A Phase II Basket Trial of Glutaminase Inhibitor (BEGIN) Telaglenastat (CB-839) HCL in Patients With NF1 Aberrations, NF1 Mutant Malignant Peripheral Nerve Sheath Tumors (MPNST), KEAP1/NRF2 and LKB1 Aberrant Tumors
Phase: PHASE2
Conditions: Advanced Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, NF1 Mutation Positive Malignant Peripheral Nerve Sheath Tumor, Unresectable Malignant Solid Neoplasm
Sponsor: National Cancer Institute (NCI)

i 
 
To: 
Cancer Therapeutics Evaluation Program 
 
From: Funda Meric-Bernstam, M.D. 
 
Date: January 3, 2025 
 
Re: Protocol Amendment #6 of Protocol #10220: “A Phase II Basket Trial of Glutaminase Inhibitor 
(BeGIN) Telaglenastat (CB-839) HCl in Patients with NF1 Aberrations, NF1 Mutant Malignant Peripheral 
Nerve Sheath Tumors (MPNST), KEAP1/NRF2 and LKB1 Aberrant Tumors”. 
 
SUMMARY OF CHANGES—Protocol 
 
I. 
Protocol language updates for specimen transfer: 
 
# 
Section 
Changes 
1. 
Title page 
Update Dr. Schwartz’s contact information. 
PI Response: The requested change has been made. 
2. 
Throughout  Revise “ETCTN Biorepository” to “EET Biobank” 
 
PI Response: The requested change has been made. 
3. 
2.4.3 
Revise Section 2.4.3 to remove reference CTCs and other edits as shown: 
 
2.4.3 cfDNA and analysis by next generation sequencing (NGS) 
 
Whole blood samples will be collected to measure levels of CTCs. Because it 
has been observed that intra-tumoral genetic heterogeneity is a major contributor 
to therapeutic failure across different tumor types an exploratory analysis will be 
performed to assess the concordance of the mutational status of plasma cell-free 
circulating tumor DNA and tumor tissue. 
 
Next generation sequencing will be used in this study to more comprehensively 
identify mutations in plasma cell-free circulating tumor DNA. Concordance of 
mutational status between plasma  cell-free circulating tumor DNA and tumor 
tissue in solid tumor patients will be assessed both before and after study drug 
administration. It is anticipated that the mutations identified in plasma cell-free 
circulating tumor DNA and tissue samples obtained at the same timepoints will 
provide a better understanding of the capabilities of the assay platforms, as well 
as reconcile the longitudinal changes of genomic information from different 
sample sources within an individual patient. 
 
These data will be used to explore whether plasma cell-free circulating tumor 
DNA can be used for precision medicine-based patient selection, as well as 
identify mutations that may be unresponsive to Telaglenastat (CB-839)  HCl. 
 
Genomic alterations including amplification or deletion and expression of genes 

ii 
 
# 
Section 
Changes 
and the proteins they encode may be investigated in sources of tumor tissue that 
are obtained from a patient. Such tissue may include samples obtained via per
protocol procedures, archival samples predating the study or ad hoc samples 
obtained for routine clinical purposes during the study. An example of the latter, 
is surgical resection of a single tumor/metastasis that is recommended to be 
removed for standard clinical care. 
 
PI Response: The requested change has been made. 
4. 
2.4.6 
Revise the first paragraph as shown to clarify have the germline control will be used: 
Whenever possible, tumor DNA will be analyzed along with normal tissue DNA 
from the same patient in order to determine what somatic mutations are present 
in the tumor have a reference for comparison and define somatic vs.germline 
events. 
 
PI Response: The requested change has been made. 
5. 
2.4.8 
Revise the second paragraph as shown to clarify the method for RNAseq: 
Tissue will be macrodissected and total RNA isolated using a Qiagen protocol. 
An Illumina sequencing library will be performed using the mRNA Seq sample 
preparation generated using an Illumina RNA Exome library preparation kit. 
Samples will be sequenced on an Illumina HiSeq instrument with 9 samples per 
lane NovaSeq instrument, yielding approximately 7 million reads per sample. 
Sequencing reads will be matched to a collection of human transcripts. 
Logarithm of the normalized number of the matching reads will be used as a 
measure of the corresponding gene expression. Only genes with large enough 
counts of matching reads will be used in the analysis. We estimate that about 
15,000 genes will be analyzed. 
 
PI Response: The requested change has been made. 
6. 
5.5.2 
The EET Biobank is moving to a new facility effective 10/7/24.  Revise the Shipping 
Address for the EET Biobank to the following: 
EET Biobank 
2200 International Street 
Columbus, OH 43228 
PH: (614) 722-2865 
FAX: (614) 722-2897 
E-mail:  BPCBank@nationwidechildrens.org 
 
PI Response: The requested change has been made. 
7. 
5.5.3 
Revise the Contact Information for Assistance to update the EET Biobank’s phone 
number as follows: 
For all queries, please use the contact information below:  
EET Biobank 
Phone: (614) 722-2865 

iii
 
# 
Section 
Changes 
E-mail: BPCBank@nationwidechildrens.org 
8. 
5.7 
Revise the row in the Biomarker Table for WES/RNAseq as shown: 
5 
WES/ 
RNAse
q 
WES/ 
RNAs
eq 
Exploratory 
To confirm 
retrospectiv
ely 
eligibility 
mutations. 
Hypothesis 
generating 
M/O Mandato
ry pre-
treatment 
Optional 
on week 
4 and at 
progressi
on 
DNA, 
cDNA, 
and 
RNA 
from 
FFPE 
Tissue* 
PBMC 
Germline 
DNA from 
blood in 
pre-
treatment 
Steck-Tube 
(control for 
WES 
control 
only) 
3-6 
cores 
PBM
C 
from 
one 
Strec
k 
tube 
NCI 
MoCha
 
PI Response: The requested change has been made. 
9. 
5.9.1.2  
For cfDNA, replace the current text in Section 5.9.1.2 with the following revised text: 
 
5.9.1.2 Site Performing Correlative Study 
 
This study will be conducted at the MoCha, Frederick National Laboratory for Cancer 
Research (FNLCR) under the supervision of Chris Karlovich, Ph.D. 
(chris.karlovich@nih.gov). 
 
5.9.1.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative 
Study 
 
Specimens will be shipped from the EET Biobank to: 
 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.91.4 Contact information for notification of specimen shipment 
 
Thomas Forbes, mochasamplereceiving@nih.gov 
 
PI Response: The requested change has been made. 
 

iv
 
# 
Section 
Changes 
10. 
5.9.2.2  
For WES and RNAseq, replace the current text in Section 5.9.2.2 with the following 
revised text: 
 
5.9.2.2 Site Performing Correlative Study 
 
This study will be conducted at the MoCha, Frederick National Laboratory for Cancer 
Research (FNLCR) under the supervision of Chris Karlovich, Ph.D. 
(chris.karlovich@nih.gov). 
 
5.9.2.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative 
Study 
 
Specimens will be shipped from the EET Biobank to: 
 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.9.2.4 Contact information for notification of specimen shipment 
 
Thomas Forbes, mochasamplereceiving@nih.gov 
 
PI Response: The requested change has been made. 
 
11. 
5.9.3.2 
Update Gopal Singh to Dr. Yiling Lu 
 
PI Response: The requested change has been made. 
12. 
10.3.3 
The template AE reporting tables have been updated. Please replace the AE reporting 
table in the protocol with the attached corresponding updated table 
 
PI Response: The requested change has been made. 
13. 
Appendix E 
Please remove Appendix E as it refers to an outdated ETCTN BMCI Laboratory 
Manual  
 
PI Response: The requested change has been made. 
14. 
Appendix F 
Revise the sections on WES and RNAseq as follows: 
 
Whole-Exome Sequencing/Targeted-Exome Sequencing (WES/TES) 
 
DNA libraries will be generated using the Agilent SureSelect XT Target 
Enrichment System, and quantitated via digital droplet (ddPCR) 
fluorescence based quantitation. Library samples are denatured, diluted, and 
clustered on the cBot clonal amplification systemtn in preparation for 
sequencing on the Illumina HiSeq 2500 then loaded on a flow cell prior to 

v 
 
# 
Section 
Changes 
sequencing on a NovaSeq 6000 or NovaSeq X. 
 
RNA-Seq 
 
RNA libraries will be generated using the Aglient SureSelect XT 
Enrichment System, and quantitated via ddPCR Illumina RNA Exome kit 
and final libraries are quantified by a fluorescence quantitation. Library 
samples are denatured, diluted, and clustered on the cBot clonal 
amplification systemtn in preparation for sequencing on the Illumina HiSeq 
2500 loaded onto a flow cell and sequenced on a NovaSeq 6000 or NovaSeq 
X. 
 
Refer to the ETCTN BMCI Laboratory Manual for additional details, 
including pipeline and data analysis specifications for next generation 
sequencing assays. 
 
PI Response: The requested change has been made. 
 
15. 
2.2.4 
Per the recent Executive Order regarding Defending Women 
(https://www.whitehouse.gov/presidential-actions/2025/01/defending-women-from-
gender-ideology-extremism-and-restoring-biological-truth-to-the-federal-government/), 
DCTD/CTEP is making investigators aware of several changes that are being 
introduced to comply with this Order.  CTEP is requiring that the term ‘gender’ in the 
protocol be amended so that ‘gender’ is replaced with the word ‘sex’.  
 
PI Response: The protocol has been amended so that ‘gender’ is replaced with the 
word ‘sex’.  
 
 
II.  PI-initiated changes: 
 
# 
Section 
Changes 
1. 
Title Page 
PI Response: The statistician and their contact information has been updated as 
follows:   
 
Old contact:  
Statistician:     
Ewan Kwiatkowski, PhD     
Unit 1411     
1400 Pressler St.     
Houston, TX 77030-4009     
(P) 713-563-4282 
(F) 713-563-4242   
EKwiatkowski@mdanderson.org 
 
New contacts: 

vi
 
Statistician(s):     
Jing Ning, PhD 
The University of Texas MD Anderson Cancer Center 
7007 Bertner Ave 
Houston, TX 77030 
713-792-5310 
jning@mdanderson.org  
 
Wei Qiao, PhD 
The University of Texas MD Anderson Cancer Center 
7007 Bertner Ave 
Houston, TX 77030 
713-794-4163 
wqiao@mdanderson.org 
 
2. 
Appendices 
F, G, and H 
PI Response: The appendices F, G, H have been revised to E, F, G respectively to 
account for the requested deletion of the original Appendix E (#12 above). 
 

NCI Protocol #: 10220 
Version Date:  January 3, 2025  
 
1 
 
 
           NCI Protocol #: 10220 
 
Local Protocol #: NCI10220 
 
ClinicalTrials.gov Identifier: NCT03872427 
 
TITLE: A PHASE II BASKET TRIAL OF GLUTAMINASE INHIBITOR (BEGIN) 
Telaglenastat (CB-839)  HCL IN PATIENTS WITH NF1 ABERRATIONS, NF1 
MUTANT MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNST), 
KEAP1/NRF2 AND LKB1 ABERRANT TUMORS 
 
Corresponding Organization: LAO-TX035 / University of Texas MD Anderson Cancer 
Center LAO 
 
Principal Investigator: 
Funda Meric-Bernstam, MD 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 455 
Houston, TX 77030, USA 
713-563-1930 
fmeric@mdanderson.org 
 
 
Co- Principal Investigators: 
Gary K. Schwartz, MD 
Case Comprehensive Cancer Center 
10900 Euclid Ave 
Cleveland, OH 44106 
216-368-1994 
gks37@case.edu 
 
 
             Participating Organizations 
 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 

NCI Protocol #: 10220 
Version Date:  January 3, 2025  
 
2 
 
 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
Statisticians: 
Jing Ning, PhD  
 
 
 
Wei Qiao, PhD 
The University of Texas MD Anderson  
The University of Texas MD Anderson  
Cancer Center  
 
 
 
Cancer Center 
7007 Bertner Ave 
 
 
 
7007 Bertner Ave 
Houston, TX 77030 
 
 
 
Houston, TX 77030 
713-792-5310 
 
 
 
 
713-794-4163 
jning@mdanderson.org  
 
 
wqiao@mdanderson.org 
 
        Responsible Data Manager: 
Sefi Samuel 
 Unit 455 
1515 Holcombe Blvd. 
Houston, TX 77030-4009 
(P) 713-794-1565 
(F) 713-792-3983 
SSamuel2@mdanderson.org 
 
Study Coordinator (Primary): 
 
Study Coordinator: 
 Ming Sun  
 
 
 
Anjali Raina 
Unit 455 
 
 
 
 
Unit 455 
1515 Holcombe Blvd. 
 
 
1515 Holcombe Blvd. 
Houston TX 77030-4009 
 
 
Houston, TX 77030-4009 
(P)  713-745-3407  
 
 
(P) 713-792-3238 
(F) 713-794-4130 
 
 
 
(F) 713-794-4130 
 MSun6@mdanderson.org    
 
ARaina@mdanderson.org 
 
 
NCI-Supplied Agent: Telaglenastat (CB-839) HCl (NSC# 795998) 
 
IND #: 
 
IND Sponsor: DCTD, NCI 
 
 
Protocol Type / Version # / Version Date: 
Original / Version #1 / April 13, 2018 
Revision / Version #2 / June 22, 2018 
Revision / Version #3 / August 20, 2018 
Revision / Version #4 / December 21, 2018 

NCI Protocol #: 10220 
Version Date:  January 3, 2025  
 
3 
 
Revision / Version #5 / February 7, 2019 
Revision / Version #6 / February 21, 2019 
Revision / Version #7 / May 3, 2019 
Revision / Version #8 / May 29, 2019 
                                                                                               Amendment 01 / Version #9 / August 28, 2019 
                                                                                               Amendment 02 / Version #10 / November 21, 2019 
   Amendment 03 / Version #11 / August 25, 2020 
   Amendment 04/ Version #12/ September 7, 2021 
   Amendment 05/ Version #13/ May 30, 2023 
   Amendment 06/Version #14/January 3, 2025 
 

NCI Protocol #: 10220 
Version Date:  January 3, 2025  
 
4 
 
SCHEMA 
 
 
*Within each cohort, we will employ an optimal Simon two-stage design. Specifically, within 
each cohort, we will enroll 9 patients, and if 0 respond, the study will be stopped early for futility 
within that cohort. Otherwise, an additional 18 patients will be enrolled, and if there are 4 or 
more responses out of the total sample of 27 patients, we will conclude that the treatment is 
worthy of further consideration within that cohort. This design has an overall type-I error rate of 
5% (one-sided) within each cohort, and provides 88% power to reject the null hypothesis that the 
response rate is 0.05 when the true response rate is 0.25. Within a given cohort, this design has a 
63% chance of stopping early and an expected total enrollment of 15.7 patients under the null 
hypothesis (i.e. if the true response rate were 0.05). 
 
