients is that they may have an opportunity to receive a treatment on a clinical trial that would 
not otherwise be available to them. 
 
Additional Consent Considerations 
 
As it is expected that some brain cancer patients will have cognitive impairment, it is appropriate 
to include adults with impaired decision making capacity. 
 
Patients may be able to provide consent independently at the time of enrollment, but may have 
cognitive decline while on a study. If there is noticeable decline that includes loss of ability to 
understand or communicate effectively, and patient is going to continue on trial, then consent from 
an LAR may be appropriate to continue participation in a clinical trial. 


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Neuro-Oncology Consent Process Note 
 
Please select one of the following consent processes that will be followed for the above patient. 
 
◻ The patient has full cognitive and physical ability to independently provide consent with 
a signature to participate in this clinical trial. 
 
◻ The patient has full cognitive ability and is able to provide verbal consent to participate in 
this clinical trial; however, s/he is not physically able to provide a signature due to a 
neurologic impairment. If possible, the participant will “make their mark” on the consent 
document. I, as the investigator, attest that the patient has provided verbal consent to 
participate in this trial, and the process has been witnessed by the patient’s family 
member or a representative outside of the study team. 
 
◻ The patient has significant cognitive impairment and is unable to independently provide 
consent. I, as the investigator, believe that participation in the clinical trial is a good 
treatment option for this patient. I attest that this has been discussed with the patient’s 
Legally Authorized Representative (LAR), who understands his/her obligation as a 
surrogate decision maker. The LAR has agreed to participation in the clinical trial. 
 
 
 
 
 
Investigator’s Signature 
Date 


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Appendix D: Sample Informed Consent Form 
 
The use of ‘you’ throughout this document refers to the research subject as an adult or child. If the research subject is less than 
18 years old, the subject’s parent or legal guardian must provide written consent for the child to participate in this study. 
 
 
INTRODUCTION 
Before agreeing to participate in this research study, it is important that you read and understand the 
following explanation of the proposed procedures. This document describes the purpose, procedures, 
benefits, risks, discomforts and precautions of the study. It also describes the alternative procedures that are 
available to you and your right to withdraw from the study at any time. No guarantees or assurances can be 
made as to the results of the study. You must be completely truthful with your study doctor regarding your 
health history, including past and present usage of both prescription and non-prescription medications, 
including herbals. If you are not completely truthful with your study doctor you may harm yourself by 
participating in this study. This form tells you about a research study. Research studies are voluntary and 
include only those who wish to participate. We may learn about new things that make you want to stop 
being in the study. If this happens, you will be informed. You can then decide if you want to continue to be 
in the study. 
 
The study doctor may remove you from this study for any reason. Any new information about the study 
medicine will be given to you so you may decide to continue in the study or leave it. 
 
You may be taken out of the study if: 
1. Staying in the study would be harmful. 
2. You need treatment not allowed in this study. 
3. You fail to follow instructions. 
4. The study is cancelled. 
5. Your disease progresses. 
 
If you should decide to leave the study, you should tell the study doctor or study staff. They will make sure 
that proper procedures are followed and a final visit is made for your safety 
 
Why is this research study being done? 
This study is being done to test the feasibility of combining the approved drug therapy temozolomide 
(Temodar) with an experimental drug called indoximod. “Experimental” means the drug has not been 
approved by any Authority that regulates new medicines, including the US Food and Drug Administration 
(FDA). 
 
Temozolomide is an oral medicine that is approved for commercial use as a prescribed drug by the FDA 
for the treatment of brain cancer. The experimental (study) drug, indoximod, is an oral medication that 
blocks an enzyme (a type of protein that affects other proteins in the body) called IDO. Doctors think that 
tumors use IDO to escape attack by your body’s immune system. By blocking this IDO enzyme, indoximod 
may help your body attack the tumor cells more effectively. Indoximod given along with various 
chemotherapy agents such as temozolomide may increase the effectiveness of the chemotherapy. 
 
Why am I being asked to take part in this study? 
You are being asked to take part in this research study because you have brain cancer. 
 
How many people will take part in the study? 
This study will have two parts, a dose-escalation phase (the first part of the study) and then later, a dose- 
expansion part (the second part of the study). Enrollment for the first part of the study is now complete and 


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12 people were asked to participate. In the second part, approximately 132 additional people will be asked 
to participate. 
 
Do I have to take part? 
It is up to you to decide whether or not to take part. If you decide not to participate in the research study, 
your decision will not affect the medical treatment and care you are entitled to receive. If you do decide to 
take part after reading this Informed Consent Form, you will be asked to indicate your consent to participate 
in this study by signing and dating this Informed Consent Form. 
 
If you decide to take part, you are still free to withdraw from study procedures and/or study treatment at 
any time. If you do not want to take part in the study, your study doctor will discuss different options that 
are available to you. These options may include: 
• 
Treatment with other chemotherapy drugs such as temozolomide alone; 
• 
Treatment with medications that will make you feel more comfortable, but have no effect on your 
cancer; 
• 
Other experimental treatments; 
• 
No treatment 
 
What will happen if I take part in this study? 
Indoximod will be given to you orally twice a day for 28 day cycles. You will be asked to visit the clinic 
during weeks 1 and 3 of the first cycle. In Cycle 2 and subsequent cycles, you will attend the clinic every 
other week as long as you are receiving the treatment. Your doctor will tell you the dose of Indoximod 
before you begin study treatment. 
 
Subjects will be treated in one of the two phases of this study: dose-escalation or dose-expansion. The 
dose-escalation phase occurs first and enrollment has been completed for this portion of the study. You 
are being asked to participate in the dose expansion phase of the study. 
 
Screening 
The screening period is held within 14 days before starting the study treatment to find out if you can be in 
the study. During this period, you will need to come to the clinic or study site for multiple tests. More than 
one screening visit may be required. If these tests show that you can be in the study and you choose to take 
part, then you will be entered in the study. The following screening examinations, tests, or procedures will 
be performed after you have given consent to participate in this study: 
 
• 
Medical history, including information about you and your cancer, previous treatments for your 
cancer and other medications you are taking or have taken. Certain medications are not allowed to 
be taken during the study treatment. 
• 
Complete physical exam including vital signs (heart rate, temperature, breathing rate, blood 
pressure, height and weight) 
• 
Performance Status (questions about your ability to perform everyday activities) 
• 
Your tumor size will be measured by MRI [Magnetic Resonance Image; combines a series images 
taken from many different angles and computer processing to create cross-sectional images of the 
brain]. 
• 
Standard blood tests, using up to 6 teaspoons of blood, to measure your liver and kidney function, 
white blood cells, red blood cells and platelets, your blood sugar and blood electrolytes and if you 
are female and able to become pregnant, to confirm you are not pregnant. You will not be allowed 
to enter the study of you are pregnant or lactating. 


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• 
Research blood tests will be taken to monitor how your body will be affected by the drug. These 
initial tests will serve as a guide to see how your body reacts after you have received the study drug 
throughout the study. 
• 
An ECG to determine if your heart is healthy enough for treatment. 
• 
Additionally, 3 ½ teaspoons of blood will be drawn and stored for future testing of an enzyme that 
is released in tumors, called IDO enzyme (this is an immune suppressing enzyme released by the 
tumor and indoximod seems to block this enzyme). This is an optional test that may help us better 
understand who will respond to study treatment with indoximod. You will sign a separate consent 
for this testing. 
 
On Study Procedures 
 
• 
Approximately 1 teaspoon of blood will be taken for an analysis of white blood cells at weeks 1, 
and 3, and then on the first day of each cycle for the time you are receiving study drug. After that 
time this test will be performed once every 6 months during your follow up visits. 
• 
At week 1 of each Cycle, approximately 3 ½ teaspoons of blood will be drawn and stored for future 
testing of an enzyme that is released in tumors, called IDO enzyme (this is an immune suppressing 
enzyme released by the tumor and indoximod seems to block this enzyme). This is an optional test 
that may help us better understand who will respond to study treatment with indoximod. You will 
sign a separate consent for this testing. 
• 
ECG – An electrocardiogram will be taken 1 hour after the first dose of indoximod for the first 9 
subjects enrolled in phase II. Twelve additional patients will receive an electrocardiogram 3 hours 
after first dose of indoximod and again on Cycle 2, Day 1 after morning indoximod dose 
administration, and at the end of therapy visit. These tests are used to confirm there are no changes 
to the activity of your heart after taking the study medication for short and longer periods of time. 
The research staff will let you know if you are participating in this portion of the trial. 
 
