A Phase Ib Study of Osimertinib (AZD9291) and Telaglenastat (CB-839) HCl in Patients With EGFR Mutant Non-Small Cell Lung Cancer
Phase: PHASE1
Conditions: Advanced Lung Non-Small Cell Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 10216 
Version Date:  09/17/2024 
1 
 
 
 To:             CTEP Protocol and Information Office 
From:       Dwight Owen, M.D. 
Date:  
TBD 
Re: 
Amendment 19 of Protocol #10216:  “A Phase Ib Study of Osimertinib (AZD9291) and 
Telaglenastat (CB-839) HCl in Patients with EGFR Mutant Non-Small Cell Lung Cancer” 
 
 
SUMMARY OF CHANGES – Protocol 
 
I. Comments Requiring a Response – Major Issues: 
# 
Section 
Comments 
1. 
3.4.5 
Updated safety guidance needs to be integrated after/before Section 3.4.4: 
Should participants with HIV infection be included, patients are only eligible if 
they meet all the following criteria:  
• Undetectable viral RNA load for 6 months  
• CD4+ count of >350 cells/μL  
• No history of AIDS-defining opportunistic infection within the past 12 months  
• Stable for at least 4 weeks on the same anti-HIV medications  
   
In patients with HIV, viral RNA load and CD4+ cell count should be monitored 
per local standard of care (e.g., every 3 months).  
  
PI Response: This has been added. 
 
CTEP Comment: 
Because the study accrual is permanently closed, CTEP will not approve 
eligibility changes to this protocol. 
PI Response: This has been deleted. 
 
 
2 5.5.5 
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: This has been corrected. 
 
 

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Version Date:  09/17/2024 
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II. Comments Requiring a Response– Administrative & Editorial Issues: 
# 
Section 
Comments 
2. 
13.5, 
13.6 
Please delete the following language from the Protocol: 
 
13.5 Genomic Data Sharing Plan 
 
The investigators and statistician and/or bioinformaticians for a study will have 
access to all data on mutations and variants stored in the Theradex Data Base and 
the GDC.  This information will be sequestered from access throughout the study 
until it is analyzed for purposes of reporting and publishing of the study results.  As 
specified in the CRADA for the agents used in the clinical study, the pharmaceutical 
collaborator will have at least 6 months, longer if needed for a regulatory filing, to 
review the data and or receive copies of the data once the study is completed and 
analyzed, or sooner, if specified for purposes of generating Intellectual Property.  
Once these timeframes have been exceeded, the data will be available through a 
Data Access Committee (DAC) in the GDC following NCI and Collaborator review 
of the proposals.  
 
13.6   Incidental/Secondary Findings Disclosure Procedure 
 
Given the potential clinical implications conferred by detecting a germline and/or 
somatic mutation in one of the proven cancer susceptibility genes, this protocol will 
use the following disclosure procedure, consistent with the recommendations of the 
American College of Medical and Genomics (ACMG) (Green et al., 2013 and Kalia 
et al., 2016): 
 
The NCI Molecular Characterization Laboratory will review the mutations/variants 
once at the time of initial specimen evaluation according to the most recent version 
of the ACMG guidance on variants.  The NCI Molecular Characterization 
Laboratory will not re-review all specimens received if a new version of the ACMG 
guidance is published after the initial review. 
 
For each participant with a pathogenic or likely pathogenic germline and/or somatic 
variant detected in the WES of blood (as defined in the ACMG guidance), the NCI 
Molecular Characterization Laboratory will report to the Program Director or 
Scientific Officer the UPID and variant(s) identified.  The Program Director or 
Scientific Officer will contact Theradex to obtain the name of the protocol, 
investigator treating the patient, and the Principal Investigator of the grant.  The 
treating physician will be contacted by phone and in writing to ask the patient 
whether he or she is interested in learning more about the finding. 
 
If the patient wants to know more, the physician should contact the Program Director 
for more information about the mutation/variant.  The treating physician and a 

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Version Date:  09/17/2024 
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# 
Section 
Comments 
medical genetics counselor should meet with the patient to discuss the importance 
and meaning of the finding, but not the finding itself, and notify the patient that this 
research finding must be confirmed by Sanger sequencing at the patient’s/patient 
insurer’s expense in a Clinical Laboratory Improvement Amendments (CLIA)-
approved laboratory.  The treating physician and genetic counselor should inform 
the patient of the confirmed result and its meaning and significance to the patient.  
If desired, the patient may elect to undergo genetic counseling and confirmatory 
CLIA-approved clinical testing on his or her own.  Neither the research laboratory 
nor the National Cancer Institute will be responsible for the costs incurred for any 
confirmatory genetic testing or counseling.  
PI Response:  This has been deleted. 
3. 
Global 
Sections are numbers incorrectly.  
Please revert to the original numbering. (ex. 6.1- 6.5 and 8.1- 8.1.5) 
PI Response:  This has been updated. 
 
4. 
6.1 
 
Agent Administration 
Remove: 
All protocol therapy with CB-839 will end on 10/31/24. After that date, patients 
may remain on osimertinib single agent at the investigator discretion until meeting 
other off therapy criteria. 
With:  
All protocol therapy with Telaglenastat (CB-839) will end on 2/28/25. The clinical 
supply of Telaglenastat will no longer be available after the terminal lot shelf life 
dating of 2/28/25 is reached. After that date, patients may remain on Osimertinib 
single agent at the investigator discretion until meeting other off therapy criteria. 
PI Response:  This has been updated. 
 
 
III. Recommendations: 
# 
Section 
Comments 
5. 
9.2 
Section 9.2 now contains the following statement: 
 
“With a total of 16 patients in MTD/RP2D (6 +10), we will have a 95% lower-limit 
confidence interval of 12.3% to rule out the null ORR rate of 10% when the target ORR is 
30% using the exact (Clopper-Pearson) method.” 
 
This statement is somewhat confusing. To help clarify, please modify the language to 
include the number of responses necessary to rule out a null of 0.1 at the one-sided 0.05 
level (in this case, I believe that number is 5). This can be addressed at the time of the next 
amendment.  

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Version Date:  09/17/2024 
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# 
Section 
Comments 
PI Response: This section has been updated. 
6. 
5.11.1.2 
For WES/RNAseq, revise this section to update the site performing correlative 
study: 
 
5.11.1.2 Site(s) Performing Correlative Study 
 
WES and RNAseq will be performed on archival samples by the MoCha, 
Frederick National Laboratory for Cancer Research (FNLCR) under the 
supervision of Chris Karlovich, Ph.D. (chris.karlovich@nih.gov). 
 
PI Response: This section has been updated. 
 
 
 
 
 
IV. Company Comments – Requiring a Response:  
# 
Section 
Comments 
7. 
3.4.5 
Updated safety guidance needs to be integrated after/before Section 3.4.4: 
Should participants with HIV infection be included, patients are only eligible if 
they meet all the following criteria:  
• Undetectable viral RNA load for 6 months  
• CD4+ count of >350 cells/μL  
• No history of AIDS-defining opportunistic infection within the past 12 months  
• Stable for at least 4 weeks on the same anti-HIV medications  
   
In patients with HIV, viral RNA load and CD4+ cell count should be monitored 
per local standard of care (e.g., every 3 months).  
  
PI Response: This has been added. 
 
8. 
P69 
Per a recent safety update, the section on SJS and  needs to be updated to include 
toxic epidermal necrolysis (TEN): 
Erythema Multiforme, and Stevens-Johnson syndrome and Toxic epidermal 
necrolysis  
Case reports of Erythema multiforme (EM) and toxic epidermal necrolysis have 
been uncommonly reported, and Stevens-Johnson syndrome (SJS) have been 
uncommonly and rarely reported, respectively, in association with osimertinib 
treatment. Before initiating treatment, patients should be advised of signs and 

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# 
Section 
Comments 
symptoms of EM, and SJS and TEN. If signs and symptoms suggestive of EM 
develop, close patient monitoring and drug interruption or discontinuation of 
osimertinib should be considered. If signs and symptoms suggestive of SJS appear, 
osimertinib should be interrupted. Osimertinib should be or discontinued 
immediately if SJS or TEN is diagnosed.  
PI Response: Updated as requested 
9. 
9.2 
Additional clarity is needed about the change in power brought about by the 
change in sample size. The new text is OK, but if less than 5/16 (31%) respond the 
lower limit will cross the 10% boundary, this could perhaps be clearer.  Also, the 
analysis of 16 rather than 21 patients is almost a 25% drop so any efficacy analysis 
should be treated with even more caution than previously advised. Any efficacy 
analysis should be treated with even more caution than previously advised. 
PI Response: This section has been updated. 
10. 
5.1.1 
and 
5.1.2 
Revise footnote #1 in each of the Specimen Collection Tables to the following: 
 
1For archival tissue, a copy of the anatomic pathology report corresponding to 
the tissue collection procedure must be sent with the tissue and uploaded to 
Rave.  If submitting slides, then slides must be processed in order, and numbered 
sequentially (e.g., H&E stained slide is created first and labeled 1, unstained slides 
are then created and numbered 2 – 51).  Refer to section 5.3 for additional 
information. 
PI Response: Updated as recommended 
11. 
5.5.1 
and 
5.5.2 
Revise the beginning of Section 5.5 as shown below to clarify the forms: 
 
5.5.1 General Shipping Information 
 
5.5.1.1 Required Forms for Specimen Submissions  
 
Specimen 
Required Forms 
Archival  
1. Shipping List 
2. Anatomic Pathology Report correspon
tissue collection procedure 
 
Blood  
1. Shipping List 
 
Each document submitted with the specimen must be labeled with a label 
printed from the STS, or the Universal ID and Patient Study ID.  
 
Minimum required personally identifiable information: 
• Remove patient identifiers such as name, date of birth, medical record 
number, social security number, and insurance information from the 
pathology or other clinical reports. 

NCI Protocol #: 10216 
Version Date:  09/17/2024 
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# 
Section 
Comments 
• Do not remove the date of procedure, surgical pathology ID (SPID) 
number, block number, and diagnosis.   
 
 
5.5.2  Specimen Shipping Instructions 
 
When kits are provided, the shipping container 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. 
 
• Ambient Blood (cfDNA Streck tubes) is shipped at room temperature on 
Monday through Friday. Please select Saturday delivery if shipping blood 
on a Friday. Ship blood in cfDNA Streck tubes shipped in ambient 
shipping containers provided by the EET Biobank. 
 
• Frozen specimens (plasma) may be shipped on Monday through 
Thursday. Frozen specimens are batch shipped. Shipments should contain 
no more than 31 cryovials so that sufficient dry ice can be included to 
completely encase the specimens in order to maintain specimen integrity 
during shipment. 
 
• FFPE tissue block or slides may be shipped on Monday through 
Thursday. Slides are shipped in containers provided by the submitting site. 
 
PI Response: Updated as recommended. 
 
12. 
5.5.5 
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 
E-mail: BPCBank@nationwidechildrens.org 
 
PI Response: Updated as recommended. 
 
13. 
5.8 
In the Biomarker Table, replace the current laboratory text for WES, 
WES/RNAseq, and cfDNA sequencing with the following new text: 
 
Chris Karlovich / MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) 
PI Response: Updated as recommended. 
14. 5.10.2.2
-
5.10.2.5 
For WES, revise these sections to update the site performing correlative study, 
shipping, and shipping contact information and remove the assay information: 
 
5.10.2.2 Site(s) Performing Correlative Study 

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Version Date:  09/17/2024 
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# 
Section 
Comments 
 
WES will be performed on archival tumor and germline samples by the MoCha, 
Frederick National Laboratory for Cancer Research (FNLCR) under the 
supervision of Chris Karlovich, Ph.D. (chris.karlovich@nih.gov). 
 
5.10.2.3Assay Information 
 
DNA libraries will be generated using the Agilent SureSelect XT 
Target Enrichment System and quantitated via digital droplet PCR 
(ddPCR). Library samples are denatured, diluted, and clustered on the 
cBot clonal amplification system in preparation for sequencing on the 
Illumina HiSeq 2500. 
 
5.10.2.3 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 
 
5.10.2.4 Contact information for notification of specimen shipment 
 
Thomas Forbes, mochasamplereceiving@nih.gov 
 
PI Response: Updated as recommended. 
15. 5.11.1.2
-
5.11.1.5 
For WES/RNAseq, revise these sections to update the site performing correlative 
study, shipping, and shipping contact information and remove the assay 
information: 
 
5.11.1.2 Site(s) Performing Correlative Study 
 
WES and RNAseq will be performed on archival samples by the MoCha, 
Frederick National Laboratory for Cancer Research (FNLCR) under the 
supervision of Chris Karlovich, Ph.D. (chris.karlovich@nih.gov). 
5.11.1.3 Assay Information  
WES 
DNA libraries will be generated using the Agilent SureSelect XT Target 
Enrichment System and quantitated via ddPCR. Library samples are 
denatured, diluted, and clustered on the cBot clonal amplification system 
in preparation for sequencing on the Illumina HiSeq 2500. 
 

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Version Date:  09/17/2024 
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# 
Section 
Comments 
RNAseq 
 
RNA libraries will be generated using the Agilent SureSelect XT Target 
Enrichment System and quantitated via ddPCR. Library samples are 
denatured, diluted, and clustered on the cBot clonal amplification 
system in preparation for sequencing on the Illumina HiSeq 2500. 
 
5.11.1.3 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 
 
5.11.1.4 Contact information for notification of specimen shipment: 
 
Thomas Forbes, mochasamplereceiving@nih.gov 
 
PI Response: Updated as recommended. 
16. 5.11.2.2
-
5.11.2.4 
For cfDNA, revise these sections to update the site performing correlative study, 
shipping, and shipping contact information: 
 
5.11.2.2 Site(s) Performing Correlative Study 
 
This study will be performed at the MoCha, Frederick National Laboratory for 
Cancer Research (FNLCR) under the supervision of Chris Karlovich, Ph.D. 
(chris.karlovich@nih.gov). 
 
5.11.3.3 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 
 
5.11.3.4 Contact information for notification of specimen shipment: 
 
Thomas Forbes, mochasamplereceiving@nih.gov 

NCI Protocol #: 10216 
Version Date:  09/17/2024 
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# 
Section 
Comments 
 
PI Response: Updated as recommended. 
17. 
9 
• 
The target and threshold can be easily improved.  If they are updating the 
protocol, they should do this.  
• 
With the current design, there is a significant risk (45%) of failing to meet the 
target, and the trial being a formal failure, even if the therapy works as expected / 
hoped. 
  
• 
Agreed: If we observe 5/16 (31%) then the 90% and 95% confidence intervals 
exclude 10%.  
• 
If the underlying rate is 30%, then we could observe 5+/16 in our data with 55% 
probability.  Thus, if the underlying rate is 30%, there is only 55% power.  
• 
Consider one of the following alternatives:  
o 
If you increase alpha (up to 10% one-sided), then 4 or more out of 17 
gives 80% power.  The 95% lower-limit confidence interval with 4/17 is 
10.7%.  If there are 5 or more success out of 17, then you can claim 
significance at 5% one-sided.  
o 
If you cannot go above 16 sample size, then 4 or more out of 16 gives 
75% power with alpha at 10% one-sided.  The 95% lower-limit 
confidence interval with 4/16 is 11.3%.  If there are 5 or more out of 16, 
then you can claim significance at 5% one-sided.  
o 
Otherwise go for an estimation approach, that is the sample size section 
shows the size of the confidence interval for potential results, without 
specifying a specific target,  
PI Response: Since this is a Phase 1b study to obtain preliminary efficacy data, 
we have updated the protocol using Option 3 from the alternatives. We stated: 
With a total of 16 patients at MTD/RP2D (6 + 10), we will estimate the ORR with 
a 95% confidence interval half-width of less than 25.4%, using the Clopper-
Pearson exact method. 
 
V. Changes by Lead Site:  
 
17. Protocol 
Version 
Updated amendment number and protocol version date. 
 
18. 
Header 
Updated header version date. 
19. 
2.3 
Section updated to include rationale for dose selection for expansion 
cohort. 
20. 
2.4.7 
5.12 
Removed PET criteria as The Wright Center of Imaging has moved from 
OSU. 
21. 
6.1 
Section updated for expansion cohort size. 
22. 
9.1 
Section updated for expansion cohort size. 
23. 
All 
Deleted / Adjusted page breaks and line spacing. 

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Version Date:  09/17/2024 
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24. 
5.7 
Updated contact information and shipping instructions for Osimertinib 
pharmacologist to Dr. Mitch A. Phelps at the Ohio State University 
 
25. 
Title 
Page 
Updated Osimertinib (AZD9291) Pharmacologist Investigator from Jill 
Kolesar (UKY) to Mitch Phelps (OSU) 
 
VI. Changes in Response to RRA dated 8/20/24:  
 
25. 
10.3.2 
Updated AE Reporting Tables per FDA Reporting Requirements For 
Serious Adverse Events (21 CFR Part 312) 
26. 10.1.1.2 Updated CAEPR for AZD9291 (Osimertinib, NSC 781254) (Version 2.9, 
May 23, 2024) 
 
Added New Risk: 
• 
Rare but Serious: Skin and subcutaneous disorders - Other 
(erythema dyschromicum perstans); Toxic epidermal necrolysis 
• 
Also Reported on Osimertinib Trials But With Insufficient 
Evidence for Attribution: Cardiac disorders - Other (atrial 
thrombosis); Skin hyperpigmentation 
 
Decrease in Risk Attribution:  
• 
Changed to Less Likely from Likely: Paronychia 
• 
Changed to Also Reported on Osimertinib Trials But With 
Insufficient Evidence for Attribution from Less Likely: 
Alopecia 
 
 
PLEASE NOTE:  The specific detailed changes listed here compare the new 
revised CAEPR Version 2.9, and associated risk information for the ICD, to the 
most recent CAEPR Version 2.8.   If your trial contains an older CAEPR 
version (i.e., does NOT currently contain CAEPR Version 2.8), you MUST 
include a description of any additional changes resulting from migration from 
the older CAEPR version. 
 
 
 

NCI Protocol #: 10216 
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NCI Protocol #: 
10216 
 
Local Protocol #: 
OSU 19016 
 
ClinicalTrials.gov Identifier: NCT03831932 
 
TITLE: A Phase Ib Study of Osimertinib (AZD9291) and Telaglenastat (CB-839) HCl in Patients 
with EGFR Mutant Non-Small Cell Lung Cancer 
 
Corresponding Organization:  LAO-OH007 / Ohio State University Comprehensive Cancer 
Center LAO 
 
Principal Investigator: 
Dwight Owen, M.D. 
Ohio State University James Comprehensive Cancer Center 
A450B Starling Loving Hall 
320 W 10th Ave 
Columbus, OH 43210 
Tel: 614-685-2039 
Fax: 614-293-1470 
Dwight.Owen@osumc.edu 
 
Investigator 
Jennifer Eads, M.D. 
University of Pennsylvania 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
Tel: (215) 615-1725 
Fax: (215) 349-8551 
jennifer.eads@uphs.upenn.edu 
 
Investigator 
Afshin Dowlati, M.D. 
Case Western Reserve University 
11100 Euclid Ave 
Lakeside 1200 
Cleveland, OH 44106 
Tel: 216-844-5181 
Fax: 216-844-5234 
afshin.dowlati@uhhospitals.org 
 
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 

NCI Protocol #: 10216 
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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 
EDDOP / Early Drug Development Opportunity Program 
 
Statistician: 
Study Coordinator: 
Lai Wei, Ph.D., M.S. 
OSU Clinical Trials Office 
Center for Biostatistics 
 Multi-Center Trial Coordinator 
320H Lincoln Tower, 1800 Cannon Drive 
Fax: (614)-366- 
6652Columbus, OH 43210 
Tel: 614-293-6449 
Lai.wei@osumc.edu 
Email: OSUCCC-CTO-MCTP@osumc.edu 
 
Imaging Co-Investigator: 
Telaglenastat (CB-839) HCl Pharmacologist 
Investigator: 
Michael Knopp, M.D., Ph.D. 
Joel M. Reid, Ph.D. 
Ohio State University 
Mayo Clinic Cancer Center 
395 W 12th Ave, Rm 430 
200 First Street SW 
Columbus, OH-43210 
Rochester, MN 55905 
Tel:(614) 293-9998 
Tel: (507) 284-0822 
Fax: (614) 293-9275 
Fax: (507) 293-0107 
knopp.16@osu.edu 
reid@mayo.edu 
 
Osimertinib (AZD9291) Pharmacologist Investigator: 
Mitch A. Phelps, Ph.D. 
Ohio State University 
506 Riffe Building 
Columbus, OH 43210 
Tel: (614) 688-4370  
phelps.32@osu.edu   
 
Multi-Center Trial Program: 
Clinical Trials Office 
The Ohio State University Comprehensive Cancer Center 
Fax: (614)-366-6652 
E: OSUCCC-CTO-MCTP@osumc.edu 
 
NCI-Supplied Agent(s): Telaglenastat (CB-839) HCl (NSC 795998), Osimertinib (NSC 781254) 
IND #: 
 
IND Sponsor: DCTD, NCI 

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13
 
 
 
Protocol Type / Version # / Version Date: 
Original / June 19, 2018 
Revision 1 / August 14, 2018 
Revision 2 / September 4, 2018 
Revision 3 / October 5, 2018 
Revision 4 / November 21, 2018 
Revision 5 / December 28, 2018 
Revision 6a / February 22, 2019 
Amendment 1 / May 7, 2019 
Amendment 2 / July 2, 2019 
Amendment 3 / August 20, 2019 
Amendment 4 / September 27, 2019 
Amendment 5 / October 10, 2019 
Amendment 6 / June 11, 2020 
Amendment 7 / July 13, 2020 
Amendment 8 / September 10th, 2020 
(Disapproved) 
Amendment 9 / September 25th, 2020 
Amendment 10 / November 25, 2020 
Amendment 11 / December 16, 2020 
Amendment 12 / March 03, 2021 
Amendment 13 / April 5, 2022 
Amendment 14 / March 17, 2023 
Amendment 15 / May 2, 2023 
Amendment 16 / March 11, 2024 
 
(Disapproved) 
Amendment 17 / May 3, 2024 
(Disapproved) 
Amendment 18 / August 23, 2024 
(Disapproved) 
Amendment 19 / September 17, 2024 
 
 
 
 
 
 
 
    

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SCHEMA 
Dose Escalation Study Design: 
 
EGFR: epidermal growth factor receptor; BID: twice daily; CT, computed tomography; 18F-FDG-PET: 
fludeoxyglucose positron emission tomography; PK: pharmacokinetics; DLT: dose-limiting toxicity; NSCLC: 
non-small cell lung cancer 
 
 
Expansion Cohort Study Design: 
 
MTD: maximum tolerated dose. PET: positron emission tomography; RECIST: Response Evaluation Criteria In Solid 
Tumors. TKI: tyrosine kinase inhibitor; 

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Table of Contents 
SCHEMA ............................................................................................................................................. 4 
1. OBJECTIVES ................................................................................................................................. 9 
1.1 Primary Objectives .................................................................................................................... 9 
1.2 Secondary Objectives ................................................................................................................ 9 
1.3 Exploratory/Correlative Objectives ........................................................................................... 9 
2. BACKGROUND ........................................................................................................................... 10 
2.1 Study Disease(s) ...................................................................................................................... 10 
2.2 CTEP IND Agents ................................................................................................................... 10 
2.3 Rationale .................................................................................................................................. 19 
2.4 Correlative Studies Background .............................................................................................. 23 
3. PATIENT SELECTION .............................................................................................................. 25 
3.1 Overall Eligibility Criteria ...................................................................................................... 25 
3.2 Exclusion Criteria .................................................................................................................... 27 
3.3 Phase 2-Specific Inclusion Criteria ......................................................................................... 30 
3.4 Restrictions .............................................................................................................................. 30 
3.5 Inclusion of Women and Minorities ........................................................................................ 31 
4. REGISTRATION PROCEDURES ............................................................................................. 31 
4.1 Investigator and Research Associate Registration with CTEP ............................................... 32 
4.2 Site Registration ...................................................................................................................... 34 
4.3 Patient Registration ................................................................................................................. 36 
4.4 General Guidelines .................................................................................................................. 39 
5. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ................................................ 40 