The Recommended Phase 2 dose for Telaglenastat (CB-839) HCl monotherapy is 800 mg BID. 
We will use this as the starting dose for this Basket trial. If patient develops toxicity then the dose 
can be reduced as per table below: 
 
Dose Reductions of Telaglenastat (CB-839) HCl 
Dose Level 
Telaglenastat (CB-839) 
HCl Dose 
Starting dose 
800 mg BID 
First dose reduction 
600 mg BID 
Second dose reduction 
400 mg BID 
Third dose reduction 
Discontinue 
Telaglenastat (CB-839) 
HCl 

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Version Date:  January 3, 2025  
 
5 
 
TABLE OF CONTENTS 
 
TITLE PAGE 
 
SCHEMA………………………………………………………………………………………….4 
TABLE OF CONTENTS ................................................................................................................. 5 
1. 
OBJECTIVES………………………………………………………………………    …..8 
1.1 
Primary Objectives ................................................................................................... 8 
1.2 
Secondary Objectives ............................................................................................... 8 
1.3 
Exploratory objectives: ............................................................................................ 8 
2. 
BACKGROUND ................................................................................................................. 8 
2.1 
Study Disease(s) ....................................................................................................... 8 
2.2 
 Telaglenastat (CB-839) HCl ................................................................................. 10 
2.3 
Rationale ................................................................................................................ 13 
2.4 
Correlative Studies Background ............................................................................ 18 
3. 
PATIENT SELECTION .................................................................................................... 23 
3.1 
Eligibility Criteria .................................................................................................. 23 
3.2 
Exclusion Criteria .................................................................................................. 24 
3.3 
Inclusion of Women and Minorities ...................................................................... 25 
4. 
REGISTRATION PROCEDURES ................................................................................... 25 
4.1 
Investigator and Research Associate Registration with CTEP .............................. 26 
4.2 
Site Registration ..................................................................................................... 28 
4.3 
Patient Registration ................................................................................................ 29 
4.4 
General Guidelines ................................................................................................. 30 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ......................................... 31 
5.1 
Summary Table for Specimen Collection .............................................................. 31 
5.2 
Specimen Procurement Kits and Scheduling ......................................................... 32 
5.3 
Specimen Tracking System Instructions ................................................................ 33 
5.4 
Specimen Collection .............................................................................................. 36 
5.5 
Shipping Specimens from Clinical Site to the EET Biobank ................................ 39 
5.6 
Shipping  to  the  Mayo  Clinic  Cancer   Center   Pharmacology   Shared 
Resource ................................................................................................................. 41 
5.7 
Biomarker Plan ...................................................................................................... 42 
5.8 
Integrated Correlative Studies ................................................................................ 44 
5.9 
Exploratory/Ancillary Correlative Studies ............................................................. 44 
6. 
TREATMENTPLAN ......................................................................................................... 46 
6.1 
Agent Administration ............................................................................................. 46 
6.2 
General Concomitant Medication and Supportive Care Guidelines ...................... 47 
6.3 
Duration of Therapy ............................................................................................... 47 

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6.4 
Duration of Follow Up ........................................................................................... 48 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................ 48 
8. 
PHARMACEUTICAL INFORMATION .......................................................................... 50 
8.1 
 Telaglenastat (CB-839) HCl ................................................................................. 50 
9. 
STATISTICAL CONSIDERATIONS ............................................................................... 53 
9.1 
Study Design/Endpoints ......................................................................................... 53 
9.2 
Sample Size/Accrual Rate ...................................................................................... 53 
9.3 
Analysis of Secondary Endpoints .......................................................................... 54 
9.4 
Reporting and Exclusions ...................................................................................... 55 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................ 55 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ..................... 56 
10.2 
Adverse Event Characteristics ............................................................................... 57 
10.3 
Expedited Adverse Event Reporting ...................................................................... 58 
10.4 
Routine Adverse Event Reporting ......................................................................... 60 
10.5 
Pregnancy ............................................................................................................... 60 
10.6 
Secondary Malignancy ........................................................................................... 60 
10.7 
Second Malignancy ................................................................................................ 61 
11. 
STUDY CALENDAR ....................................................................................................... 62 
12. 
MEASUREMENT OF EFFECT ........................................................................................ 64 
12.1 
Antitumor Effect – Solid Tumors .......................................................................... 64 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ............................................................................................................. 70 
13.1 
Study Oversight...................................................................................................... 71 
13.2 
Data Reporting ....................................................................................................... 71 
13.3 
CTEP Multicenter Guidelines ................................................................................ 73 
13.4 
Collaborative Agreements Language ..................................................................... 73 
14. 
REFERENCES 76 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................ 78 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD ............................................................................................................... 79 
APPENDIX C 
INTEGRAL BIOMARKER ASSAY...................................................... 82 
APPENDIX D 
INTEGRATED BIOMARKER - METABOLOMICS ........................... 83 
APPENDIX E 
ASSAY INFORMATION ......................................................................96 
APPENDIX F 
CYP2C9 SUBSTRATES ........................................................................ 97 

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APPENDIX G 
MEDICATION DIARY.......................................................................... 98 
 

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8 
 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 
To assess the best overall response rate (BORR) achieved by 6 months of Telaglenastat 
(CB-839) HCl treatment in specific pathway aberrant tumors (MPNST, NF1, 
KEAP1/NRF2 & STK11/ LKB1 ) 
 
1.2 
Secondary Objectives 
 
1.2.1 
To determine the safety, PFS, TTP and OS. 
1.2.2 
To determine the ORR (highest objective response achieved between start of therapy and 
progression), TTR and CBR of Telaglenastat (CB-839) HCl 
1.2.3 
Correlative Objectives: To assess pharmacodynamic changes and adaptive responses and 
correlate with response to treatment as well as disease progression 
 
1.3 
Exploratory objectives: 
 
1.3.1 
Correlate 18F-FDG PET/CT pre-therapy and 8-weeks post-therapy response to 
Telaglenastat (CB-839) HCl therapy 
1.3.2 
Evaluate changes in level of circulating tumor DNA at baseline, one month on-treatment 
and time of progression (MoCHA Labs) to treatment response. 
1.3.3 
Quantify the peripheral blood concentrations of the metabolites: Aspartate, Glutamate, 
Glutamine and Arginine (@Mayo clinic Oncometabolomics core) and correlate with 
response. 
1.3.4 
Evaluate the PD effect of Telaglenastat (CB-839) HCl on systemic levels of the TCA 
cycle metabolites in peripheral blood (baseline and one month) as part of the protocol. 
1.3.5 
Evaluate tumor by Reverse phase protein array (@core facility at MD Anderson) and 
RNA seq to evaluate changes from pre-treatment, during treatment and post treatment 
specimens. 
1.3.6 
Perform PDX modelling-co-clinical trials (@Dr. Funda Meric-Bernstam’s lab MD 
Anderson) to understand response / resistance mechanisms and also evaluate combination 
therapies for future development. 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
NF1 mutant malignant peripheral nerve sheath tumor (MPNST), NF1 mutant cancers, KEAP1/NRF2 & 
STK11/LKB1 pathway aberrant tumors 
 
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused due to the 
loss and/or mutation of NF1 tumor suppressor gene(1). The NF1 gene codes for a Ras GTPase 
activating protein called Neurofibromin (NF) and mutational inactivation and/or loss of NF1 can 
lead to altered Ras-MAPK signaling. Many patients with NF1 are often at risk of developing 
cancers such as gliomas, neurofibromas and malignant peripheral nerve sheath tumors 

NCI Protocol #: 10220 
Version Date:  January 3, 2025  
 
9 
 
(MPNSTs) among others. MPNSTs are soft-tissue tumors that are highly aggressive with a very 
poor prognosis. NF1 associated MPNSTs are often fatal and there are not many treatment 
options available to treat these therapeutically resistant tumors(1). 
 
Mutations involving the NF1 gene in somatic cells have been demonstrated in a variety of solid 
tumors(2).  However, none of the mutation types are specific for a group of tumors or a 
particular tumor type. Although mutations in the somatic NF1 gene locus have been found, the 
cause and effect relationship has not been established; rather, there is a suggestion of an interplay 
of this mutation with other genetic and environmental factors that may lead to an increased risk 
of tumor development(2). In a pilot project to characterize cancer genomes, Ding et al. 
conducted mutation analysis in 188 primary lung adenocarcinomas(3). Among the 26 
significantly mutated genes associated with adenocarcinoma of the lung, 16 mutations involved 
the NF1 gene in 13 tumors. There were 4 nonsense mutations, 5 splice-site mutations, and 1 
frame shift mutation in the NF1 coding region (3). Reports on the type of mutation involving 
NF1 in colorectal adenocarcinoma vary widely; loss of heterozygosity (LOH) involving NF1 
gene may occur in 14%–57% of colorectal carcinomas(4).  Alhiquist et al. have reported a gain 
in parts of or even complete duplication of the NF1 gene in 17% of colorectal carcinomas(5). Li 
et al. have reported three cases of adenocarcinoma of the colon, myelodysplastic syndrome, and 
anaplastic astrocytoma, which also had NF1 mutations involving the GRD domain(6). Finally, 
Sangha et al. reported reduced to absent NF1 in 5 out of 18 ovarian epithelial cancer cell lines 
and 9 out of 41 primary ovarian serous carcinomas(7). 
 
CRISPR–Cas9-based genetic screening and metabolomic analyses have revealed that KEAP1- 
NRF2-mutated cancers depend on increased glutaminolysis and are vulnerable to glutaminase 
inhibition.  We analyzed clinical and next generation sequencing data from patients treated at 
MD Anderson Cancer Center and performed bioinformatic analyses of alteration frequency using 
TCGA data on cBio Portal to characterize KEAP1-NRF2 alterations and used Kaplan-Meier 
analysis to identify associations with overall survival (OS)(8). Among 189 patients with KEAP1 
or NRF2 alterations (alts) at MDACC (97 with each, 5 with both), median age was 65 years 
(range: 18-89), 52% were females, 80% Caucasian, 11% Hispanic, and 5% African-American. 
KEAP1-NRF2 alts were most common in NSCLC (19%), cholangiocarcinoma (8%), breast 
(7%), and renal cell CA (7%). Mean number of co-occurring alts was 8 (range: 0-73). We 
identified 69 unique alts in KEAP1, most commonly Q619del (11%) and V369A (9%), and 68 
unique alts in NRF2, most commonly E79Q (6%) and G31A (6%). Median OS in the entire 
cohort was 966 days. Of the 1505 co-alts identified with KEAP1, most common were TP53 
(57%), ARID1A/B/2 (55%), PI3K-encoding genes (37%), and NOTCH1 (29%). Of the 817 
unique co-alts identified with NRF2 alts, most common were TP53 (52%), PI3K-encoding genes 
(36%), ARID 1A/B/2 (25%), and BRCA1/2 (19%). Co-alts in TP53, SWI/SNF complex, mTOR 
pathway, and NOTCH pathway genes did not impact survival. In TCGA, KEAP1-NRF2 alts 
were most common in NSCLC (26%), uterine (15%), breast (10%), and cholangiocarcinoma 
(9%). KEAP1-NRF2 alts were associated with decreased survival in lung adenocarcinoma 
(LUAD), 49 vs 33 months, log rank p = 0.02. KEAP1-NRF2 alts are prevalent across diverse 
tumor types and associated with decreased survival in LUAD(8). They most frequently co-occur 
with alts in TP53, SWI/SNF complex, and mTOR pathway genes but these co-occurring alts did 
not impact survival in our cohort. 

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Version Date:  January 3, 2025  
 
10 
 
The serine/threonine kinase and tumor suppressor STL11/LKB1 is mutated in 30% of NSCLC 
tumors, and recent evidence points to a prominent role in NSCLC metastasis(9). The tumor 
suppressor LKB1 is mutated in 20-30% of non-small cell lung cancers (NSCLCs) and ranks as 
the 3rd highest mutated gene in lung adenocarcinoma after p53 and Ras(9). Consequently, LKB1 
has moved from a relatively understudied protein to a major player in NSCLC, especially 
NSCLC metastasis. In addition In addition to mutation, structural variations and partial copy 
losses involving STK11 showing evidence for having functional relevance have been described 
in various malignancies(10). 
 
There is an unmet therapeutic need for advanced-stage cancer patients with NF1 mutant 
malignant peripheral nerve sheath tumor (MPNST), NF1 mutant cancers, KEAP1/NRF2 & 
STK11/LKB1 pathway aberrant tumors. 
 
2.2 
Telaglenastat (CB-839) HCl 
 
Telaglenastat (CB-839) HCl is a first-in-class, orally available inhibitor of glutaminase activity 
(Investigator’s Brochure). There are two glutaminase genes, GLS and GLS2, with the latter 
being primarily expressed in the liver. GLS is more broadly expressed and has two known 
splice variants, the longer KGA and the shorter GAC, differing in their carboxyl-terminal. Both 
GLS isoforms catabolize glutamine into glutamate, and the functional differences between the 
two isoforms is unknown. Telaglenastat (CB-839)  HCl specifically inhibits both isoforms of 
GLS, but not GLS2. 
 
Telaglenastat (CB-839) HCl shows anti-tumor activity in multiple nonclinical models has been 
studied in clinical trials in patients with cancer as a monotherapy and in combination with 
standard anticancer agents in hematological cancers (including acute myeloid leukemia, acute 
lymphoblastic leukemia, multiple myeloma, and non-Hodgkin lymphoma) and solid tumors 
(including triple-negative breast cancer, melanoma, non-small cell lung cancer, and renal cell 
carcinoma) (Investigator’s Brochure). 
 
2.2.1 
Mechanism of Action 
 
Many cancer types have an altered metabolic profile and use glutamine as an energy source. 
Glutaminase (GLS) converts glutamine to glutamate, which can support several cellular 
pathways, including the tricarboxylic acid (TCA) cycle for energy production, redox balance, 
and amino acid synthesis (11). Many tumors have been demonstrated to overexpress GLS, 
particularly the shorter glutaminase C (GAC) isoform, and these tumors are sensitive to the 
withdrawal of glutamine from culture medium in vitro(12, 13). This overexpression of GLS can 
be stimulated by overexpression of Myc(14, 15). 
 
Telaglenastat (CB-839) HCl is a selective, allosteric, noncompetitive inhibitor of both isoforms 
of GLS. It has been shown to reversibly bind to the activation loop of GAC and induce 
formation of inactive tetramers(16) . This inactivation of GLS results in an increase of glutamine 
and a decrease of glutamate and several TCA cycle intermediates within cancer cells, leading to 
a decrease in cell proliferation and/or an increase in cell death(13, 17). The decrease in cellular 
viability can be reversed by addition of α-ketoglutarate, suggesting that reduction in TCA cycle 
intermediates is the primary mechanism by which Telaglenastat (CB-839) HCl exerts its 
antiproliferative and pro-apoptotic 

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effects (Investigator’s Brochure). 
 
2.2.2 
Summary of Nonclinical Experience 
 
The selectivity of  Telaglenastat (CB-839) HCl was tested in vitro as an inhibitor of radioligand 
binding to 66 different receptors derived from mammalian tissue (Investigator’s Brochure). At 
10 µM  Telaglenastat (CB-839) HCl, significant inhibition of radioligand binding was observed 
against the human adenosine A3 receptor (50%), the hERG potassium channel (64%), and the 
sodium channel, site 2 (57%). 
Minimal functional impact was observed with either the hERG channel (18% inhibition in a 
patch clamp assay) or the sodium channel (no agonist or antagonist activity in the guinea pig 
atrium). 
 
In mice bearing HCC1806 tumors treated with a single dose of 200 mg/kg Telaglenastat (CB-
839) HCl, the tumor and all examined tissues were exposed to Telaglenastat (CB-839) HCl, 
although exposure within the brain was 20-fold less than in the plasma (Investigator’s Brochure). 
In mice given a single dose of 
Telaglenastat (CB-839) HCl ranging from 2.5 to 400 mg/kg, maximum glutaminase inhibition, 
glutamine increase, and glutamate and aspartate decreases within the tumor plateaued when 
plasma concentrations exceeded ~300 nM, which was achieved with twice daily (BID) dosing 
of ≥100 mg/kg. 
 
In rats, the maximum feasible dose (due to volume and solubility) of 500 mg/kg of Telaglenastat 
(CB-839) HCl was well tolerated during a four-week toxicity study, and a Severely Toxic Dose 
of 10% was not identified (Investigator’s Brochure). There were no clinical observations related 
to Telaglenastat (CB-839) HCl at the maximum dose, nor any notable findings in a gross 
necropsy. The concentrations of alkaline phosphatase were slightly decreased, while 
triglycerides and cholesterol levels were modestly increased compared to controls. While 
statistically significant, these were considered to be non-adverse, fully reversible, and without 
histology correlates. There was a 1-2 second decrease in prothrombin time, which reversed 
during a 14-day non-dosing recovery period. 
 