Additionally, a biopsy of your tumor is usually done as part of routine care to make the diagnosis of cancer 
prior to starting this course or most courses of treatment. If there is any extra preserved tissue from the 
biopsy remaining after it has been used to make a diagnosis, a small portion of the tissue will be requested 
as part of this study to look for the presence of the IDO/TDO enzyme. A separate biopsy will not be done 
for research purposes alone. It is not required for participation in this study, and you do not have to agree 
to provide the tumor sample. If you say no, you can still participate in the main study. This testing will 
not benefit you directly or change how your disease is treated. 
I agree to have left over tumor tissue provided for this study to test for IDO and TDO expression. 
 
  
 YES 
  
NO 
  
Initials 
 
 
 
Treatment regimen 
If you continue to be eligible for study participation after screening, you will begin taking 6 capsules of 
indoximod (study drug) two times per day. Indoximod comes in 200mg capsules. No food should be taken 
for at least 2 hours before and at least 1 hour after taking the morning and evening doses. You must 
swallow the capsules whole with a full glass of water and not chew them. It is very important that you 
follow these instructions listed above because they could change the safety and how well the study drug 
works. 


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Bottles containing indoximod capsules will be given to you periodically. It is very important that you take 
this medicine just as the doctor tells you. Do not miss any capsules. It is important to tell the study staff 
about any other medications you are taking during the study, including prescription drugs, over-the-counter 
medicines and vitamins. You will be asked to complete dosing diaries while you are taking the study 
medication and it will be distributed to you at the start of the study. You must bring your dosing diary and 
indoximod bottle(s) back to the clinic at regular intervals so the study staff can make sure you are taking 
your indoximod as you should. The study staff will review the dosing diary with you to ensure accuracy 
and assess compliance. 
 
Temozolomide (Temodar) will be taken orally for 5 days and this will be repeated every 28 days. 
Temozolomide will be started at bedtime on an empty stomach. Anti-nausea medication is recommended 
approximately 1 hour prior to the oral dose. Your doctor will discuss this with you. If vomiting occurs after 
a dose is administered, you should wait until the next scheduled dose. Capsules should not be opened or 
chewed. 
 
If you have any side effects during the treatment period, you and your doctor will decide if you should 
continue in the study. 
 
DOSE-EXPANSION PHASE: 
Subjects participating in this phase of the study will receive one of the dose levels of indoximod determined 
from the dose-escalation phase plus additional treatment as outlined below. This was determined to be 
1200mg twice daily. There are 3 groups in this part of the study. 
 
1- Indoximod and Temozolomide: In this group you will be getting temozolomide and indoximod (at 
1200 mg twice daily) 
2- Indoximod, Bevacizumab and Temozolomide: If you are getting a standard brain tumor medication 
called bevacizumab (Avastin) and your disease progresses, you will continue to take the Avastin, 
along with temozolomide and indoximod (at 1200 mg twice daily). If you have previously taken 
bevacizumab and your disease progressed and your physician stopped the bevacizumab, you will 
only take the temozolomide and indoximod. 
3- Indoximod, temozolomide and radiation: If you are a candidate for radiation, you will be getting it 
along with temozolomide and indoximod (at 1200 mg twice daily). 
 
You will return to your doctor’s office at regular intervals so that your disease can be monitored and routine 
blood tests and safety evaluations can be carried out. Please tell your study doctor or study staff if you have 
any unusual symptoms. You will be closely monitored for any side effects and you should report any 
changes in the way you feel to your study doctor. If you experience any side effects, your study doctor may 
instruct you to stop the study drug temporarily and restart at the same or lower dose after the side effect has 
resolved. 
 
How long will you be asked to be on the study? 
 
You may continue to receive the study treatment as long as your cancer does not get worse. Your 
participation in the study may end at any time if your doctor thinks it is in your best interest to stop or you 
decide you do not wish to receive any more study treatment. Even if you decide to stop study treatment 
you may continue to be followed by routine office visits every 3 months for up to 2 years and telephone 
calls every 6 months to check on the status of your disease for up to 5 years. 
 
COSTS 
This is a treatment study. There will be no cost to you for the supply of the study drug (indoximod) during 
your participation in the study. You will not be charged for any of the tests and procedures performed solely 


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for research purposes. All study-related testing (tests performed for research purposes only) will be 
provided to you by the study at no charge. Tests and procedures that are standard of care for your disease 
(not part of this research study) will be billed to your insurance or Medicare. Tests and standard procedures 
that are routine care for your disease that are not paid for by the study, and will be charged to your insurance 
or Medicare, if applicable. This includes medications that are typically given to patients receiving treatment 
for your disease (such as temozolomide and/or bevacizumab). You will be responsible for all co-pays. You 
or your insurance company will be charged for standard medical care and for any hospitalizations. It is 
possible that your insurance or Medicare will not pay routine care charges because the treatment is taking 
place within a research study. If this happens, you will be responsible for these charges. A member of the 
research team will contact your insurance company to determine the additional costs you may be 
responsible for paying. Your study doctor will inform you of the potential cost to you. 
You will not be paid to take part in this research study. 
 
Even though it probably won’t happen, it is possible that the manufacturer may not continue to provide the 
indoximod to the study site for some reason. If this would occur, other possible options are: 
 
• 
You might be able to get the indoximod from the manufacturer or your pharmacy, but you or your 
insurance company may have to pay for it. 
 
• 
If there is no indoximod available at all, no one will be able to get more and the study would close. 
 
If a problem with getting indoximod occurs, your study doctor will talk to you about these options. 
 
What are the potential benefits if you take part in the study? 
 
We do not know if you will get any health benefits by taking part in this study. We do not know if the 
experimental study treatment will help you. That is why we are doing this study. We hope that what we 
may learn can benefit you and others in the future. 
What are the risks if you take part in the study? 
INDOXIMOD 
The following may be related risks and side effects of the indoximod therapy that have been observed in 
patients that have received it: 
 
Likely: Likely to happen to 20% or more of patients 
• 
Fatigue or feeling tired 
• 
Nausea 
• 
Anorexia or loss of appetite 
• 
Decrease in red blood cells (anemia) 
• 
Diarrhea 
 
Less Likely: Likely to happen to 10 to 19% of patients 
• 
Decrease in white blood cells (neutrophils and lymphocytes) 
• 
Abdominal pain 
• 
Shortness of breath (dyspnea) 
• 
Rash 
• 
Vomiting 
• 
Constipation 
• 
Decrease in platelets 


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• 
Headache 
• 
Hair loss (alopecia) 
 
Rare: Likely to happen to less than 10% 
• 
Dizziness 
• 
Lung Infections 
• 
Increase in blood potassium, glucose and creatinine 
• 
Sleeplessness (insomnia) 
• 
Low blood levels of sodium (hyponatremia) 
• 
Multi-organ failure 
• 
Low Blood Pressure (Hypotension) 
• 
Dehydration 
• 
Ringing in ears 
• 
Fever associated with low white blood cells (febrile neutropenia) 
• 
Mouth sores 
• 
Redness, pain, numbness, and possible peeling of the skin of the hands and feet 
 
Autoimmune Events 
Autoimmunity is a term that describes when your immune system begins to attack normal cells in your 
body. Two patients out of 48 in a completed indoximod study developed an autoimmune reaction in their 
pituitary gland called hypophysitis. Both of these patients received prior experimental immune therapies 
which may have increased the risk of this occurring, but there is a distinct possibility that this may occur 
with indoximod alone. 
 
One of the two hypophysitis patients were on low dose steroids and thyroid hormone as long as they were 
alive, and one of the patients was able to stop the steroids but remained on thyroid hormone for the rest of 
her life. To date, none of the patients who did not receive prior immune therapies have developed this side 
effect. The pituitary gland is considered the “master gland” which coordinates the function of your other 
glands such as your thyroid, adrenals, and gonads (ovaries/testicles). If it does function properly (pituitary 
insufficiency) you may experience symptoms of 
• 
weakness 
• 
fatigue 
• 
loss of libido (lack of interest in sex) 
• 
You may need to take hormone replacement therapy to treat these or other symptoms. 
 
Another hormone called ACTH (a hormone secreted by the pituitary gland), excites the adrenal gland (a 
gland situated above the kidneys) to make steroids, particularly cortisol. If there is a decline in ACTH 
(ACTH deficiency) you may experience 
• 
weight loss 
• 
lack of appetite (anorexia) 
• 
weakness 
• 
nausea 
• 
vomiting 
• 
low blood pressure (hypotension). 
 
Stopping the study drug and using steroids to calm the immune system are effective in many cases of 
autoimmune disease, but there is a risk of chronic autoimmune disease requiring treatment for longer 
periods of time. We will monitor you closely for any signs of autoimmune conditions and treat you for them 
if necessary. Prior experience with other immunotherapy agents seems to indicate those who do develop 


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these autoimmune events may have a higher likelihood of their cancers responding to treatment, but it is 
not known if this is the case with indoximod. 
 
