Clinical trial NCT03875313
Conditions: Solid Tumor Clear Cell Renal Cell Carcinoma TNBC - Triple-Negative Breast Cancer Colorectal Cancer CRC RCC ccRCC
Keywords: Tumor Metabolism Glutaminase Inhibitor CB-839 telaglenastat talazoparib PARP Inhibitor DNA Damage DNA Repair Homologous recombination deficiency HRD BRCA 1 BRCA 2
Sponsor: Calithera Biosciences, Inc
Start date: 2019-05-20; Completion date: 2020-07-29
Enrollment: 33 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1b/2 study to determine the recommended phase 2 dose (RP2D), safety and tolerability, pharmacokinetics (PK) and clinical activity of the glutaminase inhibitor CB-839 with the poly adenosine diphosphate ribose polymerase (PARP) inhibitor talazoparib in participants with advanced/metastatic solid tumors.

Detailed description:

Arms: arm 1: 600 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with advanced or metastatic solid tumors. arm 2: 800 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with incurable/locally advanced or metastatic clear cell renal cell carcinoma (ccRCC) who received ≥ 2 prior systemic regimens including ≥ 1 vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) therapy. arm 3: 800 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with incurable/locally advanced or metastatic triple-negative breast cancer (TNBC) estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-negative who received ≥ 1 prior line of cytotoxic chemotherapy with no prior poly adenosine diphosphate ribose polymerase (PARP) inhibitor therapy for TNBC or platinum-based chemotherapy for metastatic TNBC. arm 4: 800 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with with incurable/locally advanced or metastatic colorectal cancer (CRC) who received appropriate oxaliplatin or irinotecan- and fluorouracil (5-FU)-based chemotherapy with or without bevacizumab. arm 5: 800 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with other tumor types (prostate, urinary bladder, pancreas, and stomach).
Interventions: intervention 1: CB-839 intervention 2: Talazoparib
Intervention descriptions: intervention 1: CB-839 oral tablets administered twice daily with food at the assigned dose level on 28 day cycles with talazoparib. intervention 2: Talazoparib oral tablets administered at the standard dose once daily with or without food on 28 day cycles with CB-839.

Protocol documents:
Prot_000.pdf: 
Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
 
Confidential 
Page 1 of 104 
 
 
 
 
A Phase 1b/2 open label, Dose Escalation and Expansion Study of 
the Glutaminase Inhibitor Telaglenastat (CB-839) in Combination 
with the PARP inhibitor Talazoparib in Patients with Advanced or 
Metastatic Solid Tumors 
 
CX-839-011  
IND Number 
118397 
Sponsor 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Sponsor Contact  
Samuel Whiting, MD, PhD 
SVP, Clinical Development 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Phone:  870-1087650- 
Original Version 
21 December 2018 
Amendment 1 
10 April 2019 
 
Confidentiality Statement 
This document contains information that is confidential and proprietary to the Sponsor.  This 
information is being provided to you solely for the purpose of evaluating and/or conducting a clinical 
study for the Sponsor.  You may disclose the contents of this document only to study personnel under 
your supervision, institutional review boards (IRBs)/independent ethics committees (IECs), or duly 
authorized representatives of regulatory agencies for this purpose under the condition that they maintain 
confidentiality.  The contents of this document may not be used in any other clinical study, disclosed to 
any other person or entity, and/or published without the prior written permission of the Sponsor.  The 
foregoing shall not apply to disclosure required by any regulations; however, you will give prompt 
notice to the Sponsor of any such disclosure.  All other nonpublic information provided by the Sponsor 
and any information that may be added to this document also is confidential and proprietary to the 
Sponsor and must be kept in confidence in the same manner as the contents of this document. 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 2 of 104 
 
INVESTIGATOR’S AGREEMENT 
I have read the protocol entitled, “A Phase 1b/2 open label, dose escalation and expansion 
study of the glutaminase inhibitor telaglenastat (CB-839) in combination with the PARP 
inhibitor talazoparib in patients with advanced or metastatic solid tumors,” and agree to 
conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol.  
 