In marmoset monkeys receiving up to 125 mg/kg BID of Telaglenastat (CB-839) HCl for 28 
days, Telaglenastat (CB-839) HCl was well tolerated with no mortality, nor notable clinical 
observations (Investigator’s Brochure). In sporadic animals receiving the mid- and high-dose, 
two liver enzymes, γ-glutamyl- transpeptidase and glutamate dehydrogenase, were significantly 
elevated at sacrifice, while other liver function tests were within normal limits. This correlated 
with minimal to slight bile duct hyperplasia. These findings were not observed in animals which 
underwent a 14-day non-dosing recovery period before sacrifice. The Highest Non Severely 
Toxic Dose was not defined. 
 
2.2.3 
Summary of Clinical Experience 
 
As of January 23, 2018, 161 patients have received Telaglenastat (CB-839) HCl as 
monotherapy, and 250 patients have received Telaglenastat (CB-839) HCl in combination with 
other agents in phase 1 and early phase 2 trials (Investigator’s Brochure). A summary of clinical 
data from company-sponsored Telaglenastat (CB-839) HCl trials as of January 23, 2018 is 

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presented below. Details of all ongoing studies can be found in the most recent Telaglenastat 
(CB-839) HCl Investigator’s Brochure. 
2.2.4 
Clinical PK and PD 
 
The pharmacokinetics (PK) data from patients in all three monotherapy studies were collected 
(pre-dose, 0.5, 1, 2, 4, 6, 8 hours post-dose) on Cycle 1, Day 1 (C1D1) and C1D15 
(Investigator’s Brochure). Patients treated with either 100-1000 mg of Telaglenastat (CB-839) 
HCl TID or 600-1000 mg of Telaglenastat (CB-839)  HCl BID showed a high inter- and intra-
patient variability in Telaglenastat (CB-839) 
HCl exposures, and dose proportionality could not be established with statistical significance. In 
general, Telaglenastat (CB-839)  HCl plasma exposure (expressed as area under the 
concentration-time curve from time 0 to 8 hours [AUC0-8hr]) increased with dose over the range 
from 100 to 600 mg TID. However, at doses of 600 mg and above, the high variation within 
dose groups made it difficult to determine exposure differences. For patients with at least three 
time points, the average terminal half-life (t1/2) was ~4 hours. The median accumulation ratio 
was ~2.0 at C1D15 versus C1D1. 
 
Some of the observed variability can be attributed to differences in food intake and co- 
administration of proton pump inhibitors (PPI) (Investigator’s Brochure). Food-effect studies 
comparing patients taking 600 mg of Telaglenastat (CB-839)  HCl TID without food to patients 
receiving 600 mg of Telaglenastat (CB-839)  HCl BID with meals revealed a 1.3-fold increase in 
AUC0-8hr on C1D1. Although this result was not significant, similar exposure was observed at 
steady-state (C1D15) in both the 600 mg BID fed and 600 mg TID fasted groups despite the 
daily dose being 1/3 lower on the BID schedule. Concomitant PPI administration had a 
significant decrease in AUC0-8hr in patients on the 600 mg BID schedule.  The PPI effect may be 
due to reduced absorption at higher stomach pH because of the pH-dependent solubility of 
Telaglenastat (CB-839)  HCl. There were no statistically significant differences in the exposure 
of Telaglenastat (CB-839)  HCl in various demographic groups, including age, sexgender, race, 
or body weight. Combination of Telaglenastat (CB-839)  HCl with either everolimus or 
paclitaxel had no effect on exposure to Telaglenastat (CB-839)  HCl, while the combination of 
Telaglenastat (CB-839)  HCl with azacytidine increased the steady-state (C1D15) AUC0-8hr and 
maximum serum concentration (Cmax) of Telaglenastat (CB-839)  HCl. 
 
Pharmacodynamic response in these trials was assessed as glutaminase activity in platelets and 
peripheral blood mononuclear cells (PBMCs) four hours after the first dose of Telaglenastat 
(CB-839)  HCl on C1D1, or in solid tumor biopsy samples collected on C1D1 in early dose 
cohorts on study CX- 839-001 (Investigator’s Brochure). A greater than 90% glutaminase 
inhibition was observed in platelets when Telaglenastat (CB-839)  HCl levels exceeded 250 
ng/mL. Several patients who received Telaglenastat (CB-839)  at the 600 mg BID dose level did 
not achieve > 90% inhibition of glutaminase in platelets, while all of the patients at 800 mg BID 
had > 90% inhibition. In solid tumor biopsies, a 75% inhibition of glutaminase activity was 
observed.  Plasma glutamine concentrations were also monitored four hours post-dose on C1D1 
and C1D15. All dose groups showed a 1.5- to 2-fold increase in plasma glutamine levels on 
C1D15, confirming glutaminase inhibition. 
 
2.2.5 
Clinical Safety Summary 
 

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As of January 23, 2018, 161 patients have received Telaglenastat (CB-839)  HCl as 
monotherapy, and 250 patients have received Telaglenastat (CB-839)  HCl in combination with 
other agents in phase 1 and early phase 2 trials (Investigator’s Brochure). Among 59 patients 
who received Telaglenastat (CB-839)  HCl monotherapy on the TID (fasted) schedule over a 
dose range of 100-1000 mg, two dose limiting toxicities 
(DLTs) have been observed: one at 250 mg TID (grade 3 elevated creatinine) and one at 400 mg 
TID (grade 3/4 elevated liver function tests (LFTs)). No DLTs have been reported on the 
monotherapy BID (fed state) schedule up to a dose of 800 mg. DLTs reported in combination 
cohorts have been: Grade 4 neutropenia (400 mg BID with 80 mg/m2 IV paclitaxel weekly for 
three weeks in every four week cycle and 400 mg BID with 4 mg once daily (QD) pomalidomide 
for 21 days out of every 28 day cycle and 40 mg each week (QW) of dexamethasone), grade 3 
pruritic rash (400 mg BID with 10 mg everolimus QD), grade 3 alanine aminotransferase (ALT) 
increase (800 mg BID with 240 mg IV nivolumab once every two weeks), and grade 4 platelet 
count decrease (600 mg dose with 60 mg cabozantinib QD).  Although a maximum tolerated 
dose (MTD) has not been defined for either monotherapy or combination therapy, 800 mg BID is 
the highest dose that is confirmed to be safe and well tolerated in single-agent and combination 
Telaglenastat (CB-839)  HCl studies. The 800 mg BID dose also exhibits robust exposure and 
pharmacodynamics effects, and has been declared recommended Phase 2 Dose (RP2D). 
 
The largest monotherapy study of Telaglenastat (CB-839)  HCl (CX-839-001) included 120 
patients, 32 receiving between 100 to 800 mg of Telaglenastat (CB-839)  HCl TID without food 
and 88 receiving between 600 to 1000 mg of Telaglenastat (CB-839)  HCl with food 
(Investigator’s Brochure). On the BID schedule, 72.7% of patients experienced an AE, the most 
common of which were fatigue, elevated LFTs, gastrointestinal AEs, and photophobia. These 
AEs were typically grade 1/2, reversible, and manageable without dose interruption or 
modification. Grade 3 LFTs were significantly reduced (2.3% of patients) on the BID schedule. 
One grade 3 AE of anemia was also considered to be related to Telaglenastat (CB-839)  HCl. 
 
As of the January 23, 2018, a total of 201 SAEs across monotherapy and combination therapy 
have been recorded (Investigator’s Brochure). Twenty-two patients experienced at least one 
SAE that was considered at least possibly related to Telaglenastat (CB-839)  HCl treatment. 
The SAEs include increased alanine aminotransferase, increased aspartate aminotransferase, 
anaemia, increased blood creatinine, death, dyspnoea, hepatitis, hyperglycaemia, hypertension, 
hypotension, hypoxia, meningitis aseptic, myositis, nausea, pyrexia seizure, stomatitis, 
tachycardia, and vomiting. 
 
2.2.6 
Clinical Efficacy Summary 
 
Patients with multiple tumor types have been included in studies with Telaglenastat (CB-839)  
HCl as a monotherapy of in combination with other agents. As of January 23, 2018, 74 patients 
receiving the BID monotherapy regimen (of 88 enrolled) were RECIST evaluable for tumor 
response. 
Best overall response of SD or better has been observed in 46% (34 patients) in a variety of 
malignancies, including renal cell carcinoma (RCC), triple-negative breast cancer (TNBC), non- 
small cell lung cancer (NSCLC), and a variety of tumors with TCA-cycle alterations. Of the 27 
evaluable RCC patients, thirteen (48%) had a BOR of SD or better, including one patient with 
durable (1 year) PR. 

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2.3 
Rationale 
 
There is an unmet therapeutic need for advanced-stage cancer patients with NF1 mutant 
malignant peripheral nerve sheath tumor (MPNST), NF1 mutant cancers, KEAP1/NRF2 & 
STK11/LKB1 pathway aberrant tumors. To fill the therapeutic needs, we propose a basket 
clinical trial with Telaglenastat (CB-839)  HCl (NSC# 795998), a potent and selective reversible 
inhibitor of glutaminase-1 activity. It follows that the new experimental therapeutic agent 
Telaglenastat (CB-839)  HCl acts as an allosteric and noncompetitive inhibitor of both splice 
variants of the broadly expressed glutaminase-1 (gene symbol: GLS, selectivity ~0.028 µM ± 
0.007), but does not inhibit glutaminase-2 (GLS2, selectivity >1000 µM), which is the variant 
predominantly found in the human liver . Telaglenastat (CB-839)  HCl has antineoplastic and 
has pro-apoptotic activity in a variety of human tumor cell lines, including triple-negative breast 
cancer (TNBC), clear cell renal cell carcinoma (RCC), and mesothelioma, as well as 
hematological cell lines of relapsed or refractory leukemia, multiple myeloma (MM) and non-
Hodgkin’s lymphoma (NHL). Among 24 non-small cell lung cancer cell lines, 11 (46%) of 24 
cell lines showed substantial and significant 72-hour 1 µM Telaglenastat (CB-839)  HCl 
monotherapy cytotoxicity. Unpublished phase 1 studies of orally-administered Telaglenastat 
(CB-839) HCl monotherapy have found so far that the agent is well tolerated, has no maximum 
tolerated dose (MTD) identified, and has a 600 mg twice daily (BID) with food for a 
recommended Phase II dose. Known pharmacology data are presented in Table 1. 
Pharmacodynamic studies in the phase 1 trials show an up to 96% reduction in patient tumor 
glutaminase-1 activity after a 21-day Telaglenastat (CB-839)  HCl drug exposure(18). 
Telaglenastat (CB-839)  HCl monotherapy provides minimal (<5%) clinical activity in phase I 
trials. As such, investigators and Calithera Biosciences, Inc. seek Telaglenastat (CB-839) 
HCl-agent trials with NCI CTEP. In prior work, Calithera Biosciences, Inc. has determined 
tumor GLS activity and blood or tumor levels of glutamine, glutamate, and aspartate after 
Telaglenastat (CB-839)  HCl drug exposure. Inhibition of GLS activity in tumor confirms 
desired pharmacodynamic effect of Telaglenastat (CB-839)  HCl (Fig. 2). Tandem mass 
spectroscopy studies of tumor or of blood samples have shown (a) desired rise in glutamine 
levels after Telaglenastat (CB-839)  HCl, (b) fall in glutamate levels after Telaglenastat (CB-
839)  HCl, and (c) fall in Krebs cycle downstream aspartate levels. 
 
Table 1. Average ± SD of Telaglenastat (CB-839)  HCl pharmacokinetic variables 
Telaglenastat 
(CB-839)  HCl 
N 
AUC0-8h 
(h*mg/L) 
Cmax 
(µg/mL) 
Cmax/dose 
(µg/L/mg) 
Tmax 
(h) 
Half-life 
(h) 
600 mg BID 
48 
7.9 ± 5.8 
1.6 ± 1.1 
1.3 ± 0.9 
4.2 ± 2.5 
4 ± NC 
800-1000 mg BID 
5 
5.0 ± 4.7 
1.0 ± 0.8 
0.5 ± 0.4 
2.8 ± 2.7 
4 ± NC 
Abbreviations: N = number of patients; AUC = area under the curve; Cmax = maximum plasma 
concentration, Tmax = time to reach maximum plasma concentration; SD = standard deviation; 
h = hour; BID = twice daily by mouth; NC = not captured 
Molecular Weight of Telaglenastat (CB-839)  HCl: 571.579 g/mol 
 
2.3.1 
Preclinical data with Telaglenastat (CB-839)  HCl (NSC# 795998) 
 
NF1 mutation and NF1 mutant MPNST 
 

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Approximately 20% of KRAS-mutant 
LUAD tumors carry loss-of-function 
mutations in the KEAP1 gene encoding 
Kelch-like ECH-associated protein 1, a 
negative regulator of nuclear factor 
erythroid 2-like 2 (NFE2L2; hereafter 
NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. 
The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress 
response in lung tumorigenesis. Using a CRISPR-Cas9-based approach in a mouse model of 
KRAS-driven LUAD, the effects of Keap1 loss in lung cancer progression were examined. It 
has been shown that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD in 
mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic 
analyses, it was shown that Keap1- or Nrf2-mutant cancers are dependent on increased 
glutaminolysis, and this property can be therapeutically exploited through the pharmacological 
inhibition of glutaminase by CB-839(20). (Fig. 3) This provides a rationale for stratification of 
human patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung 
tumors as likely to respond to glutaminase inhibition. 
 
Figure 3: Keap1-mutant cells display a robust sensitivity to glutaminase inhibition (Nature 
Medicine)(20) 
 
 
STK11/ LKB1 aberrations: An integrative analysis of genomic, transcriptomic and proteomic 
data from early-stage and chemo-refractory LUAC and identified three robust subsets of KRAS- 
mutant LUAC dominated, respectively, by co-occurring genetic events in STK11/LKB1 (the KL 
subgroup)(21). KL tumors had high rates of KEAP1 mutational inactivation and expressed lower 
levels of immune markers, including PD-L1, while NRF2 is upregulated in LKB1 deficient 
cells(21). Hence Tumors with STK11/ LKB1 aberrations should also be considered for potential 

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subgroup for GLS studies (personal communication Heymach et al) 
 
TCGA data: Analysis of the TCGA data shows that NF1 aberrations, KEAP1/NRF2 & 
STK11/LKB1 pathway aberrant tumors are seen across tumor types (Figure 4 A,B and C). 
 
 
 
Figure 4 A, B and C 
 
 
 
 

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Given their distribution in multiple tumor types and strong rationale of pre-clinical sensitivity to 
glutaminase inhibition we propose a basket trial ( BeGIN – Basket trial of Glutaminase 
inhibition) with single agent Telaglenastat (CB-839)  HCl in pts with NF1 mutant Malignant 
peripheral nerve sheath tumor (MPNST), NF1 mutant other cancers, KEAP1/NRF2 & 
STK11/LKB1 pathway aberrant tumors. 
 
2.4 
Correlative Studies Background 
 
2.4.1 
Positron Emission Response Criteria in Solid Tumors (PERCIST) 1.0  Criteria  
for the assessment of Tumour Response to Treatment 
 
18Fluorodeoxyglucose (18F-FDG) PET is especially valuable in assessing activity of anticancer 
therapies that stabilize disease rather than shrink tumors (cytostatic vs. cytocidal), and has been 
demonstrated to be important in assessing response to treatment in some specific tumors (e.g., 
gastrointestinal solid tumors)(22, 23). Since Telaglenastat (CB-839)  HCl targets the metabolic 
pathway we hypothesize that (18F-FDG) PET may be useful in evaluating metabolic response. 
 
Reduced metabolic activity has been shown to indicate response to treatment and/or improved 
survival in patients with multiple cancers(24). Some tumors may be more suitable for assessment 
of response to treatment by metabolic activity than by anatomic measurements,  especially  those 
with bone metastases or with RECIST non-measurable disease(25). Moreover, FDG PET can 
provide more rapid response data than anatomical-based measurements(26, 27). 
 