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5.1 Summary Table for Biospecimen Collection .......................................................................... 40 
5.2 Specimen Procurement Kits and Scheduling .......................................................................... 44 
5.3 Specimen Collection, Processing, and Submission ................................................................. 44 
5.4 Specimen Tracking System Instructions ................................................................................. 46 
5.5 Shipping of Specimen(s) from Clinical Sites to the EET Biobank ......................................... 50 
5.6 Shipping of Telaglenastat (CB-839) HCl Pharmacokinetics (PK) Plasma from Clinical Sites 
to Mayo Clinic Cancer Center ................................................................................................ 53 
5.7 Shipping of Osimertinib (AZD9291) Pharmacokinetics (PK) Plasma from Clinical Sites to 
Ohio State University .............................................................................................................. 54 
5.8 Biomarker Plan ........................................................................................................................ 49 
5.9 Integral Laboratory or Imaging Studies .................................................................................. 52 
5.10 Integrated Correlative Studies ................................................................................................. 52 
5.11 Exploratory/Ancillary Correlative Studies .............................................................................. 55 
5.12 Special Studies ........................................................................................................................ 58 
6. TREATMENT PLAN ................................................................................................................... 59 
6.1 Agent Administration .............................................................................................................. 59 
6.2 Definition of Dose-Limiting Toxicity ..................................................................................... 62 
6.3 General Concomitant Medication and Supportive Care Guidelines ....................................... 63 
6.4 Duration of Therapy ................................................................................................................ 64 
6.5 Duration of Follow-Up ............................................................................................................ 65 
7. DOSING DELAYS/DOSE MODIFICATIONS Telaglenastat (CB-839) HCl 65 
8. PHARMACEUTICAL INFORMATION ................................................................................... 72 
8.1 CTEP IND Agents ................................................................................................................... 72 
9. STATISTICAL CONSIDERATIONS ........................................................................................ 78 
9.1 Study Design/Endpoints. ......................................................................................................... 78 
9.2 Sample Size/Accrual Rate ....................................................................................................... 79 

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9.3 Stratification Factors ............................................................................................................... 81 
9.4 Analysis of Secondary and Exploratory Endpoints ................................................................. 81 
9.5 Reporting and Exclusions ........................................................................................................ 81 
10. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .................................. 82 
10.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ................................... 82 
10.2 Adverse Event Characteristics ................................................................................................. 86 
10.3 Expedited Adverse Event Reporting ....................................................................................... 86 
10.4 Routine Adverse Event Reporting ........................................................................................... 89 
10.5 Pregnancy ................................................................................................................................ 90 
10.6 Overdose ................................................................................................................................. 91 
10.7 Secondary Malignancy ............................................................................................................ 91 
10.8 Second Malignancy ................................................................................................................. 91 
11. STUDY CALENDAR ................................................................................................................. 92 
11.1 Study Calendar ........................................................................................................................ 93 
12. MEASUREMENT OF EFFECT ............................................................................................... 96 
12.1 Antitumor Effect – Solid Tumors ............................................................................................ 96 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS 
. .............................................................................................................................................. 102 
13.1 Study Oversight ..................................................................................................................... 102 
13.2 Data Reporting ...................................................................................................................... 103 
13.3 Data and Safety Monitoring .................................................................................................. 105 
13.4 Collaborative Agreements Language .................................................................................... 106 
13.5 Genomic Data Sharing Plan .................................................................................................. 107 
13.6 Incidental/Secondary Findings Disclosure Procedure ........................................................... 107 
13.7 Data Quality Portal ................................................................................................................ 108 

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14. REFERENCES .......................................................................................................................... 109 
APPENDIX A  PERFORMANCE STATUS CRITERIA .......................................................... 114 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD… ............................................................................................................................... 114 
APPENDIX C  CYTOCHROME P450 (CYP) 2C9 SUBSTRATES ......................................... 115 
APPENDIX D GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH 
CONCOMITANT MEDICATIONS ................................................................................. 116 
APPENDIX E ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW ............................................. 120 
APPENDIX F DEFINITION OF WOMEN OF CHILDBEARING POTENTIAL AND 
ACCEPTABLE CONTRACEPTIVE METHODS .......................................................... 124 
APPENDIX G  PATIENT DIARY ............................................................................................... 125 

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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To assess the safety and tolerability of Osimertinib (AZD9291) and Telaglenastat 
(CB-839) HCl and determine the RP2D in patients with metastatic, EGFR 
activating mutation-positive NSCLC. 
 
1.2 
Secondary Objectives 
 
1.2.1 To determine toxicity profile of the combination of Osimertinib (AZD9291) and 
Telaglenastat (CB-839) HCl in patients with metastatic EGFR activating mutation 
positive NSCLC. 
 
1.2.2 To assess the PK of Telaglenastat (CB-839) HCl and Osimertinib (AZD9291) in 
patients with metastatic EGFR activating mutation positive NSCLC. 
 
1.3 
Exploratory/Correlative Objectives 
 
1.3.1 To determine the progression free survival (PFS) of Osimertinib (AZD9291) and 
Telaglenastat (CB-839) HCl in patients with EGFR mutation positive NSCLC who have 
developed PD on front-line EGFR inhibitor therapy. 
 
1.3.2 To determine the overall survival (OS) of Osimertinib (AZD9291) and Telaglenastat 
(CB-839) HCl in patients with EGFR mutation positive NSCLC who have developed 
PD on front-line EGFR inhibitor therapy 
 
1.3.3 To assess cell-free DNA (cfDNA) and measure changes with response to treatment as 
well as disease progression (EGFR sensitizing mutations, T790M resistance mutation, 
recognized bypass mechanisms). 
 
1.3.4 To assess circulating levels of glutamine, glutamate, aspartate and asparagine, and 
measure changes with response to treatment as well as disease progression. 
 
1.3.5 To assess 18F-FDG-PET parameters at baseline and after treatment to evaluate changes 
with response to treatment as well as emergence of disease resistance or progression 
(expansion cohort, select patients only). 
 
1.3.6 To perform molecular profiling assays on malignant and normal tissues, including, but 
not limited to, whole exome sequencing (WES) and RNA sequencing (RNAseq), in order 
to: 

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1.3.6.1 To identify potential predictive and prognostic biomarkers beyond any genomic 
alteration by which treatment may be assigned, and 
 
1.3.6.2 To identify resistance mechanisms using genomic DNA- and RNA-based assessment 
platforms. 
 
 
2. 
BACKGROUND 
 
2.1 
Study Disease(s) 
 
Lung cancer is the second most common malignancy in both males and females with 222,500 
patients diagnosed annually. It is also the leading cause of cancer related death in both men and 
women, with 155,870 patients dying of their disease every year (Siegel et al., 2017). Amongst 
all lung cancers, NSCLC accounts for approximately 83% of all lung cancers, and non-squamous 
NSCLC (including mostly adenocarcinoma), accounts for 50-55% of lung cancers (Noone et al., 
2018). Within the past decade, there have been significant improvements in the treatment of 
NSCLC and many of the current treatment recommendations are dependent on a patients 
underlying genomic profile (Ettinger et al., 2017). Despite these advances that allow us to 
provide molecularly targeted therapies for patients, there are still significant limitations, 
particularly for patient populations who do not harbor genomic abnormalities that allow them to 
fit within the algorithm for treatment with these agents. It is these patients especially who are 
most in need of additional treatment options. 
 
One major decision point in selecting therapy for a patient with NSCLC is first to identify if they 
harbor an activating/sensitizing mutation in the EGFR gene. Activating mutations in the EGFR 
gene are relatively uncommon in Western countries where they occur in approximately 10% of 
patients (Hirsch and Bunn, 2009). The most commonly identified mutations are in either exon 
19 (45%) or exon 21 (40%) (Jin et al., 2016). Those who do harbor such a mutation are treated 
in the front-line setting with an EGFR inhibitor such as erlotinib, gefitinib, or afatinib as these 
agents demonstrate clinical benefit in the form of both response to therapy and PFS (Langer, 
2013). More recently, based on the FLAURA study, Osimertinib (AZD9291) was approved in 
the first line treatment of patients with an EGFR exon 19 or L858R mutation (Soria et al., 2018). 
However, many patients are still on treatment with first line TKI therapy, and Osimertinib 
(AZD9291) is not approved in all countries for first line therapy. Unfortunately, like most 
cancers, patients ultimately develop resistance to these agents and a common mechanism of 
resistance is the development of a T790M mutation within the EGFR gene, occurring in 
approximately 60% of patients treated with EGFR inhibitors (Pao et al., 2005; Tanaka et al., 
2017). Currently, the management of patients who progress on first line TKI is an area of unmet 
clinical need. 
 
2.2 
CTEP IND Agents 
 
2.2.1 Telaglenastat (CB-839) HCl 
 
Telaglenastat (CB-839) HCl is a first-in-class, orally available inhibitor of glutaminase (GLS) 

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activity (CB-839 Investigator's Brochure, 2017). There are two GLS 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 kidney-type glutaminase (KGA) and the shorter glutaminase C 
(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 and 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 (AML), 
acute lymphoblastic leukemia (ALL), multiple myeloma (MM), and non-Hodgkin lymphoma 
(NHL) and solid tumors (including triple-negative breast cancer [TNBC], melanoma, NSCLC, 
and renal cell carcinoma [RCC]) (CB-839 Investigator's Brochure, 2017). 
 
2.2.1.1 Mechanism of Action 
 
Many cancer types have an altered metabolic profile and use glutamine as an energy source. 
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 
(reviewed in Altman et al., 2016). Many tumors have been demonstrated to overexpress GLS, 
particularly the shorter GAC isoform, and these tumors are sensitive to the withdrawal of 
glutamine from culture medium in vitro (Gross et al., 2014; Jacque et al., 2015). This 
overexpression of GLS can be stimulated by overexpression of Myc (Wise et al., 2008; Gao et 
al., 2009). 
 
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 the 
formation of inactive tetramers (Stalnecker et al., 2017). 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 (Gross et 
al., 2014; Matre et al., 2016). The decrease in cellular viability can be reversed by addition of α- 
ketoglutarate, suggesting that the reduction in TCA cycle intermediates is the primary 
mechanism by which Telaglenastat (CB-839) HCl exerts its antiproliferative and pro-apoptotic 
effects (CB-839 Investigator's Brochure, 2017). 
 
2.2.1.2 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 (CB-839 
Investigator's Brochure, 2017). At 10 mcM Telaglenastat (CB-839) HCl, significant inhibition 
of radioligand binding was observed against the human adenosine A3 receptor (50%), the 
human ether-à-go- go-related gene (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). 

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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 (CB-839 Investigator's Brochure, 
2017). In mice given a single dose of Telaglenastat (CB-839) HCl ranging from 2.5 to 400 mg/kg, 
maximum GLS inhibition, glutamine increase, and glutamate and aspartate decreases within the 
tumor plateaued when plasma concentrations exceeded ~300 nM, which was achieved with 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 4-week toxicity study, and a severely 
toxic dose of 10% was not identified (CB-839 Investigator's Brochure, 2017). 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 (CB-839 Investigator's Brochure, 2017). 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 (LFTs) 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. 
 
2.2.1.3 Summary of Clinical Experience 
 
As of January 23, 2017, 161 patients have received Telaglenastat (CB-839) HCl as 
monotherapy, and 94 patients have received Telaglenastat (CB-839) HCl in combination with 
other agents in phase 1 and early phase 2 trials (CB-839 Investigator's Brochure, 2017). A 
summary of clinical data from company-sponsored Telaglenastat (CB-839) HCl trials as of 
January 23, 2017 is presented below. Details of all ongoing studies can be found in the most 
recent Telaglenastat (CB-839) HCl Investigator’s Brochure. 
 
2.2.1.3.1 
Clinical PK and Pharmacodynamics 
 
The 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 (CB-839 Investigator's Brochure, 2017). 
Patients treated with either 100-1000 mg of Telaglenastat (CB-839) HCl three times a day (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 AUC 
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 

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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) (CB-839 Investigator's Brochure, 2017). 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, gender, race, or body weight. 
 
Pharmacodynamic response in these trials was assessed as glutaminase (GLS) activity in 
platelets and peripheral blood mononuclear cells (PBMCs) 4 hours after the first dose of CB-389 
HCl on C1D1, or in solid tumor biopsy samples collected on C2D1 in early dose cohorts on 
study CX-839-001 (CB-839 Investigator's Brochure, 2017). A greater than 90% GLS inhibition 
was observed in platelets when Telaglenastat (CB-839) HCl levels exceeded 250 ng/mL. In 
solid tumor biopsies, a 75% inhibition of GLS activity was observed. Plasma glutamine 
concentrations were also monitored 4 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 GLS 
inhibition. 
 
2.2.1.3.2 
Clinical Safety Summary 
 
Among 59 patients who received Telaglenastat (CB-839) HCl monotherapy on the TID (fasted) 
schedule over a dose range of 100-1000 mg, two DLTs have been observed: one at 250 mg TID 
(grade 3 elevated creatinine) and one at 400 mg TID (grade 3/4 elevated LFTs) (CB-839 
Investigator's Brochure, 2017). 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 intravenous [IV] paclitaxel weekly for 3 weeks in 
every 4 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 largest monotherapy study of Telaglenastat (CB-839) HCl, CX-839-001) included 120 
patients with solid tumors, 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 BID 

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with food (CB-839 Investigator's Brochure, 2017). On the BID schedule, 69.3% of patients 
experienced an adverse event (AE), the most common of which were fatigue, elevated LFTs, 
gastrointestinal (GI) 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, 2017, a total of 127 serious AEs (SAEs) across monotherapy and 
combination therapy have been recorded (CB-839 Investigator's Brochure, 2017). Seven patients 
experienced at least one SAE that was considered at least possibly related to Telaglenastat (CB- 
839) HCl treatment: increased creatinine (one patient), increased aspartate aminotransferase 
(AST) and/or ALT (two patients), seizure (one patient), stomatitis (one patient), dyspnea (one 
patient), and one patient with three concurrent SAEs of hypotension, tachycardia, and pyrexia. 
 
2.2.1.3.3 
Clinical Efficacy Summary 
 
Patients with multiple tumor types have been included in studies with Telaglenastat (CB-839) 
HCl as a monotherapy or in combination with other agents (CB-839 Investigator's Brochure, 
2017). In monotherapy cohorts, best overall response of stable disease (SD) or better has been 
observed in a variety of malignancies, including TNBC, NSCLC, RCC, MM, and leukemia. In 
clear cell RCC patients receiving Telaglenastat (CB-839) HCl in combination with everolimus, 
seven of eight (87.5%) evaluable patients achieved disease control at 16 weeks, which is notable 
when compared to two recent phase 3 studies of everolimus alone, where ~50% of patients had 
PD at 16 weeks 
 
2.2.2 Osimertinib (AZD9291) 
 
Osimertinib (AZD9291) is a potent irreversible TKI of both the single epidermal growth 
factor receptor mutation (EGFRm; TKI sensitivity-conferring mutation) and dual 
EGFRm/T790M (TKI resistance-conferring mutation) receptor forms of EGFR (Osimertinib 
(AZD9291) Investigator's Brochure, 2018). Activation of the EGFR TK triggers a cascade 
of intracellular downstream signaling events affecting cell proliferation, survival, 
angiogenesis and, potentially, metastasis. 
 
Osimertinib (AZD9291) has shown antitumor activity in vitro against several lung cancer cell 
lines (H1975, PC9VanR, CALU3, CALU6, and H2073), and in vivo in murine xenograft models 
(H1975 [EGFR L858R/T790M] and H3255 [L858R]) (Osimertinib (AZD9291) Investigator's 
Brochure, 2018). Data from an AstraZeneca-sponsored study (Study D5160C001, the AURA 
study) in pretreated NSCLC patients with centrally-tested EGFR T790M mutation-positive 
tumors showed that treatment with Osimertinib (AZD9291) resulted in tumor shrinkage, with an 
investigator-assessed objective response rate (ORR) of 58.6% across all doses. 
 
On March 30, 2017, the U.S. Food and Drug Administration (FDA) granted regular approval to 
Osimertinib (AZD9291) (as TAGRISSO®, AstraZeneca Pharmaceuticals) for the treatment of 
patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA- 
approved test, whose disease has progressed on or after EGFR TKI therapy (U.S. Food and 
Drug Administration, 2017). 

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On April 18, 2018, the FDA approved Osimertinib (AZD9291) (as TAGRISSO®, 
AstraZeneca Pharmaceuticals) for the first-line treatment of patients with metastatic NSCLC 
whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an 
FDA-approved test (U.S. Food and Drug Administration, 2018). 
 
2.2.2.1 Mechanism of Action 
 
Osimertinib (AZD9291) is kinase inhibitor of EGFR and binds irreversibly to certain mutant 
forms of EGFR (T790M, L858R, and exon 19 deletion) at approximately 9-fold lower 
concentrations than wild- type (Osimertinib (AZD9291) Investigator's Brochure, 2018). 
Activation of the EGFR tyrosine kinase (TK) triggers a cascade of intracellular downstream 
signaling events affecting cell proliferation, survival, angiogenesis and, potentially, metastasis. 
Receptor activation leads to phosphorylation of specific tyrosine residues within the cytoplasmic 
tail (Normanno et al., 2006) These phosphorylated residues serve as docking sites for proteins 
containing Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains, including 
containing (Shc), growth factor receptor binding protein 10 (Grb7), Grb2, CT10 regulator of 
kinase (Crk), non-catalytic region of tyrosine kinase adaptor protein 1 (Nck), the phospholipase 
Cγ (PLCγ), the intracellular kinases Src and phosphoinositide 3-kinase (PI3K), the protein 
tyrosine phosphatases Src homology-2 domain containing protein tyrosine phosphatase-1 
(SHP1) and SHP2, and the Casitas B-lineage lymphoma (Cbl) E3 ubiquitin ligase (Yaffe, 2002; 
Marmor and Yarden, 2004; Normanno et al., 2006). All ligands induce activation of the rat 
sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/mitogen- 
activated protein kinase (RAS/RAF/MEK/MAPK) pathway through either Grb2 or Shc adaptor 
proteins (Carpenter, 2003; Citri et al., 2003; Jorissen et al., 2003; Normanno et al., 2006). ErbB 
receptors also activate PI3K by recruitment of the p85 regulatory subunit to the activated 
receptors (Soltoff and Cantley, 1996; Normanno et al., 2006). 
 
2.2.2.2 Summary of Nonclinical Experience 
 
Biochemical studies showed Osimertinib (AZD9291) to be a potent and selective irreversible 
inhibitor of isolated mutant EGFRs with a margin of selectivity against wild-type EGFR 
(apparent half maximal inhibitory concentrations [IC50] <12 nM for mutant vs. 184 nM for wild- 
type EGFR) (Osimertinib (AZD9291) Investigator's Brochure, 2018). Oral (PO) Osimertinib 
(AZD9291) treatment resulted in dose- related tumor growth inhibition in the lung cancer cell 
line H1975 (EGFR L858R/T790M) murine xenograft model, with profound regression being 
achieved at doses above 2.5 mg/kg after QD administration for 14 days. 
 
The toxicological profile of Osimertinib (AZD9291) has been evaluated in rats and dogs in 
studies of up to 6 and 9 months duration, respectively (Osimertinib (AZD9291) Investigator's 
Brochure, 2018). The main findings comprised atrophic, inflammatory and/or degenerative 
changes affecting the epithelia of the eye (cornea), GI tract (including tongue), skin, and male 
and female reproductive tracts. 
These findings occurred at plasma concentrations that were below those seen in patients at the 80 
mg therapeutic dose. The AEs that were observed following 1 month of dosing were largely 
reversible within 1 month of cessation of dosing. Osimertinib (AZD9291) had marked AEs on 
embryonic survival plus early postnatal viability and growth when administered to pregnant or 
lactating rats. 

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2.2.2.3 Summary of Clinical Experience 
 
As of the data cut-off date (DCO) of November 12, 2017, 3,178 patients or healthy volunteers 
have been exposed to study treatment (Osimertinib (AZD9291) alone [including those crossed 
over from comparator treatment to Osimertinib (AZD9291) monotherapy], Osimertinib 
(AZD9291) in combination with another treatment, or comparator) in AstraZeneca-sponsored 
clinical studies (Osimertinib (AZD9291) Investigator's Brochure, 2018). Of these, 3,060 were 
NSCLC patients and 118 were healthy volunteers. As of November 12, 2017, 2,258 patients 
have received Osimertinib (AZD9291) monotherapy only, 229 have received Osimertinib 
(AZD9291) in combination with another treatment, 167 crossed over during the study from 
comparator treatment to Osimertinib (AZD9291) monotherapy and 524 patients were exposed to 
comparator treatment only, including placebo. Hence, a total of 2654 patients or healthy 
volunteers have been dosed with Osimertinib (AZD9291). An additional 4743 NSCLC patients 
have participated in the Osimertinib (AZD9291) Early Access Program and 3020 patients 
participated in the real- world evidence study (ASTRIS D5160C00022). 
 
2.2.2.3.1 
Clinical PK and Pharmacodynamics 
 
Osimertinib (AZD9291) PK parameters have been characterized in healthy subjects and 
NSCLC patients (Osimertinib (AZD9291) Investigator's Brochure, 2018). Based on population 
PK analysis, Osimertinib (AZD9291) apparent plasma clearance is 14.3 L/h, apparent volume 
of distribution is 918 L, and t1/2 is approximately 44 hours. The area under the plasma 
concentration-time curve (AUC) and maximum serum concentration (Cmax) of Osimertinib 
(AZD9291) increased dose proportionally over 20 mg to 240 mg dose range (0.25 to 3 times the 
recommended dosage) after PO administration and exhibited linear PK. Administration of 
Osimertinib (AZD9291) PO QD resulted in approximately 3-fold accumulation with steady 
state exposures achieved after 15 days of dosing. At steady state, the Cmax to minimal serum 
concentration (Cmin) ratio was 1.6-fold. The median time to Cmax of Osimertinib (AZD9291) 
was 6 hours (range 3 to 24 hours). The absolute bioavailability of Osimertinib (AZD9291) is 
70% (90% confidence interval [CI] 67, 73). Neither food nor gastric pH affects the exposure of 
Osimertinib (AZD9291). 
 
Based on clinical drug-drug interaction (DDI) studies, interactions with strong CYP3A4 
inhibitors are unlikely but strong CYP3A4 inducers can decrease the exposure of (Osimertinib 
(AZD9291) Investigator's Brochure, 2018). Osimertinib (AZD9291) may also increase the 
exposure of co-administered breast cancer resistance protein (BCRP) substrates. Clinical PK 
interactions with co- administered CYP3A4 substrates are unlikely. No clinically significant 
differences in the PK of Osimertinib (AZD9291) were observed based on age, sex, ethnicity, 
body weight, smoking status, mild or moderate or severe renal impairment (creatinine clearance 
[CLcr] >15 mL/min by Cockcroft- Gault) or mild or moderate hepatic impairment (mild: Child 
Pugh A or total bilirubin less than or equal to the upper limit of normal [ULN] and AST greater 
than ULN or total bilirubin between 1 to 1.5 times ULN and any AST; moderate: Child Pugh B 
or total bilirubin between 
1.5 to 3 times ULN and any AST). 
 