Note: Indoximod in combination with other agents could cause an exacerbation (worsening) of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
Possible Side Effects and Risks of the Temozolomide (Temodar) 
 
During the study you will receive an anti-cancer drug called temozolomide (Temodar). This drug is 
approved by the FDA. This drug is also given orally for 5 days every 28 days. This drug, like many other 
anti-cancer drugs, has side effects which include: 
 
Most common side effects (occur in 10% or more of patients): 
• 
Low white blood cell levels – increases risk of infection (Pneumocystis jirovecii 
pneumonia) 
• 
Low platelet levels – increases risk of bleeding 
• 
Nausea/ Vomiting 
• 
Diarrhea 
• 
Generalized fatigue or weakness 
• 
Hair loss 
• 
Fluid retention in ankles or abdomen 
• 
Headache 
 
Less common side effects (occur in <10% of patients): 
• 
Allergic-type reaction, may include flushing, rash, itching. 
• 
Abnormalities in liver function levels as determined by blood tests 
• 
Muscle pain 
• 
Joint pain 
• 
Low red blood cell levels – increases risk of anemia and the need for blood transfusions 
• 
Sleeping disturbance 
• 
Upper respiratory tract infection. 
 
Rare side effects (<1% of patients): 
 
• 
Elevated liver enzymes. 
• 
Secondary malignancies like leukemia. 
 
To avoid the problem of pneumocystis jirovecii pneumonia, your study doctor may ask you to take an 
antibiotic while taking temozolomide. 
 
Unknown Risks 
 
You might have side effects or discomforts that are not listed in this form. Some side effects may not be 
known yet. New ones could happen to you. Tell the study doctor or study staff right away if you have any 
problems. 
 
Risks associated with standard care and alternative treatment: 


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As with any medication or chemotherapy treatment, there may be risks, known or unknown. The most 
common temporary side effects for some chemotherapy drugs may include: 
 
• 
Nausea and vomiting 
• 
Loss of appetite 
• 
Hair loss 
• 
Mouth sores 
• 
Higher risk of infection (due to decreased white blood cells) 
• 
Bruising or bleeding 
• 
Fatigue (feeling tired) 
• 
Changes in your menstrual cycle if you are female (e.g. irregular periods to symptoms of 
menopause [end of menstruation]) 
 
A more complete listing of side effects for other therapies may be available for you to review if you wish. 
Please talk with your study doctor about the risks of both this experimental therapy and any alternative 
methods of treatment that are available. 
 
We will tell you as soon as we can, if we find out more information about the side effects that are 
caused by the experimental drug. During the course of this study, we may find out more information that 
could be important to you. This includes information that, once learned, might cause you to change your 
mind about your willingness to be in this study. We will notify you as soon as possible if such information 
becomes available. 
Is there any risk to your unborn children if you take part in this study? 
For Females: 
If you are pregnant, you may not participate in this study, because there may be risks to you and your unborn 
baby. Breastfeeding (nursing) mothers will not be included in this study, since it is not known whether the 
drugs in this study will be passed on to the baby in the mother’s milk. If you are currently breastfeeding 
and wish to continue, your study doctor may recommend another treatment. 
 
If you are a female of childbearing potential (able to become pregnant), you will be given a pregnancy 
test at no cost to you before beginning any study treatment. 
 
Tell one of the study doctors right away if: 
• 
You are pregnant 
• 
You get pregnant 
• 
You are breastfeeding 
 
If you are male: 
We do not know what the study drug will do to your sperm. Should you get a woman pregnant, there could 
be harm to the unborn baby. You and your partner should use at least one effective birth control method 
(two are preferable when possible) if you are having sexual intercourse with a woman of childbearing 
potential. 
 
For males and females: 
Whether you are male or female, there may be risks to your unborn children. If you take part in this study, 
you must use at least one effective birth control method (two are preferable when possible) as discussed 
with your study doctor. Examples of acceptable birth control methods include: 
• 
Oral birth control pills 


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• 
Birth control patch 
• 
Implanted (injectable contraceptive hormones or mechanical products such as intrauterine device) 
• 
Barrier methods (diaphragm, condoms, spermicidal) 
• 
Tubal ligation or vasectomy 
• 
Abstinence 
 
Certain birth control methods may not be a good choice for you (for example some patients with breast 
cancer should not use birth control methods that contain hormones). You should discuss the method of birth 
control which is best for you to use both during study treatment and for a period of time after study 
treatment. Also, if you are a sexually active male or premenopausal female, the study staff will review your 
birth control use at each study visit. Use of contraception or abstinence should continue for a minimum of 
one month after completion of the study. 
 
Please place your initials in the appropriate box below: 
 
 
I am surgically sterile (hysterectomy, tubal ligation or vasectomy) or have gone through menopause 
(no period for 24 consecutive months). 
 
 
I understand and agree to use contraception during study treatment and for the time recommended 
by my study doctor and for at least one month after study treatment is over. 
 
 
Whether you are female or male, you should tell your study doctor immediately if you become pregnant or 
if your partner becomes pregnant. The long-term effects of the study treatment on fertility are unknown. 
This means that it is unknown if study treatment with these medications will affect your ability to have 
children in the future. 
 
Compensation for injury 
 
If you become ill or are hurt while you are in the study, get the medical care that you need right away. 
 
Sponsor Compensation 
 
Your safety is the major concern of every member of the research team. If you experience physical injury 
or illness as a result of participating in this research study, the sponsor will reimburse you for reasonable 
and necessary medical expenses when the injury is found to be the result of the study drug used as indicated 
in the research plan and is not the result of negligence or misconduct of any agent or employee of 
<<CLINICAL INSTITUTION>>>. Financial compensation for lost wages or other non-medical costs will 
not be provided. Agreeing to participate in this study and signing this document does not waive your rights 
in the event of negligence on the part of the Hospital or research staff. 
 
You still have the right to seek compensation for injury related to malpractice, negligence, fault, guilt or 
blame of those involved in the research. 
 
VOLUNTARY PARTICIPATION/STUDY WITHDRAWAL 
Your participation in this study is voluntary. You may refuse to take part and/or decide to withdraw consent 
and stop participating in the study at any time. You will not have any penalties and you will not lose any 
benefits that you currently have at this site. 


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Your decision will not affect your usual medical care. Your decision will not affect your relationship with 
the study doctor or this institution in any way. If you choose not to take part, you will still be offered all 
available care that meets your needs and disease. If you choose to stop the study, you will still have all 
available care that meets your needs and disease. 
 
Your taking part in this study may be stopped at any time without your consent. Your study doctor or 
someone authorized by the sponsor may stop you from taking part in this study: 
• 
If you do not follow the study doctor's instructions 
• 
If we find out you should not be in the study 
• 
If the study is limited or stopped 
• 
For medical reasons, such as if it becomes harmful to your health to continue 
 
If you decide to withdraw consent and stop your part in the study, please contact <<<PRINCIPAL 
INVESTIGATOR>>> or one of the study staff who will tell you what you should do before leaving the 
study. You may be asked to return to the clinic for follow-up care. You may be asked to have laboratory 
tests, or physical examinations that the study doctor feels are necessary. Until you withdraw your 
permission, additional information may continue to be taken from your medical records for study follow- 
up purposes. 
 
Privacy Notice 
The researchers are asking for your written authorization before using your health information or sharing it 
with others in order to conduct the research as described. However, under certain circumstances, the 
researchers may use and disclose your health information without your written authorization if they obtain 
approval through a special process to ensure that research without your written authorization poses minimal 
risk to your privacy. Under no circumstances, however, would the researchers allow others to use your 
name or identity publicly. 
 
The researchers may also disclose your health information without your written authorization to people 
who are planning a future research project, so long as any information identifying you does not leave our 
facility. 
 
Information about people who have died may be shared with researchers using the information of deceased 
persons, as long as the researchers agree not to remove from our facility any information that identifies 
these individuals. 
 
Confidentiality 
Only the investigator, the members of the research team, the sponsor (NewLink Genetics Corporation), 
authorized officials from state and federal governments such as the Food and Drug Administration (FDA) 
or the Office of Human Research Protections (OHRP), governmental agencies in other countries where the 
study drug may be considered for approval, and authorized representatives of the <<<CLINICAL 
INSTITUTION>>> will have access to confidential data which would identify you, unless specifically 
required to be disclosed by state or federal law. 
 
Because of the need to release information to these parties, absolute confidentiality cannot be guaranteed. 
The results of this study may be presented at meetings or in publications. However, you will not be 
identified in any reports or publications resulting from the study. All reasonable steps will be taken to 
ensure confidentiality. 
 
Description of the right to access medical records 


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You will not be able to review your study-related records while the study is in progress. However, you will 
be able to review your medical records after the research study has been completed. This authorization has 
no expiration date. 
 
Who to contact during the study for questions 
<<<PRINCIPAL INVESTIGATOR>>> or one of the other study doctors can be reached at XXX-XXX- 
XXXX, 24 hours a day, seven days a week and will answer any further questions you may have at any time 
concerning the study or any problems you may be having. 
 