Principles of assessing tumor response by PERCIST are similar to RECIST in many aspects, 
except response is evaluated by metabolic rather than anatomical criteria: 
- single target lesion assessed as primary response classifier between consecutive scans 
- up to 5 target lesions for each scan (maximum of 2 per organ) provide 
secondary response classifier data 
- metabolic response criteria defined for complete response, partial response, stable 
disease and progressive disease 

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Partial Metabolic 
Response 
≥ 50% decrease from baseline 
in SUVmax-BW in most avid 
target lesion relative to 
SUVmax-BW(liver) 
≥ 50% decrease from baseline in sum 
of SUVmax-BW of all target lesions 
relative to SUVmax-BW(liver) 
Progressive 
Metabolic Disease 
≥ 50% increase from baseline 
in SUVmax-BW in most avid 
target lesion relative to 
SUVmax-BW(liver) 
≥ 50% increase from baseline in sum 
of SUVmax-BW of all target lesions 
relative to SUVmax-BW(liver) 
New (evaluable) lesions 
New (evaluable) lesions 
Stable Metabolic 
Disease 
Does not meet other criteria 
Does not meet other criteria 
 
 
2.4.3 
cfDNA and analysis by next generation sequencing (NGS) 
 
Because it has been observed that intra-tumoral genetic heterogeneity is a major contributor to 
therapeutic failure across different tumor types an exploratory analysis will be performed to 
assess the concordance of the mutational status of plasma cell-free circulating tumor DNA and 
tumor tissue. 
 
Next generation sequencing will be used in this study to more comprehensively identify 
mutations in cell-free circulating tumor DNA. Concordance of mutational status between cell-
free circulating tumor DNA and tumor tissue in solid tumor patients will be assessed both before 
and after study drug administration. It is anticipated that the mutations identified in cell-free 
circulating tumor DNA and tissue samples obtained at the same timepoints will provide a better 
understanding of the capabilities of the assay platforms, as well as reconcile the longitudinal 
changes of genomic information from different sample sources within an individual patient. 
 
These data will be used to explore whether cell-free circulating tumor DNA can be used for 
precision medicine-based patient selection, as well as identify mutations that may be 
unresponsive to Telaglenastat (CB-839)  HCl. 
 
2.4.4 
Research Biopsies 
After obtaining informed consent, patients with solid tumors will undergo a mandatory tumor 
biopsy at screening, while optional biopsies are collected only upon patient consent. Patients 

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who have had a mixed tumor response will have biopsies of two lesions that have had different 
responses, if deemed safe and possible. 
 
Patients will undergo 3-6 core biopsies mandatory at screening and optional on Week 4 and upon 
disease progression. An optional FNA core will be collected at screening, Week 4 and upon 
disease progression. FNA and cores will be used for molecular profiling, including RNA 
sequencing, DNA sequencing, and RPPA, and PDX generation. 
 
If a patient is having a planned surgery or diagnostic procedure they will not have tumor biopsy. 
Instead residual tissue from the surgery or diagnostic procedure will be collected. 
 
2.4.5 
Tumor Analysis 
We will use biopsies obtained for research studies for assessment for putative markers of 
response/progression as described below. In addition, when archival tissue is available, we will 
test archival tumor samples from patients with unusual responses or rapid progression to targeted 
therapies. Whenever available, frozen tissue will be used. When possible, if more than one 
sample is available, the most recent sample or the sample that corresponds to the site in which 
the response was observed will be prioritized for molecular characterization. However, where 
possible, samples from multiple sites if available will be compared to determine the molecular 
heterogeneity between sites that could contribute to unexpected responses. Archival tissue will 
only be used if the pathology collaborators determine that archival tissue can be used for 
research, while reserving adequate archival tissue for patient care needs. 
 
The technologies used to characterize the tumor will depend on availability of frozen tumor, and 
specimen amount available. The technologies to be used is likely to evolve over the next few 
years, thus we will use state of the art and emerging technologies to comprehensively 
characterize the tumors from unusual responders. Findings identified with non-CLIA 
technologies will be verified with CLIA approaches as they become available. 
 
2.4.6 
DNA Sequencing 
Whenever possible, tumor DNA will be analyzed along with normal tissue DNA from the same 
patient in order to determine what somatic mutations are present in the tumor. 
 
Mutation status of key oncogenes including NF1, KEAP1, NRF2, and STK11/LKB1 pathway 
genes will be evaluated. The candidate genes will be assessed for target resequencing of genomic 
areas of interest, SNP genotyping, and copy number variation analysis through a combination of 
approaches. This could either be PCR or capture based selection of candidate genes. 
 
Next generation sequencing is newer technology that allows for massive parallel sequencing, that 
is high-throughput, with decreased time and cost of sequencing.   When frozen tumor is 
available, selected tumors from patients who have had dramatic responses (partial or complete 
responses or rapid progression), will be characterized in depth with next-generation sequencing. 
Exome sequencing, or full genomic sequencing will be performed. As technology becomes 
available, this will be extended to FFPE tissue. Samples may also be sent to commercial partners 
(eg Myriad, Foundation Medicine or Asuragen) for high-throughput candidate gene testing. 
Commercial collaborators will be blinded to patient identifiers. 

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2.4.7 
Reverse Phase Proteomic Arrays (RPPA) 
 
When samples are available from responders as well as non-responders to allow for comparison, 
we will also assess activation status of key cell signaling pathways by functional proteomics. 
 
We hypothesize that differences in functional proteomic profile may be associated with clinical 
benefit from targeted therapies. RPPA is a quantitative, sensitive, and reproducible proteomic 
technology. RPPAs involve the ‘dot’ array of lysates on nitrocellulose-coated slides and thus it is 
essential that using antibodies be validated as monospecific. The assays will quantitated using 
analysis of total and phosphopeptides and standard cell lysates placed on each slide. 
 
2.4.8 
Transcriptional Profiling of RNA 
 
We hypothesize that RNA expression signature of tumor tissue collected at baseline, during 
treatment and upon progression may predict clinical benefit from targeted therapies. RNA 
expression signature will be assessed when samples are available from responders as well as 
non-responders to allow for comparison. 
 
Tissue will be macrodissected and total RNA isolated using a Qiagen protocol. An Illumina 
sequencing library will be generated using an Illumina RNA Exome library preparation kit. 
Samples will be sequenced on an Illumina  NovaSeq instrument, yielding approximately 7 
million reads per sample. Sequencing reads will be matched to a collection of human transcripts. 
Logarithm of the normalized number of the matching reads will be used as a measure of the 
corresponding gene expression. Only genes with large enough counts of matching reads will be 
used in the analysis. We estimate that about 15,000 genes will be analyzed. 
 
2.4.9 
PDX Models 
 
To explore mechanisms of resistance of NF1-aberrant tumors to glutaminase inhibition using pre- 
and post-treatment tumor biopsies obtained from patients treated on a clinical trial of Telaglenastat 
(CB-839)  HCl, and patient-derived xenograft (PDX) models. 
 
CLIA certified molecular profiling is required for study entry. We will enroll patients into the 
different baskets. The primary end-point is radiographic response. If there are 4 or more 
responses out of the total sample of 27 patients, we will conclude that the treatment is worthy of 
further consideration. This optimal Simon two-stage design with a one-sided type-I error rate of 
5% provides 88% power to compare a null response rate of 5% and an alternative response rate 
of 25%. Patients will undergo matched pre- and post-treatment (week 4 and upon progression) 
biopsies that will be used to elucidate pharmacodynamic changes and adaptive responses by 
transcriptome and proteomic (RNAseq and RPPA) analyses. These changes will be correlated 
with response to treatment. The in vitro studies will inform the studies performed on these 
clinical samples. Finally, PDX models will be developed from tumor specimens obtained from 
patients with treated on this or other studies. These new models will provide an opportunity to 
test the effects of possible new drug combinations designed to overcome Telaglenastat (CB-839)  
HCl resistance. 

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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 
Patients must have histologically confirmed malignancy that is metastatic or 
unresectable. 
 
3.1.2 
Patient must have histopathologic confirmation of advanced solid tumor with NF1 
mutation, NF1 mutant MPNST, KEAP1/NRF2 mutant and STK11/LKB1 mutant tumors 
(Molecular profiling performed in any CLIA certified lab (Including tumor and cfDNA), 
eg. Caris, FoundationOne, FoundationAct, Oncomine, Guardant etc.) 
NOTE: For all cohorts annotation for actionability will be performed by the 
PRECISION ONCOLOGY DECISION SUPPORT (PODS) TEAM SHEIKH 
KHALIFA BIN ZAYED AL NAHYAN INSTITUTE FOR PERSONALIZED 
CANCER THERAPY (IPCT) 
THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER 
6565 MD ANDERSON BLVD, HOUSTON, TX 77030 
EMAIL: emailPCT@mdanderson.org 
WEBPAGE: https://pct.mdanderson.org/#/ 
 
3.1.3 Patient must have no standard therapies available. 
3.1.4 Patient must be aged greater than 18 years old for all cohorts. 
 
3.1.5 
Patients for NF1 mutant MPNST and NF1 mutant non-MPNST cohorts must be ≥ 40 kg. 
 
3.1.6 
Patient must be at least 4 weeks since any prior surgery or radiotherapy. 
 
3.1.7 
Females of childbearing potential must have a negative serum pregnancy test (≤ 14 days) 
prior to start of trial treatment. 
 
3.1.8 
RECIST measurable disease and biopsiable targetable lesion. 
 
3.1.9 
Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non- 
nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. See Section 12 for the 
evaluation of measurable disease. 
 
3.1.10 Patients with treated brain metastases are eligible if there is no evidence of progression 
for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination 
and brain imaging (MRI or CT) during the screening period. 
 
3.1.11 HIV-infected patients on effective anti-retroviral therapy with undetectable viral load 
within 6 months are eligible for this trial. 
 
3.1.12 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 

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3.1.13 Patients must have normal organ and marrow function as defined below: 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,000/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
≤ 1.5 × institutional upper limit of normal (ULN) 
and up to 3 ml/dL for patients with Gilbert’s disease 
− 
AST(SGOT)/ALT(SGPT) 
≤3 × institutional ULN and ≤5 × institutional ULN 
for patients with liver metastases 
− 
creatinine 
≤ institutional ULN, as age appropriate 
OR 
− 
glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
 
3.1.14 The effects of Telaglenastat (CB-839)  HCl on the developing human fetus are 
unknown. For this reason and because anti-metabolic agents like Telaglenastat (CB-839)  
HCl are known to be teratogenic, women of child-bearing potential and men must agree 
to use adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately. Men treated or enrolled on this 
protocol must also agree to use adequate contraception prior to the study, for the 
duration of study participation, and 4 months after completion of Telaglenastat (CB-839)  
HCl administration. 
 
3.1.15 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study. 
 
3.2.2 
Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1). 
 
3.2.3 
Patients who are receiving any other investigational agents. 
 
3.2.4 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Telaglenastat (CB-839)  HCl. 
 
3.2.5 
Patients with glioma will be excluded. 
 
3.2.6 
Patients with active or prior history of hepatitis B or C will be excluded. 
 
3.2.7 
Telaglenastat (CB-839)  HCl is a weak in vitro inhibitor of CYP2C9. Therefore, 
patients receiving any medications or substances that are substrates of CYP2C9 are 
eligible, but should use caution with substrates that have a narrow therapeutic index. 
Because the lists of these agents are constantly changing, it is important to regularly 

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consult a frequently-updated 
medical reference. As part of the enrollment/informed consent procedures, the patient 
will be counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the-counter 
medicine or herbal product. 
 
3.2.8 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.9 
Pregnant women are excluded from this study because Telaglenastat (CB-839)  HCl is 
anti-metabolic agent with the potential for teratogenic or abortifacient effects. Because 
there is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with Telaglenastat (CB-839)  HCl, breastfeeding should be 
discontinued if the mother is treated with Telaglenastat (CB-839)  HCl. 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH- 
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research. Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification. Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources. Women of 
childbearing potential should not be routinely excluded from participation in clinical research. 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators. NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually.. To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE or acting as 
a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation 
requirements per registration type are outlined in the table below. 

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In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
NOTE: Sites must utilize the Central IRB (CIRB) as their IRB of record to participate in this 
protocol. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally. 
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office. In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 
Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 10220 protocol page located on the 
CTSU Web site. Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS. To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS. 
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen. 
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-TX035, and 
protocol #10220. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided. (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 
Requirements For 10220 Site Registration 
 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
o For applicable ETCTN studies with a radiation and/or imaging (RTI) 
component, the enrolling site must be aligned to a RTI provider. To 
manage provider associations access the Provider Association tab on the 
CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to 

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add or remove associated providers. Sites must be linked to at least one 
IROC credentialed provider to participate on trials with an RT component. 
Enrolling sites are responsible for ensuring that the appropriate 
agreements are in place with their RTI provider, and that appropriate IRB 
approvals are in place. 
• Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each 
participating site will need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be 
submitted to the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual. If an 
individual has previously completed the training for another ETCTN 
study, the training does not need to be completed again nor does the 
certificate of completion need to be resubmitted to the CTSU. However, 
new versions of the Specimen Tracking system may require new training. 
o This training will need to be completed before the first patient enrollment 
at a given site. 
o Peter Clark and Diana Vulih are the main points of contact at Theradex for 
the training (PClark@theradex.com and DVulish@theradex.com, 
Theradex phone: 609-799-7580). 
 
4.2.3 
Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org (members’ area)  Regulatory Tab 
Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.4 
Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website. 
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 

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username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements as outlined by the Lead 
Network. It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their 
affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 
OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available to users on a 24/7 basis. It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records. 
 
4.3.2 
OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations: Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type. 
• To approve slot reservations or access cohort management: Be identified to 
Theradex as the “Client Admin” for the study. 
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes. 
• If applicable, all patients have signed an appropriate consent form and Health 
Insurance Portability and Accountability Act (HIPAA) authorization form. 
 
4.3.3 
Special Instructions for Patient Enrollment 
 
The following information will be requested: 

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• Protocol Number 
• Investigator Identification 
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification: Patients must meet all the eligibility requirements listed 
in Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate 
and unique identification numbers to the patient, a Universal patient ID (UPID) and a 
Treatment patient ID. The UPID is associated with the patient and used each and every 
time the patient engages with the ETCTN Biobanking and Molecular Characterization 
portion of this protocol. The UPID contains no information or link to the treatment 
protocol. IWRS will maintain an association between the UPID for ETCTN biobanking 
and molecular characterization and any treatment protocols the patient participates in, 
thereby allowing analysis of the molecular characterization results with the clinical data. 
 
Immediately following enrollment, the institutional anatomical pathology report for the 
diagnosis under which the patient is being enrolled must be uploaded into Rave. The 
report must include the surgical pathology ID (SPID) and the IWRS-assigned UPID for 
this trial. Important: Remove any personally identifying information, including, but 
not limited to, the patient’s name, initials, and patient ID# for this treatment trial, 
from the institutional pathology report prior to submission. 
 
4.3.4 
OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 28 days. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled. The Study Coordinator should be notified of cancellations as soon as possible. 

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• 
Tumor tissue specimens collected during biopsy procedures and fixed in formalin 
must be shipped on the same day of collection. 
• 
Tissue in formalin can be collected Monday through Wednesday and shipped 
overnight for arrival on Tuesday through Thursday at the EET Biobank at 
Nationwide Children’s Hospital. 
• 
Specimens submitted frozen (e.g., frozen tissue, frozen plasma) can be collected 
on any day but must be stored frozen and shipped to the EET Biobank on 
Monday through Thursday. In the event that frozen specimens cannot be shipped 
immediately, they must be maintained at -80°C. 
• 
Fresh blood specimens may be collected and shipped Monday through Friday. 
 
5.3 
Specimen Tracking System Instructions 
 
All biospecimens collected for this trial must be submitted using the ETCTN Rave Specimen 
Tracking System (STS) unless otherwise noted. The system is accessed through special Rave 
user roles: “CRA Specimen Tracking” for data entry at the treating institutions and 
“Biorepository” for users receiving the specimens for processing and storage at reference labs 
and the Biorepository. Please refer to the Medidata Account Activation and Study Invitation 
Acceptance link on the CTSU website under the Rave/DQP tab. 
 