2.2.2.3.2 
Clinical Safety Summary 

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The AstraZeneca-sponsored AURA phase 1 trial was designed to support a robust dose selection 
decision, with 31 pre-treated patients with advanced NSCLC in the dose escalation part of the 
study and 2523 in the dose expansion part receiving the capsule formulation of Osimertinib 
(AZD9291) across the range of doses 20, 40, 80, 160, and 240 mg (Osimertinib (AZD9291) 
Investigator's Brochure, 2018). Of these, 103 patients (6 patients in the dose escalation cohort 
and 97 patients in the dose expansion cohort) were dosed at the recommended daily dose of 80 
mg PO. No DLTs were reported at any dose level in the escalation cohorts of AURA phase 1 
during the 21-day DLT evaluation period, and therefore a MTD has not been defined. The most 
commonly reported AEs were rash (grouped terms) (78%), diarrhea (73%), dry skin (grouped 
terms) (58%), paronychia (grouped terms) (50%) and stomatitis (47%). Osimertinib (AZD9291) 
appeared less tolerable at doses above 80 mg; an approximate doubling in the incidence of skin 
disorders, nail effects and diarrhea were observed at doses higher than 80 mg, with severe 
Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥3 instances of these events 
occurring more frequently at the 160 mg and 240 mg doses. Additionally, a substantive increase 
in dose reductions due to AEs was observed at doses of 160 mg (20.3%) and 240 mg (57.1%), 
compared to 80 mg (1.0%). 
 
FLAURA was a randomized phase 3 study designed to test efficacy of Osimertinib (AZD9291) 
in patients with EGFR-mutated NSCLC vs. Standard of Care first line TKI (Osimertinib 
(AZD9291) Investigator's Brochure, 2018; Soria et al., 2018). AEs were reported in the majority 
of patients in both treatment arms: 273 (97.3%) with Osimertinib (AZD9291) and 271 (97.8%) 
with Standard of Care. A similar proportion of patients in both arms had AEs assessed by 
investigators to be possibly related to study treatment: Osimertinib (AZD9291), 253 (90.7%) 
patients, Standard of Care, 255 (92.1%) patients. AEs were predominantly mild or moderate 
severity, with a lower incidence of AEs of CTCAE Grade ≥3 in the Osimertinib (AZD9291) arm 
compared with Standard of Care: CTCAE Grade ≥3 AEs were reported in 95 (34.1%) patients in 
the Osimertinib (AZD9291) arm compared with 124 (44.8%) patients in the Standard of Care 
arm. A similar proportion of patients in the 2 treatment arms reported SAEs, and AEs with an 
outcome of death (CTCAE Grade 5) were reported in a low but numerically higher proportion of 
patients in the Standard of Care arm. A lower proportion of patients had AEs leading to drug 
discontinuation in the Osimertinib (AZD9291) arm compared with the Standard of Care arm. 
 
Serious AEs occurred in a similar proportion of patients in the 2 treatment arms. The most 
frequently reported SAEs in the Osimertinib (AZD9291) arm (≥1% of patients) were 
pneumonia (7 [2.5%] patients), ILD and pulmonary embolism (4 [1.4%] each), and pleural 
effusion (3 [1.1%) (Osimertinib (AZD9291) Investigator's Brochure, 2018; Soria et al., 2018). 
The most frequently reported SAEs in the Standard of Care arm (≥1% of patients) were: 
pneumonia (7 [2.5%] patients), vomiting (5 [1.8%]), diarrhea (4 [1.4%]), and ILD, pleural 
effusion, dyspnea, sepsis, and drug- induced liver injury (3 [1.1%] each). Serious AEs were 
considered to be possibly related to study treatment by the investigator in a similar proportion 
of patients in the 2 treatment arms (Osimertinib (AZD9291): 22 [7.9%]; Standard of Care: 23 
[8.3%]). 
 
The proportion of patients who had CTCAE Grade ≥3 AEs was lower in the Osimertinib 
(AZD9291) arm (95 [34.1%] patients) compared with the Standard of Care arm (124 [44.8%] 
patients) (Osimertinib (AZD9291) Investigator's Brochure, 2018; Soria et al., 2018). CTCAE 

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Grade ≥3 events were reported in a wide range of preferred terms covering multiple system 
organ classes (SOCs); most AEs were single events. The only CTCAE Grade ≥3 events 
reported by more than 5 patients in the Osimertinib (AZD9291) arm were decreased appetite (7 
[2.5%] patients) and diarrhea, pneumonia and electrocardiogram interval measured from the 
beginning of the Q wave, R wave, S Wave (QRS) complex to the end of the T wave (ECG QT) 
prolonged (each in [2.2%] patients). AEs led to discontinuation of treatment in a lower 
proportion of patients in the Osimertinib (AZD9291) arm (37 [13.3%]) than in the Standard of 
Care arm (49 [17.7%]), indicating that Osimertinib (AZD9291) was at least as well tolerated as 
the Standard of Care comparator. 
 
2.2.2.3.3 
Clinical Efficacy Summary 
 
In the dose expansion population of AURA phase 1, clinical activity was observed in patients 
with T790M mutation positive tumors (92/157 patients with a confirmed objective response) at 
all doses investigated (20 mg to 240 mg dose range), without any apparent trend (Mok et al., 
2017; Osimertinib (AZD9291) Investigator's Brochure, 2018). ORRs based on investigator 
assessment ranged from 50.0% to 65.6%, with highest ORR of 65.6% (95% CI: 52.3, 77.3) 
being observed at the 80 mg dose. Doses of 160 mg and higher appeared unlikely to provide 
any additional efficacy benefit. Responses were durable across all doses, with a median DoR of 
11.1 months (38.0% maturity) and a median PFS of 10.9 months (42.9% maturity). In pre- 
treated patients with centrally-tested EGFR T790M mutation negative tumors in the AURA 
phase 1 component; investigator assessed analyses, the ORR was 24.6% (95% CI: 15.1, 36.5) in 
17 of 69 EGFR patients. Median PFS was 3.0 months (95% CI: 2.1, 4.2; 88.4% maturity) in 
patients with centrally confirmed T790M mutation negative NSCLC. 
 
In the AURA3 phase 3 study, the median duration of PFS was significantly longer with 
Osimertinib (AZD9291) than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 
months; HR; 0.30; 95% CI, 0.23 to 0.41; P<0.001) (Mok et al., 2017; Osimertinib (AZD9291) 
Investigator's Brochure, 2018). 
 
The ORR was significantly better with Osimertinib (AZD9291) (71%; 95% CI, 65 to 76) than 
with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective 
response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the 
central nervous system (CNS), the median duration of PFS was longer among patients receiving 
Osimertinib (AZD9291) than among those receiving platinum therapy plus pemetrexed (8.5 
months vs. 4.2 months; hazard ratio [HR], 0.32; 95% CI, 0.21 to 0.49). 
 
In the FLAURA phase 3 study, the median PFS was significantly longer with Osimertinib 
(AZD9291) than with standard EGFR TKIs (18.9 months vs. 10.2 months; HR for disease 
progression or death, 0.46; 95% CI, 0.37 to 0.57; P<0.001) (Osimertinib (AZD9291) 
Investigator's Brochure, 2018; Soria et al., 2018). The ORR was similar in the two groups: 
80% with Osimertinib (AZD9291) and 76% with standard EGFR TKIs (odds ratio, 1.27; 95% 
CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 
22.0) with Osimertinib (AZD9291) versus 8.5 months (95% CI, 7.3 to 9.8) with standard 
EGFR-TKIs. In a subsequent report on the final analysis of overall survival from the FLAURA 
trial, Ramalingam et al reported that the median overall survival was 38.6 months (95% 
confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 

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to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 
0.046) (Ramalingam et al, 2019)). 
 
2.3 
Rationale 
 
Osimertinib (AZD9291) is a third generation EGFR inhibitor that has demonstrated activity in 
patients with EGFR activating mutation positive NSCLC who progressed on front-line EGFR 
inhibitor therapy despite the acquisition of a T790M gene mutation, indicating that it is able to 
overcome this resistance to therapy. As such, it has been approved for the treatment of EGFR 
activating mutation positive and T790M mutation positive NSCLC in the second-line setting 
(Janne et al., 2015; Mok et al., 2017). More recently, based on the FLAURA trial mentioned 
above, Osimertinib (AZD9291) has received FDA approval in the first line treatment of 
metastatic EGFR-positive NSCLC (Soria et al., 2018). Although the improvement in overall 
survival is encouraging, unfortunately, eventually all patients progress on front-line EGFR 
inhibitor therapy with osimertinib. As such, the objective of this clinical trial is to identify a way 
to overcome resistance to front-line EGFR inhibitor therapy. To date, no single mechanism of 
resistance has been identified in these patients, although the most commonly described findings 
at time of osimertinib progression including MET amplification and EGFR amplification, as well 
as EGFR independent pathways including BRAF as well as histologic transformation (Romero et 
al, 2020; Roper et al, 2020). Preclinical studies have demonstrated that HIF-1 signaling pathway, 
PI3K-Akt pathway, and oxidative phosphorylation are upregulated in osimertinib resistant 
NSCLC cell lines, while glycolysis/gluconeogenesis is downregulated (Ma et al, 2020). 
 
It has been shown that many cancer cells rely on two major pathways of metabolism for growth: 
glucose metabolism, which is driven by the EGFR pathway, and glutamine metabolism (Wise et 
al., 2008; Gao et al., 2009; Wang et al., 2010; Gross et al., 2014). While cellular growth may be 
inhibited by blocking glucose metabolism (and is the reason why EGFR inhibition is effective in 
the presence of EGFR activating mutations), there is no therapeutic intervention that additionally 
address the glutamine pathway which, if inhibited, may also result in growth inhibition. It is 
therefore our hypothesis that in patients who have received front-line EGFR inhibitor therapy 
and developed resistance, the addition of an agent that inhibits the glutamine pathway will 
overcome this resistance and that dual pathway inhibition will result in enhanced cellular 
toxicity. Lastly, given the role of glutamine in HIF-1 signaling (Ma et al, 2020) and oxidative 
phosphorylation (Chen et al, 2020), the addition of CB-839 to osimertinib may prolong disease 
control in these patients. 
 
It has been shown in preclinical studies that synergy exists when NSCLC cells are treated with a 
combination of an EGFR inhibitor and a glutaminase inhibitor (Telaglenastat (CB-839) HCl) 
(Momcilovic et al., 2017). As erlotinib has been the most commonly used agent for the front- 
line treatment of NSCLC, many of the preclinical studies assessing the combination have been 
performed with erlotinib. In a NSCLC cell line (HCC827, an EGFR activating mutation positive 
cell line) study, cell survival was found to be diminished with the administration of erlotinib (as 
would be expected) as well as with single agent Telaglenastat (CB-839) HCl. However, 
combinatorial administration of erlotinib and Telaglenastat (CB-839) HCl resulted in an even 
greater decrease in cell survival in a dose dependent manner. This combination was found to be 
synergistic (see Figure 1 below) suggesting that dual inhibition of the glucose and glutamine 

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metabolic pathways is more efficacious that inhibition of a single metabolic pathway. 
 
 
Figure 1: Erlotinib and Telaglenastat (CB-839) HCl Cooperate to Inhibit Growth of EGFR Mutant Cell Lines 
In Vitro (From Momcilovic et al., 2017). 
 
This was further evidenced in a xenograft model where mice with HCC827 NSCLC tumor 
xenografts were treated with single agent erlotinib, single agent Telaglenastat (CB-839) HCl or 
the combination (Momcilovic et al., 2017). Single-agent Telaglenastat (CB-839) HCl did not 
generate a significant change in tumor growth while single-agent erlotinib did result in tumor 
shrinkage. In mice receiving the combination of erlotinib and Telaglenastat (CB-839) HCl, 
however, there was a significantly greater decrease in the size of the tumor xenograft as 
compared to mice treated with either erlotinib or Telaglenastat (CB-839) HCl as a single agent 
control. The fact that the combination was better than erlotinib alone is significant as this 
suggests improved disease control with combinatorial treatment as compared to standard single 
agent EGFR inhibition therapy. 
 
 
Figure 2: Erlotinib and Telaglenastat (CB-839) HCl Cooperate to Inhibit Growth of EGFR Mutant 
Xenografts In Vivo (From Momcilovic et al., 2017). 

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Recently, the FLAURA trial, a randomized phase 3 trial of Osimertinib (AZD9291) vs. Standard 
of Care treatment with EGFR inhibitor therapy for first-line treatment of patients with EGFR 
activating mutation positive NSCLC, reported an improved PFS of 18.9 months with 
Osimertinib (AZD9291) compared to the Standard of Care (median PFS 10.2 months, HR 0.46, 
P<0.001) (Soria et al., 2018). Given these positive results demonstrating superiority with 
Osimertinib (AZD9291), Osimertinib (AZD9291) has replaced erlotinib (and other earlier 
generation EGFR inhibitors) as the front-line treatment of choice for metastatic EGFR activating 
mutation positive NSCLC. As such, preclinical data assessing the combination of Osimertinib 
(AZD9291) and Telaglenastat (CB-839) HCl were conducted (Figure 3, Calithera internal, 
unpublished data). The synergistic activity of Osimertinib (AZD9291) and Telaglenastat (CB- 
839) HCl was assessed in two EGFR mutation positive NSCLC cell lines, HCC827 (T790M 
mutation negative) and H1975 (T790M mutation positive). In both of these studies, cell growth 
inhibition was observed in a dose-dependent manner and synergistic activity was observed in 
both the T790M mutation-positive and -negative groups. 
 
 
Figure 3: Synergistic activity of Osimertinib (AZD9291) and Telaglenastat (CB-839) HCl in HCC827 (A) 
and H1975 
(B) cell lines. This synergy was seen in T790M positive and negative lines (From Calithera internal, 
unpublished data). 
 
These studies provide additional preclinical data that the combination of an EGFR inhibitor and 
Telaglenastat (CB-839) HCl is synergistic, particularly when Osimertinib (AZD9291) is used as 
the EGFR inhibitor, and that this combination is efficacious even in T790M mutation negative 
NSCLC. Finally, to evaluate whether combination therapy could induce responses in vivo, 
mouse xenograft studies were performed which showed synergistic activity for Telaglenastat 
(CB-839) HCl and Osimertinib (AZD9291) (Figure 4A and 4B). 
 
Based on the above preclinical data demonstrating synergistic activity between EGFR inhibitors 

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(including Osimertinib (AZD9291)) and the glutaminase inhibitor, Telaglenastat (CB-839) HCl, 
this phase 1/2 study is proposed to assess this drug combination in patients with metastatic 
EGFR activating mutation positive NSCLC who have progressed on front-line EGFR inhibitor 
therapy and are known to be T790M mutation-negative. We hypothesize that this combination 
will be more efficacious as compared to the historical control of Osimertinib (AZD9291) alone 
in this patient population. 
 
Figure 4: Synergistic activity of Osimertinib (AZD9291) and Telaglenastat (CB-839) HCl in HCC827 (A) 
and H1975 
(B) xenograft models. A) Female scid/bg mice were implanted subcutaneously with 5 x 106 HCC827 lung 
adenocarcinoma cells. On Day 14 post-implant, mice were randomized into groups of n=10/group to receive 
the following: 1) Vehicle (25% hydroxypropyl-B-cyclodextrin) orally BID; 2) Telaglenastat (CB-839) HCl 
at 200 mg/kg orally BID; 3) Osimertinib (AZD9291) at 0.25 mg/kg orally once daily; or 4) Telaglenastat 
(CB-839) HCl at 200 mg/kg PO BID and Osimertinib (AZD9291) orally once daily. Tumors were measured 
with calipers three times per week and tumor volume calculated using the formula tumor volume (mm3) = 
(a x b2/2) where ‘b’ is the smallest diameter and ‘a’ is the largest perpendicular diameter. ***P <0.001 
(ANOVA) versus both monotherapies. B) Female scid/bg mice were implanted subcutaneously with 2.5 x 
106 H1975 lung adenocarcinoma cells. On Day 12 post-implant, mice were randomized into groups of 
n=10/group to receive the following: 1) Vehicle (25% hydroxypropyl-B-cyclodextrin) orally BID; 2) 
Telaglenastat (CB-839) HCl at 200 mg/kg orally BID; 3) Osimertinib (AZD9291) at 1 mg/kg orally once 
daily; or 4) Telaglenastat (CB-839) HCl at 200 mg/kg PO BID and Osimertinib (AZD9291) orally once 
daily. Tumors were measured with calipers three times per week and tumor volume calculated using the 
formula tumor volume (mm3) = (a x b2/2) where ‘b’ is the smallest diameter and ‘a’ is the largest 
perpendicular diameter. ****P <0.0001 (ANOVA) versus both monotherapies. 
 
Pharmacokinetics of Osimertinib (AZD9291) and Telaglenastat (CB-839) HCl 
 
Since Telaglenastat (CB-839) HCl is a substrate of efflux pumps, co-administration of 
Telaglenastat (CB-839) HCl and Osimertinib (AZD9291), an efflux pump inhibitor, may 
increase intracellular concentrations of Telaglenastat (CB-839) HCl and result in lower plasma 
concentrations. Both Osimertinib (AZD9291) and Telaglenastat (CB-839) HCl are oral agents 
with Osimertinib (AZD9291) administered QD (regardless of presence/absence of food) and 
Telaglenastat (CB-839) HCl administered BID with food. Given that both agents are absorbed 
within the gut, under these differing conditions and utilizing an overlapping pump mechanism, a 
DDI that may affect the absorption and blood levels of either of these agents could be possible 
and to date has not been explored. The question of whether these agents can be co-administered 
without affecting absorption of either Telaglenastat (CB-839) HCl or Osimertinib (AZD9291) is 
therefore relevant and as such, a phase 1 component is necessary to evaluate this drug 
combination and to obtain thorough PK information at a number of dose levels. 

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Rationale for expansion cohort 
 
In order to gain additional data regarding safety and tolerability of combination Telaglenastat 
(CB-839) HCl and Osimertinib (AZD9291), as well as to confirm PK findings above, an 
expansion cohort of 10 patients treated at RP2D will be conducted. This expansion cohort will 
include only patients who have experience disease progression on first line Osimertinib 
(AZD9291) which has become the standard first line treatment for EGFR mutation positive 
NSCLC. The expansion cohort will allow for additional analysis of biospecimens to understand 
the metabolic and molecular changes that occur during treatment with CB-839 and osimertinib. 
Lastly, the expansion cohort will provide additional information regarding preliminary efficacy 
of the combination in these patients. 
 
Rationale for dose selection for expansion cohort 
 
In the expansion cohort, patients will receive combination Telaglenastat (CB-839) HCl at 800 mg 
orally twice daily and Osimertinib (AZD9291) 80 mg orally daily. This is based on results of the dose 
escalation cohort where combination Telaglenastat (CB-839) HCl and Osimertinib (AZD9291) at 
these doses were  associated with acceptable safety and toxicity profile. In total, 12 patients were 
treated with combination Telaglenastat (CB-839) HCl and Osimertinib (AZD9291) in the dose 
escalation study, with one patient experiencing DLT at dose level 3 (grade 3 mucositis and grade 2 
pneumonitis, which is protocol defined DLT). Both mucositis and pneumonitis are known toxicities 
with osimertinib, and both resolved with supportive care and withholding of study therapy. Treatment 
related serious adverse events (TRSAE) occurred in 2 patients, including grade 3 lymphocyte count 
decreased (attributed to osimertinib) in one patient as well as grade 3 fatigue (attributed as possibly 
related to both study agents and likely related to disease), and grade 3 failure to thrive (attributed as 
possibly related to CB-839 and definitely related to disease). The most common treatment related 
adverse events of any grade were nausea (n=6, 50%, all grade 1 or 2), fatigue (n=4, 33%), and 
decreased white blood cell count (n=4, 33%). Best response was complete response (CR) in 1 patient, 
stable disease (SD) in 7 patients, and disease progression in 4 patients. Of note, all 6 patients treated at 
the highest dose level tested had stable disease as best response after experiencing progression on 
osimertinib. As 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, and there were no new safety 
concerns as well as evidence of clinical activity seen in the dose escalation cohort, Telaglenastat (CB-
839) HCl at 800 mg orally twice daily and Osimertinib (AZD9291) 80 mg orally daily was chosen for 
the expansion cohort.  
 
 
2.4 
Correlative Studies Background 
 
The molecular landscape of cancer is just beginning to be defined. However, we do not know 
enough about the genomic and molecular landscape of tumors from patients who enter early 
phase clinical trials. With this study, we will attempt to learn more about specific molecular 
features of cancers from this patient subgroup. It is particularly important to learn, as early as 
possible, if there are molecular features within a particular malignant histology or across 
malignant histologies that can inform about potential response or resistance to treatments in early 
phase clinical trials. Such knowledge will be used to design more efficient later stage clinical 
trials for more efficient and more effective drug development. 

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2.4.1 EGFR Mutational Status (Integral, Standard of Care) 
 
Given the importance of EGFR genotyping in predicting the activity of all TKI therapy including 
Osimertinib (AZD9291), genotyping for EGFR mutational status will performed on all patients 
on study. This is considered routine practice upon progressive disease on first line TKI. 
 
EGFR mutational status will be assessed in local/referral Clinical Laboratory Improvement 
Amendments (CLIA)-certified laboratories as part of the Standard of Care procedures for 
patients with NSCLC. 
 
2.4.2 Quantification of Plasma Glutamine, Glutamate, Aspartate, and Asparagine 
Concentrations (Integrated) 
 
Telaglenastat (CB-839) HCl is a selective, allosteric, noncompetitive inhibitor of both isoforms 
of GLS. 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 (Gross et al., 2014; Matre et al., 2016). The plasma 
levels of glutamine, glutamate, aspartate, and asparagine will be measured at various time points 
to determine the changes as a result of Telaglenastat (CB-839) HCl monotherapy or 
Telaglenastat (CB-839) HCl and Osimertinib (AZD9291) combination therapy. The changes in 
the systemic levels of these metabolites provide key pharmacodynamic information on the 
effects of glutaminase inhibition. 
Measurement of plasma concentrations of glutamine, glutamate, aspartate, and asparagine will be 
performed using validated liquid chromatography tandem-MS (LC/MS/MS) assays by the Mayo 
Clinic Cancer Center’s Metabolomics Resource Core under the direction of Dr. Ian Lanza. 
 
2.4.3 Whole Exome Sequencing to Confirm EGFR Mutational Status (Integrated) 
 
The importance of EGFR testing is outline above in Section 2.4.1. In order to confirm EGFR 
mutational status, including sensitizing and resistance mutations (i.e., T790M), whole exome 
sequencing (WES) will be performed on archival tumor as an integrated biomarker at the 
Frederick National Laboratory for Cancer Research (FNLCR), Molecular Characterization 
Laboratory (MoCha). 
 
2.4.4 Pharmacokinetics (Integrated) 
Blood levels of Osimertinib (AZD9291) and Telaglenastat (CB-839) HCl will be assessed to 
evaluate drug-drug interactions, and to compare to established pharmacokinetic profiles from 
prior single-agent trials. Since Telaglenastat (CB-839) HCl is a substrate of efflux pumps, co- 
administration of Telaglenastat (CB- 839) HCl and Osimertinib (AZD9291), the efflux pump 
inhibitor, may increase intracellular concentrations of Telaglenastat (CB-839) HCl and result in 
lower plasma concentrations. 
 
2.4.5 Whole Exome Sequencing / RNA sequencing (Exploratory) 
 
In order to determine possible biomarkers for response to treatment with Osimertinib 
(AZD9291) and Telaglenastat (CB-839) HCl, WES and RNA sequencing (RNAseq) will be 

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performed on the archival/baseline tumor specimen. Recent studies have demonstrated the 
importance of co- mutations in EGFR-mutated NSCLC, and potential primary resistance 
mechanisms to Osimertinib (AZD9291) have been elucidated, including regulators of cell cycle 
such as CDK4/6 (Blakely et al., 2017) as well as additional EGFR mutations L718 and L792 
(Yang et al., 2018). Evaluation for these and other mutations at baseline will be performed to 
identify biomarkers associated with drug activity. 
 