If you have any questions or concerns about the “rights of research subjects”, you may contact the 
<<<CLINICAL INSTITUTION>>> of Human Research Protection at XXX-XXX-XXXX. 
 
Authorization to Use or Disclose (Release) Health Information that Identifies You for a Research 
Study 
 
Use and Sharing of Study Data That Identify You: HIPAA Authorization to Use and Disclose Your 
Protected Health Information 
By signing this form, you authorize <<<CLINICAL INSTITUTION, PRINCIPAL INVESTIGATOR>>> 
and their study staff to use and disclose your Protected Health Information in connection with this Study as 
further described in this authorization. This authorization is designed to comply with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA) and its implementing regulations; namely, the Privacy 
Rule. 
 
What is Protected Health Information? Protected Health Information or “PHI” are records that identify you 
which are created or collected in the course of this study. This PHI may include, but is not limited to, your 
name, address, telephone number, date of birth, government-issued identification number, and medical 
records and charts, including the results of all tests and procedures performed during this study. 
 
For what purposes can your PHI be used or disclosed by the study doctor or staff? Your PHI may be used 
or disclosed by the study doctor or staff in order to conduct this study, as necessary for your study-related 
treatment or payment for such treatment, to allow the Institution to conduct its normal business operations, 
and to ensure that information relating to this study is available to the parties that need it for study purposes. 
Another type of disclosure may be to regulatory authorities (e.g., the U.S. Food and Drug Administration 
[FDA]), Institutional Review Boards or other persons required by law to properly conduct and monitor this 
study, including those verifying the proper collection of study data. PHI may also be used by the study 
doctor or staff to determine your health, vital status or contact information should you withdraw from 
treatment or are lost to follow-up. 
 
With whom will the study doctor and staff share your PHI? Your PHI may be shared with the following 
persons or organizations: 
• 
Domestic and foreign regulatory/health authorities, e.g., the U.S. Food and Drug Agency (FDA) 
• 
Affiliated Institutional Review Boards or Independent Ethics Committees and privacy boards 
• 
NewLink Genetics Corporation (the sponsor) 
• 
Health care providers who provide services to you in connection with this study 
• 
Other individuals and organizations that analyze or your health information in connection with this 
study, such as laboratories and other study sites participating in this study 
• 
Other individuals and organizations that assist in determining your health, vital status or contact 
information should you withdraw from treatment or are otherwise lost to follow-up 


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Will the PHI disclosed per this authorization be re-disclosed? Please be aware that after disclosure by the 
Institution, study doctor, or study staff, there is the possibility that your PHI may be shared with other 
entities and may no longer be protected by applicable privacy laws and regulations. 
 
What rights do you have to review your PHI? You have the right to request access to your PHI from the 
study doctor named above, but to ensure proper evaluation of test results your access to these records may 
not be allowed until after this study has been completed. 
 
Does this authorization expire and can you revoke authorization for the use and disclosure of your PHI? 
This authorization does not expire. However, you may revoke it by providing written notice to the study 
doctor that you are revoking the Institution’s, study doctor’s and study staff’s authorization to use or 
disclose your protected health information/PHI. If you revoke this authorization, you will not be allowed 
to continue your participation in this study and neither the Institution, the study doctor, nor the study staff 
will be able to use or disclose your PHI generated from this study except to the extent that they or the study 
sponsor has already relied on this information to conduct the study. 
 
Can you refuse to sign this authorization? You have the right to refuse to sign this consent, but you will 
not be allowed to participate in this study. In addition, while your doctor and other treatment providers 
cannot require you to sign this authorization as a condition of providing general treatment, they may require 
it for study-related treatment. 
 
Please note that you may change your mind and revoke (take back) this Authorization in writing, at any 
time. Even if you revoke your Authorization, <<<PRINCIPAL INVESTIGATOR>>> and the study staff 
may still use or disclose your information they already have obtained about you as necessary to maintain 
the integrity or reliability of the current research. To revoke this Authorization, you must write to: 
<<<PRINCIPAL INVESTIGATOR, INSTITUTION, ADDRESS>>> 
 
This Authorization does not have an expiration date. 
 
STATEMENT OF SUBJECT CONSENT 
 
I have read this form and its contents were explained to me. I agree to be in this research study for the 
purposes listed above. All of my questions were answered to my satisfaction. I will receive a signed and 
dated copy of this form for my records. I am not giving up any of my legal rights by signing this form. 
 
 
Printed Name of Research Subject 
 
  
/  
/  
 
 
Signature of Research Subject 
Date 
 
 
STATEMENT OF SUBJECT CONSENT/PARENTAL PERMISSION 
 
This study has been explained to me. I voluntarily agree to allow my child to take part in this study. I have 
had the opportunity to ask questions. I understand that the doctors listed in this form can answer future 
questions I may have about this study and my child’s rights. By signing this form I understand that I am 
not giving up any of the patient rights. I understand that signing this consent does not take the place of any 
other consents I have signed. I understand that I will be given a copy of this consent to keep. 
 
 


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Parent/Guardian Signature (if patient < 18 yrs) 
(Date) 
 
 
 
Parent/Guardian Printed Name (if patient < 18 yrs)          (Date) 
 
 
Witness Statement (required for all subjects) 
 
My signature indicates that I was present during the entire informed consent process interview and that the 
information in the form was presented and reviewed with the subject and that informed consent was freely 
given by the subject or the subject’s legally authorized representative. 
 
My signature also indicates that I was present when the subject signed this form. 
 
  
/  
/  
 
 
Signature of Witness 
Date 
 
 
Printed Name of Witness 
 
STATEMENT OF PERSON EXPLAINING CONSENT 
 
I have carefully explained to the subject the nature and purpose of the above study. There has been an 
opportunity for the subject to ask questions about this research study. I have been available to answer any 
questions that the subject has about this study. 
 
  
/  
/  
 
 
Signature of Person Explaining Consent 
Date 
 
 
Printed Name of Person Explaining Consent 
 
INVESTIGATOR STATEMENT 
I acknowledge that I have discussed the above study with this participant and answered all of his/her 
questions. They have voluntarily agreed to participate. I have documented this action in the subject’s 
medical record source documents or research chart source documents, as applicable. A copy of this signed 
document will be placed in the subject’s medical record or research chart, as applicable. A copy of this 
document will be given to the subject or the subject’s legally authorized representative. 
 
 
 
Printed name of Investigator obtaining consent 
 
  
/  
/  
 
 
Signature of Investigator obtaining Consent 
Date 


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Appendix E: Sub-Study Consent Form Template 
 
Addendum to the Consent 
Consent to take and store additional blood samples 
 
The use of ‘you’ throughout this document refers to the research subject as an adult or child. If the research subject is less than 
18 years old, the subject’s parent or legal guardian must provide written consent for the child to participate in this study. 
 
 
We are asking you to allow us to take and store an additional sample of your blood. This is an optional test 
that may help us better understand who will respond to treatment with indoximod. 
 
This means we will take an additional 18 mL (about 3½ teaspoons) of blood to be stored for subsequent 
(later) genetic analysis of an enzyme that is released in tumors, called IDO enzyme. The IDO enzyme is an 
immune suppressing enzyme released by the tumor and indoximod seems to block this enzyme. 
 
These samples may be stored at NewLink Genetics Corporation within a climate controlled, restricted 
access area requiring key cards for entry. These samples will be used for future research to help us better 
understand who may respond to treatment with indoximod. 
 
These samples will only have subject identifiers consisting of your initials followed by your study subject 
number (XX-111). No one except your physician or clinical research team will be able to connect your 
coded health information to you. 
 
You can decide if you want us to store and use your samples for this future analysis of the IDO enzyme. 
 
You do not have to agree to these optional samples of blood in order to take part in the study that has been 
previously explained to you. 
 
Please initial your choice below: 
 
  
 I give my consent to provide an additional 18 mL of blood for that purpose on the first day of each 
treatment cycle. 
 
  
 I do not give my consent to provide an additional 18 mL of blood for that purpose. 
 
Even if you sign this consent, you have the right to withdraw your samples at any time. To do so, please 
submit a written request to Dr. XXXXXXX at: 
Attn: Principal Investigator, MD 
Institution Name 
Address 
City, State Zip 
 
STATEMENT OF SUBJECT CONSENT 
 
I have read this form and its contents were explained to me. I agree to be in this research sub-study for the 
purposes listed above. All of my questions were answered to my satisfaction. I will receive a signed and 
dated copy of this form for my records. I am not giving up any of my legal rights by signing this form. 
 