Important: Failure to complete required fields in STS may result in a delay in sample 
processing. Any case reimbursements associated with sample submissions will not be credited 
if samples requiring STS submission are not logged into STS. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software. 
 
For questions regarding the Specimen Tracking System, please contact the Theradex Help Desk 
at CTMSSupport@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
5.3.1 
Specimen Labeling 
 
5.3.1.1 Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date and time (to be added by hand) 

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5.3.1.2 Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers (e.g., formalin jar): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., FFPE Block, Formalin Fixed Tissue, Fresh Tissue in Media, 
etc.) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number 
• Block number from the corresponding pathology report (archival only) 
• Collection date [if the study also requires recording the collection time on the label, 
include the time] (to be added by hand) 
 
5.3.1.3 Example of Specimen Label 
 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide. 
 
 
The QR code in the above example is for the Specimen ID shown on the second line. 
NOTE: The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. The last alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 
 
5.3.2 Overview of Process at Treating Site 

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5.3.2.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system. OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization and any prescribed slot 
assignments. If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis: 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.3.2.2 Rave Specimen Tracking Process Steps 
 
Step 1: Complete the Histology and Disease form (but do not upload reports until a 
specimen label can be applied to them) and the Baseline forms regarding Prior 
Therapies. Enter the initial clinical specimen data: 
• Specimen Tracking Enrollment CRF: Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, number of labels 
needed (include extra labels to apply to reports to be uploaded). CRF generates 
unique Specimen ID. 
 
Step 2: Print labels using report in EDC and collect specimen. 
• Label specimen containers and write collection date (and time for PK and 
oncometabolite samples) on each label. 
• After collection, store labeled specimens as described in Section 5.3.1. 
• Apply an extra specimen label to each report before scanning. Return to the 
Histology and Disease form to upload any initial Pathology, Radiology, 
Molecular Reports (up to 4), Surgical reports and Pathology Verification form 
(when applicable). Return to Specimen Tracking Enrollment CRF to upload 
any molecular report (one per specimen) and/or specimen specific pathology or 
related report (one per specimen). Uploaded reports should have PHI data like 
name, mailing address, medical record number or SSN redacted. Do not redact 
SPID, block number or relevant dates. 
 
Step 3: Complete specimen data entry. 
• Specimen Transmittal Form: Enter Collection date and time and other required 
specimen details. 
 
Step 4: When ready to ship, enter shipment information. 
• Shipping Status CRF: Enter tracking number, your contact information, 

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recipient, number of containers and ship date once for the 1st specimen in a 
shipment. 
• Copy Shipping CRF: Select additional specimens to add to an existing shipment 
referenced by the tracking number. 
 
Step 5: Print shipping list report and prepare to ship. 
• Print two copies of the shipping list, one to provide in the box, the other for your 
own records. 
• Print pathology or other required reports to include in the box. Be sure the printed 
copy includes the specimen label. 
 
Step 6: Send email notification. 
• For only one of the specimens in the shipment, click “Send Email Alert” 
checkbox on the Shipping Status CRF to email recipient. 
 
Step 7: Ship the specimen(s). 
 
5.4 
Specimen Collection 
 
5.4.1 Tumor Core Biopsies and Fine-Needle Aspiration 
 
Core needle biopsy (CNB) tumor tissues will be collected for molecular profiling. CNB or fine- 
needle aspiration (FNA) tumor tissue will be collected for PDX generation. Core biopsies at 
least 1 cm in length will be obtained through Interventional Radiology by a percutaneous 
approach using a 16-18-gauge needle; FNA will be obtained for PDX generation, if available. 
Only percutaneous biopsies will be performed on patients with solid tumors. However, 
excisional biopsy or endoscopic biopsy is allowed if medically indicated and can be used for 
analysis. 
 
At each tissue collection time point, at least 5 cores are requested. Each Core should be 
numbered sequentially in the order in which it was collected. 
 
If four or five cores are obtained, then fix Cores 1 and 2 in formalin, snap-freeze Core 3, suspend 
Core/FNA 4 in DMEM, and fix Core 5 in formalin. If more than 5 cores can be obtained, fix the 
additional cores (Cores 6-8) in formalin. 
 
If only three or fewer cores can be obtained, then fix all Cores in formalin. 
 
5.4.2 Formalin-Fixed Tumor Biopsies 
 
1. Label formalin-filled containers according to instructions in section 5.3.1. 
2. Obtain 16-gauge or 18-gauge core needle biopsy specimens, and place one core in 
each cassette. 
3. Snap the cassette lids closed and place cassettes into a formalin-filled pre-labeled 
container as soon as possible after collection to prevent air drying. Up to two 
cassettes may be placed in one formalin jar. 

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4. Secure the container lids and package containers into the shipping kit according to 
instructions in section 5.5. Keep tissue in formalin jars at room temperature until 
shipment to the EET Biobank. 
 
5.4.3 Snap-Frozen Biopsies 
 
1. Tissue should be frozen as soon as possible. Optimally, freeze within 30 minutes 
from resection. 
2. Label cryovial according to instructions in section 5.3.1. 
3. Using clean forceps place the tissue in a cryovial and freeze the tube in either vapor 
phase liquid nitrogen, on dry ice, or by immediate placement in a -70 to -80°C 
freezer. Keep frozen until shipment to the EET Biobank. 
 
5.4.4 DMEM Suspended Biopsies 
1. Tissue (core or FNA) should placed on ice immediately following collection. 
2. Label cryovial according to instructions in section 5.3.1. 
3. Wash tissue with ice-cold DMEM containing 1% penicillin/streptomycin and transfer 
into labeled cryovial. 
4. Centrifuge tissue at 2000rpm x 2 minutes. 
5. Resuspended in 50 μL DMEM. 
6. Freeze the tube in either vapor phase liquid nitrogen, on dry ice, or by immediate 
placement in a -70 to -80°C freezer. Keep frozen until shipment to the EET 
Biobank. 
 
5.4.5 Blood Collection 
 
5.4.5.1 Collection of Blood in cfDNA Streck Tube 
 
1. Label two 10 mL cfDNA Streck tube according to the instructions in section 5.3.1. 
2. Collect 20 mL of blood into the pre-labeled tube and gently invert to mix. Note: 
blood must be thoroughly mixed to ensure preservation of specimen. 
3. After collection, blood in cfDNA Streck tubes should never be refrigerated, as 
this will compromise the specimen. Blood collected in cfDNA Streck tubes is stable 
at room temperature. 
 
5.4.5.2 Collection of Blood in EDTA Tube for Plasma Processing 
 
1. Label EDTA tube(s) according to the instructions in section 5.3.1. 
2. Collect 10 mL of whole blood in EDTA (purple top) tube(s). After collection, keep 
blood at 4°C and process immediately (within 30-60 minutes of collection). 
3. Process plasma by centrifuging for 10 minutes at 1,200 x g at room temperature. 
4. Using a clean transfer pipette, transfer 1 mL of plasma into each of the labeled 
cryovials (using the label printed from the ETCTN Specimen Tracking System or 
following the instructions in section 5.3.1). Avoid picking up the blood cells when 
aliquoting by keeping the pipet above the cell layers and leaving a small amount of 
plasma in the tube. Tightly secure the cap of the vials before storage. Document the 

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time the plasma is processed. 
5. Store plasma cryovials upright in a specimen box or rack in an -70°C to -90°C or 
colder freezer prior to delivering to laboratory. Do not allow specimens to thaw after 
freezing. Document the time the plasma is frozen. 
6. Record the time the sample was processed to plasma and when the plasma is stored at 
-80°C. 
 
5.4.5.3 Collection of Blood in EDTA Tube for PK Plasma Processing for Mayo Clinic 
 
1. All “prior to drug administration” samples should be collected after at least 8 hours of 
fasting. Instruct patients to bring dose to the clinic and take dose (with food) after the 
baseline PK sample has been obtained on the days where PK sampling will occur. 
2. Label both 3 mL EDTA (purple top) tubes for Telaglenastat (CB-839)  HCl samples. 
3. Collect blood in pre-labeled tube and gently invert tube to mix. Place on wet ice (or store 
at 4°C) until processing. 
4. Blood must be processed for plasma isolation within 20 minutes of collection. The time 
at which the sample was collected from the patient and the time at which the plasma was 
stored in an aliquot at -80°C must be recorded in the Specimen Tracking System for 
every sample to ensure adequate handling. 
5. Centrifuge blood at 1,000 – 1,300 x g (relative centrifugal force [RCF]) for 10 minutes in 
a refrigerated centrifuge kept at 4°C. 
6. Following centrifugation, remove the plasma (top yellowish or clearish layer) and create 
aliquots in equal volumes of at least 0.5 mL in labeled 2 mL screw-top cryovials. Refer 
to Section 5.4.1.2 for labeling instructions. 
7. Tube labels must contain the information indicated in Section 5.4.1.2. These data should 
be recorded in nurse’s notes, on the flow sheet, and on the pharmacology reporting form 
that is to be sent with the samples. 
8. Freeze vials immediately upright in a -70 to -80°C freezer until shipment to the Mayo 
Clinic Cancer Center Pharmacology Shared Resource. See Section 5.6 for shipping 
instructions and address. 
 
5.4.5.4 Collection of Blood in EDTA Tube for Oncometabolite Analysis 
 
1. All “prior to drug administration” samples should be collected after at least 8 hours of 
fasting. Instruct patients to bring dose to the clinic and take dose (with food) after the 
baseline oncometabolite sample has been obtained on the days where oncometabolite 
sampling will occur. 
2. Label both 3 mL EDTA (purple top) tubes for Telaglenastat (CB-839)  HCl samples. 
3. Collect blood in pre-labeled tube and gently invert tube to mix. Place on wet ice (or store 
at 4°C) until processing. 
4. The peripheral blood sample must be centrifuged within 30 to 60 minutes of collection at 
4°C with a centrifuge speed of 2000 x g for 15 minutes. 
5. After centrifugation, remove plasma (top yellowish or clearish layer) and create 0.5 mL 
aliquots in labeled 2 mL screw-top cryovials. 
6. Immediately freeze the aliquots upright in a -70 to -80°C freezer until shipment to the 
EET Biobank according to the instructions below. The time at which the sample 

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was collected from the patient and the time at which the plasma was stored in an aliquot 
at -80°C must be recorded in the Specimen Tracking System for every sample to ensure 
adequate handling. 
 
5.5 
Shipping Specimens from Clinical Site to the EET Biobank 
 
Core biopsies that are fixed in formalin and fresh blood should be shipped as one 
shipment at ambient temperature, whenever possible. The same box sent with kit 
contents should be used to ship specimens to the EET Biobank. In winter months, 
please include extra insulation, such as bubble wrap, inside the shipping container. 
 
For formalin-fixed biopsies, if the corresponding anatomical pathology report is not 
available at the time of shipment, then the surgical and/or radiology report must be 
uploaded to the ETCTN specimen tracking system and included in the package, or the 
specimen will not be processed. 
 
5.5.1 
Specimen Shipping Instructions 
 
Tissue in formalin must be shipped on the day of collection. Collect and ship on Monday 
through Wednesday. 
 
Frozen specimens may be shipped on Monday through Thursday. 
 
Fresh blood may be shipped on Monday through Friday. Please select “Saturday 
Delivery” when shipping fresh blood on a Friday. 
 
5.5.1.1 Shipping Blood in an Ambient Shipper 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed. 
2. Prepare the SAF-T-TEMP Gel Pak for shipment. Note: If contents of the Pak are 
crunchy, place Pak in a warm water bath until gel is smooth. Do not refrigerate, freeze, 
or microwave. 
3. Place the SAF-T-TEMP Pak in bottom of insulated chest. Note: The insulated chest must 
be shipped inside the provided cardboard box(es). 
4. Place the blood collection tubes in zip-lock bags. 
5. Next, place blood into a biohazard envelope with absorbent material. Expel as much air 
as possible and seal the envelope securely. 
6. Place the biohazard envelope into a Tyvek envelope. Expel as much air as possible and 
seal securely. 
7. Place packaged blood collection tube(s) and a copy of the shipping manifest from the 
Sample Tracking System on top of SAF-T-TEMP Pak. 
8. Place the lid on the insulated chest. 

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9. Close the outer flaps of the shipping box and tape shut. 
10. Attach a shipping label to the top of the shipping container. 
11. Attach an Exempt Human Specimen sticker to the side of the box. 
12. Ship specimens via overnight courier to the address below. FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt. 
 
5.5.1.2 Shipping Frozen and Ambient Specimens in a Dual-Chamber Kit 
 
The Dual Chambered Specimen Procurement Kit is constructed to allow the shipment of 
frozen (on dry ice) and ambient (room temperature) specimens in the same container. Dry 
ice may be placed in either compartment of the kit but should not be put in both. The 
dual chambered kit is only used for shipments that contain both frozen and ambient 
specimens. If formalin-fixed tissue is shipped separately (not in the same shipment as 
frozen specimens), then it must be shipped using institutional shipping supplies. 
 
• Frozen specimens may be shipped on Monday through Thursday. Ensure that 
sufficient dry ice is included to completely encase the specimens to maintain 
specimen integrity during shipment. 
• Formalin-fixed tissue may only be shipped on Monday through Wednesday. 
 
1. 
Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are 
tightly sealed. If included in the shipment, formalin jar lids should be wrapped in 
parafilm. 
2. 
Pre-fill one of the kit chambers about 1/3 with dry ice. 
3. 
Place the specimens in zip-lock bags. Use a separate zip-lock bag for each 
specimen type. 
4. 
Two biohazard envelopes are provided so that ambient and frozen specimens can 
be packaged separately. 
• Place the zip-lock bags containing room temperature specimens in a biohazard 
envelope with absorbent material. Expel as much air as possible and seal the 
envelope securely. 
• Place the zip-lock bags containing frozen specimens into the other biohazard 
envelope containing absorbent material. Expel as much air as possible and seal 
securely. 
5. 
Put each secondary envelope into a Tyvek envelope. Expel as much air as 
possible and seal each envelope securely. 
6. 
Quickly place the Tyvek envelope containing frozen specimens (e.g., frozen 
tumor, serum, etc.) in the kit compartment that is pre-filled with dry ice. Place the 
Tyvek envelope on top of the dry ice.  Cover the specimens with additional dry 
ice until the compartment is almost completely full. 
7. 
Place the Styrofoam lid on top to secure specimens during shipment. Do not tape 
the inner chamber shut. 
8. 
Place the Tyvek envelope containing ambient temperature specimens (e.g., 
formalin-fixed tissue) in the other kit compartment at room temperature. 
9. 
Insert a copy of the required forms into a plastic bag and place in the kit chamber 

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with the ambient specimens. 
10. Place the Styrofoam lid on top of the kit compartment to secure specimens during 
shipment. Do not tape the inner chamber shut. 
11. Close the outer lid of the Specimen Procurement Kit and tape it shut with durable 
sealing tape. Do not completely seal the container. 
12. Complete a FedEx air bill and attach to top of shipping container. 
13. Complete a dry ice label. 
14. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
15. Ship specimens via overnight courier to the address below. FedEx Priority 
Overnight is strongly recommended to prevent delays in package receipt. 
 
5.5.2 Shipping Address 
 
Ship to the address below. Ship formalin-fixed and fresh blood specimens the same day of 
specimen collection. Do not ship specimens the day before a holiday. 
 
EET Biobank 
2200 International Street 
Columbus, OH 43228 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred. 
 
NOTE: The EET Biobank FedEx Account will not be provided to submitting institutions. 
 
5.5.3 Contact Information for Assistance 
For all queries, please use the contact information below: 
EET Biobank 
Phone: (614) 722-2865 
E-mail: BPCBank@nationwidechildrens.org 
 
5.6 
Shipping to the Mayo Clinic Cancer Center Pharmacology Shared Resource 
 
5.6.1 Plasma Pharmacokinetics Instructions 
 
Samples should be processed at the local sites as described in Section 5.3.3.2. 
 