2.4.6 Cell-Free DNA Analysis (Exploratory) 
 
cfDNA will be assessed for EGFR mutational status, T790M mutational status and resistance 
mechanisms at different time points in this study. Peripheral blood will be collected for cfDNA 
at baseline, after one month of treatment, and at time of progression. In the phase 1 study, 
cfDNA will also be collected on C1D15 after single agent Telaglenastat (CB-839) HCl prior to 
initiation of combination therapy. cfDNA for EGFR status will be compared with 
archival/baseline specimen for concordance. Blood based assays for detection of resistance 
mechanisms are widely used in clinical practice, and have also yielded information about 
resistance mechanisms to treatment (Blakely et al., 2017). 
 
 
3. 
PATIENT SELECTION 
 
3.1 
Overall Eligibility Criteria 
 
3.1.1 Histologically confirmed, Stage IV NSCLC, with advanced or metastatic disease. 
 
3.1.2 Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in 
combination with other EGFR mutations) as per local assessment of a tissue 
biopsy/cytology specimen. The tissue biopsy must have been obtained since the time 
of disease progression on most recent targeted therapy. “Liquid” (i.e.blood based) 
biopsies cannot be used for eligibility determination. 
 
 
3.1.3 Patients must have had progressive disease on prior EGFR inhibitor therapy (gefitinib, 
erlotinib, afatinib, or osimertinib). There is no limit to lines of prior TKI therapy. 
Prior Osimertinib (AZD9291) therapy is permitted. 
 
3.1.4 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, magnetic resonance imaging (MRI), or calipers by 
clinical exam. See Section 12 for the evaluation of measurable disease. 
 
3.1.5 Age >18 years. NSCLC is exceedingly rare in patients <18 years of age. Because no 
dosing or AE data are currently available on the use of Telaglenastat (CB-839) HCl in 
combination with Osimertinib (AZD9291) in patients <18 years of age, children are 

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excluded from this study. 
 
3.1.6 Eastern Cooperative Oncology Group (ECOG) performance status <2 (Karnofsky ≥60%, 
see Appendix A). 
 
3.1.7 Must be able to swallow pills. 
 
3.1.8 Life expectancy >3 months. 
 
3.1.9 Patients must have adequate organ and marrow function as defined below: 
 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
hemoglobin 
≥90 g/L 
− 
total bilirubin 
≤1.5 × institutional ULN 
and up to 3 mg/dL for patients with Gilbert’s 
disease 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional ULN and ≤5 × institutional 
ULN for patients with liver metastases 
− 
creatinine 
within 1.5 × ULN 
OR 
− 
glomerular filtration rate (GFR)  ≥50 mL/min/1.73 m2 [measured or calculated by 
Cockcroft and Gault equation] —confirmation of 
creatinine clearance is only required for patients 
with creatinine levels above institutional upper limit 
of normal. 
 
3.1.10 Should participants with HBV infection be included, patients are only eligible if they meet 
all the following criteria: 
• Demonstrated absence of HCV co-infection or history of HCV co-infection (Note that the 
sponsor’s 3.1.11 is more lenient because it allows for history of HBC) 
• Demonstrated absence of HIV infection 
• Participants with active HBV infection are eligible if they are: 
Receiving anti-viral treatment for at least 6 weeks prior to study treatment, HBV DNA is 
suppressed to <100 IU/mL and transaminase levels are below ULN. 
Participants with a resolved or chronic infection HBV are eligible if they are: 
 
Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc IgG]. In addition, 
patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment and 6- 
12 months (TBD by hepatologist) post treatment 
Or 
Positive for HBsAg, but for > 6 months have had transaminases levels below ULN and HBV 
DNA levels below <100 IU/mL (i.e., are in an inactive carrier state). In addition, patients must 

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be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment and 6-12 months 
(TBD by hepatologist) post treatment. Refer to section 3.4. 
 
3.1.11 If history of hepatitis C virus (HCV) infection, must be treated and have an undetectable 
HCV viral load. 
 
3.1.12 Patients with treated brain metastases are eligible if follow-up brain imaging after 
central nervous system (CNS)-directed therapy shows no evidence of progression. 
 
3.1.13 Patients with new or progressive brain metastases (active brain metastases) or 
leptomeningeal disease are eligible if the treating physician determines that immediate 
CNS specific treatment is not required and is unlikely to be required during the first cycle 
of therapy. Patients on corticosteroids for the treatment of brain metastases will be 
permitted as long as the dose is is ≤ 10 mg of prednisone-equivalent and has not been 
increased within 2 weeks of screening. 
 
3.1.14 Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial. 
 
3.1.15 Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification. To be eligible 
for this trial, patients should be class 2B or better. 
 
3.1.16 Ability to understand and the willingness to sign a written informed consent document. 
Participants with impaired decision-making capacity (IDMC) who have a legally- 
authorized representative (LAR) and/or family member available will also be eligible. 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have not recovered from AEs due to prior systemic anti-cancer therapy 
(i.e., have residual toxicities > grade 1), with the exception of alopecia. Note: 
Subjects with irreversible toxicity that in the opinion of the treating physician is not 
reasonably expected to be exacerbated by the investigational treatment may be 
included (e.g., hearing loss, hormone deficiency requiring replacement therapy). 
 
3.2.2 Previous enrollment in the present study. 
 
3.2.3 Past medical history of interstitial lung disease, drug-induced interstitial lung disease, 
radiation pneumonitis requiring steroid treatment, or any evidence of clinically active 
interstitial lung disease. 
 
3.2.4 Patients who are receiving any other investigational agent within five half-lives of the 
compound or 3 months, whichever is greater. Patients who have received prior 
immunotherapy may be included only if time from last immunotherapy is at least 3 months 
(ie 90 days). 

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3.2.5 Spinal cord compression, symptomatic and unstable brain metastases except for those 
patients who have completed definitive therapy, and have had a stable neurological status 
for at least 2 weeks after completion of definitive therapy. Patients may be on 
corticosteroids (≤ 10 mg of prednisone-equivalent) to control brain metastases if they 
have been on a stable dose for 2 weeks (14 days) prior to the start of study treatment and 
are clinically asymptomatic.” 
 
3.2.6 Patients with an uncontrolled intercurrent illness. 
 
3.2.7 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Telaglenastat (CB-839) HCl, Osimertinib (AZD9291), or other agents 
used in study. Patients with hypersensitivity to to any of the inactive excipients thereof 
should also be excluded. 
 
3.2.9 Currently receiving (or unable to stop use prior to receiving the first dose of study 
treatment) medications or herbal supplements known to be potent inducers of CYP3A4 
(wash-out periods vary; see Appendix D [Guidance Regarding Potential Interactions with 
Concomitant Medications]) All patients must try to avoid concomitant use of any 
medications, herbal supplements and/or ingestion of foods with known inducer effects on 
CYP3A4. 
 
3.2.10 Pregnant women are excluded from this study because Telaglenastat (CB-839) HCl is a 
glutaminase inhibitor with the potential for teratogenic or abortifacient effects. Because 
there is an unknown but potential risk for AEs in nursing infants secondary to treatment 
of the mother with Telaglenastat (CB-839) HCl and Osimertinib (AZD9291), 
breastfeeding should be discontinued if the mother is treated with Telaglenastat (CB- 
839) HCl and Osimertinib (AZD9291). Breastfeeding patients will be excluded. These 
potential risks may also apply to other agents used in this study. 
 
3.2.11 Patients with a significant history of cardiovascular disease (e.g., MI, thrombotic or 
thromboembolic event in the last 6 months). 
 
3.2.12 Any of the following cardiac criteria: 
a) 
Mean resting corrected QT interval (QTc using Fredericia’s formula [QTcF]) >470 
msec (Fridericia’s Criteria for Corrected QT interval [QTc] Calculation: 
Fridericia’s formula QTcF = (QT/RR0.33). RR is the time from the interval of 1 
QRS complex to the next measured in seconds and is commonly calculated as 
(60/HR) (Hosmane et al., 2006) 
b) 
Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG (e.g., complete left bundle branch block, third degree heart block, 
second degree heart block) 
c) 
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, electrolyte abnormalities (including: Serum/plasma 

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potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < 
LLN , congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age in first degree relatives, or any 
concomitant medication known to prolong the QT interval and cause Torsades de 
Pointes. 
d) 
Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) as assessed 
by either multigated acquisition (MUGA) scan or echocardiogram (ECHO). 
 
3.2.13 Patients with active malignancies other than NSCLC or patients with prior curatively 
treated malignancy at high risk of relapse during the study period with the exception of 
localized squamous or basal cell skin cancers, ductal carcinoma in-situ (DCIS), or 
indolent cancer currently on observation (i.e. CLL or low-risk prostate cancer). 
 
3.2.14 Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension and active bleeding diatheses, which in the investigator’s opinion makes it 
undesirable for the patient to participate in the trial or which would jeopardise 
compliance with the protocol, or active infection with human immunodeficiency virus 
(HIV). Screening for chronic conditions is not required. 
 
3.2.15 Patients with symptomatic CNS metastases who are neurologically unstable. 
 
3.2.16 Patients who are at risk for impaired absorption of oral medication including, but not 
limited to, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to 
swallow the formulated product or previous significant bowel resection that would 
preclude adequate absorption of Telaglenastat (CB-839) HCl and Osimertinib 
(AZD9291). 
 
3.2.17 Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements. 
 
3.2.18 Involvement in the planning and/or conduct of the study (applies to both Investigator 
staff and/or staff at the study site). 

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3.3 
Expansion Cohort Specific Inclusion Criteria 
 
3.3.1 Patients must have had progressive disease on prior first line EGFR inhibitor therapy with 
osimertinib. 
 
3.4 
Restrictions 
 
3.4.1 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 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. 
 
3.4.2 The effects of Telaglenastat (CB-839) HCl and Osimertinib (AZD9291) on the 
developing human fetus are unknown. For this reason and because glutaminase inhibitor 
and EGFR TKI agents are known to be teratogenic, women of child-bearing potential 
must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and up to 6 
weeks after receiving last dose of study treatment. 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 and 
Osimertinib (AZD9291) administration. For further details please refer to Appendix F 
(Definition of Women of Childbearing Potential and Acceptable Contraceptive 
Methods). 
 
3.4.3 Patients who have received prior treatment with immune-oncology (IO) therapies should 
be closely monitored for an appropriate period of time after the last dose of the IO 
treatment, in accordance with the respective IO label, as immune mediated adverse 
reactions with the IO therapy may occur at any time during or after discontinuation of 
therapy. The stop date of the prior IO drug therapy should be captured in the case report 
forms. 
 
3.4.4 In patients with resolved or chronic hepatitis B infection (inactive carrier state) or active 
controlled HBV infection on treatment with osimertinib: 
 
a. Recommend monthly monitoring of ALT/AST, HBV DNA levels and HBsAg (if 
negative at baseline) 
b. Where liver signs and symptoms of viral reactivation appear (HBV DNA levels 
exceeding 10-fold from baseline or ≥100 IU/ml (if baseline HBV DNA levels are 
undetectable) or conversion of HBsAg negative to positive): 
 
Expert hepatologist/specialist oversight of the patient is required. Consider interruption 

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or discontinuation of study treatment, based on risk-benefit assessment 
 
3.4.5 In terms of reproductive restrictions, the use of osimertinib in the approved setting needs 
to follow the current approved local safety guidance. 
 
3.4.6 Once enrolled all patients must try to avoid concomitant use of medications, herbal 
supplements and/or ingestion of foods that are known to be strong inducers of CYP3A4 
whenever feasible, but patients may receive any medication that is clinically indicated for 
treatment of adverse events. Such drugs must have been discontinued for an appropriate 
period before they enter screening and for a period of 3 months after the last dose of 
Osimertinib (AZD9291). All concomitant medications should be captured on the eCRF. 
Guidance on medicines to avoid, medications that require close monitoring and on 
washout periods is provided (see Appendix A). 
 
If medically feasible, patients taking regular medication, with the exception of potent 
inducers of CYP3A4 (see above), should be maintained on it throughout the study period. 
Patients taking concomitant medications whose disposition is dependent upon BCRP and/or 
P-glycoprotein (P-gp) and which have a narrow therapeutic index should be closely 
monitored for signs of changed tolerability as a result of increased exposure of the 
concomitant medication whilst receiving Osimertinib (AZD9291). Guidance on medications 
to avoid, medications that require close monitoring and on washout periods is provided 
(seeAppendix D “Guidance regarding Potential Interactions with Concomitant 
Medications”). 
 
Patients taking rosuvastatin should have creatine phosphokinase levels monitored (due to 
BCRP-mediated increase in exposure). If the patient experiences any potentially relevant 
AEs suggestive of muscle toxicity including unexplained muscle pain, tenderness, or 
weakness, particularly if accompanied by malaise or fever, rosuvastatin must be stopped 
and any appropriate further management should be taken. 
 
 
3.5 
Inclusion of Women and Minorities 
 
National Institute of Health (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 

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• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval, and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as the 
CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., Alliance). 
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval 
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate their 
intent to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or protocol 
level. Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and on 
at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile, and 
• Holds the appropriate CTEP registration type for the protocol. 
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Regulatory Documents 
Download the site registration forms from the protocol-specific page located on the CTSU members’ 

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website. Permission to view and download this protocol and its supporting documents is restricted 
based on person and site roster assignment. To participate, the institution and its associated 
investigators and staff must be associated with the LPO or a Participating Organization on the 
protocol. 
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o 
Enter the protocol number in the search field at the top of the protocol tree, or 
o 
Click on the By Lead Organization folder to expand, then select LAO-OH007, and 
protocol number 10240, 
 
• Click on Documents, select Site Registration, and download and complete the forms provided. 
(Note: For sites under the CIRB initiative, IRB data will load automatically to the CTSU as 
described above.) 
 
4.2.2 Requirements For NCI 10216 Site Registration 
 
• 
Site Initiation Teleconference 
• 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 Please contact STS Support at Theradex for the training (STS.Support@theradex.com, 
Theradex phone: 609-799-7580). 
 
 
4.2.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website. 
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website → Regulatory 
→ Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
 

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4.2.4 Checking Site Registration Status 
 
You can verify your site’s registration status on the members’ side of the CTSU website. 
 
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration 
• Enter your 5-character CTEP Institution Code and click on Go 

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Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined above. 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 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access: 
 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations: Be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar. 
Registrars must hold a minimum of an AP registration type. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar 
task on the DTL for the site. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and 
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records. 
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 

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4.3.2 Special Instructions for Patient Enrollment 
This Study will use the ETCTN Specimen Tracking System (STS). 
 
•  All biospecimens collected for this trial must be submitted using the ETCTN 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. 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment initiation 
to check slot availability. Registration staff should ensure that a slot is available and secured for 
the patient before completing an enrollment. OSU will register all patients, including subsite 
patients, using IWRS. 
 
The OPEN system will provide the site with a printable confirmation of registration and treatment 
information. Please print this confirmation for your records. 
 
Patients will be registered after meeting all entry requirements, clearance by the Protocol 
Coordinator, and signing of the informed consent. 
 
OSU patients will be registered by the OSU research coordinator, as per their standard practice. 
 
Subsite patients will have eligibility verified and will be entered on study centrally at the Ohio State University 
by the Multi-Institution Program Coordinator. All subsites must email the Multi-Institution Program 
Coordinator to verify slot availabilities prior to consenting patients. 
 
The required forms, including Eligibility Criteria Checklist and Registration Form, can be found in the 
Supplemental Forms Document. 
 
To register a subsite patient, the following documents must be completed by the subsite research 
team and faxed or securely e-mailed to the Multi-Institution Program Coordinator: 
• Copy of all baseline tests required per the protocol calendar. Tests must be within 
the specified window. 
• Signed Patient Consent Form 
• Signed Patient HIPAA Authorization Form 
• Consent Documentation Note 

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• Completed & Signed Eligibility Checklist (refer to Supplemental Forms Document) 
• Registration Form (refer to Supplemental Forms Document) 
• Source documents verifying every inclusion & exclusion criteria 
o 
Note: every inclusion and exclusion criteria must be documented in the patient’s 
medical record 
 
Upon receipt of registration documents, the Multi-Institution Program Coordinator will send an 
email confirmation of receipt. If confirmation of receipt is not received within 1 hour of 
submission, please call or page the Multi-Institution Program Coordinator. 
 
Upon receipt of all required registration documents and upon verification the subsite patient 
meets all eligibility criteria, the Multi-Institution Program Coordinator will: 
• Assign the patient a study sequence ID 
• Register the patient on the study 
• Fax and/or e-mail to the subsite the completed Registration Form with the assigned 
study sequence ID as confirmation of patient registration 
 
Each participating institution will order study agents directly. Agents may be ordered by a 
participating site only after the initial IRB approval for the site has been forwarded to the 
Multi- Institution Program Coordinator. 
 
Patient sequence IDs will be assigned in the following fashion: 
• A-BCD 
o A = CTEP Site ID 
o BCD = sequential numbers by order of enrollment 
For the ETCTN Biobanking and Molecular Characterization Initiative, the following 
information will be requested: 
• 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 

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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. 
 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 5 days. Issues that would 
cause treatment delays should be discussed with the PI. 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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slides, then slides must be processed in order, and numbered sequentially (e.g., H&E stained 
slide is created first and labeled 1, unstained slides are then created and numbered 2 – 51).  
Refer to section 5.3 for additional information. 

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5.2 
Specimen Procurement Kits and Scheduling 
 
5.2.1 Specimen Shipping Kits from the EET Biobank 
 
Kits for collection and shipment of specimens to the EET Biobank can be ordered online via the 
Kit Management System: https://kits.bpc-apps.nchri.org/. 
 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit. Please note that protocol may include more than 
one type of kit. Each user may order two kit types per protocol per day (daily max = 6 kits). 
Kits are shipped ground, so please allow 5-7 days for receipt. A complete list of kit contents for 
each kit type is located on the Kit Management system website. 
 
Note: Kits or supplies are only provided for specimens shipped to the Biorepository. 
Institutional supplies must be used for all other specimen collection and processing. 
 
 
5.2.2 Scheduling of Specimen Collections 
 
Blood in cfDNA Streck tubes may be collected and shipped to the EET Biobank on Monday 
through Friday. Please select “Saturday Delivery” if shipping blood on a Friday. If Streck 
tubes cannot be shipped immediately, then they should be stored at room temperature until 
shipment. 
 
Frozen plasma can be shipped to the EET Biobank on Monday through Thursday. Do not send  
frozen specimens for Saturday delivery. Processed plasma specimens must be stored in a -70 to - 
80°C freezer until shipment. 
 
Formalin-fixed paraffin-embedded (FFPE) tissue block or slides can be shipped to the EET 
Biobank on Monday through Thursday. FFPE specimens should be stored at room temperature 
until shipment. 
 
5.3 
Specimen Collection, Processing, and Submission 
 
5.3.1 Collection and Processing of Tumor Tissue 
 
• FFPE tumor tissue block(s) must be submitted. The optimal block is at least 70% 
tumor. Specimen size requirement is as follows: 
o Surface area: 25 mm2 is optimal. Minimum is 5 mm2. 
o Volume: 1 mm3 optimal. Minimum volume is 0.2 mm3, however the success of 
DNA extraction decreases at suboptimal tissue volume. 
 
If an existing block cannot be submitted, the following are requested, if available: 
• One (1) H&E slide 
• Thirty to fifty (30-50) 5-10 micron unstained air-dried uncharged slides 

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5.3.2 Collection and Processing of Whole Blood in EDTA for Pharmacokinetic Analysis 
(Telaglenastat [CB- 839] HCL and Osimertinib (AZD9291)). 
 
1. Refer to the Summary Table for Biospecimen Collection (Section 5.1) for the time points 
for this collection. 
2. All “pre-dose / 0 hour” or “baseline” 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 all days where PK sampling will occur. 
3. Label both 3 mL (for Telaglenastat (CB-839) HCl samples) and 6 mL (for 
Osimertinib (AZD9291) samples) EDTA (purple top) tubes. 
4. Collect blood in pre-labeled tube and gently invert tube to mix. Place on wet ice (or store 
at 4°C) until processing. 
5. 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. 
6. Centrifuge blood at 1000 – 1300 x g (relative centrifugal force [RCF]) for 10 minutes in a 
refrigerated centrifuge kept at 4°C. 
7. Following centrifugation, remove the plasma (top yellowish or clearish layer) and create 
1 mL aliquots in labeled 2 mL screw-top cryovials. Refer to Section 5.4 for labeling 
instructions. 
8.  Tube labels must contain the information indicated in Section 5.4.1.2. These data should 
also be recorded in nurse’s notes, on the flow sheet, and on the pharmacology reporting 
form that is to be sent with the samples 
9. Freeze vials immediately upright in a -70 to -80°C freezer until shipment to the Mayo 
Clinical Cancer Center (Telaglenastat (CB-839) HCl PK specimens) and/or Ohio State 
University (Osimertinib (AZD9291) HCl PK specimens). See Sections 5.6 and 5.7 for 
shipping instructions and addresses. 
 
5.3.3 Collection and Processing of Whole Blood in EDTA for Oncometabolite Analysis 
 
1. Peripheral blood will be collected at: baseline, C2D1, and at time of disease progression. 
2. Label a 3 mL EDTA tube. 
3. Collect 3 mL of blood into the 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. Refer to Section 5.4 for labeling 
instructions. 
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 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. 

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5.3.4 Collection of Whole Blood in cfDNA Streck Tubes 
 
1. Label two cfDNA Streck tubes. Refer to Section 5.4 for labeling instructions. 
2. Invert tube to mix. Note: blood must be thoroughly mixed to ensure preservation of 
the specimen. 
3. After collection, blood in cfDNA Streck tubes should never be refrigerated as this will 
compromise the specimens. Blood collected in cfDNA Streck tubes is stable at room 
temperature. 
4. Ship on day of collection (whenever possible) to the EET Biobank according to 
instructions below. 
 
5.4 Specimen Tracking System Instructions 
 
5.4.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
• 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 portion 
of this or any other protocol that uses the ETCTN Specimen Tracking System. 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), collection date, block number, and the IWRS-assigned UPID and 
patient study ID for this trial. For newly acquired biopsies, the radiology and operative report(s) must 
also be uploaded into Rave. Important: Remove any personally identifying information, 
including, but not limited to, the patient’s name, date of birth, initials, medical record number, 
and patient contact information from the institutional pathology report prior to submission. 
 
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 STS Support at 

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STS.Support@theradex.com. 
 
The Shipping List report must be included with all sample submissions. 
 
5.4.2 Specimen Labeling 
 
5.4.2.1 Tissue 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., formalin-fixed paraffin-embedded [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 (when applicable) 
• Block number from the corresponding pathology report (archival only) 
• Collection date (to be added by hand) 
 
5.4.2.2 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) 
 
Label plasma samples for PK (all collections and processed/shipping samples) and oncometabolites 
(all collections) with: 
• Patient study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point (i.e., baseline, 0, 1, 2, 4, and 8 hours after the PO dose of Telaglenastat 
(CB-839) HCl) 
• Specimen type (e.g., blood, plasma) 
• Collection date and time (to be added by hand)( i.e., C1D1 0.5 hour) 
 
These same 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. The pharmacology reporting form that is to be 
sent with the samples should also contain patient’s Age, Height, Weight, Dose level and Actual 
Dose given. The Specimen labels should be taped on to the sample vials. 