 
Printed Name of Research Subject 


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/  
/  
 
 
Signature of Research Subject 
Date 
 
 
STATEMENT OF SUBJECT CONSENT/PARENTAL PERMISSION 
 
This study has been explained to me. I voluntarily agree to allow my child to take part in this study. I have 
had the opportunity to ask questions. I understand that the doctors listed in this form can answer future 
questions I may have about this study and my child’s rights. By signing this form I understand that I am 
not giving up any of the patient rights. I understand that signing this consent does not take the place of any 
other consents I have signed. I understand that I will be given a copy of this consent to keep. 
 
 
Parent/Guardian Signature (if patient < 18 yrs) 
(Date) 
 
 
 
Parent/Guardian Printed Name (if patient < 18 yrs)          (Date) 
 
 
STATEMENT OF PERSON EXPLAINING CONSENT 
 
I have carefully explained to the subject the nature and purpose of the above sub-study. There has been an 
opportunity for the subject to ask questions about this research sub-study. I have been available to answer 
any questions that the subject has about this sub-study. 
 
  
/  
/  
 
Signature of Person Explaining Consent 
Date 
 
 
Printed Name of Person Explaining Consent 

SAP_001.pdf: 
NewLink Genetics Corporation 
 
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 NewLink Genetics Corporation 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title: 
A Phase 1/2 Study of the Combination of Indoximod and 
Temozolomide for Adult Patients with Temozolomide-
Refractory Primary Malignant Brain Tumors 
 
 
 
Protocol Number: 
NLG-2102 
Phase: 
Phase 1/2 
Sponsor: 
NewLink Genetics Corporation, 
Iowa State University Research Park, 
2503 South Loop Drive, Suite 5100, 
Ames, Iowa, USA 50010 
 
Author: 
Summit Analytical, LLC 
8354 Northfield Blvd., Bldg. G Suite 3700 
Denver, CO 80238 
 
SAP Date: 
2019-09-18 
Status: 
FINAL V1.0 
 
 




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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ............................................................................................................................... 3 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS................................................................... 6 
3. 
INTRODUCTION ......................................................................................................................................... 8 
3.1. 
Preface .............................................................................................................................................. 8 
3.2. 
Purpose of Analyses .......................................................................................................................... 8 
3.3. 
Summary of Statistical Analysis Changes to the Protocol ................................................................ 8 
4. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................... 10 
4.1. 
Study Objectives ............................................................................................................................. 10 
4.1.1. 
Primary Objective ......................................................................................................... 10 
4.1.2. 
Secondary Objectives .................................................................................................... 10 
4.2. 
Study Endpoints .............................................................................................................................. 10 
5. 
STUDY METHODS .................................................................................................................................... 12 
5.1. 
Overall Study Design ...................................................................................................................... 12 
5.2. 
Randomization and Blinding........................................................................................................... 17 
5.3. 
Analysis Variables .......................................................................................................................... 17 
6. 
SAMPLE SIZE ............................................................................................................................................ 17 
7. 
GENERAL CONSIDERATIONS ............................................................................................................... 18 
7.1. 
Analysis Populations ....................................................................................................................... 18 
7.1.1. 
Safety ............................................................................................................................ 18 
7.1.2. 
Intent-to-Treat ............................................................................................................... 18 
7.1.3. 
Efficacy Evaluable (EE) ................................................................................................ 18 
7.2. 
Covariates and Subgroups ............................................................................................................... 18 
7.3. 
Management of Analysis Data ........................................................................................................ 18 
7.3.1. 
Data Handling ............................................................................................................... 18 
7.3.2. 
Missing Data ................................................................................................................. 19 
7.3.2.1. 
Handling of Missing Date Values ............................................................ 19 
7.3.2.2. 
Imputation Methods ................................................................................. 19 
7.3.3. 
Handling of Early Termination Visit Information ......................................................... 19 
7.3.4. 
Pooling of Investigational Sites ..................................................................................... 19 
7.3.5. 
Coding Conventions for Events and Medications ......................................................... 20 
7.3.6. 
Baseline ......................................................................................................................... 20 
7.3.7. 
Analysis Software ......................................................................................................... 20 
7.3.8. 
Study Data ..................................................................................................................... 20 
7.4. 
Planned Study Analyses .................................................................................................................. 21 
7.4.1. 
Statistical Summaries: Descriptive and Inferential ....................................................... 21 
7.4.2. 
Interim Analyses and Data Safety Monitoring .............................................................. 22 
7.4.3. 
Final Analysis ............................................................................................................... 22 
7.5. 
Multiple Testing Procedures ........................................................................................................... 22 
8. 
SUMMARY OF STUDY DATA ................................................................................................................ 22 
8.1. 
Patient Summary Grouping ............................................................................................................. 22 
8.2. 
Patient Disposition .......................................................................................................................... 22 
8.3. 
Protocol Deviations ......................................................................................................................... 22 
8.4. 
Demographics and Baseline Cancer Characteristics ....................................................................... 23 




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LIST OF TABLES 
 
Table 1. Dose Levels (Phase 1 portion) .................................................................................................... 12 
  
 
 
 
 








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However, historical control is not available. This SAP will not make comparison between study 
data and historical control, and that specific secondary endpoint will be removed. 
Protocol specifies that the Efficacy Evaluable population is the population to be used for 
efficacy analysis, and this SAP adds the ITT population as another population for efficacy 
analyses. Further, this SAP refines the definition of Efficacy Evaluable population as subjects 
who have received at least one dose of study drug and at least one post-baseline RANO 
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4. 
STUDY OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints defined in the protocol include safety and efficacy. Objectives 
and pre-specified endpoints are as follows: 
4.1. 
Study Objectives 
4.1.1. 
Primary Objective 
Phase 1 component: To determine the recommended Phase 2 doses (RP2D) of indoximod and 
temozolomide in combination for treatment of progressive high-grade glioma (including 
glioblastoma multiforme (GBM)) or gliosarcoma. 
 
Phase 2 component: To evaluate efficacy as measured by six-month progression-free survival 
(PFS) of indoximod plus temozolomide (with or without bevacizumab or stereotactic radiation 
therapy) in patients with progressive GBM. 
 
4.1.2. 
Secondary Objectives 
 
Phase 1: 
1. To determine the adverse event (AE) profile and identify regimen-limiting toxicities 
(RLT) of indoximod plus temozolomide in combination therapy. 
2. To determine the pharmacokinetic profile of indoximod in the setting of this treatment 
regimen. 
 
Phase 2: 
1. To determine efficacy as measured by overall response rate (ORR), overall survival, 
safety, and tolerability of indoximod plus temozolomide in patients with progressive 
GBM. 
2. To determine ORR, safety, and tolerability of indoximod plus temozolomide and 
bevacizumab in GBM patients whose disease progressed during therapy with a 
bevacizumab-based regimen. 
3. To determine ORR, safety, and tolerability of indoximod plus temozolomide and 
stereotactic radiosurgery (SRS) in GBM patients who may reasonably benefit from 
tumor debulking.  
 
4.2. 
Study Endpoints 
 
Phase 1 Primary Endpoint: 
The primary endpoint of Phase 1 is Regimen Limiting Toxicity for the purpose of the 
 
will be based on the dose escalation method. 
 
Phase 1 Secondary Endpoints: 


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The secondary endpoints of Phase 1 include: 
- Incident rates of AEs 
- Incident rates of SAEs 
- Incidents of RLTs 
- Frequency with which laboratory tests are out of normal ranges 
- Vital Signs including blood pressure, pulse and temperature. 
- Total dose of temozolomide delivered 
- Number of patients with grade 3 non-hematological toxicity that is treatment related 
that results in  
- the delay of temozolomide treatment by greater than 4 weeks.  
- a delay in starting the second cycle by more than 2 weeks due to toxicity 
attributable to test agent indoximod. 
- Number of subjects experiencing dose modification in each of the prescribed study 
drugs. 
- Pharmacokinetics (PK) (specified in a separate document). 
 
Phase 2 Primary Endpoint: 
The primary endpoint of Phase 2 is 6-month PFS.  
 
Phase 2 Secondary Endpoints: 
 
The secondary efficacy endpoints for Phase 2 include  
- Best overall response,  
- Proportion of subjects who reached stable disease (SD) and maintained as such, 
- Overall survival (OS). 
- Incident rates of AEs 
- Incident rates of SAEs 
- Frequency with which laboratory tests are out of normal ranges 
- Vital Signs including blood pressure, pulse and temperature. 
- Total dose of temozolomide delivered 
- Number of subjects experiencing dose modification in each of the prescribed study 
drugs. 
 
 






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responses will be assessed based using Response Assessment in Neuro-Oncology (RANO) 
criteria. 
 
Safety will be evaluated by following the guidelines provided in the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. 
 