1. Place the plasma specimens in zip-lock bags. Use a separate zip-lock bag for each time 
point and collection. 

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42 
 
2. Place the zip-lock bags in a biohazard bag containing absorbent material. Expel as much 
air as possible and seal the envelope. 
3. Layer the bottom of a Styrofoam container with dry ice until it is approximately one-third 
full. Place the biohazard bag containing frozen specimens on top of the dry ice. Cover the 
specimens with the dry ice until the compartment is almost completely full. 
4. Insert a copy of the specimen manifest from the Specimen Tracking System into a plastic 
bag and place in the kit chamber. 
5. Place the Styrofoam lid on top to secure specimens during shipment. Do not seal the 
Styrofoam container. 
6. Place the Styrofoam container into a card board box. Close the card board lid with durable 
sealing tape. 
7. Complete a FedEx air bill and attach to top of shipping container. 
8. Complete a dry ice label. 
9. Attach the dry ice UN1845 label and an Exempt Human Specimen sticker or UN3373 
sticker to the side of the shipping container. 
10. Arrange for courier pickup. Note: FedEx Priority Overnight is strongly recommended for 
next day delivery to prevent delays in package receipt. 
 
5.6.2 Plasma Pharmacokinetics Shipping Address 
 
Ship by FedEx First Overnight Courier on dry ice to the following Mayo Clinic Cancer Center 
Pharmacology Shared Resource for storage and analysis. Please ship samples Mondays to 
Thursday only and send an email to reid@mayo.edu prior to shipment to alert us of a shipment. 
 
Attn: Joel Reid, Ph.D. 
Mayo Clinic 
221 4th Avenue SW 
Guggenheim- 17-37 
Rochester, MN 55905 
Phone: (507) 284-0822 
Fax: (507) 293-0107 
Email: reid@mayo.edu 

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44 
 
 
5 
WES/ RNAseq 
WES/ RNAseq 
Exploratory 
To confirm 
retrospectively 
eligibility mutations. 
Hypothesis generating 
M/O 
Mandatory 
pre-treatment 
Optional on 
week 4 and at 
progression 
DNA,  
and RNA 
from FFPE 
Tissue* 
 
Germline DNA 
from blood in 
pre-treatment 
Streck-Tube 
(control for 
WES control 
only) 
3-6 cores 
PBMC from 
one Streck 
tube 
NCI MoCha 

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46 
 
 
5.8 
Integrated Correlative Studies 
 
5.8.1 Quantification of Serum Glutamine, Glutamate, Aspartate, Asparagine – Integrated 
Laboratory Correlative Study 
 
5.8.1.1 
Specimen(s) Receipt and Processing at the EET Biobank 
 
Upon receipt, frozen plasma vials will be accessioned, barcoded, and banked in a - 
80°C freezer until distribution for testing. 
5.8.1.2 
Site(s) Performing Correlative Study 
Ian R. Lanza, Ph.D. 
Metabolomics Core Director 
Mayo Clinic Hospital, Saint Marys Campus 
Alfred Building, Fifth Floor, Room 417 
200 First St. SW 
Rochester, MN 55905 
Phone: 507-255-8147 
Email: lanza.ian@mayo.edu 
 
5.9 
Exploratory/Ancillary Correlative Studies 
 
5.9.1 
Circulating tumor DNA (cfDNA) – Exploratory/Ancillary Laboratory Correlative Study 
#1 
 
5.9.1.1 Specimen(s) Receipt and Processing at the EET Biobank 
 
Upon receipt, plasma will be processed from blood in cfDNA Streck tubes. Plasma will 
be stored in 1-mL aliquots in a -80°C freezer until distribution for testing. 
 
5.9.1.2 
Site Performing Correlative Study 
 
This study will be conducted at the MoCha, Frederick National 
Laboratory for Cancer Research (FNLCR) under the supervision 
of Chris Karlovich, Ph.D. (chris.karlovich@nih.gov). 
 
5.9.1.3    Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
   Specimens will be shipped from the EET Biobank to: 
 
   MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
    1050 Boyles St. 
    Bldg. 459, Rm. 125 
    Frederick, MD 21702 
    Attn: Alyssa Chapman or Ruth Thornton 
 
5.9.1.4 Contact information for notification of specimen shipment 
 

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    Thomas Forbes, mochasamplereceiving@nih.gov 
 
5.9.2 
Whole Exome Sequencing and RNA Sequencing – Exploratory/Ancillary Laboratory 
Correlative Study #2 
 
5.9.2.1 
Specimen(s) Receipt and Processing at the EET Biobank 
 
Formalin-fixed tissue at Screening and Week 4, and Progression/Relapse time points 
will be used for this assay. Tissue in formalin will be processed and embedded upon 
receipt at the EET Biobank, and slides will be cut from the biopsies. For all tumor 
specimens, the first section will be stained with H&E for pathology quality control 
review to assess tumor content; unstained slides will be macrodissected, if needed, 
and scraped for DNA and RNA co-extraction. DNA will be banked in a stock vial 
and RNA will be divided into 5 aliquots; all nucleic acids will be stored in a - 80°C 
freezer until distribution for testing. 
 
DNA will be extracted from blood collected in cfDNA Streck tubes at the Screening 
time point following plasma processing. DNA will be stored in a -80°C freezer until 
distribution for testing. 
 
5.9.2.2 
Site Performing Correlative Study 
 
This study will be conducted at the MoCha, Frederick National Laboratory for 
Cancer Research (FNLCR) under the supervision of Chris Karlovich, Ph.D. 
(chris.karlovich@nih.gov). 
 
5.9.2.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.9.2.4 
Contact information for notification of specimen shipment 
 
Thomas Forbes, mochasamplereceiving@nih.gov. 
 
5.9.3 
RPPA and PDX – Exploratory/Ancillary Laboratory Correlative Study #3 
 
5.9.3.1 
Specimen(s) Receipt and Processing at the EET Biobank 
 
The snap frozen tissue core (Core 3) collected at Screening, Week 4, and 
Progression/Relapse time points will be used for RPPA analysis. Upon receipt, snap- 
frozen tissue will be accessioned, barcoded, and banked in a liquid nitrogen vapor 
phase freezer until distribution. 

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DMEM suspended core/FNA (Core/FNA 4) from Screening, Week 4, and 
Progression/Relapse time points will be used for the exploratory PDX generation. 
Upon receipt, DMEM suspended tissue will be accessioned, barcoded, and banked in 
a liquid nitrogen vapor phase freezer until distribution. 
5.9.3.2 
Site(s) Performing Correlative Study 
Dr. Yiling Lu 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd., Room B7.4606 
Houston, TX 77030 
Phone: (713) 563-7529 
Email: gsingh@mdanderson.org 
 
6. TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 10. Appropriate dose modifications are described in Section 7. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
This phase 2 basket clinical trial utilizes single agent CB 839 HCl at the recommended phase 2 
dose at 800 mg (Table 2 and 3). 
 
Table 2. Treatment Plan for Telaglenastat (CB-839)  HCl as a single agent 
Category 
Treatment Plan 
Telaglenastat (CB-839)  HCl 
agent dose 
800 mg 
Telaglenastat (CB-839)  HCl 
administration and 
schedule 
Telaglenastat (CB-839)  HCl dose by mouth twice daily, 
approximately 12 hours apart, immediately after a meal on 
day 1 to day 28, repeated every 28 days 
Duration of treatment 
Repeated every 28 days until unacceptable toxicity or 
disease progression. Refer to Section 6.3 for additional 
stopping criteria. 
Duration of the study 
Upon completion of follow-up procedures. 
Duration of follow-up 
Every 3 months (±) 14 days after the last administered 
treatment dose 
 
If patient develop toxicity then the dose can be reduced as per Table 3. 
 
Table 3. Dose Reductions of Telaglenastat (CB-839)  HCl 
Dose Level 
Telaglenastat (CB-839)  
HCl Dose 

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Starting dose 
800 mg BID 
First dose reduction 
600 mg BID 
Second dose reduction 
400 mg BID 
Third dose reduction 
Discontinue 
Telaglenastat (CB-839)  
HCl 
 
The patient will be requested to maintain a medication diary of each dose of medication. The 
medication diary will be returned to clinic staff at each clinic visit. 
6.1.1 Telaglenastat (CB-839)  HCl 
 
When taken with food, Telaglenastat (CB-839)  HCl has demonstrated a slightly higher (~1.3 
fold) absorption, and patients have experienced significantly fewer incidences of elevated LFTs 
compared to the fasted state. Telaglenastat (CB-839)  HCl should be taken with breakfast and 
dinner, roughly 12 hours apart. 
 
6.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of Telaglenastat (CB-839)  HCl with other 
concomitantly administered drugs, the case report form must capture the concurrent use of all 
other drugs, over- the-counter medications, or alternative therapies. The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential for drug 
interactions. The study team should check a frequently-updated medical reference for a list of 
drugs to avoid or minimize use of. Appendix B (Patient Drug Information Handout and Wallet 
Card) should be provided to patients if available. 
 
Telaglenastat (CB-839)  HCl is metabolized by human hepatocytes primarily through amide 
hydrolysis. Telaglenastat (CB-839)  HCl does not appear to induce CYP drug-metabolizing 
enzymes and only weakly inhibits CYP2C9 (~40-50% inhibition at 5µM) in vitro. Although 
Telaglenastat (CB-839)  HCl is not expected to inhibit CYP2C9 at the exposure levels planned, 
caution is warranted when administering Telaglenastat (CB-839)  HCl to patients taking drugs 
that are highly dependent on CYP2C9 for metabolism and have a narrow therapeutic index. A 
list of medications that are CYP2C9 substrates is provided in Appendix D. 
 
Preliminary PK data generated in single agent Phase 1 studies indicate that concomitant use of 
proton pump inhibitors (PPIs) may reduce absorption of Telaglenastat (CB-839)  HCl, resulting 
in decreased systemic exposure. Although patients are not required to discontinue their use of 
these agents, the strong preference is for patients to discontinue PPIs prior to joining the study. 
Antagonists of the H2 histamine receptor (e.g., ranitidine, famotidine, etc.) may be substituted 
for PPIs. For patients unable to discontinue PPI therapy or that require restarting PPI therapy 
while on study, administration of Telaglenastat (CB-839)  HCl with an acidic beverage (e.g., 
orange juice) or supplement (e.g., citric acid) may be an option. If an acidic beverage/oral 
supplement is administered along with the Telaglenastat (CB-839)  HCl dose, it should be 
recorded on the appropriate eCRF, including the identity of the beverage/supplement, dosage, 
and start and stop dates of administration. 
 

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6.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
6.3.1 
Disease progression 
 
6.3.2 
Intercurrent illness that prevents further administration of treatment 
 
6.3.3 
Unacceptable adverse event(s) 
 
6.3.4 
Patient decides to withdraw from the study 
 
6.3.5 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
6.3.6 
Clinical progression 
 
6.3.7 
Patient non-compliance 
 
6.3.8 
Pregnancy 
 
o All women of childbearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
6.3.9 
Termination of the study by sponsor 
 
6.3.10 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.4 
Duration of Follow Up 
 
Patients will be followed every 3 months (±) 14 days after the last administered treatment dose 
or until death, whichever occurs first. Patients removed from study for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
 
Based on available data, adverse events that are most likely to be observed with Telaglenastat 
(CB-839)  HCl treatment include fatigue, gastrointestinal events (nausea, vomiting, anorexia), 
photophobia and elevated liver function tests. Careful application of the dose modification 
guidelines and close observation of the subjects should minimize the potential risk of dosing 

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with Telaglenastat (CB-839)  HCl. The study personnel must be able to recognize and diagnose 
these potential adverse events and initiate prompt intervention. Guidelines for Telaglenastat 
(CB-839)  dosage modification for clinically significant non-hematological and hematological 
toxicities that cannot be clearly determined to be unrelated to study drug, as well as for their 
management, are listed below. 
 
Dose Level 
Telaglenastat (CB-839)  
HCl Dose 
Starting dose 
800 mg BID 
First dose reduction 
600 mg BID 
 
Second dose reduction 
400 mg BID 
Third dose reduction 
Discontinue 
Telaglenastat (CB-839)  
HCl 
 
Dose Modification Guidelines for Hematologic Toxicity 
 
Toxicity Grade (CTCAE v5) 
Telaglenastat 
(CB-839)  
HCl 
Grade 3/4 Anemia 
(< 8.0 g/dL Hgb) 
Hold and resume at the same dose level upon 
resolution to ≤ Grade 1 or baseline 
Grade 3/4 Neutropenia 
(ANC < 1000/μL) 
Hold and resume at the same dose level upon 
resolution to ≤ Grade 1 or baseline. 
Grade 3/4 Thrombocytopenia 
(Platelets < 50,000/μL) 
Hold and resume at the same dose level upon 
resolution to ≤ Grade 1 or baseline. 
ANC = absolute neutrophil count, Hgb = hemoglobin. 
 
Dose Modification Guidelines for Nonhematologic Toxicity 
 
Toxicity Grade (CTCAE v5) 
Telaglenastat 
(CB-839)  
HCl 
Nonhematologic laboratory 
Grade ≥ 3 events determined 
to be clinically significant and 
attributable to study drug(s), 
except for abnormal liver tests 
If symptoms are not tolerable, hold and resume at 
the same dose level upon recovery to ≤ Grade 1 or 
baseline. If toxicity recurs, hold and restart at next 
lower dose. 

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Grade ≥ 3 abnormal liver 
function tests 
Dose reductions should be considered in any patient 
who develops drug-related Grade 2 elevated ALT, 
AST, or bilirubin lasting longer than 1 week. 
A patient who develops Grade ≥ 3 elevated ALT, 
AST, or bilirubin should have study treatment held 
and restarted at a reduced dose after ALT, AST, and 
bilirubin levels resolve to at least Grade ≤ 1 or 
baseline. 
In patients with recurrence of drug-related Grade ≥ 3 
elevated ALT, AST, or bilirubin at the lowest dose 
level, study treatment should be discontinued. 
In patients who develop ALT/AST elevations > 3 × 
ULN in combination with a bilirubin elevation > 2 × 
ULN without reasonable other explanation, drug- 
induced liver injury should be suspected and 
 
treatment interrupted. Reinstitution of study 
treatment after recovery of ALT, AST, and bilirubin 
to Grade 1 or baseline level must be discussed and 
approved by the Drug Monitor. 
Non-laboratory Grade ≥3 AEs 
determined to be clinically 
significant and attributable to 
the study drug 
For Grade 3 AEs: Hold and resume at the same dose 
level or the next lower dose level of Telaglenastat 
(CB-839)  upon recovery to ≤ Grade 1 or baseline. 
For Grade 4 AEs: Permanently discontinue 
Telaglenastat (CB-839). 
 
Telaglenastat (CB-839)  HCl treatment may be delayed for up to 2 weeks from the last dose. 
Delays longer than 2 weeks are allowed only in cases where the delay was due to a non-drug 
related cause. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 10.1. 
 
8.1 
Telaglenastat (CB-839)  HCl 
 
8.1.1 Telaglenastat (CB-839)  HCl (NSC# 795998) 
 
Chemical Name: 
N-[5-[4-[6-[[2-[3-(trifluoromethoxy)phenyl]acetyl]amino]-3- 
pyridazinyl]butyl]-1,3,4-thiadiazol-2-yl]-2-pyridineacetamide 
 

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53 
 
 
Classification: 
Glutaminase Inhibitor 
 
Molecular Formula:  C26H24F3N7O3S 
M.W.: 571.57 
 
Mode of Action: Telaglenastat (CB-839)  HCl is a potent and selective reversible inhibitor of 
glutaminase activity. It is an allosteric and noncompetitive inhibitor of both GAC (“glutaminase 
C”) and KGA (“kidney glutaminase”) isoforms of glutaminase (GLS), but does not inhibit 
glutaminase-2. 
 