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5.4.2.3 Example of Specimen Label Generated by STS 
 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens folder. 
A generated PDF is emailed to the user as a result of saving that form. 
 
The following image is an example of a tissue specimen label printed on a label that is 0.5” high and 
1.28” wide. 
 
 
 
 
The QR code in the above example is for the Specimen ID shown on the second line. 
 
Labels may be printed on a special purpose label printer, one label at a time, or on a standard laser 
printer, multiple labels per page. Theradex recommends the use of these low temperature waterproof 
labels for standard laser printers: https://www.labtag.com/shop/product/cryo-laser-labels-1-28-x-0-5- 
cl-23-colors-available/ 
 
The last line item on the label includes the following 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. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification 
 
Space is provided at the bottom of the label for the handwritten date and optional time. The 
last line on the example label is for the handwritten date and optional time. 
 
5.4.3 Overview of Process at Treating Site 
 
5.4.3.1 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. 

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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. 
 
5.4.3.2 Rave Specimen Tracking Process Steps 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate participant. 
 
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, and number of labels needed (include 
extra labels to apply to reports to be uploaded). CRF generates unique Specimen ID. 
 
Step 2: Print labels using the Print Labels CRF located in the All Specimens folder, then collect 
specimen. 
• Label specimen containers and write collection date and time on each label. After collection, 
store labeled specimens as described in Section 5.4.2. 
• 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), and 
Surgical (or Operative) reports. 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) and/or the Tissue Biopsy Verification form (when applicable). Uploaded 
reports should have protected health information (PHI) data, like name, date of birth, mailing 
address, medical record number or social security number (SSN), redacted. Do not redact 
SPID, block number, diagnosis or relevant dates (such as collection date), and include 
the UPID and patient study ID on each document (either by adding a label or hand- 
writing). 
 
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, recipient, number of 
sample containers and ship date once for the first specimen in a shipment. 
• Copy Shipping CRF: In the specimen folders for additional specimens (if any) that will be 
shipped with the initial specimen, please use the Copy Shipping form to derive common data 
into additional Shipping Status forms. A few unique fields will still need to be entered in 

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Shipping Status. 
 
Step 5: Print shipping list report and prepare to ship. 
• Shipping List report is available at the site level. 
• 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). 
 
Step 8: Monitor the Receiving Status form located in each specimen folder for acknowledgment of 
receipt and adequacy. 
 
 
5.5 
Shipping of Specimen(s) from Clinical Sites to the EET Biobank 
 
5.5.1 General Shipping Information 
 
5.5.1.1 Required Forms for Specimen Submissions 
 
 
Tissue 
Required Forms 
Archival 
1. Shipping List 
2. Corresponding Pathology Report 
Blood 
1. Shipping List 
 
Each document submitted with the specimen must be labeled with a label printed from the STS, or 
the Universal ID and Patient Study ID. 
 
Minimum required personally identifiable information: 
• Remove patient identifiers such as name, date of birth, medical record number, social security 
number, and insurance information from the pathology or other clinical reports. 
• Do not remove the date of procedure, surgical pathology ID (SPID) number, block number, and 
diagnosis.   
 
5.5.2 Schedule of Shipment 
 
When kits are provided, the shipping container sent with kit contents should be used to ship 
specimens to the EET Biobank. In winter months, please include extra insulation, such as bubble 

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wrap, inside the shipping container. 
 
 
• Ambient Blood (cfDNA Streck tubes) is shipped at room temperature on Monday through Friday. 
Please select Saturday delivery if shipping blood on a Friday. Ship blood in cfDNA Streck tubes 
shipped in ambient shipping containers provided by the EET Biobank. 
 
• Frozen specimens (plasma) may be shipped on Monday through Thursday. Frozen specimens are 
batch shipped. Shipments should contain no more than 31 cryovials so that sufficient dry ice can be 
included to completely encase the specimens in order to maintain specimen integrity during 
shipment. 
 
• FFPE tissue block or slides may be shipped on Monday through Thursday. Slides are shipped in 
containers provided by the submitting site. 
 
5.5.3 Packaging Instructions for Blood (Streck Tubes) 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 the SAF-T-TEAP Pak. 
8. 
Place the lid on the insulated chest. 
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 listed below. FedEx Priority 
Overnight is strongly recommended to prevent delays in package receipt. 
 
5.5.4 Packaging Instructions for Frozen Plasma 
 
Frozen plasma samples should be batch shipping in a Single Chambered Specimen Procurement Kit. 
No more than 21 cryovials of plasma should be included in each Single Chambered Kit. 
 
1. Place the plasma specimens in zip-lock bags. Use a separate zip-lock bag for eachtime 
point and collection time (i.e., oncometabolites). 
2. Place the zip-lock bags in a biohazard envelope containing absorbent material. Expel as 

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much air as possible and seal the envelope. 
3. Put the secondary envelope into a Tyvek envelope. Expel as much air as possible and seal 
the envelope. 
4. Place the Tyvek envelope in the kit compartment filled with dry ice. Layer the bottom of 
the compartment with dry ice until it is approximately one-third full. Place the Tyvek 
envelope containing frozen specimens on top of the dry ice. Cover the specimens with the 
dry ice until the compartment is almost completely full. 
5. Insert a copy of the specimen manifest from the Specimen Tracking System into a plastic 
bag and place in the kit chamber. 
6. Place the Styrofoam lid on top to secure specimens during shipment. Do not tape the inner 
chamber shut. 
7. Close the outer lid of the Specimen Procurement Kit and tape it shut with filament or other 
durable sealing tape. Do not completely seal the container. 
8. Complete a FedEx air bill and attach to top of shipping container. 
9. Complete a dry ice label. 
10. Attach the dry ice UN1845 label and an Exempt Human Specimen sticker or UN3373 
sticker to the side of the shipping container. 
11. Arrange for courier pickup. Note: FedEx Priority Overnight is strongly recommended for 
next day delivery to prevent delays in packagereceipt. 
 
5.5.5 Shipping Instructions and Addresses 
 
Ship specimens to the address below. FedEx Priority Overnight is strongly recommended to 
prevent delays in package receipt. Do not ship specimens the day before a holiday. 
 
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 
 
FedEx Priority Overnight service is very strongly preferred. There is no central Courier 
account for this study. Sites are responsible for all costs for overnight shipment per sample 
shipment to the EET Biobank, utilizing the site screening and base intervention payments. 
 
NOTE: The EET Biobank FedEx Account will not be provided to submitting institutions. 
 
Contact Information for Assistance 
 
For all queries, please use the contact information below:  
 
EET Biobank 
Phone: (614) 722-2865 
E-mail: BPCBank@nationwidechildrens.org 
 

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5.6 
Shipping of Telaglenastat (CB-839) HCl Pharmacokinetics (PK) Plasma 
from Clinical Sites to Mayo Clinic Cancer Center 
 
5.6.1 Schedule of Shipment 
 
• Frozen specimens (plasma) may be shipped on Monday through Thursday. Frozen 
specimens are batch shipped. 
 
5.6.2 Packing Instructions for Frozen Plasma 
 
Frozen plasma samples should be batch shipped at the completion of each patient cycle using the 
instructions below: 
 
1. Place the plasma specimens in zip-lock bags. Use a separate zip-lock bag for each time 
point and collection. 
2. Place the zip-lock bags in a biohazard bag containing absorbent material. Expel as much 
air as possible and seal the bag. 
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 container. 
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 ofshipping 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 packagereceipt. 
 
5.6.3 Shipping Address and Contact Information 
 
Ship plasma for PK analysis overnight courier on dry ice to the Mayo Clinic Cancer Center 
Pharmacology Shared Resource for processing and storage. 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 

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Email: reid@mayo.edu 
 
5.7 
Shipping of Osimertinib (AZD9291) Pharmacokinetics (PK) Plasma from 
Clinical Sites to Ohio State University  
 
5.7.1 Schedule of Shipment 
 
• Frozen specimens (plasma) may be shipped on Monday through Wednesday. For 
study sub-sites, plasma samples may be shipped in batches but preferably no longer 
than 3 months after sample collection.  
 
5.7.2 Packing Instructions for Frozen Plasma 
 
Frozen plasma samples should be batch shipped using the instructions below: 
 
1. Specimen should be stored through the end of collection for each participant and shipped as a 
batch, on dry ice, by participant (more than one participant / shipment is acceptable).  
2. The OSU PhASR lab may contact the study team to request shipment off-schedule. 
3. Please ship only 1 aliquot to the OSU PhASR laboratory within each shipment. Once receipt is 
confirmed, the back-up aliquot(s) may also be shipped. The back-up aliquots can be shipped at 
a later date with subsequent batches of samples for other participants. 
 
Preparing the Specimen Shipment: 
 
1. Samples should be stored in cardboard boxes (5 1/8" x 5 1/8" x 2", LxWxH) with dividers. 
2. Please organize the samples by Patient and Timepoint in the box. 
3. Do not store in plastic bags (they break on dry ice and labels will detach). 
4. A copy of each of the pharmacokinetic sample collection forms (Appendix X) for the respective 
patients or a sample list/manifest should be included with each shipment.  
5. To prevent problems with illegible writing on tubes, consider numbering them (in addition to a 
sample label) and numbering samples on the sample list/manifest. The RAVE system does 
provide unique sample identifiers which are useful for these purposes. 
6. Note the study number, PI, and the drugs used/to be measured.  
7. A name, phone number and email address should be included with samples so that receipt can 
be acknowledged.  
8. Please notify the lab by email (phasr@osumc.edu) at least 24 hours prior to shipment 
9. Place the box in a Styrofoam container filled with dry ice. Layer the bottom with dry ice until it 
is approximately one-third full. Place the box containing frozen specimens on top of the dry ice. 
Cover the specimens with the dry ice until the compartment is almost completely full.  
10. Insert a copy of the specimen manifest from the Specimen Tracking System into a plastic bag 
and place in the container.  
11. Place the Styrofoam lid on top to secure specimens during shipment.  
12. Close the lid with filament or other durable sealing tape. Do not completely seal the container.  
13. Complete a FedEx air bill and attach to top of shipping container.  
14. Complete a dry ice label.  
15. Attach the dry ice UN1845 label and an Exempt Human Specimen sticker or UN3373 sticker to 
the side of the shipping container. 
16. Arrange for courier pickup. Note: FedEx Priority Overnight is strongly recommended for next 

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day delivery to prevent delays in package receipt. 
 
5.7.3 Shipping Address and Contact Information 
 
Ship plasma for PK analysis overnight courier on dry ice to the Ohio State University for 
processing and storage. 
 
The OSUCCC Pharmacoanalytical Shared Resource 
Attn: Nicole Abbott, Ph.D. 
441 Biomedical Research Tower 
460 West 12th Avenue 
Columbus, OH 43210 
Phone: (614)688-0578 
 
Contact Information for Assistance 
 
 
OSUCCC PhASR Lab 
PhASR@osumc.edu 
Nicole Abbott, PhD can be reached at (614) 688-0578 
Mitch Phelps, PhD can be reached at (614) 832-2547 
 

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5.9 
Integral Laboratory or Imaging Studies 
 
5.9.1 EGFR Mutational Status (Standard of Care) 
 
EGFR mutational status will be assessed in local laboratories as part of the Standard of Care 
procedures for patients with NSCLC on a CLIA-certified assay. This is considered routine 
practice upon progressive disease on first line TKI. EGFR mutational status will later be 
confirmed retrospectively at the NCI MoCha laboratory using WES. 
 
5.10 
Integrated Correlative Studies 
 
5.10.1 Quantification of Plasma Glutamine, Glutamate, Aspartate, and Asparagine 
Concentrations 
 
The plasma levels of glutamine, glutamate, aspartate, and asparagine will be measured at various 
time points to determine the changes as a result of Telaglenastat (CB-839) HCl monotherapy or 
Telaglenastat (CB-839) HCl and Osimertinib (AZD9291) combination therapy. The changes in 
the systemic levels of these metabolites provide key pharmacodynamic information on the 
effects of glutaminase inhibition. 
 
5.10.1.1 Specimen Receipt and Processing at the EET Biobank 
 
Upon receipt at the EET Biobank, frozen aliquots of plasma will be received, barcoded, and 
stored in a -80°C freezer until distribution for testing. Samples will then be distributed to the 
testing site. 
 
5.10.1.2 Site(s) Performing Correlative Study 
 
This test will be performed at the Mayo Clinic Metabolomics Core (Lab PI: Ian Lanza), which is 
one of six NIH-funded state of the art metabolomics facilities with special expertise in measuring 
these levels via liquid chromatography/mass spectrometry (LC-MS). 
 
5.10.2 Whole Exome Sequencing (WES) to Confirm EGFR Mutational Status 
 
In order to provide centralized confirmation of EGFR mutational status, WES will be performed 
on archival tumor as an integrated biomarker. 
 
5.10.2.1 Specimen Receipt and Processing at the EET Biobank 
 
Archival formalin-fixed paraffin-embedded tissue (block or slides) will be used for this assay. If 
a block is received, then the EET Biobank will cut and H&E stain slides. A pathology quality 
control review to assess tumor content and annotate slides for macrodissection will be completed 
for all tissue received. 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. 

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Any additional FFPE tissue blocks or slides will banked at room temperature. 
 
DNA will be extracted from blood collected in cfDNA Streck tubes at the baseline time point, 
following plasma processing. DNA will be stored in a -80°C freezer until distribution for testing. 
 
5.10.2.2 Site(s) Performing Correlative Study 
 
WES will be performed on archival tumor and germline samples by the MoCha, Frederick National 
Laboratory for Cancer Research (FNLCR) under the supervision of Chris Karlovich, Ph.D. 
(chris.karlovich@nih.gov). 
 
5.10.2.3 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 
 
5.10.2.4 Contact information for notification of specimen shipment 
 
Thomas Forbes, mochasamplereceiving@nih.gov  
5.10.3 Telaglenastat (CB-839) HCl Pharmacokinetics 
 
Blood levels of Osimertinib (AZD9291) and Telaglenastat (CB-839) HCl will be assessed to 
evaluate for drug- drug interactions, and to compare with established pharmacokinetic profiles 
from prior single- agent trials. Since Telaglenastat (CB-839) HCl is a substrate of efflux pumps, 
co-administration of Telaglenastat (CB-839) HCl and Osimertinib (AZD9291), the efflux pump 
inhibitor, may increase intracellular concentrations of Telaglenastat (CB-839) HCl and result in 
lower plasma concentrations. 
 
5.10.3.1 Hypothesis and Rationale 
 
In those patients with inadequate drug exposure, inhibition of glutaminase activity and other 
cellular effects of glutaminase inhibition as described in Section 2.2.1 will be limited. These 
studies are necessary to characterize the PK and drug exposure of Telaglenastat (CB-839) HCl 
when used in combination with Osimertinib (AZD9291) in patients with metastatic EGFR 
activating mutation positive NSCLC, to assess pharmacodynamic relationships with plasma 
oncometabolites such as glutamate, glutamine, aspartate, asparagine and clinical response 
endpoints, and to determine the effect of Osimertinib (AZD9291) on the Telaglenastat (CB-839) 
HCl PK. 

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5.10.3.2 Assay Validity and Appropriateness for Study 
 
Plasma concentrations of Telaglenastat (CB-839) HCl will be measured by LC/MS/MS 
methods developed in the Mayo Clinic Cancer Center Pharmacology Shared Resource. The 
Shared Resource, directed by Dr. Joel Reid, is fully equipped to carry out pharmacologic 
investigations, including two exquisitely sensitive Xevo TQ-S mass spectrometers with 
Accuity UPLC systems to carry out the bioanalytical measurements and licenses for Phoenix 
WINNONLIN, NONMEM and PsN Pirana to carry out standard and population 
PK/pharmacodynamics analyses. The laboratory has developed or modified assays for more 
than 85 antitumor agents, served as a central analytical and PK resource laboratory for 9 
published NCI-sponsored phase 1 and phase 2 trials with vorinostat (for example: Galanis et 
al., Fouladi et al., and Lee et al.) and serves as one of the pharmacology resource laboratories 
for the Children’s Oncology Group (Galanis et al., 2009; Fouladi et al., 2010; Lee et al., 2012). 
The approach to assay development and implementation of criteria for system suitability, 
quality assurance, and ongoing evaluation of specific assay data are consistent with 
recommendations from two FDA-sponsored conferences on analytical methods validation 
(Shah et al., 1991; Shah et al., 2000) that are described in a recent FDA guidance document 
"Guidance for Industry: Bioanalytical Method Validation" (Draft Guidance, 2013). In 
particular, as the lab develops a specific high-performance liquid chromatography (HPLC) or 
other method for measurement of drug and relevant metabolites, they incorporate standard 
assessments of drug extraction efficiency, sensitivity, linearity, precision, accuracy, storage 
stability, and other parameters relevant to the particular method. 
Assay performance is thoroughly validated before implementation in the clinical trial and 
monitored on a routine basis during the course of the clinical trial by inclusion of appropriate 
quality assurance samples. 
 
5.10.3.3 Specimen Receipt and Processing at the Mayo Clinic Cancer Center 
 
Frozen plasma aliquots will be received at the Mayo Clinical Cancer Center. Upon receipt, 
plasma will be accessioned, barcoded, and stored in a -80°C freezer until distribution for testing. 
 
5.10.3.4 Site(s) Performing Correlative Study 
 
Samples will be analyzed in the Pharmacology Core of the Mayo Clinic Cancer Center, which 
has developed validated assays for over 85 separate anticancer drugs during the course of its 
existence. This assay will be performed under the direction of Dr. Joel Reid. 
 
5.10.4 Osimertinib (AZD9291) Pharmacokinetics 
 
5.10.4.1 Hypothesis and Rationale 
 
Osimertinib (AZD9291) is a moderate inhibitor of BCRP and Telaglenastat (CB-839) HCl is a 
substrate of efflux pumps. Therefore, the most likely drug interaction is increased plasma 
concentration of Telaglenastat (CB-839) HCl. However, since both drugs are orally 
administered, an impact on Osimertinib (AZD9291) pharmacokinetics cannot be ruled out 
without pharmacokinetic studies. The primary endpoint will be comparing the AUC0-8hr in this 
study to a prior ETCTN single agent Osimertinib (AZD9291) study (9903). Css concentrations 

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of Cycle 2 Day 1 and subsequent cycles will also be evaluated as potential biomarkers of 
efficacy and toxicity. 
 
5.10.4.2 Assay Validity and Appropriateness for Study 
 
LC/MS/MS is the analytical standard for quantitation of drug plasma concentrations due to its sensitivity 
and accuracy. A LC/MS/MS assay for the analysis of Osimertinib (AZD9291), AZ5104, and AZ7550 was 
developed and validated based on a previously published method (Rood et al., 2016). Following SALLE 
extraction, samples were analyzed with a Shimadzu Nexera X2 series interfaced with a Sciex QTRAP® 
6500+ MS/MS. Liquid chromatography was performed using a Waters® Acquity UPLC® BEH C8 column. 
MS/MS data was obtained in positive ion mode (ESI+) with Osimertinib (AZD9291) at m/z 500.118 → 
72.092, AZ5104 at m/z 486.761 → 72.092, AZ7550 at m/z 486.761 → 430.178, and pazopanib at m/z 
438.717 → 358.146. 
 
Stock solutions of 100 mcg/mL of Osimertinib (AZD9291) were used to obtain nine validation 
samples in human heparin plasma (1000, 800, 500, 200, 100, 50, 3, and 1 ng/mL). Each sample 
was measured analytically on three separate days. The standard curve was linear from 1 – 1000 
ng/mL, R2 = 0.987 with an inter-day variability of 3.74% for high standard (1000 ng/mL), n = 3 
and 12.46%for low standard (1 ng/mL), n = 3 over three days. The lower limit of quantification 
(LLOQ) was 3 ng/mL and limit of detection (LOD) was 1 ng/mL. 
 
We will use a validated LC/MS/MS assay for the analysis of Osimertinib (AZD9291) and 
metabolites analysis. As these are blood samples, obtaining the samples represents minimal risk 
however, careful consideration to patient inconvenience for sample collection was conducted. 
Given the large body of Osimertinib (AZD9291) PK information and the small likelihood of a 
drug interaction effecting Osimertinib (AZD9291) plasma concentrations, as described above, 
the AUC0-8hr will be used as the primary endpoint, to minimize subject sampling burden. 
 
5.10.4.3 Specimen Receipt and Processing at the Ohio State University  
 
Frozen plasma aliquots will be received at the Ohio State University. Upon receipt, plasma 
will be accessioned, barcoded, and stored in a -80°C freezer until distribution for testing. 
 
5.10.4.4 Site(s) Performing Correlative Study 
 
Dr. Mitch Phelps' lab at the Ohio State University, will conduct the proposed studies. Mitch A. 
Phelps, PhD is Director of the OSU Comprehensive Cancer Center Pharmacoanalytical Shared 
Resource, which supports pharmacokinetic (PK)/pharmacodynamic (PD) study design and 
conduct for pre-clinical and clinical drug development. Dr. Phelps has directed PK/PD studies 
in preclinical disease models and in early phase clinical trials for nearly ten years.  His research 
group focuses on development of small molecule and oligonucleotide anticancer and immune-
modulatory agents here at OSU, using statistical modeling and simulation of PK/PD data to 
understand how genetic and other factors contribute to differences in therapy outcomes among 
individuals.  
 
 
 

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5.11 
Exploratory/Ancillary Correlative Studies 
 
5.11.1 Whole Exome Sequencing / RNA sequencing 
 
In order to determine possible biomarkers for response to treatment with Osimertinib (AZD9291) 
and Telaglenastat (CB-839) HCl, WES and RNA sequencing will be performed on the 
archival/baseline tumor specimen. Recent studies have demonstrated the importance of co- 
mutations in EGFR-mutated NSCLC, and potential primary resistance mechanisms to 
Osimertinib (AZD9291) have been elucidated, including regulators of cell cycle such as CDK4/6 
(Blakely et al., 2017) as well as additional EGFR mutations L718 and L792 (Yang et al., 2018). 
Evaluation for these and other mutations at baseline will be performed to identify biomarkers 
associated with drug activity 
 
5.11.1.1 Specimen Receipt and Processing at the EET Biobank 
 
Archival formalin-fixed paraffin-embedded tissue (block or slides) will be used for this assay. If a block is 
received, then the EET Biobank will cut and H&E stain slides. A pathology quality control review to assess 
tumor content and annotate slides for macrodissection will be completed for all tissue received. 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. 
Any additional FFPE tissue blocks or slides will banked at room temperature. 
 
DNA will be extracted from blood collected in cfDNA Streck tubes at the baseline time point, 
following plasma processing. DNA will be stored in a -80°C freezer until distribution for testing. 
 
5.11.1.2 Site(s) Performing Correlative Study 
 
WES and RNAseq will be performed on archival samples by the MoCha, Frederick National Laboratory 
for Cancer Research (FNLCR) under the supervision of Chris Karlovich, Ph.D. 
(chris.karlovich@nih.gov). 
 
5.11.1.3 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 
 
5.11.1.4 Contact information for notification of specimen shipment: 
 
Thomas Forbes, mochasamplereceiving@nih.gov 

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5.11.2 Cell-Free DNA Analysis 
 
Peripheral blood will be collected to assess cfDNA for EGFR mutational status, T790M 
mutational status, and resistance mechanisms. cfDNA for EGFR status will be compared with 
archival/baseline specimen for concordance. Blood based assays for detection of resistance 
mechanisms are widely used in clinical practice, and have also yielded information about 
resistance mechanisms to treatment (Blakely et al., 2017). 
 
5.11.2.1 Specimen Receipt and Processing at the EET Biobank 
 
Blood received in cfDNA Streck tubes will be processed for plasma upon receipt at the EET 
Biobank. The baseline cfDNA Streck tube will also be processed for DNA (to be used for other 
correlative studies), and the buffy coat from other time points will also be processed and stored. 
Plasma will be stored in 1 mL aliquots in a -80°C freezer until distribution for testing. Buffy coat 
will also be stored in a -80°C freezer. 
 