 
 














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Figure 1 
SDTM, ADaM, and TFL Development and Validation 
 
Where: 
1. Development, Validation, and Maintenance of SDTM domains. 
2. Development and Validation of Analysis Data Sets (ADaM), with input source the 
appropriate SDTM domains. 
3. Development and Validation of draft and then final Tables, Figures, and Listings 
(TFL), with input data source the SDTM domains and analysis specific ADaM data 
sets. 
7.4. 
Planned Study Analyses 
7.4.1. 
Statistical Summaries: Descriptive and Inferential 
In general, inferential statistical analyses will be two-sided, and a difference resulting in a p-
value of less than or equal to 0.05 will be considered statistically significant. All p-values will 
be rounded to and displayed in four decimals.  If a p-value less than 0.0001 occurs, it will be 
shown in tables as <0.0001. 
Descriptive summaries of variables will be provided where appropriate. In general, for 
continuous variables, the number of non-missing values (n) and the mean, median, standard 
deviation, minimum, and maximum will be tabulated.  For categorical variables, the counts 
and proportions of each value will be tabulated.   


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All collected data will be presented in listings.  Data not subject to analysis according to this 
plan will not appear in any tables or graphs but will be included in the data listings. 
7.4.2. 
Interim Analyses and Data Safety Monitoring  
No interim analysis is planned for this study. This trial will use a Data Safety Monitoring 
Committee (DSMC) during Phase 2.  The DSMC will meet quarterly.  
7.4.3. 
Final Analysis 
The final study analysis will be completed after all patients have completed their end of therapy 
visit days and the database has been locked.  
7.5. 
Multiple Testing Procedures 
There will be no adjustments for multiplicity and no formal multiple testing procedures are to 
be implemented with this analysis plan. 
 
8. 
SUMMARY OF STUDY DATA 
8.1. 
Patient Summary Grouping 
All tables and listings will be presented by actual dose level administrated and overall for Phase 
1 dose escalation. The planned dose cohorts are starting at 600 mg BID for up to 6 patients, 
then followed by 1000 mg BID and 1200 mg BID if needed. Screen failure patients are not 
included in analysis sets. Patients who withdraw from the study prior to dosing may be replaced 
but will not be replaced after dosing. Phase 1 and Phase 2 will be presented separately. In 
addition, as each cohort in the Phase 2 expansion is enrolled separately and has potentially 
different expected rates of PFS, each cohort in Phase 2 will also be reported separately.  
 
8.2. 
Patient Disposition 
Patient disposition will be summarized and will include the number and percentage of patients 
included in the Safety, ITT and EE populations. The reasons for withdrawal for the patients 
who discontinue treatment and discontinue the study will also be summarized. All results will 
be presented for each phase, dose and cohort.  
Data on study completion information, including the reason for treatment discontinuation and 
study discontinuation will be presented in a patient listing. 
8.3. 
Protocol Deviations 
All subject-level protocol violations will be presented in a patient listing.  


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8.4. 
Demographics and Baseline Cancer Characteristics  
Descriptive summaries of patient demographics will be provided including age, sex, race, and 
ethnicity baseline ECOG score, weight, height, body mass index (BMI), defined as weight (kg) 
/ height(m)^2.  All demographic and baseline cancer characteristics will be summarized for 
each phase, dose and cohort using the ITT and EE populations. 
 
All demographic and baseline information will be presented in a patient listing. 
8.5. 
Medical History and Cancer Status 
Patient medical history along with their cancer status will be collected during the screening 
period.  
The number and percentage of patients with any medical history will be summarized overall 
and for each system organ class (SOC) and preferred term (PT). Details on cancer status will 
also be summarized.   
Baseline cancer status including current tumor type, location and grade, time from initial 
brain tumor diagnosis to date of ICF, number of prior tumor relapses and resection, radiation 
type and duration, site radiated, total radiation dose, prior treatment with interstitial 
brachytherapy, stereotactic radiosurgery or implanted chemotherapy sources, 
progression/recurrence after this treatment, method to confirm progressive disease and 
surgery data 
Medical history, as well as cancer status, will be summarized for each phase, dose and cohort 
using the ITT and EE populations. 
Patient medical history and cancer status data will be presented in a patient listing. 
8.6. 
Concomitant Medications  
All medications taken by subjects at the time of enrollment or then after will be reported. The 
number and percentage of patients who take concomitant medications will be summarized in 
tables by Anatomical Therapeutic Chemical (ATC) level IV and preferred term.   
For all medication tables, medications will be counted once for a patient using it, regardless of 
the number of times it was reported on the eCRF.  
A concomitant medication is defined as any medications taken or ongoing on or after first dose 
date up to last visit after the last dose.. 
Concomitant medications will be summarized for each phase, dose and cohort using the ITT 
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10.2. 
Adverse Events  
Treatment-emergent adverse events (TEAEs) are defined as any AEs occurred on or after first 
dose date or worsening of existing events up to 30 days post last dose.  
 
TEAEs are summarized by frequency and percentage of patients and tabulated by SOC and 
PT, by greatest relationship to indoximod, to temozolomide, to bevacizumab, and to SRS/SRT 
respectively, by maximum Severity grade. Serious adverse events (SAEs), TEAEs leading to 
treatment discontinuation and death are summarized. Patients with multiple TEAEs are only 
counted once within a summary category.  
 
AE Severity grade will be assessed using the CTCAE grading.  
 
The following summary tables and patient level listings will be presented for TEAE data:  
• 
Overall Summary of AEs 
• 
TEAEs by SOC and PT 
• 
TEAEs by SOC and PT, and Relationship to indoximod, temozolomide, 
bevacizumab and SRS/SRT separately. 
 
• 
TEAEs by SOC and PT, and Maximum Severity Grade 
• 
SAEs by SOC and PT 
 
All AEs including both treatment-emergent and non-treatment-emergent events will be 
presented in patient listings. 
 
10.3. 
Regimen Limiting Toxicity 
RLTs, which are only reported for Phase 1, are defined as toxicities that delay the planned 
administration of the next cycle of the backbone chemotherapy. Toxicity grades are evaluated 
according to NCI CTCAE version 4.03.   
 
RLTs will be presented in a patient listing. 
 
10.4. 
Vital Signs, ECG, Laboratory Tests and Physical Examinations 
 
Vital signs, ECG, laboratory results, ECOG, physical examination will be summarized by visit, 
overall and by phase, dose and cohort.  
10.4.1. 
Vital Signs 
Descriptive statistics of observed vital sign data and change from baseline will be presented by 
visit, including systolic blood pressure, diastolic blood pressure, temperature, heart rate and 
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All vital sign data will be summarized using the Safety population and will be presented in 
patient listings.  
10.4.2. 
ECG 
ECG observed data and change from baseline including heart rate, PR interval, QRS duration, 
QTc interval will be presented by visit, overall and by phase, dose and cohort.  
 
All ECG data will be summarized using the Safety population and will be presented in patient 
listings.  
10.4.3. 
Clinical Laboratory Evaluations  
Clinical laboratory results including hematology, blood chemistry will be summarized by visit, 
overall and by phase, dose and cohort for the observed value as well as for change from 
baseline value. Other parameters such as c-reactive protein, endocrine functions, thyroid 
evaluation and TSH, T3, T4 evaluation will only be listed and not summarized.     
Patient listings of individual laboratory parameters with normal ranges and abnormality 
assessments will also be presented by patient.  Laboratory listings will include date collected, 
study day and observed laboratory values with low/normal/high or abnormal/normal flags.  
All laboratory will be presented using the Safety population. 
10.4.4. 
Physical, and ECOG Scale 
Anthropometrics data including height and weight and BSA, and their change from baseline 
will be summarized by visit, overall and by phase, dose and cohort. ECOG scores will be 
summarized by using actual scores and changes from baseline, by visit, overall and by phase, 
dose and cohort.  
All physical, ECOG data will be summarized using the Safety population and will be presented 
in patient listings. 
10.5. 
Other Safety Measures 
All other safety data will be presented in listings.  
If additional safety measures not described herein are requested after study results are 
reviewed, these additional safety parameters and/or analyses will be completed and will be 
fully described and documented as post-hoc in the final clinical study report (CSR).   The SAP 
will not be amended to complete any other safety measures identified as post-hoc. 
 
11. 
PHARMACOKINETIC ANALYSES  
 


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PK summaries will be captured in a separate SAP. 
 