How Supplied: Telaglenastat (CB-839)  HCl is supplied as 200 mg white to off-white oval coated 
tablets. Each tablet contains 200 mg Telaglenastat (CB-839)  HCl salt which is equivalent to 188 
mg of Telaglenastat (CB-839)  free base. Tablet excipients include microcrystalline cellulose, 
lactose monohydrate, sodium starch glycolate, magnesium stearate, and Opadry II White (coating). 
The approximate dimensions (L x W x H) are 
14.5 mm x 6.9 mm x 6.0 mm (0.57” x 0.273” x 0.236”). Each 50-count bottle is sealed with a 
tamper-evident seal and a child-proof cap. Tablets can be transferred to another bottle per 
institutional procedure prior to dispensing. 
 
In late 2021 PMB will transition to a new formulation of telaglenastat (CB-839) HCl. This 
new telaglenastat (CB-839) HCl formulation is supplied as 200 mg purple, oval, 
coated tablets embossed with the letters “TEL” on one side of the tablet. Each tablet 
contains 200 mg CB-839 HCL salt which is equivalent to 188 mg of CB-839 free base. 
Tablet excipients include microcrystalline cellulose, lactose monohydrate, sodium starch 
glycolate, magnesium stearate, and Opadry® II 85F90035 Purple (coating). This color is 
free from potentially allergenic dyes and is an approved color for US and EU markets. The 
approximate dimensions (L x W x H) are 14.5 mm x 6.9 mm x 6.0 mm (0.57” x 0.273” x 
0.236”). 
 
Each 240-count bottle is sealed with a tamper-evident seal and a child-proof cap. The 
packaging consists of white opaque high-density polyethylene (HDPE) plastic bottles 
closed with a child resistant cap (CRC) and sealed with a tamper-evident induction seal. 
No rayon in bottle. Tablets can be transferred to another bottle per institutional procedure 
prior to dispensing. 
 
Storage: Store at room temperature (20°C-25°C). Excursions +/- 5°C are permitted. 
If a storage temperature excursion is identified, promptly return Telaglenastat (CB-839)  HCl to 
(20°C-25°C) and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.

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54 
 
 
Stability: Stability studies are ongoing. 
 
Route of Administration: Oral, approximately 12 hours apart, with food. Administer the first 
dose immediately after breakfast, the second dose approximately 12 hours later. Doses should be 
taken at approximately the same times each day. Missed doses may be taken if it is not more than 
three hours past the scheduled administration time for the missed dose. Vomited doses should not 
be made up. 
 
Metabolism: In in vitro studies, Telaglenastat (CB-839)  HCl is metabolized by amide hydrolysis 
and to a lesser extent, P450-mediated hydroxylation. 
 
Potential Drug Interactions: In in vitro data, Telaglenastat (CB-839)  HCl is a weak o inhibitor 
of CYP2C9; therefore, concomitant medications that are metabolized by CYP2C9 should either be 
given with caution (including closely monitoring for signs of toxicity or altered efficacy) or 
substituted with a non-CYP2C9 substrate. Telaglenastat (CB-839)  HCl is not an inhibitor of 
CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP3A4 nor an inducer of CYP1A2, 
CYP2B6, and CYP3A4. 
 
Telaglenastat (CB-839)  HCl requires low pH conditions for optimal solubilization. Concomitant 
use of proton pump inhibitors (PPIs) should be avoided due to significantly reduced exposure to 
Telaglenastat (CB-839)  HCl. Patients may be switched to shorter acting agents such as histamine 
H2 receptor antagonists (H2RA) and as-needed antacid buffering agents (e.g. calcium carbonate, 
magnesium hydroxide and aluminum hydroxide) since, based on limited clinical data, they do not 
appear to result in a significant reduction of Telaglenastat (CB-839)  HCl exposure. It is 
recommended that Telaglenastat (CB-839)  HCl be dosed at least 2 hours before or at least 2 hours 
after antacid therapy. 
 
Patient Care Implications: Women of child-bearing potential must have a negative pregnancy test 
prior to starting Telaglenastat (CB-839)  HCl and use two forms of effective birth control while 
receiving Telaglenastat (CB-839)  HCl. 
 
Availability 
Telaglenastat (CB-839)  HCl is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Telaglenastat (CB-839)  HCl is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.4). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 

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(FDF). If there are several participating investigators at one institution, CTEP- 
supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution. 
 
Sites may order initial agent supplies when a subject is being screened for enrollment 
onto the study. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status. For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time. 
Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page. Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.3 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application. Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, 
a “current” password, and active person registration status. Questions about IB access 
may be directed to the PMB IB Coordinator via email. 
 
 
8.1.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• IB Coordinator: IBCoordinator@mail.nih.gov 
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 

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Ho: CB 839 - 
Response Rate 
(RR) in disease 
Ha: Target RR 
of combination 
in disease 
Calculation 
Statistic & 
Significance 
Responsible 
investigator 
5 % 
25 % 
ORR = pre-therapy 
It is a one-sample 
Kenneth 
sum longest diameters 
binomial test with 
Hess 
(5 or less lesions) / 
alpha = 5%. 
post-therapy sum 
longest diameters 
(same 5 or less lesions) 
 
3. Pharmacodynamic tumor oncometabolite levels of glutamine, glutamate, and aspartate 
between 0 and 8 hours post- Telaglenastat (CB-839)  HCl dose among patients with 
persistent or recurrent metastatic cancers. 
 
We will assess PD changes before and after treatment using the Wilcoxon signed rank 
test. For normally distributed data, with 27 patients we can detect a standardized mean 
difference (mean difference divided by standard deviation of differences) = 0.6 with 85% 
power assuming a two-sided 5% alpha. We will correlate these changes with response to 
treatment using Wilcoxon rank sum test. We will also perform a ROC curve analysis. 
With 27 patients, if the response rate is roughly 50%, we can detect an area under the 
ROC curve = 0.83 as significantly higher than 0.5 (the null value) with 85% power 
assuming a 5% alpha. 
 
Assuming 20 patients have data, we will have 85% power to detect a standardized effect 
size of 0.706 using a paired t-test and we can detect an area under the ROC curve of 
0.887. Assuming 15 patients have data, we will have 85% power to detect a standardized 
effect size of 0.832 using a paired t-test and we can detect an area under the ROC curve 
of 0.947. 
 
9.4 
Reporting and Exclusions 
 
9.4.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with CB- 
839 HCl. 
 
9.4.2 Evaluation of Response 
 
All patients who receive at least one dose of study drug are evaluable for response. 
Patients who are enrolled but who do not receive any study drug may be replaced. 
 
10. 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 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 

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• For expedited reporting purposes only: 
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 CTEP-AERS 
 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps- 
ctep.nci.nih.gov/ctepaers). The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm 
). These requirements are briefly outlined in the tables below (Section 10.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals: Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter. CTEP-AERS provides a copy feature for 
other e-mail recipients. 
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be provided. 

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10.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
N/A 
 
10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS. In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP. 
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to 
describe the event: 
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 

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Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 

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11. STUDY CALENDAR 
 
Cycles 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Onward14 
EOT 
FU/EOS15 
Days 
w/in-28d 
1 
8 
15 
22 
1 
8 
15 
22 
1 
Every 3 
Months 
Window 
-3d 
± 3d 
± 3d 
± 3d 
± 3d ± 3d ± 3d ± 3d 
± 3d 
± 3d 
± 14d 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X------------------------------------------------------------------------------------------------------- 
X 
Adverse event evaluation 
X------------------------------------------------------------------------------------------------------- 
X 
Physical exam1 
X 
X 
X 
X 
X 
X 
X 
Performance status (PS)1 
X 
X 
X 
X 
X 
X 
X 
Vital signs1 
X 
X 
X 
X 
X 
X 
X 
Weight1 
X 
X 
X 
X 
X 
X 
X 
Height1 
X 
Pregnancy Test (B-HCG)2 
X 
X 
X 
X 
Hematology: CBC w/diff, 
plts3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation: PT/PTT/INR11 
X 
X 
X 
Serum chemistry3, 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis3, 5 
X 
As clinically indicated 
12-Lead EKG6 
X 
As clinically indicated 
Radiologic evaluation7 
( CT, MRI or PET/ CT ) 
X 
X 
X 
Tumor measurements8 
X 
X 
X 
Tumor-specific markers, such 
as CA19-9, CA-125, CEA, 
PSA etc. 9 
X 
X 
X 
Whole blood for 
oncometabolomics10 
X 
X 
X 
Whole blood for 
pharmacokinetics (PK)10 
X 
X 
Whole blood for exploratory 
genetic biomarkers11 
X 
X 
X 
X 
Tumor Biopsy12 
X 
X 
X 
Study Drug: Telaglenastat 
(CB-839)  HCl13 
X --------------------------------------------------------------------------------------- X 
Survival14 
X 
Footnote: 
1. 
Physical exam, PS, Vital sign and weight will be performed at Screening, C1-2 D1 and 15, C3 onward D1 and at End of 
Treatment (EOT). Height will be done at screening. 
2. 
Required of all females of child-bearing potential. Screening serum pregnancy test must occur within 3 days prior to C1D1. 
Urine pregnancy tests will be performed on D1 of every cycle. 

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3. 
Does not need to be repeated if the Screening sample was obtained within 3 days prior to C1D1 unless a clinically significant 
change is indicated. 
4. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. Serum chemistry should be determined at the times indicated. 
5. 
All patients with treatment-emergent proteinuria that is > 2+ on urine dipstick are required to have a quantitative urine protein 
evaluation on a random sample and a calculation of the urine protein/urine creatinine ratio. If the results demonstrate 
nephrotic range proteinuria, a 24-hr total urine protein evaluation should be performed. 
6. 
12-Lead EKG (single) will be performed at screening and as clinically indicated. 
7. 
Radiologic evaluation (CT or MRI or PET-CT) will be performed at screening within 28 days prior to C1D1, every 2 cycles 
(8 weeks), +/- 7 days, for the first 13 cycles, then every 3 cycles (12 weeks) +/- 7 days and EOT.  
8. 
Tumor measurement: Per RECIST v1.1 for solid tumors and per Modified RECIST (Byrne and Nowak 2004) for pleural 
mesothelioma. Tumor measurements are repeated every 2 cycles (every 8 weeks) +/- 7 days, for the first 13 cycles, then 
every 3 cycles (12 weeks) +/- 7 days and EOT. Documentation (radiologic) must be provided for patients removed from 
study for progressive disease. 
9. 
Tumor-specific markers, such as CA19-9, CA-125, CEA, PSA, etc. will be tested at the time with radiologic evaluation. 
10. Whole blood sample for oncometabolomics and pharmacokinetics will be collected on Day 1 and Day 15 prior to drug 
administration and after drug administration at 0.5, 1, 2, 4, and 8 hours. In addition, oncometabolomics will be collected on 
Week 4 (C1D22) post Telaglenastat (CB-839)  HCl dose. All “prior to drug administration” samples should be collected after 
at least 8 hours of fasting (the patient must not eat or drink anything but water). All “after drug administration” samples 
should be collected after patients are dosed with Telaglenastat (CB-839) HCl immediately after a meal. 
11. Optional whole blood sample for exploratory genetic and biomarker testing for cfDNA and WES/RNASeq will be collected at 
screening, at C1D22, C2D22 and disease progression (EOT) for patients who are consented for such analysis under fasting 
conditions. 
12. Tumor Biopsy: Tumor biopsy at screening are required for all patients for exploratory analyses. In addition, archival tissue 
samples will be collected if available. Optional on-treatment biopsy will be collected on week 4 (C1D22 ± 3 days) and upon 
disease progression at EOT. Coagulation tests must be performed and evaluated prior to all biopsy procedures. Patients are 
consented for tumor biopsy. 
13. Telaglenastat (CB-839)  HCl dose by mouth twice daily, immediately after a meal on continuous dose from day 1 to day                 28 in a 
28-day cycle. 
Dosing may occur prior to, during, or after the clinic visit, according to the patient’s usual administration schedule. 
14. For patients with ≥ SD for at least 13 cycles who are on a steady dose for ≥ 2 cycles, study assessments may be reduced to 
every 3 cycles (i.e., at Cycles 16, 19, 22, etc.) and 3 cycles worth of study medication can be provided at clinic visits. 
15. FU/EOS = Follow Up/End of Study: Patient will be followed for survival every 3 months (±) 14 days after EOT visit. This 
may be by telephone contact. 

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12. MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 12 weeks. 
In addition to a baseline scan, confirmatory scans should also be obtained at least 4 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with Telaglenastat (CB-839)  HCl. 
 
Evaluable for objective response. All patients who receive at least one dose of study drug 
are evaluable for response. Patients who are enrolled but who do not receive any study 
drug may be replaced. 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
 
12.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area are considered non- 
measurable unless there has been clear evidence of progression of the subject lesion 
following radiation therapy. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in 
follow-up, only the short axis will be measured and followed. 

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Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- 
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non- 
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters. If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum. The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 

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69 
 
 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed. 
 
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 

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Endoscopy, Laparoscopy The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008]. In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG- 
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 

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greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.1.4 Response Criteria 
 
12.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm). 
(Note: the appearance of one or more new lesions is also considered progressions). 
 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. No FDG-PET at baseline and a positive FDG-PET at 
follow-up: If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed 
as a new site of disease on CT, additional follow-up CT scans are needed to 
determine if there is truly progression occurring at that site (if so, the date of PD will 
be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is not progressing 
on the basis of the anatomic images, this is not PD. (Note: A ‘positive’ FDG-PET 
scan lesion means one which is FDG avid with an uptake greater than twice that of 
the surrounding tissue on the attenuation corrected image.) 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 

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Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
12.1.4.3 
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. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. It is required for this 
study. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment. 

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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
FDG-PET response will not be used in the evaluation of best overall response. 
 
12.1.5 Duration of Response 
 
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 progressive 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, including the baseline measurements. 
 
12.1.6 Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the time from the date of enrollment to the earliest 
date of progression or death. Progression-free survival (PFS) will be summarized by histology, if 
data warrant, using Kaplan-Meier quartile estimates along with 2-sided 95% CIs. If the subject 
does not have a documented date of progression or death, PFS will be censored at the date of the 
last adequate assessment. Further details on rules for censoring will be provided in the RAP. 
Progression-free survival (PFS) will be reported at the time of final analyses, regardless of the 
maturity of the data and then be updated when at least 70% of events are met. 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10.0 
(Adverse Events: List and Reporting Requirements). 

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13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section. The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal. 
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance. Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study. This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave. Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS). To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Rave Read-Only, Rave CRA (Lab Admin), Rave SLA, or 
Rave Investigator) on either the LPO or participating organization roster at the enrolling site. To 
hold the Rave CRA role or Rave CRA (Lab Admin) role, the user must hold a minimum of an 
AP registration type. To hold the Rave Investigator role, the individual must be registered as an 
NPIVR or IVR. Associates can hold read-only roles in Rave. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 

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to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e- 
mail at ctsucontact@westat.com. 
 
13.2.1 Method 
 
For studies assigned for CTMS Routine Monitoring: 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP). Information on CTMS reporting is available at: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. On- 
site audits will be conducted on an 18-36 month basis as part of routine cancer center site 
visits. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission. For CTMS monitored studies, after users 
have activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 
or by email at CTMSSupport@theradex.com for additional support with Rave and 
completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave. 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks. The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS. Metrics for timeliness will be followed and 
assessed on a quarterly basis. For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received. Queries will be issued by CTMS directly within Rave. The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve. Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP. Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm 
) and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 

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recommended phase 2 dose (RP2D) and a description of any dose-limiting toxicities 
(DLTs). CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics- 
resources/interoperability-and-semantics/metadata-and-models). Customized eCRFs will 
be included when appropriate to meet unique study requirements. The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation. CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex. CDUS submissions are performed by Theradex 
on a monthly basis. The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm 
). 
 