5.11.2.2 Site(s) Performing Correlative Study 
 
This study will be performed at the MoCha, Frederick National Laboratory for Cancer Research (FNLCR) 
under the supervision of Chris Karlovich, Ph.D. (chris.karlovich@nih.gov). 
 
5.11.3.3 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 
 
5.11.3.4 Contact information for notification of specimen shipment: 
 
Thomas Forbes, mochasamplereceiving@nih.gov 

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6 
TREATMENT PLAN 
 
6.1 Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported AEs 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. 
 
Dose Escalation Treatment Plan: A single arm dose escalation portion of the study will first be 
performed to determine the optimal dosing strategy where three dose levels will be assessed. 
Extensive PK studies will also be conducted to assess for any potential drug-drug interactions 
through the obtaining of peripheral blood. Eligible patients will initially receive treatment with 
single agent Telaglenastat (CB-839) HCl BID according to the dose escalation strategy and PK 
sampling will be done on Day 15. Starting on Day 16, patients will then go on to receive both 
Osimertinib (AZD9291) 80 mg PO QD as well as Telaglenastat (CB-839) HCl PO BID at the 
same dose as initially provided during the monotherapy portion of the study and a second set of 
PK analyses will be conducted on Day 1 of Cycle 2 for both Osimertinib (AZD9291) and 
Telaglenastat (CB-839) HCl (see table below). Peripheral blood will also be obtained for a PK 
assessment at the beginning of each 28- day treatment cycle starting with Cycle 2. An assessment 
for response to treatment will be conducted with a CT of the chest, abdomen, and pelvis (C/A/P) 
every 2 months as is standard practice. 
Patients will continue to receive treatment until the time of disease progression, unacceptable 
toxicity, or treatment is discontinued based on patient/physician preference. 
 
Patients enrolled to the dose escalation portion of the study will be treated according to a dose 
escalation schedule where three different dose levels will be assessed. For all dose levels, the 
Osimertinib (AZD9291) dose will be set at 80 mg PO QD. The dose levels of Telaglenastat (CB- 
839) HCl are as follows: 
1) 400 mg PO BID; 2) 600 mg PO BID; 3) 800 mg PO BID. Dose Level -1 will be 200 mg 
Telaglenastat (CB- 839) HCl BID. 
 
Phase 1 Dose Escalation Schedule 
Dose Level 
Dose* 
Telaglenastat (CB-839) 
HCl (mg) orally BID 
Osimertinib (AZD9291) 
(mg) orally daily 
Level -1 
200 mg 
80 mg 
Level 1 
(Starting Dose) 
400 mg 
80 mg 
Level 2 
600 mg 
80 mg 
Level 3 
800 mg 
80 mg 
BID = twice daily, QD = once daily 
*Dosing is given orally on a continuous schedule 

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Regimen Description 
Agent 
Premedications 
Dose* 
Route 
Schedule 
Cycle 
Length 
Telaglenastat 
(CB-839) HCl 
None 
Varying** (400- 
800 mg, 2-4 
tablets) 
PO BID with 
food 
Continuous 
28 days 
(4 
weeks) 
Osimertinib 
(AZD9291) 
None 
80 mg (1 tablet) PO QD 
Phase 1: 
Continuous 
starting on 
C1D16 
Phase 2: 
Continuous 
 
 
 
Expansion Cohort Treatment Plan: A 10-patient expansion cohort study will then be performed 
at the maximum tolerated dose (MTD) identified in the dose escalation study. Eligible patients 
will receive Osimertinib (AZD9291) 80 mg PO QD as well as Telaglenastat (CB-839) HCl PO 
BID at doses determined during the phase 1 portion of the study. An assessment for response to 
treatment will be conducted with a CT C/A/P every 2 months. Peripheral blood specimens will 
be collected at baseline, one-month post-treatment and at the time of RECIST progression to 
assess cfDNA for EGFR mutational status, T790M mutational status and EGFR resistance 
mechanisms as well as to assess changes in the metabolites glutamine, glutamate, aspartate and 
asparagine. Patients will continue with treatment until the time of disease progression, 
unacceptable toxicity, or treatment is discontinued based on patient/physician preference. 
 
Patients enrolled to the expansion cohort of the study will be treated with Osimertinib 
(AZD9291) 80 mg PO QD as well as Telaglenastat (CB-839) HCl PO BID at 800mg BID which 
was evaluated in the dose escalation portion of the study and found to be safe. The initial dose of 
Osimertinib (AZD9291) 80 mg QD can be reduced to 40 mg QD for patients enrolled to the 
phase 2 study as detailed in Section 7. Patients will be treated until the time of disease 
progression, unacceptable toxicity, or treatment is discontinued per patient/physician preference. 
Patients will be followed for 30 days after completion of therapy unless treatment related 
toxicities have not resolved to grade 1 in which case they will be followed until toxicities have 
resolved to grade 1. 
 
Patients will be requested to maintain a medication diary of each dose of medication. The 
medication diary (Appendix G) will be returned to clinic staff at the end of each course. 
 
All protocol therapy with Telaglenastat (CB-839) will end on 2/28/25. The clinical 
supply of Telaglenastat will no longer be available after the terminal lot shelf life dating 
of 2/28/25 is reached. After that date, patients may remain on Osimertinib single agent 
at the investigator discretion until meeting other off therapy criteria. 
PO = by mouth, QD = once daily, BID = twice daily 
* Dosing is given orally on a continuous schedule 
**Doses as appropriate for assigned dose level. 

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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. 
 
6.1.2 Osimertinib (AZD9291) 
 
Based on the results from the definitive food effect study and supporting results from the 
exploratory study, it is recommended that Osimertinib (AZD9291) can be taken with or 
without food. 
 
6.1.3 Other Modalities or Procedures 
N/A 
 
 
6.2 
Definition of Dose-Limiting Toxicity 
 
The DLT period will be 28 days (of combined treatment) and patients will continue therapy until 
the time of disease progression, unacceptable toxicity, or per patient/physician preference. To be 
evaluable for a DLT, patients must have started the combination therapy portion of the study. 
Patients who complete the DLT period and receive at least 75% of scheduled days of treatment 
will be evaluable for safety endpoints. Patients who discontinue combined treatment during the 
28-day evaluation period for any reason other than treatment-related or dose-limiting toxicity 
will not be evaluable. Non-evaluable patients will be replaced. A DLT will be defined as any AE 
that cannot be determined to be unrelated to study treatment, occurs within the first 28 days of 
combination treatment, and that meets at least one of the following criteria. Non-hematologic 
DLTs will be defined as grade 3 or higher toxicities according to the CTCAE version 5.0 except 
the following— grade 3 nausea, vomiting, or diarrhea lasting <48 hours and controlled by 
optimal antiemetic/antidiarrheal therapy; clinical laboratory abnormalities that are reversible to 
≤grade 1 or baseline status within 72 hours with outpatient care and/or monitoring or that are not 
considered clinically significant by the PI. Grade 3 rash attributed to the combination will be 
considered a DLT if grade 3 despite maximal medical management (including oral antibiotic, 
topical or oral steroids) for >72 hours. Hematologic DLTs will be defined as the following— 
grade 4 or higher neutropenia [absolute neutrophil count (ANC) < 0.5 x 109/L]; grade 3 or 
higher febrile neutropenia (ANC <1.0 x 109/L with a fever ≥ 38.3 °C); grade 4 or higher 
thrombocytopenia (<25.0 x 109/L); and grade 3 or higher thrombocytopenia associated with 
grade 3 or higher bleeding. Patients will be followed for 30 days after completion of therapy 
unless treatment-related toxicities have not resolved to grade 1 in which case they will be 
followed until toxicities have resolved to grade 1. Any grade of pneumonitis will also be 
considered a DLT. 
 
Dose escalation will proceed within each cohort according to the following scheme. DLT is 
defined above. 
 

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Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered). Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose. Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the RP2D. At least 6 patients must be 
entered at the RP2D. 
 
6.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of Telaglenastat (CB-839) HCl and Osimertinib 
(AZD9291) with other concomitantly administered drugs, the Case Report Form (CRF) must 
capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies. The PI should be alerted if the patient is taking any agent known to affect or with the 
potential for drug interactions. The potential targets for drug interaction can involve, but are not 
limited to CYP450, glucuronidation, P-glycoprotein, protein binding, or reduced absorption 
from proton- pump inhibitors. Check the study agent Investigator’s Brochure for potential 
sources of 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, and Appendix D 
(Guidance Regarding Potential Interactions with Concomitant Medications) for additional 
information on concurrent medications. 
 
6.3.1 Radiotherapy 
 
Radiotherapy will be permitted if deemed clinically beneficial by the treating physician for 
palliation of painful bone disease or in cases of symptomatic CNS disease amenable to 
stereotactic radiation. Whole brain radiation and radiation of target lesions is not permitted. 
Study treatment should be held for 3 days before and after radiotherapy. 
 
6.3.2 Osimertinib (AZD9291), CYP 3A4 and BCRP 
 

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Because there is a potential for interaction of Osimertinib (AZD9291) with other concomitantly 
administered drugs, the CRF must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies. The PI should be alerted if the patient is taking any agent 
known to affect or with the potential for drug interactions. In vitro studies demonstrate that 
Osimertinib (AZD9291) and its active metabolites are primarily metabolized by CYP 3A4 
enzymes. Potent inducers of CYP 3A4 are therefore contraindicated and a wash-out period is 
required (duration of wash-out varies, See Appendix D [Guidance Regarding Potential 
Interactions With Concomitant Medications]). 
Patients taking rosuvastatin should have creatine phosphokinase levels monitored (due to BCRP- 
mediated increase in exposure). If the patient experiences any potentially relevant AEs 
suggestive of muscle toxicity including unexplained muscle pain, tenderness, or weakness, 
particularly if accompanied by malaise or fever, rosuvastatin must be stopped and any 
appropriate further management should be taken. 
 
6.3.3 Telaglenastat (CB-839) HCl and CYP2C9 
 
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 5 mcM) 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 C (Cytochrome P450 
[CYP] 2C9 Substrates). 
 
6.3.4 Telaglenastat (CB-839) HCl and Proton Pump Inhibitors 
 
Preliminary PK data generated in single agent phase 1 studies indicate that concomitant use of 
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 electronic CRF (eCRF), including the identity of the beverage/supplement, dosage, 
and start and stop dates of administration. 
 
To aid absorption, it is recommended that Telaglenastat (CB-839) HCl is taken at least 2 hours 
before or at least 10 hours after H2 receptor agonist therapy, or at least 2 hours before or at least 
2 hours after other antacid therapy. 
 
6.4 
Duration of Therapy 
 

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In the absence of treatment delays due to AE(s), treatment may continue until one of the 
following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable AE(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• 
Clinical progression 
• 
Patient non-compliance 
• 
Pregnancy 
o All women of child bearing 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. 
• 
Termination of the study by sponsor 
• 
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 CRF. 
 
6.5 Duration of Follow-Up 
 
Patients will be followed for 30 days after removal from study or until death, whichever occurs 
first. Patients removed from study for unacceptable AE(s) will be followed until resolution or 
stabilization of the AE. 
 
 
7 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Telaglenastat (CB-839) HCl 
 
Based on available data, AEs that are most likely to be observed with Telaglenastat (CB-839) 
HCl treatment include fatigue, GI events (nausea, vomiting, anorexia), photophobia, and elevated 
LFTs. Careful application of the dose-escalating rules and close observation of the subjects 
should minimize the potential risk of dosing with Telaglenastat (CB-839) HCl. The study 
personnel must be able to recognize and diagnose these potential AEs and initiate prompt 
intervention. In general, grade 1 events should be managed with appropriate supportive care, 
dosing can be interrupted for persistent drug-related grade 2 events, and the dose should be 
reduced for most Telaglenastat (CB-839) HCl-related grade 3/4 toxicities. In particular, regular 
monitoring of LFTs is recommended. Grade >2 elevations in ALT or total bilirubin should lead 
to an interruption of study drug and grade ≥3 events should lead to dose reduction upon 
restarting Telaglenastat (CB-839) HCl. 
 

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Blood Bilirubin 
Increase 
Management/Next Dose for 
Telaglenastat (CB-839) 
HCl 
Management/Next Dose for 
Osimertinib 
(AZD9291) 
Grade 1 
No change in dose. 
No change in dose 
Grade 2 
Hold until ≤ grade 1. Resume at 
same dose level. 
Hold until ≤ grade 1. Resume at 
same dose level. 
Grade 3 
Hold* until ≤ grade 1. Resume at 
one dose level lower, if indicated.** 
Hold* until ≤ grade 1. Resume at 
one dose level lower, if indicated.** 
Grade 4 
Hold* until ≤ grade 1. Resume at 
one dose level lower, if indicated.** 
Hold* until ≤ grade 1. Resume at 
one dose level lower, if indicated.** 
 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > 2 dose reductions of Telaglenastat (CB-839) HCl or > 1 dose reduction 
in Osimertinib (AZD9291) must go off protocol therapy. 
 
 
Alanine 
Aminotransferase 
Increased 
Management/Next Dose for 
Telaglenastat (CB-839) 
HCl 
Management/Next Dose for 
Osimertinib 
(AZD9291) 
Grade 1 
No change in dose. 
No change in dose 
Grade 2 
Hold until ≤ grade 1. Resume at 
same dose level. 
Hold until ≤ grade 1. Resume at 
same dose level. 
Grade 3 
Hold* until ≤ grade 1. Resume at 
one dose level lower, if indicated.** 
Hold* until ≤ grade 1. Resume at 
one dose level lower, if indicated.** 
Grade 4 
Hold* until ≤ grade 1. Resume at 
one dose level lower, if indicated.** 
Hold* until ≤ grade 1. Resume at 
one dose level lower, if indicated.** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
 
Alanine 
Aminotransferase 
Increased 
Management/Next Dose for 
Telaglenastat (CB-839) 
HCl 
Management/Next Dose for 
Osimertinib 
(AZD9291) 
** Patients requiring > 2 dose reductions of Telaglenastat (CB-839) HCl or > 1 dose reduction in 
Osimertinib (AZD9291) must go off protocol therapy. 
 
 
Other AEs 
Management/Next Dose for 
Telaglenastat (CB-839) 
HCl 
Management/Next Dose for 
Osimertinib 
(AZD9291)*** 
Grade 1 
No change in dose. Administer 
standard supportive care. 
No change in dose 
Grade 2 
For persistent grade 2 
toxicity****: Hold until ≤ grade 
1. Resume at same dose level. 
For persistent grade 2 
toxicity****: Hold until ≤ grade 
1. Resume at same dose level. 
Grade 3 
Reduce dose by one level if event 
is related to Telaglenastat (CB- 
839) HCl.* 
Hold* until ≤ grade 1. Resume at 
one dose level lower, if indicated.** 

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Grade 4 
Reduce dose by one level if event 
is related to 
Telaglenastat (CB-839) 
HCl.* 
Hold* until ≤ grade 1. Resume at 
one dose level lower, if indicated.** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
** Patients requiring > 2 dose reductions of Telaglenastat (CB-839) HCl or > 1 dose reduction in 
Osimertinib (AZD9291) must go off protocol therapy. 
***Osimertinib (AZD9291) must be permanently discontinued for ILD/pneumonitis or QTc 
interval prolongation with signs/symptoms of serious arrhythmia 
****Persistent grade 2 toxicities include those that do not resolve within 7 days despite optimal 
 
supportive care or result in treatment delay > 14 days 
 
 
Osimertinib (AZD9291) 
 
Dose Adjustments for Osimertinib (AZD9291): 
Dose Level 
Osimertinib 
(AZD9291) Dose 
(QD) 
Starting Dose 
80 mg 
Dose Reduction 
40 mg 
 
All patients in the phase 2 study will commence treatment with Osimertinib (AZD9291) at 80 
mg daily. If a patient experiences a persistent drug-related grade 2 event or any CTCAE grade 3 
or higher and/or unacceptable toxicity (any grade), where the clinician considers the event of 
concern to be specifically associated with Osimertinib (AZD9291) (and not attributable to the 
disease or disease-related processes for which patient is being treated), dosing will be 
interrupted, and supportive therapy administered as required in accordance with local 
practice/guidelines. If a toxicity resolves or reverts to ≤CTCAE grade 2 within 3 weeks of onset, 
treatment with Osimertinib (AZD9291) may be restarted at the same dose (80 mg) or a lower 
dose (40 mg) using the rules indicated in the above table for dose modifications and with 
discussion and agreement with the Sponsor Study Team Physician as needed. There will be no 
individual modifications to dosing schedule in response to toxicity, only potential dose reduction 
or dose interruption. If the toxicity does not resolve to ≤CTCAE grade 2 after 3 weeks, then the 
patient should be withdrawn from the study and observed until resolution of the toxicity. 
 
Dose adjustment for AEs should be in accordance with the following table: 
 
 
Dose Adjustment Information for Adverse Reactions 
Target Organ 
Adverse Reaction 
Dose Modification 

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Pulmonary 
ILD/Pneumonitis 
Permanently discontinue 
Osimertinib (AZD9291) 
Cardiac 
QTc interval greater than 500 
msec on at least 2 separate 
ECGs 
Withold Osimertinib 
(AZD9291) until QTc 
interval is less than 481 msec 
or recovery to baseline if 
baseline QTc is greater than 
or equal to 481 msec, then 
restart at a reduced dose (40 
mg) or at 80 mg (at the 
discretion of the investigator, 
to allow for situations where 
 
causality in relation to 
osimertinib may be difficult to 
determine). 
QTc interval prolongation 
with signs/symptoms of 
serious arrhythmia 
Permanently discontinue 
Osimertinib (AZD9291) 
Other 
Grade 3 or higher adverse 
reaction 
Withhold Osimertinib 
(AZD9291) for up to 3 
weeks 
If grade 3 or higher adverse 
reaction improves to grade 0- 
2 after withholding of 
Osimertinib (AZD9291) for 
up to 3 weeks 
Osimertinib (AZD9291) may 
be restarted at the same dose 
(80 mg) or a lower dose (40 
mg) 
Grade 3 or higher adverse 
reaction that does not 
improve to grade 0-2 after 
withholding for up to 3 weeks 
Permanently discontinue 
Osimertinib (AZD9291) 
 
 
On resolution of toxicity within 3 weeks: 
• If an AE subsequently requires dose interruption, Osimertinib (AZD9291) may restart 
at the same dose or the reduced dose, on resolution/improvement of the AE at the 
discretion of the Investigator. 
 
Patients experiencing any of the following AEs will not be permitted to restart study 
treatment: 
• Interstitial Lung Disease (ILD) 
• QTc interval prolongation with signs/symptoms of serious arrhythmia 
 

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There is no dose reduction allowed below 40 mg. If a patient experiences toxicity such that 40 
mg is no longer considered tolerable, the patient should discontinue study treatment. 
It is recommended that all patients follow a program of sun protective measures while 
receiving study drug and for 3 to 4 weeks after discontinuing study drug. 
 
Interstitial Lung Disease (ILD)/Pneumonitis-like toxicity: 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality suggestive 
of interstitial lung disease is observed, an interruption in study treatment dosing is recommended, 
and the AstraZeneca study team should be informed. It is strongly recommended to perform a 
full diagnostic workup, to exclude alternative causes such as lymphangitic carcinomatosis, 
infection, allergy, cardiogenic edema or pulmonary hemorrhage. The results of full diagnostic 
workup (including high resolution computed tomography (HRCT), blood and sputum culture, 
hematological parameters) will be captured by eCRF. In the presence of confirmatory HRCT 
scans where other causes of respiratory symptoms have been excluded, a diagnosis of interstitial 
lung disease should be considered and study treatment permanently discontinued 
 
Management of Keratitis 
Keratitis was reported in 0.7% (n=6) of the 833 patients treated with Osimertinib (AZD9291) in 
the AURA studies. Patients presenting with signs and symptoms suggestive of keratitis such as 
acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, 
and/or red eye should be referred promptly to an ophthalmology specialist. 
 
Management of QTC Prolongation 
For QTc interval greater than 500 msec on at least 2 separate ECGs, withhold Osimertinib 
(AZD9291) until QTc interval is less than 481 msec, or until recovery to baseline if baseline QTc 
is greater than or equal to 481 msec. Osimertinib (AZD9291) can then be restarted at a reduced 
dose. If the toxicity does not resolve to grade ≤2 within 21 days, the patient will be permanently 
withdrawn from study treatment. 
 
For QTc interval prolongation with signs/symptoms of serious arrhythmia, Osimertinib 
(AZD9291) must be permanently discontinued. 
 
Changes in Cardiac Contractility 
An Echocardiogram or MUGA scan to assess LVEF will be performed at screening (prior to first 
dose of Osimertinib (AZD9291)) and at end of treatment. Per the FDA label, echocardiogram is 
indicated at baseline and during treatment for patients with cardiac risk factors, or if clinically 
indicated. 
 
The modality of the cardiac function assessments must be consistent within a patient i.e. if 
echocardiogram is used for the screening assessment then echocardiogram should also be used 
for subsequent scans. The patients should also be examined using the same machine and operator 
whenever possible, and quantitative measurements should be taken. A 28-day follow-up 
assessment will be required if an on-treatment assessment was abnormal at the time of 
discontinuation of study therapy, to confirm reversibility of the abnormality. 

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Erythema Multiforme, and Stevens-Johnson syndrome and Toxic epidermal necrolysis  
 
Case reports of Erythema multiforme (EM) and toxic epidermal necrolysis have been uncommonly 
reported, and Stevens-Johnson syndrome (SJS) have been uncommonly and rarely reported, respectively, in 
association with osimertinib treatment. Before initiating treatment, patients should be advised of signs and 
symptoms of EM, and SJS and TEN. If signs and symptoms suggestive of EM develop, close patient 
monitoring and drug interruption or discontinuation of osimertinib should be considered. If signs and 
symptoms suggestive of SJS appear, osimertinib should be interrupted. Osimertinib should be or 
discontinued immediately if SJS or TEN is diagnosed.  
 
 
Aplastic Anemia 
Rare reports of aplastic anemia have been reported in association with osimertinib treatment. 
Some cases had a fatal outcome. Before initiating treatment, patients should be advised of signs 
and symptoms of aplastic anemia including but not limited to persistent fever, bruising, bleeding, 
and/or pallor. If signs and symptoms suggestive of aplastic anemia develop, close patient 
monitoring and drug interruption or discontinuation of osimertinib should be considered. 
Osimertinib should be discontinued in patients with confirmed aplastic anemia. 

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Dose Modifications and Supportive Care for Diarrhea 
 
 
Severity 
(CTCAE v5.0 
Grading) 
Description 
Intervention 
concerning 
Osimertinib 
(AZD9291) 
treatment 
Specific intervention 
Mild (Grade 1) 
Increase of <4 
stools per day over 
baseline; mild 
increase in ostomy 
output compared 
with baseline 
Continue 
same dose 
Stop laxatives and advise patient to drink 
at least 8-10 glasses of water of clear fluids 
per day. Consider adding loperamide. 
4 mg (2 tablets) of loperamide to be taken 
immediately, followed by 2 mg (1 tablet) 
after each loose stool until bowel 
movements cease for 12 hours. 
Moderate 
(Grade 2) 
Increase of 4-6 
stools per day 
over baseline; IV 
fluids indicated 
<24 hours; 
moderate 
increase in 
ostomy output 
compared with 
baseline; not 
interfering with 
ADL 
Continue same 
dose with 
medical 
management 
unless 
investigator 
determines 
clinically 
significant and 
persists >72 
hours. 
Start loperamide if patient not already 
taking per dosing above. 
4 mg (2 tablets) of loperamide to be taken 
immediately, followed by 2 mg (1 tablet) 
after each loose stool until bowel 
movements cease for 12 hours. If already 
on loperamide, consider adding 
diphenoxylate/atropine (lomotil) and/or 
tincture of opium. 
Then 
interrupt 
Osimertin 
ib 
(AZD929 
1) 
until grade 
≤1 and 
consider a 
dose 
reduction. 