12. 
REPORTING CONVENTIONS 
 
The following reporting conventions will be adopted for the presentation of study data.  These 
conventions will enhance the review process and help to standardize presentation with 
common notations 
 
11.1 
General Reporting Conventions 
• 
All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a CSR, where they may be in Landscape or 
Portrait Orientation. 
• 
Figures will be presented in Landscape Orientation, unless presented as part of 
the text in a CSR, where they may be in Landscape or Portrait Orientation. 
• 
Legends will be used for all figures with more than one variable or item 
displayed. 
• 
Figures will be in presented in color with dose cohorts distinguished by 
different symbols and colors.  Lines in figures should be wide enough to view 
the line after being photocopied.  
• 
Specialized text styles, such as bolding, italics, borders, shading, superscripted 
and subscripted text will not be used in tables, figures, and data listings unless 
they add significant value to the table, figure, or data listing.  
• 
Only standard keyboard characters should be used in tables and data listings. 
Special characters, such as non-printable control characters, printer-specific, 
or font-specific characters, will not be used on a table, figure, or data listing.  
Hexadecimal character representations are allowed (e.g., µ, α, β). 
• 
All titles will be centered on a page.  The International Council for 
Harmonization (ICH) numbering convention is to be used for all tables, 
figures, and data listings. 
• 
All footnotes will be left justified and at the bottom of a page.  Footnotes must 
be present on the page where they are first referenced.  Footnotes should be 
used sparingly and must add value to the table, figure, or data listing.  If more 
than four footnote lines are planned, then a cover page may be used to display 
footnotes. 
• 
Missing values for both numeric and character variables will be presented as 
blanks in a table or data listing.  A zero (0) may be used if appropriate to 
identify when the frequency of a variable is not observed. 
• 
All date values will be presented as YYYY-MM-DD (e.g., 2013-05-17) ISO 


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8601 format. 
• 
All observed time values will be presented using a 24-hour clock HH:MM:SS 
format (e.g., 01:35:45 or 11:26).  Seconds should only be reported if they 
were measured as part of the study, also in ISO 8601 format. 
• 
Time durations will be reported in mixed HH MM SS notation (e.g., 5h 32m, 
or 27h 52m 31s).  The use of decimal notation to present (display) time 
durations should be avoided (e.g. 0.083h = 5m) unless it is necessary to show 
the computation of time differences in a table, figure, or data listing, in which 
case both notations may be used to display the time duration.  
• 
All tables, figures, and data listings will have the Table, Listing, or Graph 
status (DRAFT, FINAL), and a date/time stamp on the bottom of each output.  
• 
All analysis programs developed for a table, figure, or data listing display will 
be self-contained to facilitate transfer of programs to multiple computing 
environments and transfer to a regulatory agency (if requested).  
11.2 
Population Summary Conventions 
• 
Population(s) represented on the tables or data listings will be clearly identified 
in the last title of the Table as “<name of population>” and will be identical in 
name to that identified in the protocol or SAP. 
• 
Consistent terminology will be used to define and identify a population.   
• 
Sub-population(s) or special population(s) descriptions will provide sufficient 
detail to ensure comprehension of the population (e.g., FAS Females, Per-
Protocol Males >60 years of age) used for analysis in a table or figure. 
• 
Population sizes may be presented for each treatment or dose cohort as totals in 
the column header as (N=xxx), where appropriate.  
• 
Population sizes shown with summary statistics are the samples sizes (n) of 
patients with non-missing values.  
• 
All population summaries for categorical variables will include all categories 
that were planned and for which the patients may have had a response.    
• 
All population summaries for continuous variables will include: N, mean, 
standard deviation, minimum, and maximum.  Other summaries (e.g. number 
missing, median, quartiles, 5%, 95% CIs, CV or %CV) may be used as 
appropriate. 
Unless otherwise noted, the estimated mean and median for a set of values are 
printed out to one more significant digit than the original values, and Standard 
Deviations are printed out to 2 more significant digits than the original values. 
The minimum and maximum will be reported the same significant digits as the 
original values. For example, for age: 


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N 
XX 
Mean 
XX.X 
Standard Deviation X.XX 
Median 
XX.X 
Minimum 
XX 
Maximum                 XX 
• 
All percentages are rounded and reported to xx.x%. A percentage of 100% will 
be reported as 100%.  No value of 0% will be reported.  Any computation of 
percent that results in 0% is to be presented as a blank.  
• 
Population summaries that include p-values will report the p-value to 
four decimal places with a leading zero (0.0001).  All p-values reported on 
default output from statistical software (i.e., SAS® Software version 9.4 or later) 
may be reported at the default level of precision.  P-values <0.0001 should be 
reported as <0.0001 not 0.0000. 
 
 


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12 
REFERENCES 
A'Hern, R. P, 'Sample size tables for exact single-stage phase II designs.' Statistics in 
Medicine, 20; 859-866 (2001). 
Friedman et al. J Clin Oncol. 2009 Oct 1;27(28):4733-40 
 
ICH E9 Expert Working Group. Statistical Principles for Clinical Trials: ICH Harmonized 
Tripartite Guideline., September 1998 
Kong et al. Cancer. 2008;112(9):2046.  
 
Perry et. al J Clin Oncol. 2010 Apr 20;28(12):2051-7 
 
 
 


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APPENDIX A PLANNED TABLES, LISTINGS, AND FIGURES 
Tables 
Table 14.1.1.1 Patient Disposition – Phase 1 All Enrolled 
Table 14.1.1.2 Patient Disposition – Phase 2 All Enrolled 
Table 14.1.2.1.1 Demographics and Baseline Characteristics – Phase 1 Intent-to-Treat 
Table 14.1.2.1.2 Demographics and Baseline Characteristics – Phase 1 Efficacy Evaluable 
Table 14.1.2.2.1 Demographics and Baseline Characteristics – Phase 2 Intent-to-Treat 
Table 14.1.2.2.2 Demographics and Baseline Characteristics – Phase 2 Efficacy Evaluable 
Table 14.1.3.1.1 Medical History – Phase 1 Intent-to-Treat 
Table 14.1.3.1.2 Medical History – Phase 1 Efficacy Evaluable 
Table 14.1.3.2.1 Medical History – Phase 2 Intent-to-Treat 
Table 14.1.3.2.2 Medical History – Phase 2 Efficacy Evaluable 
Table 14.1.4.1.1 Cancer Status at Screening – Phase 1 Intent-to-Treat 
Table 14.1.4.1.2 Cancer Status at Screening – Phase 1 Efficacy Evaluable 
Table 14.1.4.2.1 Cancer Status at Screening – Phase 2 Intent-to-Treat 
Table 14.1.4.2.2 Cancer Status at Screening – Phase 2 Efficacy Evaluable 
Table 14.1.5.1.1 Concomitant Medications – Phase 1 Intent-to-Treat 
Table 14.1.5.1.2 Concomitant Medications – Phase 1 Efficacy Evaluable 
Table 14.1.5.2.1 Concomitant Medications – Phase 2 Intent-to-Treat 
Table 14.1.5.2.2 Concomitant Medications – Phase 2 Efficacy Evaluable 
Table 14.1.6.1.1 Corticosteroid Administration – Phase 1 Intent-to-Treat 
Table 14.1.6.1.2 Corticosteroid Administration – Phase 1 Efficacy Evaluable 
Table 14.1.6.2.1 Corticosteroid Administration – Phase 2 Intent-to-Treat 
Table 14.1.6.2.2 Corticosteroid Administration – Phase 2 Efficacy Evaluable 
Table 14.1.7.1.1 Summary of Indoximod Administration – Phase 1 Safety Population 
Table 14.1.7.1.2 Summary of Indoximod Administration – Phase 1 Efficacy Evaluable 
Table 14.1.7.2.1 Summary of Indoximod Administration – Phase 2 Safety Population 
Table 14.1.7.2.2 Summary of Indoximod Administration – Phase 2 Efficacy Evaluable 
Table 14.1.8.1.1 Summary of Temozolomide Administration – Phase 1 Safety Population 
Table 14.1.8.1.2 Summary of Temozolomide Administration – Phase 1 Efficacy Evaluable 
Table 14.1.8.2.1 Summary of Temozolomide Administration – Phase 2 Safety Population 
Table 14.1.8.2.2 Summary of Temozolomide Administration – Phase 2 Efficacy Evaluable 
Table 14.1.9.1 Summary of Bevacizumab Administration – Phase 2 Safety Population 
Table 14.1.9.2 Summary of Bevacizumab Administration– Phase 2 Efficacy Evaluable 
Table 14.1.10.1 Summary of SRS/SRT Administration – Phase 2 Safety Population 
Table 14.1.10.2 Summary of SRS/SRT Administration – Phase 2 Evaluable Efficacy 
Table 14.1.11.1.1 Summary of Indoximod Dose Modification – Phase 1 Safety Population 
Table 14.1.11.1.2 Summary of Indoximod Dose Modification – Phase 2 Safety Population 
Table 14.1.11.2.1 Summary of Temozolomide Dose Modification – Phase 1 Safety Population 
Table 14.1.11.2.2 Summary of Temozolomide Dose Modification – Phase 2 Safety Population 