13.3 
CTEP Multicenter Guidelines 
N/A 
 
13.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 

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a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non- 
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review. Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. 
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 

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The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 

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14. REFERENCES 
 
1. 
Sheikh TN, Patwardhan PP, Cremers S, Schwartz GK. Targeted inhibition of 
glutaminase as a potential new approach for the treatment of NF1 associated soft tissue 
malignancies. Oncotarget. 2017;8:94054-68. 
2. 
Patil S, Chamberlain RS. Neoplasms associated with germline and somatic NF1 gene 
mutations. Oncologist. 2012;17:101-16. 
3. 
Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, et al. Somatic 
mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455:1069-75. 
4. 
Cawkwell L, Lewis FA, Quirke P. Frequency of allele loss of DCC, p53, RBI, WT1, 
NF1, NM23 and APC/MCC in colorectal cancer assayed by fluorescent multiplex polymerase 
chain reaction. Br J Cancer. 1994;70:813-8. 
5. 
Ahlquist T, Bottillo I, Danielsen SA, Meling GI, Rognum TO, Lind GE, et al. RAS 
signaling in colorectal carcinomas through alteration of RAS, RAF, NF1, and/or RASSF1A. 
Neoplasia. 2008;10:680-6, 2 p following 6. 
6. 
Li Y, Bollag G, Clark R, Stevens J, Conroy L, Fults D, et al. Somatic mutations in the 
neurofibromatosis 1 gene in human tumors. Cell. 1992;69:275-81. 
7. 
Sangha N, Wu R, Kuick R, Powers S, Mu D, Fiander D, et al. Neurofibromin 1 (NF1) 
defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations. 
Neoplasia. 2008;10:1362-72, following 72. 
8. 
Sen S, Hess K.R., Roszik J, Shaw KR, Heymach J, Huang. L, et al. Characterization 
of KEAP1-NRF2 genomic alterations across diverse tumor types: Co-occurring alterations, 
survival outcomes, and implications for targeting cancer metabolism. ASCO abstracts 2018. 
9. 
Marcus AI, Zhou W. LKB1 regulated pathways in lung cancer invasion and 
metastasis. J Thorac Oncol. 2010;5:1883-6. 
10. 
Zhang Y, Kwok-Shing Ng P, Kucherlapati M, Chen F, Liu Y, Tsang YH, et al. A 
Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. Cancer Cell. 
2017;31:820-32 e3. 
11. 
Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to 
cancer therapy. Nat Rev Cancer. 2016;16:619-34. 
12. 
Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L, et al. Targeting 
glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 
inhibition. Blood. 2015;126:1346-56. 
13. 
Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, et al. 
Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol 
Cancer Ther. 2014;13:890-901. 
14. 
Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc 
regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to 
glutamine addiction. Proc Natl Acad Sci U S A. 2008;105:18782-7. 
15. 
Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression 
of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. 
Nature. 2009;458:762-5. 
16. 
Stalnecker CA, Erickson JW, Cerione RA. Conformational changes in the activation 
loop of mitochondrial glutaminase C: A direct fluorescence readout that distinguishes the 
binding of allosteric inhibitors from activators. J Biol Chem. 2017;292:6095-107. 
17. 
Matre P, Velez J, Jacamo R, Qi Y, Su X, Cai T, et al. Inhibiting glutaminase in acute 

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myeloid leukemia: metabolic dependency of selected AML subtypes. Oncotarget. 2016;7:79722- 
35. 
18. 
Meric-Bernstam F, Tannir N, Harding J, Voss M, Mier J, DeMichele A, et al. Phase 1 
study of CB-839, a small molecule inhibitor of glutaminase, in combination with everolimus in 
patients (pts) with clear cell and papillary renal cell cancer (RCC). European Journal of 
Cancer.69:S12-S3. 
19. 
Sheikh TN, Patwardhan PP, Schwartz GK. Abstract 19: Neurofibromatosis type 1 
(NF1) status determines sensitivity of soft tissue sarcoma and melanoma cell lines to glutaminase 
inhibitors. Cancer research. 2016;76:19-. 
20. 
Romero R, Sayin VI, Davidson SM, Bauer MR, Singh SX, LeBoeuf SE, et al. Keap1 
loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med. 
2017. 
21. 
Skoulidis F, Byers LA, Diao L, Papadimitrakopoulou VA, Tong P, Izzo J, et al. Co- 
occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with 
distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 2015;5:860-77. 
22. 
Van den Abbeele AD. The lessons of GIST--PET and PET/CT: a new paradigm for 
imaging. Oncologist. 2008;13 Suppl 2:8-13. 
23. 
Van den Abbeele AD, Ertuk M. FDG-PET to Measure Response to Targeted 
Therapy: The Example of Gastrointestinal Stromal Tumor and Imatinib Mesylate (Gleevec). PET 
Clin. 2008;3:77-87. 
24. 
Subbiah V, Chuang HH, Gambhire D, Kairemo K. Defining Clinical Response 
Criteria and Early Response Criteria for Precision Oncology: Current State-of-the-Art and Future 
Perspectives. Diagnostics (Basel). 2017;7. 
25. 
Stroobants S, Goeminne J, Seegers M, Dimitrijevic S, Dupont P, Nuyts J, et al. 
18FDG-Positron emission tomography for the early prediction of response in advanced soft 
tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer. 2003;39:2012-20. 
26. 
O JH, Wahl RL. PERCIST in Perspective. Nucl Med Mol Imaging. 2018;52:1-4. 
27. 
Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving 
Considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50 Suppl 1:122S- 
50S. 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

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APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient  
is enrolled on a clinical trial using the 
experimental study drug, Telaglenastat (CB-839)  HCl. This clinical trial is sponsored by the 
National Cancer Institute. This form is addressed to the patient, but includes important 
information for others who care for this patient. 
 
These are the things that you as a healthcare provider need to know: 
 
Telaglenastat (CB-839)  HCl interacts with a certain specific enzyme in your liver: 
 
• The enzyme in question is CYP2C9, which may stop or slow the breakdown of drugs 
broken down by this enzyme. 
February 2018 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet. 
 
Telaglenastat (CB-839)  HCl may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial. It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study. When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort. It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions. You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial. 
 
These are the things that you and they need to know: 
 
Telaglenastat (CB-839)  HCl must be used very carefully with other medicines that use certain 
liver enzymes to be effective. Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any medicines and herbal supplements that 
are considered substrates of CYP2C9 isoenzyme. 
 
• Please be very careful! Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug. Speak to your doctors or 
pharmacist to determine if there could be any side effects. 
• Proton Pump Inhibitors (or PPIs, acid suppressing drugs) are to be avoided. Patients may 
receive shorter acting agents such as histamine H2 receptor antagonists (H2RA) and as- 
needed antacid buffering agents (e.g. calcium carbonate, magnesium hydroxide and 

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aluminum hydroxide). It is recommended that Telaglenastat (CB-839)  HCl be dosed at 
least 2 hrs before or at least 2 hr after antacid therapy. 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine. Your study doctor’s name is 
  
and he or she can be contacted at 
 
  
. 

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APPENDIX C 
INTEGRAL BIOMARKER ASSAY 
 
Patients will be enrolled on the trial based on any commercially available CLIA-certified assay 
using somatic tissue testing like Caris, FoundationOne, or Oncomine or cfDNA assays like 
FoundationAct or Guardant. Below are publically available specimen instructions and assay 
specifications: 
 
Caris 
 
 
FoundationOne 
 
 
Oncomine 
 
 
FoundationAct 
 
 
 
Guardant 
 

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APPENDIX D 
INTEGRATED BIOMARKER - METABOLOMICS 
 
As of May 14, 2018, the Biomarker Review Committee (BRC) of the Cancer Therapy Evaluation 
Program (CTEP) has approved of the Mayo Clinic Metabolomics Resource Core for the 
quantification of serum glutamine, glutamate, aspartate and asparagine. 
 
CB-839 is a bioavailable oral glutaminase inhibitor which disrupts glutamine anaplerosis into the 
TCA cycle by inhibiting the conversion of glutamine to glutamate. Thus, less carbon substrate 
from glutamine will enter into the TCA cycle. Hence, the investigators hypothesize that if there 
is effective inhibition of glutaminase (GLS1) in patients with different malignancies being 
treated with CB-839, the levels of glutamine will increase but the concurrent levels of glutamate 
and aspartate will decrease compared to baseline values. 
 
Description of Assay 
 
This assay will be used as a pharmacodynamic marker for response to the glutaminase inhibitor 
drug CB-839. 
 
L-Asparagine, L-Aspartic Acid, L-Glutamine, L-Glutamic Acid are measured by liquid 
chromatography mass spectrometry (LC-MS). Briefly, serum samples are spiked with internal 
standards then deproteinized with cold methanol followed by centrifugation at 10,000 g for 5 
minutes. The supernatant is immediately derivatized with 6-aminoquinolyl-N- 
hydroxysuccinimidyl carbamate according to Waters’ AccQ-Fluor Kit. A 10-point calibration 
standard curve underwent similar derivatization procedure after the addition of internal 
standards. Both derivatized standards and samples are analyzed on a triple quadrupole mass 
spectrometer coupled with an Ultra Pressure Liquid Chromatography system. Data acquisition is 
done using select ion monitor (SRM). Concentrations of each unknown are calculated against 
each perspective calibration curve. 

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APPENDIX E 
ASSAY INFORMATION 
 
Next-generation sequencing assays (WES and RNA-Seq) will be performed at the Molecular 
Characterization Laboratory on the purified DNA and RNA aliquots provided by the 
Biorepository. Reverse Phase Protein Array (RPPA) will be performed at the University of 
Texas MD Anderson Cancer Center (MD Anderson) on snap-frozen tissue provided by the 
Biorepository. 
 
Whole-Exome Sequencing/Targeted-Exome Sequencing (WES/TES) 
 
DNA libraries will be generated using the Agilent SureSelect XT Target Enrichment System, and 
quantitated fluorescence based quantitation. Library samples are then loaded on a flow cell prior 
to sequencing on a NovaSeq 6000 or NovaSeq X. 
 
RNA-Seq 
 
RNA libraries will be generated using the Illumina RNA Exome kit and final libraries are 
quantified by a fluorescence quantitation. Library samples are loaded onto a flow cell and 
sequenced on a NovaSeq 6000 or NovaSeq X. 
 
Reverse Phase Protein Array (RPPA) 
 
Frozen tumors will be lysed and protein extracted. Lysates will be manually serial-diluted in 5 
two-fold dilutions with lysis buffer and printed on nitrocellulose-coated slides using an Aushon 
Biosystems 2470 arrayer. Slides will be probed with approximately 300 validated primary 
antibodies followed by detection with appropriate Biotinylated secondary antibodies (Goat anti- 
Rabbit IgG, Goat anti-Mouse IgG, or Rabbit anti-Goat IgG). The signal obtained will be 
amplified using a Cytomation–catalyzed system of Avidin-Biotinylated Peroxidase (Vectastain 
Elite ABC kit from Vector Lab) binding to the secondary antibody and catalyzing Tyramide- 
Biotin conjugation to form insoluble biotinylated phenols. Signals will be visualized by a 
secondary streptavidin-conjugated HRP and DAB colorimetric reaction. The slides will be 
scanned, analyzed, and quantified using Array-Pro Analyzer software (MediaCybernetics) to 
generate spot intensity (Level 1 data). 
 
Please refer to the MD Anderson RPPA Core Facility website for additional details including 
workflow and data processing: 
https://www.mdanderson.org/research/research-resources/core-facilities/functional-proteomics- 
rppa-core/rppa-process.html 

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APPENDIX F 
CYP2C9 SUBSTRATES 
 
CYP2C9 Substrates with a narrow therapeutic index* 
 
• 
S-Warfarin (anticoagulant) 
• 
Phenytoin (antiepileptic) 
 
*Narrow therapeutic index is defined as “CYP substrates with narrow therapeutic range refers 
to drugs whose exposure-response relationship indicates that small increases in their exposure 
levels by the concomitant use of CYP inhibitors may lead to serious safety concerns (e.g., 
Torsades de Pointes).” 
 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla 
beling/ucm093664.htm 
 
Other CYP2C9 Substrates 
 
• 
NSAIDs (analgesic, antipyretic, anti-inflammatory) 
o celecoxib 
o lornoxicam 
o diclofenac 
o ibuprofen 
o naproxen 
o ketoprofen 
o piroxicam 
o meloxicam 
o suprofen 
• 
fluvastatin (statin) 
• 
sulfonylureas (antidiabetic) 
o glipizide 
o glibenclamide 
o glimepiride 
o tolbutamide 
o glyburide 
• 
irbesartan (to treat hypertension) 
• 
losartan (to treat hypertension) 
• 
sildenafil (in erectile dysfunction) 
• 
terbinafine (antifungal) 
• 
amitriptyline (tricyclic antidepressant) 
• 
fluoxetine (SSRI antidepressant) 
• 
nateglinide (antidiabetic) 
• 
rosiglitazone (antidiabetic) 
• 
tamoxifen (SERM) 
• 
torasemide (loop diuretic) 
• 
ketamine 

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APPENDIX G 
MEDICATION DIARY 
 
Study Name: A Phase II Basket Trial of Glutaminase Inhibitor (BeGIN) Telaglenastat (CB-839)  
HCl in Patients with NF1 Aberrations, NF1 Mutant Malignant Peripheral Nerve Sheath Tumors 
(MPNST), KEAP1/NRF2 and LKB1 Aberrant Tumors 
 
 
CTEP Study ID: 10220 
 
Patient Initials:   
 
 
Patient Identification Number:   
 
 
 
Instructions to the patient: 
 
PLEASE complete and return this dosing diary along with any unused Telaglenastat (CB-
839)  HCl and the container(s). You will receive a new dosing diary for each treatment 
cycle. Thank you for your participation in the very important study! 
 
You will take: Telaglenastat (CB-839)  HCl 
 
Each time you take the Telaglenastat (CB-839)  HCl study medication, your dose is 800 mg 
and is made up of four 200 mg tablets. 
 
How to store your Telaglenastat (CB-839)  HCl study medication 
The Telaglenastat (CB-839)  HCl study medication must be stored at room temperature (below 
30ºC/86ºF) at all times. Please read the medication label for additional storage instructions. 
 
How to take your Telaglenastat (CB-839)  HCl study medication 
• The Telaglenastat (CB-839)  HCl study medication is to be taken twice daily for 28 
days (1 cycle is 28 days). 
• Each dose is taken orally (by mouth) with food around the same time each morning or 
evening. Administer the first dose immediately after breakfast, the second dose 
approximately 12 hours later. 
o Please note that on Cycle 1 Days 1 and 15, your morning dose of Telaglenastat 
(CB-839)  HCl will be taken while fasting (at least 8 hours without eating or 
drinking anything but water). 
 
If you miss the daily dose according to the schedule, 
• The dose should be taken as soon as possible, but not more than 3 hours after the missed 
dose was scheduled. 
• Vomited doses should not be made up. 
 
How to complete your Telaglenastat (CB-839)  HCl dosing diary 
It is very important that you complete this dosing diary as accurately as possible and bring it 

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completed along with all remaining study medication (used and unused containers) to your next 
clinic visit. 
 
Please fill-in this dosing diary each day that you are scheduled to take study medication. Write 
the date in the box marked Date. Please record the exact time you took your study medication 
and how many tablets taken. 
 
It is important that you do not miss any of your study medication, but if you do please provide a 
reason in the “Comments” box along with any other comments you would like the doctor to 
know. 
 
Cycle number:  
 
_ 
Start date:   
 
Patient Signature:   
 

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Cycle number:   
 
Start date: 
Patient Identification Number: 
DAY 
Date 
(MM/DD/YYYY) 
Morning Dose 
Evening Dose 
Comments: 
Use the space below to make notes about things 
you would like to tell the doctor (including reasons 
for missed dose, unusual symptoms you experience, 
other medicine you have taken and anything else 
you think would be of interest.) 
Time 
Tablets 
taken 
Number 
of tablets 
taken 
Time 
Tablets 
taken 
Number 
of tablets 
taken 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 

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DAY 
Date 
(MM/DD/YYYY) 
Morning Dose 
Evening Dose 
Comments: 
Use the space below to make notes about things 
you would like to tell the doctor (including reasons 
for missed dose, unusual symptoms you experience, 
other medicine you have taken and anything else 
you think would be of interest.) 
Time 
Tablets 
taken 
Number 
of tablets 
taken 
Time 
Tablets 
taken 
Number 
of tablets 
taken 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28