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Severe 
(Grade 3) 
Increase of ≥7 
stools per day over 
baseline; 
incontinence; IV 
fluids >24 hours; 
hospitalization; 
severe increase in 
ostomy output 
compared with 
baseline; interfering 
with ADL 
Dose 
interruption 
until recovered 
to ≤grade 1 
followed by 
dose reduction. 
See grade 2; plus: 
Consider an infectious process. 
Aggressive IV fluid replacement; 
consider hospitalization to monitor 
progress. 
Life 
threatening 
(Grade 4) 
Life-threatening 
consequences (e.g., 
haemodynamic 
collapse) 
Dose 
interruption 
until recovered 
to ≤ grade 1 
followed by 
dose reduction 
See grade 3 
 
Appropriate management of diarrhea, including dose adjustments for AEs of diarrhea that are 
of CTCAE grade ≥3 or that are clinically significant and/or intolerable and considered by the 
Investigator to be causally related to Osimertinib (AZD9291), should be undertaken as per 
standard practice and guidelines for dose adjustments above. Changes in CTCAE grade of 
diarrhea will be captured in the AE eCRF. 
Nausea, vomiting, or both may be controlled with anti-emetic therapy per local practice.. 
 
 
8 
PHARMACEUTICAL INFORMATION 
 
A list of the AEs and potential risks associated with the investigational agents administered in 
this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agents 
 
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 
 
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. 

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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 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 for determination of suitability. 
 
Stability: Stability studies are ongoing. 
 
Route of Administration: PO, 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 
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 

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an inducer of CYP1A2, CYP2B6, and CYP3A4. 
 
Telaglenastat (CB-839) HCl requires low pH conditions for optimal solubilization. 
Concomitant use of 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 and at least 10 hours after treatment with H2RA therapy, and at least 2 hours 
before or at least 2 hours after other 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 Osimertinib (AZD9291) (NSC 781254) 
Chemical Name: N-(2-{[2-(Dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1- 
methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate 
 
Other Names: Tagrisso™, AZD9291 mesylate 
 
Classification: Epidermal growth factor receptor (EGFR) inhibitor 
 
Molecular Formula: C28H33N7O2.CH4O3S 
M.W.: 595.71 (mesylate salt) 
499.61 (free base) 
 
Approximate Solubility: The solubility of osimertinib free base has been measured as 7.2 
mg/mL in Simulated Gastric Fluid (pH 1.4) and 0.2 mg/mL in Fasted State Simulated 
Intestinal Fluid (pH 6.5). 
 
Mode of Action: Osimertinib (AZD9291) is a potent, oral, irreversible, tyrosine kinase 
inhibitor (TKI) of epidermal growth factor receptor (EGFR) mutation-positive (EGFRm) 
and T790M mutation-positive forms of EGFR. 
 
Description: Osimertinib mesylate is a crystalline powder. 
 
How Supplied: Osimertinib (AZD9291) tablets are supplied by AstraZeneca and 

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distributed by the Pharmaceutical Management Branch, CTEP/DCTD/NCI. Tablets are 
packaged in 30-count bottles with mannitol, microcrystalline cellulose, low-substituted 
hydroxypropyl cellulose and sodium stearyl fumarate as inactive ingredients in the 
following strengths: 
• 80 mg tablets: beige, oval and biconvex tablet marked with “AZ 80” on one side and 
plain on the reverse. 
• 40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side 
and plain on the reverse. 
 
The tablet coating contains polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, ferric 
oxide yellow, ferric oxide red and ferric oxide black. 
 
Storage: Store at room temperature 20° to 25°C (68° to 77°F), excursions permitted 
between 15 to 30°C (59 to 85°F). 
 
If a storage temperature excursion is identified, promptly return osimertinib (AZD9291) to 
controlled room temperature 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. 
 
Stability: Refer to the package label for expiration. 
 
Route of Administration: Take by mouth with or without food. If a dose of osimertinib 
(AZD9291) is missed or vomited, do not make up the missed dose and take the next dose as 
scheduled. 
 
Potential Drug Interactions: The main metabolic pathways of osimertinib (AZD9291) 
are oxidation (predominantly CYP3A4) and dealkylation in vitro. Avoid concomitant use 
of strong CYP3A4 inducers. CYP3A4 inhibitors are not likely to affect the exposure of 
osimertinib (AZD9291). Based on in vitro studies, osimertinib (AZD9291) is a competitive 
inhibitor of CYP 3A4/5 but not CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 at 
clinically relevant concentrations. Osimertinib (AZD9291) is an inducer of CYP1A2. Use 
caution with coadministration of CYP 3A4/5 and 1A2 substrates. 
 
Osimertinib (AZD9291) is a substrate of BCRP and P-gp but is unlikely to result in 
clinically relevant drug interactions. Osimertinib (AZD9291) is not a substrate of 
OATP1B1 and OATP1B3 and does not inhibit OAT1, OAT3, OATP1B1, OATP1B3, 
OCT2, MATE1 and MATE2K at clinically relevant concentrations. Based on in vitro data, 
osimertinib (AZD9291) is an inhibitor of BCRP and may increase the exposure of BCRP 
substrates. Osimertinib (AZD9291) does not inhibit P-gp at clinically relevant 
concentrations but has the potential to increase exposure of sensitive substrates. 
 
Avoid use of osimertinib (AZD9291) in patients with congenital long QT syndrome. For 
patients with normal QT interval at the trial enrollment, avoid use of concomitant drugs that 
are known to prolong QT interval and use caution with drugs that may prolong QT interval. 
Refer to a frequently updated drug information reference and to the protocol for appropriate 
cardiac monitoring. 

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8.1.3 Agent Ordering and Agent Accountability 
 
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 
(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. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
Submit agent requests through the Pharmaceutical Management Branch (PMB) Online 
Agent Order Processing (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. 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. 
 
8.1.3.1 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. 
 
8.1.4 Investigator Brochure Availability 
The current versions of the Investigator’s Brochures (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. 
 
8.1.5 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 OAOP application: https://ctepcore.nci.nih.gov/OAOP 
• CTEP IAM account: https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• IB Coordinator: IBCoordinator@mail.nih.gov 

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• 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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9 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
The dose escalation component of this study is a dose-escalation trial of Telaglenastat (CB-839) 
HCl and Osimertinib (AZD9291) in patients with metastatic EGFR activating mutation positive 
NSCLC. It has been designed to define the RP2D of Telaglenastat (CB-839) HCl and 
Osimertinib (AZD9291). Assuming DLT rate is as few as 30% at MTD, a traditional 3+3 dose 
escalation design will be adopted and 3-6 evaluable patients will be treated at each dose level. 
Dose escalation rules are defined in Section 6.2. An evaluable patient for a DLT is defined as the 
patient who must have started the combination therapy portion of the study. Patients who 
discontinue combined treatment during the 28-day evaluation period for any reason other than 
treatment-related or dose-limiting toxicity will not be evaluable. Non-evaluable patients will be 
replaced. Nine to eighteen patients are expected to be enrolled depending on the number of dose 
escalations and assuming that a total of 6 patients will be treated at the final RP2D level. The 
DLT period will be set at 28 days of combination therapy. 
 
In the 10 patient expansion cohort, we will gain additional experience and understanding 
regarding the safety, tolerability, and efficacy of combination Telaglenastat (CB-839) HCl and 
Osimertinib (AZD9291) in patients with EGFR activating mutation positive NSCLC who have 
progressed on first line EGFR TKI with osimertinib. 
 
In the expansion cohort component of the study, a safety monitoring scheme will also be 
implemented by including a stopping rule based on the number of DLTs among the first 10 
patients in the expansion cohort. Enrollment may be paused if the lower bound of the 1-sided 
80% exact binomial confidence interval of the estimated DLT excludes 30%. After the first 10 
patients have been evaluated for DLT, the study will be stopped for safety if at least 5 patients 
with DLTs are observed. The study will continue if no more than 4 patients experience DLTs. 
 
Integral testing for EGFR status will be completed locally but an integrated EGFR test will also 
be completed centrally for confirmation of EGFR status. In case a patient is deemed to be EGFR 
mutant by the local test but EGFR wild-type by the central test, that patient will not be included 
in the primary analysis. 
 
All toxicities will be summarized as the percentage of patients experiencing each type and grade 
of event according to dose level. Patients who receive at least one dose of treatment will be 
included in the analysis. 
 
The ORR will be calculated as the proportion of patients who achieve a response to therapy 
divided by the total number of evaluable patients. An evaluable patient is defined as an eligible 
patient who has received at least one dose of therapy and has centralized confirmation of positive 
EGFR mutation status. All evaluable patients will be included in calculating the ORR for the 
study along with corresponding 95% binomial CIs (assuming that the number of patients who 
respond is binomially distributed). Separately, all patients treated at the RP2D in either the dose 
expansion or the expansion cohort will be analyzed. 

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Definition of Primary Endpoints 
• Safety, tolerability and RP2D of combination therapy with Telaglenastat (CB-839) 
HCl and Osimertinib (AZD9291) in patients with metastatic EGFR activating 
mutation positive NSCLC. 
Definition of Secondary Endpoints 
• DLTs as assessed by CTCAE version 5.0 of the combination of Telaglenastat 
(CB-839) HCl and Osimertinib (AZD9291) in patients with metastatic EGFR 
activating mutation positive NSCLC. 
• PFS of patients with metastatic EGFR activating mutation positive NSCLC who 
have progressed on front-line EGFR inhibitor therapy following treatment with 
Telaglenastat (CB-839) HCl and Osimertinib (AZD9291). PFS is defined as the time 
from initiation of therapy to documented progression or death without progression. 
• OS of patients with metastatic EGFR activating mutation positive NSCLC who have 
progressed on front-line EGFR inhibitor therapy following treatment with 
Telaglenastat (CB-839) HCl and Osimertinib (AZD9291). OS is defined as the time 
from initiation of therapy to death from any cause. 
Definition of Correlative Endpoints 
• Post-Telaglenastat (CB-839) HCl PK as assessed by Telaglenastat (CB-839) HCl 
drug levels following both single agent therapy as well as combination therapy with 
Telaglenastat (CB-839) HCl and Osimertinib (AZD9291) in patients with metastatic 
EGFR activating mutation positive NSCLC. 
• Post-Osimertinib (AZD9291) PK as assessed by Osimertinib (AZD9291) drug 
levels following combination therapy with Telaglenastat (CB-839) HCl and 
Osimertinib (AZD9291) in patients with metastatic EGFR activating mutation 
positive NSCLC. 
Changes in EGFR mutational status as assessed by cfDNA in patients with metastatic 
EGFR activating mutation positive NSCLC who have progressed on front- line 
EGFR inhibitor therapy. 
• Changes in circulating levels of glutamine, glutamate, aspartate, and asparagine as 
assessed by plasma concentrations of these compounds in patients with metastatic 
EGFR activating mutation positive NSCLC who have progressed on front- line 
EGFR inhibitor therapy. 
 
9.2 
Sample Size/Accrual Rate 
 
This study plans to accrue a minimum of 9 and a maximum of 28 patients. Estimated accrual 
rate is 5 patients/month. 

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9.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
Telaglenastat (CB-839) HCl and Osimertinib (AZD9291). 
 
9.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of 
the following categories: 1) CR; 2) partial response (PR); 3) SD; 4) PD; 5) early death from 
malignant disease; 6) early death from toxicity; 7) early death because of other cause; or 9) 
unknown (not assessable, insufficient data). (Note: By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database.) 
 
All the patients who met the eligibility criteria (with the exception of those who received no 
study medication, or patients who are found to be EGFR wild-type by the central confirmation 
test) should be included in the main analysis of the ORR. Patients in response categories 4-9 
should be considered to have a treatment failure (disease progression). Thus, an incorrect 
treatment schedule or drug administration does not result in exclusion from the analysis of the 
ORR. Precise definitions for categories 4-9 will be protocol specific. 
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. The 95% CI should also be provided. 
 
 
10 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
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 Reporting System 
(CTEP-AERS) in addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential AEs associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 

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Adverse events reported on Osimertinib (AZD9291) trials, but for which there is insufficient evidence to suggest that 
there was a reasonable possibility that Osimertinib (AZD9291) caused the adverse event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Cardiac disorders - Other (atrial thrombosis); Myocardial 
infarction; Supraventricular tachycardia 
EYE DISORDERS - Eye disorders - Other (corneal epithelium defect); Eye disorders - Other (corneal erosion); Eye disorders - 
Other (eyelids pruritus); Vision decreased 
GASTROINTESTINAL DISORDERS - Dry mouth; Dyspepsia; Dysphagia; Gastritis; Gastrointestinal disorders - Other (intestinal 
ischemia); Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Fever2; Flu like symptoms; Generalized 
edema; Malaise; Non-cardiac chest pain 
INFECTIONS AND INFESTATIONS - Folliculitis; Infections and infestations - Other (pustule); Lung infection; Nail infection; 
Papulopustular rash; Rash pustular; Shingles; Upper respiratory infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and procedural complications - Other (drug 
eruption) 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; CPK increased; Creatinine 
increased; Ejection fraction decreased; GGT increased; Investigations - Other (electrocardiogram QT interval abnormal); Weight 
loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypermagnesemia; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Generalized muscle weakness; Neck pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Ischemia cerebrovascular; Stroke 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea2; Epistaxis; Hypoxia; Pleural effusion; Respiratory 
failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Eczema; Palmar-plantar erythrodysesthesia syndrome; Skin 
and subcutaneous tissue disorders - Other (onychalgia); Skin and subcutaneous tissue disorders - Other (skin fissures); Skin 
and subcutaneous tissue disorders - Other (onychomalacia); Skin and subcutaneous tissue disorders - Other (skin erosion); 
Skin hyperpigmentation; Urticaria 
VASCULAR DISORDERS - Hematoma; Thromboembolic event 
 
 
Note: Osimertinib (AZD9291) in combination with other agents could cause an exacerbation of any adverse event currently 
known to be caused by the other agent, or the combination may result in events never previously associated with either agent. 
 
10.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
• 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) 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. 

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10.3 
Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
 
The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP- 
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting, and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting. 

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All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to collect 
AEs that start during the period or persist from the previous reporting period. The 
Clinical Research Associate (CRA) will enter AEs that occur prior to the start of treatment 
on a baseline form that is not included in the Rave-CTEP-AERS integration. AEs that 
occur prior to enrollment must begin and end on the baseline Adverse Event form and 
should not be included on the standard Adverse Events form that is available at treatment 
unless there has been an increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-free 
(fields added to the form during study build do not need to be query-free for the 
integration call with CTEP-AERS to be a success). 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements. The CRA completes the report by accessing CTEP- 
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that 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 that was phoned in must be entered immediately into CTEP-AERS 
using the deep link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
 
• Study specific documents: Protocols > Documents > Education and Promotion, 
and 
• Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information > User Guides. 
 
NCI requirements for SAE reporting are available on the CTEP website: 
 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pd 
f. 
Distribution of Adverse Event Reports 

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1SAEs that occur more than 30 days after the last administration of investigational agent/intervention and have an 
attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-Hour notifications are required for all SAEs followed by a complete report 
• 
Within 5 calendar days for Grade 3-5 SAEs 
• 
Within 10 calendar days for Grade 1-2 SAEs 
2For studies using nuclear medicine or molecular imaging IND agents (NM, SPECT, or PET), the SAE reporting period is 
limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
 
Effective Date: August 30, 2024 
 
 
10.3.3 Additional Protocol-Specific Expedited Adverse Event Reporting 
 
All SAEs (Serious Adverse Events), regardless of causality, must be reported to the OSU PI 
and Multi-Institution Coordinator within 24 hours of knowledge of the event. Initial 24- 
hour notification using secure email or fax is acceptable. 
For SAEs not requiring expedited reporting via CTEP-AERS, a complete report 
accompanied by the SAE Submission Form (refer to Supplemental Forms Document) must 
be submitted to the OSU PI and Multi-Institution Coordinator via secure email or fax within 
5 days of knowledge of the event. 
 
All sites will directly report SAEs requiring expedited reporting to CTEP as outlined in 
the previous sections: AstraZeneca will receive any CTEP assessed SAE event reports, 
directly from CTEP. 
 
If the study is being conducted in multiple countries or multiple sites, Investigators or 
other site personnel inform sponsor representatives of the SAE. Sponsor/Investigators 
must inform the local authority of any SAE within 24 hours in accordance with the 
local regulations and report SAEs to IRB/IEC in the time per local requirements. 
 
10.4 
Routine Adverse Event Reporting 
 
All AEs (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. 
 
AE 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 AE CRF is used for routine AE reporting in Rave. 

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10.5 
Pregnancy 
 
Although not an AE in and of itself, pregnancy as well as its outcome must be documented via 
CTEP-AERS, and in Medidata Rave. 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. 
 
All pregnancies and outcomes of pregnancy should be reported to the Sponsor and the Company 
during the course of the study and within 6 weeks of the last dose of Osimertinib (AZD9291). 
 
Maternal exposure 
Should a pregnancy still occur, the investigational product should be discontinued immediately 
and the pregnancy reported to the Sponsor and the Company 
If a subject becomes pregnant during the course of the study Osimertinib (AZD9291) should 
be discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be handled 
as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented even 
if the subject was discontinued from the study. 
If any pregnancy occurs in the course of the study or within 6 weeks of the final dose of the 
investigational product, then the Investigator or other site personnel informs the appropriate 
Sponsor/Sponsor representatives within 1 day i.e., immediately but no later than 24 hours of 
when he or she becomes aware of it. 
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor data entry site within 1 or 5 calendar days for SAEs (see 
Section 10.3) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
Paternal exposure 
Pregnancy of the subject’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should if possible be followed up and documented. 
To capture information about a pregnancy from the partner of a male subject, the male subject’s 
partner consent must be obtained to collect information related to the pregnancy and outcome; 
the male subject should not be asked to provide this information. A consent form specific to this 

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situation must be used. The outcome of any conception occurring from the date of the first dose 
until 4 months after dosing ends should be followed up and documented. 
 
10.6 
Overdose 
In the context of a clinical study, an overdose is any dose which exceeds the daily dose that is 
defined in the clinical study protocol. A maximum tolerated dose has not been established for 
Osimertinib (AZD9291). 
Overdoses should be recorded as follows: 
• An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module 
• An overdose without associated symptoms is only reported on the Overdose eCRF module 
There is no specific treatment in the event of Osimertinib (AZD9291) overdose, and symptoms of 
overdose are not established. In the event of an overdose, physicians should follow general supportive 
measures and should treat symptomatically. 
If an overdose on a Company study drug occurs in the course of the study, then the Investigator 
or other site personnel inform the appropriate Sponsor representatives immediately, or no later 
than 24 hours of when he or she becomes aware of it. 
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor data entry site. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 10.3. 
For other overdoses, reporting must occur within 30 days. 
 
10.7 
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., AML) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 
For this trial, use the Adverse Event CRF in Rave. 
 
10.8 
Second Malignancy 

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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. 
 
 
11 STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. Scans 
and X-rays must be done <4 weeks prior to the start of therapy. In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. During emergency situations, some visits may be 
conducted remotely or by the local healthcare team, with the approval of the study chair. 

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11.1 
Study Calendar 
 
Cycle 1 
Cycle 2 
Cycle 3 onwards 
Off 
Studyf 
Pre- 
Study 
D1a 
D15p 
D16 
D1 
D2 
D15p 
D1 
Telaglenastat (CB-839) HCl 
A 
A 
Osimertinib (AZD9291) – Dose 
escalation 
Bb 
B --------------------------------------------- B 
Osimertinib (AZD9291) – 
Expansion Cohort 
B 
B 
Informed consent 
X 
Inclusion/Exclusion 
X 
X 
Telaglenastat (CB-839) HCl 
disbursement and reconciliation 
X 
X 
X 
Osimertinib (AZD9291) 
disbursement and reconciliation – 
Dose escalation 
X 
X 
X 
Osimertinib (AZD9291) 
disbursement and reconciliation – 
Expansion Cohort 
X 
X 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X 
x 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
x 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
Serum chemistryc 
X 
X 
X 
X 
X 
Urinalysisl 
X 
X 
Xd 
12-lead EKGm,d 
X 
X 
X 
Echocardiography/MUGA for 
LVEFk 
X 
X 
Full ophthalmic assessmentk 
Adverse event evaluationo 
X 
X 
X 
X 
Xo 
X 
B-HCG 
Xe 
Tumor Biopsy (archival) 
X 
Plasma from peripheral blood 
(Oncometabolites) 
Xg 
Xg 
Xg 
Xg 

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Whole blood in cfDNA Streck tubes 
Xg 
Xg 
Xg 
Xg 
Cycle 1 
Cycle 2 
Cycle 3 onwards 
Off 
Studyf 
Pre- 
Study 
D1a 
D15 
D16 
D1 
D2 
D15 
D1 
Plasma from peripheral blood 
(Pharmacokinetics – Dose 
escalation) 
Xh 
Xh 
Xh 
Xh 
Xh 
Plasma from peripheral blood 
(Pharmacokinetics – Expansion 
Cohort) 
Xi 
Xi 
Xi 
Tumor Imagingn 
Xn 
Tumor measurements are repreated every 8 weeks until progression. Documentation 
(radiologic) must be provided for patients removed from the study for progressive disease. 
A: Telaglenastat (CB-839) HCl: Dose as assigned; Dose escalation starts at 400 mg PO BID continuously 
B: Osimertinib (AZD9291): Dose as assigned; 80 mg PO QD continuously 
a: All days are +/- 5 days to account for patient and clinic schedules, holidays, etc. 
b. Osimertinib (AZD9291) is added to Telaglenastat (CB-839) HCl treatment starting on D16 of Cycle 1. 
c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, blood creatine phosphokinase, BUN, calcium, chloride, 
creatinine, glucose, LDH, magnesium, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. Important 
note: In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to Appendix E ‘Actions 
Required in Cases of Increases in Liver Biochemistry and Evaluation of Hy’s Law’, for further instructions. 
* Electrolyte abnormalities (hypokalaemia, hypomagnesaemia, hypocalcaemia) must be corrected to be within normal 
ranges prior to first dose and electrolyte levels monitored during study treatment. 
d. To be repeated if clinically indicated 
e: Serum pregnancy test (women of childbearing potential). 
f: Off-study evaluation. 
g: Peripheral blood and plasma for cfDNA and oncometabolite studies will be collected at 
baseline, C1D15 (escalation 
only), C2D1, and progression. 
h: Peripheral blood samples for dose escalation cohort PK analysis will be collected at the following timepoints: 1) 
baseline/pre-dose; 2) C1D15 before the morning dose of Telaglenastat (CB-839) HCl (0 min) and at 30 min, 1 hour, 2 
hours, 4 hours, and 8 hours following this dose; and 3) C2D1 before the morning dose of Telaglenastat (CB-839) HCl and 
Osimertinib (AZD9291) (0 min) and at 30 min, 1 hour, 2 hours, 4 hours, and 8 hours following this dose. A 24 hour (C2D2, 
pre-dose) PK collection is optional but encouraged (escalation cohort only). Peripheral blood samples (baseline / 0 hours) 
will also be collected on Day 1 of each treatment cycle starting with Cycle 3. There is no window for pre-dose research labs 
as long as done on the same calendar day. Window for post-dose labs is +/- 15 minutes. 
i: Peripheral blood samples for phase 2 PK analysis (baseline / 0 hours) will be collected at baseline and on Day 1 of each 
treatment cycle starting with Cycle 2. 
j. To be performed during screening end of treatment. Per the FDA label, echocardiogram is indicated at baseline and during 
treatment for patients with cardiac risk factors, or if clinically indicated. 
k. Full ophthalmic assessment, including slit lamp examination, should be performed if a patient experiences any visual 
symptoms (including blurring of vision), with additional tests if clinically indicated. Ophthalmology examination results 
should be collected in the eCRF. Any clinically significant findings, including those confirmed by the ophthalmologist must 
be reported as an AE. 
l. Urinalysis (dipstick) includes: Hb/Erythrocytes/Blood; Protein/Albumin; Glucose 
m. Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 5 minutes prior to assessment. 
All ECGs should be recorded with the patient in the same physical position. For each time point three ECG recordings 
should be taken at about 2 minute intervals. QTc is assessed using Fredericia’s formula. If there is a clinically significant 
abnormal ECG finding during the Treatment period, this should be recorded on the AE eCRF, according to standard adverse 
events collection and reporting processes. A 28-day follow-up assessment will be required if an on treatment assessment 
was abnormal at the time of discontinuation of study therapy, to confirm reversibility of the abnormality. 
n. Tumor measurements are repeated every 8 weeks until progression. Documentation (radiologic) must be provided for 
patients removed from study for progressive disease 

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o. The investigator will contact the patient by telephone at C2D15 for adverse event assessment following completion of 
defined DLT period. 
p. C1D15 visit and C2D15 telephone visit not required in the expansion cohort 

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12 MEASUREMENT OF EFFECT 
 
Although the clinical benefit of these drugs have not yet been established, the intent of offering 
this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability. Patients 
with measurable disease will be assessed by standard criteria. For the purposes of this study, 
patients should be re-evaluated every 8 weeks. In addition to a baseline scan, confirmatory scans 
will also be obtained at least 4 weeks following initial documentation of an objective response. 
 