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Table 14.1.11.3.1 Summary of Bevacizumab Dose Modification -  Phase 2 Safety Population 
Table 14.2.1.1 Kaplan-Meier Estimates of Six-Month Progression-Free Survival (PFS6) [1] Summary – Phase 2 Intent
Table 14.2.1.2 Kaplan-Meier Estimates of Six-Month Progression-Free Survival (PFS6) [1] Summary – Phase 2 Effica
Evaluable 
Table 14.2.2.1 Overall Response Summary – Phase 2 Intent-to-Treat 
Table 14.2.2.2 Best Overall Response Summary – Phase 2 Efficacy Evaluable 
Table 14.2.3.1 Kaplan-Meier Estimates of Overall Survival (OS) [1] – Phase 2 Intent-to-Treat 
Table 14.2.3.2 Kaplan-Meier Estimates of Overall Survival (OS) [1] – Phase 2 Efficacy Evaluable 
Table 14.2.4.1 Life Table Summary of Duration of Best Overall Response (BOR) – Phase 2 Intent-to-Treat 
Table 14.2.4.2 Life Table Summary of Duration of Best Overall Response (BOR) – Phase 2 Efficacy Evaluable 
Table 14.2.5.1 Life Table Summary of Progression-Free Survival (Kaplan-Meier) – Phase 2 Intent-to-Treat 
Table 14.2.5.2 Life Table Summary of Progression-Free Survival (Kaplan-Meier) – Phase 2 Efficacy Evaluable 
Table 14.2.6.1 Life Table Summary of Duration of Stable Disease (Kaplan-Meier) – Phase 2 Intent-to-Treat 
Table 14.2.6.2 Life Table Summary of Duration of Stable Disease (Kaplan-Meier) – Phase 2 Efficacy Evaluable 
Table 14.2.7.1 Life Table Overall Survival (Kaplan-Meier) – Phase 2 Intent-to-Treat 
Table 14.2.7.2 Life Table Overall Survival (Kaplan-Meier) – Phase 2 Efficacy Evaluable 
Table 14.3.1.1.1 TEAEs: Overall Summary – Phase 1 Safety Population 
Table 14.3.1.1.2 TEAEs: Overall Summary – Phase 2 Safety Population 
Table 14.3.1.2.1 TEAEs by SOC and PT – Phase 1 Safety Population 
Table 14.3.1.2.2 TEAEs by SOC and PT – Phase 2 Safety Population 
Table 14.3.1.3.1 TEAEs by SOC and PT, and Greatest Relationship to Indoximod – Phase 1 Safety Population 
Table 14.3.1.3.2 TEAEs by SOC and PT, and Greatest Relationship to Indoximod – Phase 2 Safety Population 
Table 14.3.1.3.3 TEAEs by SOC and PT, and Greatest Relationship to Temozolomide – Phase 1 Safety Population 
Table 14.3.1.3.4 TEAEs by SOC and PT, and Greatest Relationship to Temozolomide – Phase 2 Safety Population 
Table 14.3.1.3.5 TEAEs by SOC and PT, and Greatest Relationship to Bevacizumab – Phase 2 Safety Population 
Table 14.3.1.3.6 TEAEs by SOC and PT, and Greatest Relationship to SRS/SRT – Phase 2 Safety Population 
Table 14.3.1.4.1 TEAEs by SOC and PT, and Maximum Severity Grade – Phase 1 Safety Population 
Table 14.3.1.4.2 TEAEs by SOC and PT, and Maximum Severity Grade – Phase 2 Safety Population 
Table 14.3.1.5.1 Serious Adverse Events by SOC and PT – Phase 1 Safety Population 
Table 14.3.1.5.2 Serious Adverse Events by SOC and PT – Phase 2 Safety Population 
Table 14.3.2.1.1 Table Listing of Serious Adverse Events – Phase 1 Safety Population 
Table 14.3.2.1.2 Table Listing of Serious Adverse Events – Phase 2 Safety Population 
Table 14.3.2.3.1 Table Listing of TEAEs Leading to Death – Phase 1 Safety Population 
Table 14.3.2.3.2 Table Listing of TEAEs Leading to Death – Phase 2 Safety Population 
Table 14.3.2.4.1 Table Listing of Death Summary – Phase 1 Safety Population 
Table 14.3.2.4.2 Table Listing of Death Summary – Phase 2 Safety Population 
Table 14.3.4.1.1 Observed Values and Change from Baseline for Hematology – Phase 1 Safety Population 
Table 14.3.4.1.2 Observed Values and Change from Baseline for Hematology – Phase 2 Safety Population 
Table 14.3.4.2.1 Observed Values and Change from Baseline for Blood Chemistry – Phase 1 Safety Population 
Table 14.3.4.2.2 Observed Values and Change from Baseline for Blood Chemistry – Phase 2 Safety Population 
Table 14.3.5.1.1 Observed Values and Change from Baseline for Vital Signs – Phase 1 Safety Population 
Table 14.3.5.1.2 Observed Values and Change from Baseline for Vital Signs – Phase 2 Safety Population 


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Table 14.3.5.2.1 Observed Values and Change from Baseline for Anthropometrics – Phase 1 Safety Population 
Table 14.3.5.2.2 Observed Values and Change from Baseline for Anthropometrics – Phase 2 Safety Population 
Table 14.3.5.3.1 Observed Values and Change from Baseline for ECG – Phase 1 Safety Population 
Table 14.3.5.3.2 Observed Values and Change from Baseline for ECG – Phase 2 Safety Population 
Table 14.3.5.4.1 Notable ECG Values and Changes from Baseline – Phase 1 Safety Population 
Table 14.3.5.4.2 Notable ECG Values and Changes from Baseline - Phase 2 Safety Population 
Table 14.3.5.5.1 ECG Shift from Baseline - Phase 1 Safety Population 
Table 14.3.5.5.2 ECG Shift from Baseline - Phase 2 Safety Population 
Table 14.3.5.6.1 ECOG Shift from Baseline to Maximum Score - Phase 1 Safety Population 
Table 14.3.5.6.2 ECOG Shift from Baseline to Maximum Score - Phase 2 Safety Population 
 
Listings 
Listing 16.2.1.1 Patient Disposition All Enrolled 
Listing 16.2.1.2 Eligibility, Inclusion and Exclusion Criteria All Enrolled 
Listing 16.2.2.1 Protocol Deviation Safety Population 
Listing 16.2.3.1 Demographics and Baseline Characteristics Safety Population 
Listing 16.2.3.2 Cancer Status at Screening Safety Population 
Listing 16.2.3.3 Prior Radiation Therapy Safety Population 
Listing 16.2.3.4 Prior Systemic Therapy Safety Population 
Listing 16.2.4.1 Medical History  Safety Population 
Listing 16.2.4.2 INR at Screening Safety Population 
Listing 16.2.5.1 Concomitant Medications Safety Population 
Listing 16.2.5.2 Concomitant Therapies/Procedures Safety Population 
Listing 16.2.5.3 Corticosteroid Administration Safety Population 
Listing 16.2.6.1 Indoximod Administration Safety Population 
Listing 16.2.6.2 Temozolomide Administration Safety Population 
Listing 16.2.6.3 Bevacizumab Administration Safety Population 
Listing 16.2.6.4 SRS/SRT Administration Safety Population 
Listing 16.2.7.1 Imaging Safety Population 
Listing 16.2.8.1 Target, Non-Traget Lesions Safety Population 
Listing 16.2.8.2 RANO Responses Safety Population 
Listing 16.2.9.1 Brain MRI Safety Population 
Listing 16.2.10.1 Post-Study Anti-Cancer Therapy Safety Population 
Listing 16.2.11.1 Adverse Events Safety Population 
Listing 16.2.11.2 Treatment-Emergent Adverse Events Leading to Indoximod/Temozolomide Dose Change Safety P
Listing 16.2.11.3 Treatment Emergent Adverse Events that are Other IMEs Safety Population 
Listing 16.2.11.4 Serious Adverse Events Safety Population 
Listing 16.2.12.1 Regimen Limiting Toxicity Evaluations for Phase 1 Safety Population 
Listing 16.2.13.1 Death Summary Safety Population 
Listing 16.2.14.1 Laboratory Tests - Hematology  Safety Population 
Listing 16.2.14.2 Laboratory Tests - Chemistry  Safety Population 
Listing 16.2.14.3 Laboratory Tests – TSH, T3, T4 Evaluation Safety Population 


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Listing 16.2.14.4 Laboratory Tests – C Reaction Protein Safety Population 
Listing 16.2.14.5 Endocrine function and Thyroid Evaluation 
Listing 16.2.15.1 Vital Signs Safety Population 
Listing 16.2.16.1 ECOG Score Safety Population 
Listing 16.2.17.1 ECG Results Safety Population 
Listing 16.2.18.1 Physical Examination Safety Population 
Listing 16.2.19.1 Weight amd Height Safety Population 
Listing 16.2.20.1 PK Sample Collection Safety Population 
 
Figures 
 
 
 
 
 


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APPENDIX B ECOG PERFORMANCE STATUS SCALE