CT Imaging: The purpose of CT imaging in this trial is to assess response by RECIST v1.1. CT 
imaging and correlate changes with response to treatment as well as disease progression. CT of 
the chest, abdomen, and pelvis will be obtained on an every 2-month basis to assess response by 
RECIST v1.1. 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 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 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 and Osimertinib (AZD9291). 
 
RECIST evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable for RECIST response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
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 

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≥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 might or might not be 
considered measurable. Tumor lesions that are situated in a previously irradiated area may only 
be considered measurable if they are growing on pre-treatment imaging. 
 
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. 
 
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 

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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 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 

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guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
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 cancer antigen 125 (CA-125) response (in 
recurrent ovarian cancer) and prostate-specific antigen (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 PRs and CRs 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 SD is mandatory to 
differentiate between response or SD (an effusion may be a side effect of the treatment) and PD. 
 
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. 

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Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
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). 
 
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 CR. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
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 PI). 
 
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 

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disease progression/recurrence (taking as reference for PD 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. 
** 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. 
 
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 ‘SD’ 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 

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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 PD is objectively documented (taking as reference for PD 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 PD is objectively documented. 
 
Duration of stable disease: SD 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 (PFS) 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
 
13 STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
AE lists, guidelines, and instructions for AE reporting can be found in Section 10 (Adverse 
Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section. The Protocol PI 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 SAEs; reporting 
of expedited AEs; and accumulation of reported AEs from other trials testing the same drug(s). 
The Protocol PI and statistician have access to the data at all times through the Clinical Trial 
Management System (CTMS) web-based reporting portal. 
 
For the dose escalation portion of this study, all decisions regarding dose 
escalation/expansion/de- escalation require sign-off by the Protocol PI through the 
CTMS/IWRS. In addition, for the dose escalation portion, the Protocol PI will have at least 
monthly, or more frequently, conference calls with the Study Investigators and the CTEP 
Medical Officer(s) to review accrual, progress, and AEs and unanticipated problems. 
 
For the expansion cohort, enrollment to the expansion cohort portion of the trial will not begin 
until a protocol amendment has been submitted which summarizes the phase 1 results, the 
RP2D, and the rationale for selecting it. The amendment must be reviewed and approved by 
CTEP before enrollment to the expansion cohort can begin. 

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During the expansion cohort of the study, the Protocol PI 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 the 
expansion cohort will require sign-off by the Protocol PI 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 AEs for that 
particular study. This includes timely review of data collected on the eCRFs submitted via 
Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. To access Rave via iMedidata: 
 
• Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account, and 
• Assigned one of the following Rave roles on the relevant Lead Protocol Organization (LPO) 
or Participating Organization roster at the enrolling site: Rave CRA, Rave Read Only, Rave 
CRA (LabAdmin), Rave SLA, or Rave Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a minimum of 
an AP registration type, 
o To hold Rave Investigator role, the individual must be registered as an NPIVR or IVR, 
and 
o To hold Rave Read Only role, site staff must hold an Associates (A) registration type. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System (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 staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff 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. If an 
eLearning is required and has not yet been taken, the link to the eLearning will appear under 
the study name in iMedidata instead of the Rave EDC link; once the successful completion of 
the eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC 

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link will display under the study name. 
 
Site staff 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 to activate 
their account. Account activation instructions are located on the CTSU website in the Rave section under 
the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website in the Data Management > 
Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e- 
mail at ctsucontact@westat.com. 
 
13.2.1 Method 
 
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)-619-7862 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 Investigational Drug Branch 
(IDB), CTEP. Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, good clinical practices (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. 

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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 RP2D and a 
description of any 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 
Data and Safety Monitoring 
 
The data and safety monitoring plan will involve the continuous evaluation of safety, data 
quality and data timeliness. Investigators will conduct continuous review of data and patient 
safety at their regular Disease Group meetings (at least monthly). For each dose level, the PI, 
study coordinator, and statistician, in consultation with treating physicians as appropriate will 
review all toxicities at a given dose level to inform the model for dose level adjustments and to 
determine if the risk/benefit ratio of the trial changes. Frequency and severity of adverse events 
will be reviewed by the PI and compared to what is known about the agent/device to determine 
if the trial should be terminated before completion. Serious adverse events will be reviewed by 
the OSUCCC Data and Safety Monitoring Committee (DSMC). The PI will also submit 
progress reports that will be reviewed by the committee per the DSMC plan. 
Safety and trial review teleconferences will be scheduled and moderated by the Multi-Center 
Trial Program (MCTP). All sites involved in the study should have a representative present for 
every call to review and discuss patients on study and other applicable agenda items. 
Teleconferences will be held monthly and may be held more frequently, as needed. For studies 
closed to accrual with patients expected to remain on long-term treatment and/or follow-up, 
teleconferences may be extended to occur every two months or quarterly. Decreasing 
frequency of teleconferences requires OSU PI and MCTP approval. 
In the expansion cohort component of the study, a safety monitoring scheme will also be 
implemented by including a stopping rule based on the number of DLTs among the first 21 
patients in the first stage. Enrollment may be paused if the lower bound of the 1-sided 80% 
exact binomial confidence interval of the estimated DLT excludes 30%. At the end of the first 
stage, the study will be stopped for safety if at least 5 patients with DLTs are observed. The 
study will continue if no more than 4 patients experience DLTs. 

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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: 
 
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. 
 
1. 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”): 
 
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. 
 
2. 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. 
 
3. 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 

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studies, or PI for other studies) of Collaborator's wish to contact them. 
 
4. 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. 
 
5. 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 
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. 
 
 
13.5 Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered queries 
and form delinquencies, monitor data quality and timeliness, generate reports, and review metrics. 
 
The DQP is located on the CTSU members’ website under Data Management. The Rave Home section 
displays a table providing summary counts of Total Delinquencies and Total Queries. DQP Queries, 
DQP Delinquent Forms, and the DQP Reports modules are available to access details and reports of 
unanswered queries, delinquent forms, and timeliness reports. Review the DQP modules on a regular 
basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU website. Staff 
that have Rave study access can access the Rave study data using a direct link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, DQP 
Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on the DQP. A 
protocol must have the Calendar functionality implemented in Rave by the Lead Protocol Organization 
(LPO) for delinquent form details and reports to be available on the DQP. Site staff should contact the 
LPO Data Manager for their protocol regarding questions about Rave Calendaring functionality. 

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of receptor tyrosine kinases. Oncogene. 23:2057-2070. 
 
Matre, P., J. Velez, R. Jacamo, et al. (2016). Inhibiting glutaminase in acute myeloid leukemia: 
metabolic dependency of selected AML subtypes. Oncotarget. 7:79722-79735. 
 
Mok, T.S., Y.L. Wu, M.J. Ahn, et al. (2017). Osimertinib or platinum-pemetrexed in EGFR 
T790M-positive lung cancer. N Engl J Med. 376:629-640. 
 
Momcilovic, M., S.T. Bailey, J.T. Lee, et al. (2017). Targeted inhibition of EGFR and 
glutaminase induces metabolic crisis in EGFR mutant lung cancer. Cell Rep. 18:601-610. 
 
Noone, A.M., N. Howlader, M. Krapcho, et al. (2018). SEER Cancer Statistics Review, 1975- 
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submission, posted to the SEER web site, April 2018. 
 
Normanno, N., A. De Luca, C. Bianco, et al. (2006). Epidermal growth factor receptor (EGFR) 
signaling in cancer. Gene. 366:2-16. 
 
Oxnard, G.R., K.S. Thress, R.S. Alden, et al. (2016). Association between plasma genotyping 
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gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS 
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Ramalingam SS, Vansteenkiste J, Planchard D et al. (2019). Overall Survival with Osimertinib 
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Rood, J.J.M., M.T.J. van Bussel, J.H.M. Schellens, et al. (2016). Liquid chromatography- 
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(Osimertinib (AZD9291)) in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 
1031:80-85. 
 
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https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm605113.htm. 
 
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cancer? Mol Imaging Biol. [Epub ahead of print]. 

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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 C 
CYTOCHROME P450 (CYP) 2C9 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 D 
GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH 
CONCOMITANT MEDICATIONS 
 
The use of any natural/herbal products or other “folk remedies” should be discouraged, but use 
of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the electronic case report form (eCRF). 
 
1. Drugs Inducing CYP3A4 Metabolism That AstraZeneca Strongly Recommend Are Not 
Combined With Osimertinib (AZD9291) 
Osimertinib (AZD9291) is metabolised by CYP3A4 and CYP3A5 enzymes. 
 
A drug-drug interaction study of Osimertinib (AZD9291) evaluated in patients showed that there 
is potential for Osimertinib (AZD9291) being a victim when co-administered with strong 
inducers of CYP3A4 (Osimertinib (AZD9291) concentrations are decreased when co-dosed with 
rifampicin). 
 
The following potent inducers of CYP3A4 must not be used during this study for any patient 
receiving Osimertinib (AZD9291). 
 
D1 
Drugs Inducing CYP3A4 
 
Contraindicated drugs 
Withdrawal period prior to Osimertinib 
(AZD9291) start 
 
Carbamazepine, phenobarbital, phenytoin, 
rifampicin, rifabutin, rifapentine, St John’s Wort 
3 weeks 
Phenobarbitone 
5 weeks 
 
 
This list is not intended to be exhaustive, and a similar restriction will apply to other agents that 
are known to strongly modulate CYP3A4 activity. Appropriate medical judgment is required. 
Please contact AstraZeneca with any queries you have on this issue. 
 
2. Medicines Whose Exposures May be Affected by Osimertinib (AZD9291) 
That AstraZeneca Considers May be Allowed With Caution 
Osimertinib (AZD9291) may increase the concentration of sensitive BCRP and P-gp substrates 
(concentration of the sensitive BCRP substrate, rosuvastatin and sensitive P-gp substrate, 
fexofenadine, are increased). 
D2 
Exposure, Pharmacological Action and Toxicity May be Increased by 
Osimertinib (AZD9291) 
 
Warning of possible interaction 
Advice 
 
Rosuvastatin 
Drugs are permitted but caution should be exercised and patients 
Sulfasalazine 
Doxorubicin 
monitored closely for possible drug interactions. Please refer to 
full prescribing information for all drugs prior to 
co-administration with Osimertinib (AZD9291). 

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Daunorubicin 

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Warning of possible interaction 
Advice 
Topotecan 
Dabigatran 
Aliskiren 
Digoxin 
 
 
3. Drugs That May Prolong QT Interval 
The drugs listed in this section are taken from information provided by The Arizona Center for 
Education and Research on Therapeutics website: https://www.crediblemeds.org/ . The website 
categorizes drugs based on the risk of inducing Torsades de Pointes (TdP). 
 
During screening the drugs that patients are currently prescribed should be checked opposite the 
ArizonaCert website. 
4. Drugs with a known risk of Torsades de Pointes 
 
The following drugs prolong the QT interval and are clearly associated with a known risk of 
TdP, even when taken as recommended. These drugs must have been discontinued prior to the 
start of administration of study treatment in accordance with guidance provided in Table 3 and 
should not be co-administered with study treatment (osimertinib) and for a period of two weeks 
after discontinuing study treatment. The list of drugs may not be exhaustive and is subject to 
change as new information becomes available. As such investigators are recommended to 
search the website to provide the most up to date information. 
 
 
Table 3 Drugs with a known risk of TdP 
Drug name 
Withdrawal 
period prior to 
osimertinib 
treatment start 
Aclarubicin, Anagrelide, ciprofloxacin, clarithromycin, 
cocaine, droperidol, erythromycin, levofloxacin, ondansetron, 
papaverine hydrochloride, procainamide, sulpiride, sultopride, 
terfenadine terlipressin 
Cilostazol, Cisapride, disopyramide, dofetilide, domperidone, 
flecainide, gatifloxacin, grepafloxacin, ibutilide, moxifloxacin, 
oxaliplatin, propofol, quinidine, roxithromycin, sevoflurane, 
sotalol, sparfloxacin, thioridazine 
2 days 
 
 
 
7 days 

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Azithromycin bepridil, citalopram, chlorpromazine, 
dronedarone, escitalopram, fluconazole, halofantrine, 
haloperidol, levomepromazine, levosulpiride, mesoridazine 
14 days 
 
Donepezil, terodiline 
3 weeks 
Levomethadyl, methadone, pimozide 
4 weeks 
Arsenic trioxide*, Ibogaine 
6 weeks 
Pentamidine 
8 weeks 
Astemizole, Probucol, vandetanib 
4 months 
Amiodarone, chloroquine 
1 year 
 
* Estimated value as pharmacokinetics of arsenic trioxide has not been studied 
This list should be checked against the full and most current list presented in the CredibleMeds® 
website (https://www.crediblemeds.org/). 
Values determined from comprehensive review (internal to AZ) of each compounds PK half-life 
and determination of the washout period. 
 
 
Other TdP risk Categories 
Patients receiving drugs that prolong QT interval or may increase the risk of TdP from other TdP risk 
categories can be enrolled, notwithstanding other exclusions and restrictions, if these drugs are considered 
essential for patient management and the patient has been stable on therapy. Close monitoring with ECGs 
and electrolytes is recommended. 
 
Patients with congenital long QT syndrome (CLQTS) are excluded from this study. 
 
Guidance regardless of TdP risk category 
Following study treatment initiation if it is considered essential for patient management to give drugs 
known to prolong QTc interval, regardless of TdP risk category, close monitoring with ECGs and 
electrolytes is recommended. 

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APPENDIX E 
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW 
 
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law. It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries. Specific guidance on the managing liver abnormalities can be 
found in Section 7 of the protocol. 
 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
 
The Investigator participates, together with Sponsor clinical project representatives, in review 
and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. 
HL criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product 
(IMP). 
 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with total bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP). 
 
Hy’s Law (HL) 
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
 
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the elevations 
in transaminases and TBL must occur. 
 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination: 
• ALT ≥ 3xULN 
• AST ≥ 3xULN 

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• TBL ≥ 2xULN 
 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• Determine whether the patient meets PHL criteria (see 
• Definitions within this Appendix for definition) by reviewing laboratory reports from all 
previous visits 
• Promptly enter the laboratory data into the laboratory CRF 
 
Follow-up 
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
• Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
• Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Actions Required When Potential Hy’s Law Criteria are Met Before and 
After Starting Study Treatment) 
• Notify the Sponsor/Company 
 
The Sponsor contacts the Investigator, to provide guidance, discuss and agree on approach for 
the study patients’ follow-up and the continuous review of data. Subsequent to this contact the 
Investigator will: 
• Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
• Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Company. 
• Complete the three Liver CRF Modules as information becomes available 
• If at any time (in consultation with the Sponsor) the PHL case meets serious criteria, 
report it as an SAE using standard reporting procedures 
 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Company 
contacts the Investigator in order to review available data and agree on whether there is an 
alternative explanation for meeting PHL criteria other than DILI caused by the IMP. The 
Sponsor Physician will also be involved in this review together with other subject matter experts 
as appropriate. 
 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 

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If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF. 
• If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
• Report an SAE (report term ‘Hy’s Law’) according to standard processes. 
− 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply. 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
• Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above. 
• Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review, amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined. 
 
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting Study 
Treatment 
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on study treatment occurrence of PHL criteria being met the Investigator will: 
• Determine if there has been a significant change in the patients’ condition# compared 
with the last visit where PHL criteria were met# 
− 
If there is no significant change no action is required 
− 
If there is a significant change notify the Sponsor representative, who will inform 
the Company, then follow the subsequent process described in Potential Hy’s Law 
Criteria met of this Appendix 
 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this may 
be in consultation with the Company if there is any uncertainty. 

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Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment and has already 
met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
• Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study e.g. chronic or progressing malignant disease, severe infection 
or liver disease, or did the patient meet PHL criteria prior to starting study treatment and 
at their first on study treatment visit as described in Actions Required When Potential 
Hy’s Law Criteria are Met Before and After Starting Study Treatment? 
 
If No: follow the process described in Potential Hy’s Law Criteria met of this Appendix 
If Yes: 
Determine if there has been a significant change in the patient’s condition# compared with when 
PHL criteria were previously met 
• If there is no significant change no action is required 
If there is a significant change follow the process described above (“Potential Hy’s Law 
Criteria Met”) 
 
#A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the Company if there is any uncertainty. 
 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U 
CM174090.pdf 

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APPENDIX F 
DEFINITION OF WOMEN OF CHILDBEARING POTENTIAL 
AND ACCEPTABLE CONTRACEPTIVE METHODS 
 
Definition of Women of Childbearing Potential 
Women of Childbearing Potential (WoCBP): 
Women between menarche and menopause who have not been permanently or surgically 
sterilised and are capable of procreation. 
 
Women NOT of Childbearing Potential: 
Women who are permanently or surgically sterilised or postmenopausal (definitions below): 
 
Permanent sterilisation includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy but excludes bilateral tubal occlusion. Tubal occlusion is considered a highly 
effective method of birth control but does not absolutely exclude possibility of pregnancy. (The 
term occlusion refers to both occluding and ligating techniques that do not physically remove the 
oviducts). 
• Women who have undergone tubal occlusion should be managed on trials as if they are 
of WoCBP (e.g. undergo pregnancy testing etc., as required by the study protocol) 
• Women will be considered postmenopausal if they are amenorrhoeic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
− 
Women under 50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatments and with luteinizing hormone and follicle-stimulating hormone levels 
in the postmenopausal range 
− 
Women over 50 years of age will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatments 
 
Acceptable Contraception Methods: 
Highly effective method of birth control is defined in Note 3 in International Conference on 
Harmonisation Guidance M3 (Nonclinical Safety Studies for the Conduct of Human Clinical 
Trials for Pharmaceuticals) as one that results in a low failure rate (e.g., less than 1 percent per 
year) when used consistently and correctly. 
Note that women should have been stable on their chosen method of birth control for a minimum 
of 2 weeks before entering the trial. Generic names and examples of trade names are given. As 
trade names may vary, Investigators should check the generic name of any contraception to 
ensure suitability. 
 
Acceptable contraception methods are: 
• Total sexual abstinence (abstinence must be for the total duration of the trial and the 
follow-up period) 
• Vasectomised sexual partner plus male condom (with participant assurance that partner 
received post-vasectomy confirmation of azoospermia) 
• Tubal occlusion plus male condom 
 
123 

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• Intra-uterine device – provided coils are copper-banded, plus male condom 
• Intra-uterine system (IUS) levonorgestrel IUS (e.g., Mirena), plus male condom 
• Medroxyprogesterone injections (Depo-Provera) plus male condom 
• Etonogestrel implants (e.g., Implanon, Norplan) plus male condom 
• Normal and low dose combined oral contraceptive pills, plus male condom 
• Norelgestromin / ethinylestradiol transdermal system plus male condom 
• Intravaginal device (e.g., ethinylestradiol and etonogestrel) plus male condom 
• Cerazette (desogestrel) plus male condom (Cerazette is currently the only highly 
efficacious progesterone based pill) 
 
Unacceptable Contraception Methods: 
The following methods are considered not to be highly effective and are therefore not acceptable 
contraceptive methods in AstraZeneca clinical trials: 
• Triphasic combined oral contraceptives 
• All progesterone only pills except, Cerazette 
• All barrier methods, if intended to be used alone 
• Non-copper containing intra-uterine devices 
• Fertility awareness methods 
• Coitus interruptus 

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APPENDIX G 
PATIENT DIARY 
PATIENT’S MEDICATION DIARY – PAGE 1 of 2 
 
Today’s date  
Agents_Telaglenastat (CB-839) HCl and Osimertinib (AZD9291)  
 
Patient Name 
(initials acceptable)  Patient Study ID 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for every 4 weeks. 
2. 
You will take your dose of Telaglenastat (CB-839) HCl twice daily by mouth, approximately 12 hours apart, in the morning 
and in the evening. You will take 
200 mg tablet(s), every day. Take Telaglenastat (CB-839) HCl with food, 
immediately after breakfast and after dinner. Doses should be taken at approximately the same times each day. Missed doses 
may be taken if it is not more than 3 hours past the scheduled administration time for the missed dose. Vomited doses should 
not be made up. 
3. 
You will take your dose of Osimertinib (AZD9291) once daily by mouth, at approximately the same time every day. You 
will take 
of 
mg tablet(s), every day. If you are in the dose escalation portion, you will only be taking Osimertinib (AZD9291) from Day 
16 of Cycle 1. You may take Osimertinib (AZD9291) with or without food. If a dose of Osimertinib (AZD9291) is missed 
or vomited, do not make up the missed dose and take the next dose as scheduled. 
4. 
Record the date, the number of tablets you took, and when you took them. 
5. 
If you have any comments or notice any side effects, please record them in the Comments column. 
6. 
Please return the forms to your physician when you go for your next appointment. 
Day 
Date 
Telaglenastat (CB-839) HCl 
Osimerti 
nib 
(AZD929 
1) 
Comments 
What time was 
dose taken? 
# of 200 mg 
tablets taken 
What time was 
dose taken? 
# of 
mg 
tablets taken 
AM 
PM 
AM 
PM 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
CTEP-assigned Protocol # 10216 
 
Local Protocol #  
  

NCI Protocol #: 10216 
Version Date: 09/17/2024 
126 
 
 
18 
19 
 
PATIENT’S MEDICATION DIARY – PAGE 2 of 2 
 
Day 
Date 
Telaglenastat (CB-839) HCl 
Osimertinib (AZD9291) 
Comments 
What time was 
dose taken? 
# of 200 mg 
tablets taken 
What time was 
dose taken? 
# of 
mg 
tablets taken 
AM 
PM 
AM 
PM 
20 
21 
22 
23 
24 
25 
26 
27 
28 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment  
 
2. 
Date patient was removed from study  
 
3. 
Patient’s planned total daily dose  
 
4. 
Total number of pills taken this month 
 
5. 
Physician/Nurse/Data Manager’s Signature