 
 
____________________________________     
Printed Name of Investigator 
 
 
____________________________________ 
Signature of Investigator 
 
 
_____________________________________ 
Date 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 3 of 104 
 
CONTACT PAGE 
Emergency Contacts 
Safety Physician and Medical Monitor 
Name:  Samuel Whiting, MD, PhD 
Address:  Calithera Biosciences, Inc. 
343 Oyster Point Blvd. Suite 200 
South San Francisco, CA  
Phone: 650-870-1087 
Mobile: 206-909-9879 
Email: swhiting@calithera.com   
Clinical Scientist and Medical Monitor 
Name: Hema Parmar, PhD 
Address: Calithera Biosciences, Inc. 
 343 Oyster Point Blvd. Suite 200 
 South San Francisco, CA  
Phone: 650-870-1096 
Mobile: 650-243-7561 
Email: hparmar@calithera.com  
 
Calithera Director Clinical Operations  
Name:     Tina Woo 
Address:  Calithera Biosciences, Inc. 
343 Oyster Point Blvd. Suite 200 
South San Francisco, CA  
Phone (Office): 650-870-1028 
Email:  twoo@calithera.com   
 
 
 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 4 of 104 
 
Serious Adverse Event (SAE) Reporting Contact 
CRO Safety Lead 
Name: Nikolina Zoko 
Address:  Oreskoviceva 20A, 10 000 Zagreb, Croatia 
Phone (Office): +385 1 46 28 186 
Central Safety Office: +44 (0) 1483 307920 
 
SAE Reporting Details (to be used when submitting the SAE forms): 
Central Safety Fax: +1 800 727 8347 
Email: calithera@primevigilance.com    
 
 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 5 of 104 
 
TABLE OF CONTENTS 
CONTENTS 
INVESTIGATOR’S AGREEMENT 
........................................................................................... 
2 
CONTACT PAGE 
......................................................................................................................... 
3 
TABLE OF CONTENTS 
.............................................................................................................. 
5 
LIST OF TABLES ........................................................................................................................ 
8 
LIST OF FIGURES ...................................................................................................................... 
9 
1.0 
SUMMARY 
...................................................................................................................... 
10 
 
Protocol Number and Title of Study 
..................................................................... 
10 
 
Rationale Summary 
............................................................................................... 
10 
 
Study Design Summary 
......................................................................................... 
11 
 
Study Population Summary 
................................................................................... 
11 
 
Study Treatment Summary 
.................................................................................... 
11 
 
Study Schema 
........................................................................................................ 
12 
 
Schedule of Study Assessments 
............................................................................ 
12 
 
Collection Schedule for Pharmacokinetic Sampling 
............................................. 
17 
2.0 
CORE PROTOCOL ....................................................................................................... 
18 
 
Study Objectives and Endpoints ........................................................................... 
18 
 
Study Population 
................................................................................................... 
21 
 
Inclusion Criteria: Part 1, Dose Escalation 
........................................... 
21 
 
Disease-Specific Inclusion Criteria: Part 2, Cohort Expansion 
............ 
21 
 
Inclusion Criteria: All Patients (Part 1, Dose Escalation, and Part 2, 
Cohort Expansion) 
................................................................................ 
21 
 
Exclusion Criteria: All Patients (Part 1, Dose Escalation, and Part 2, 
Cohort Expansion) 
................................................................................ 
23 
 
Part 1, Dose Escalation 
......................................................................... 
25 
 
Dose Modification Guidelines for Treatment-Related Hematological 
and Non-Hematological Toxicities 
....................................................... 
27 
 
Duration of Study and End of Study Definition 
................................... 
33 
 
Total Time on Study for Each Patient 
.................................................. 
33 
 
Study Assessments 
................................................................................................ 
33 
 
Overview .............................................................................................. 
33 
 
Summary of Statistical Analysis Plan 
................................................................... 
34 
3.0 
PROTOCOL DETAILS ................................................................................................. 
35 
 
Background and Rationale 
.................................................................................... 
35 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 6 of 104 
 
 
Glutaminase and PARP Inhibitors 
........................................................ 
35 
 
Clear Cell Renal Cell Carcinoma (ccRCC) 
.......................................... 
36 
 
Triple-Negative Breast Cancer 
............................................................. 
36 
 
Colorectal Cancer 
................................................................................. 
37 
 
Telaglenastat 
......................................................................................... 
37 
 
Talazoparib 
........................................................................................... 
43 
 
Justification of Doses Used in this Clinical Study 
............................... 
48 
 
General Study Procedures 
..................................................................................... 
48 
 
Informed Consent 
................................................................................. 
48 
 
Screen Failures ..................................................................................... 
49 
 
Methods of Treatment Assignment 
...................................................... 
50 
 
Dispensation of Study Treatment and Returned Study Treatment 
....... 
50 
 
Concomitant Treatment 
........................................................................ 
50 
 
Measurements of Treatment Compliance 
............................................. 
51 
 
Study Periods and Specific Procedures 
................................................ 
51 
 
Discontinuation of Study Treatment .................................................... 
53 
 
Tumor Assessments 
.............................................................................. 
54 
 Tumor Biopsies (Part 2, Cohort Expansion Patients Only) 
.................. 
55 
 Pharmacokinetics 
.................................................................................. 
55 
 Biomarkers ........................................................................................... 
55 
 
Safety Assessments 
............................................................................................... 
55 
 
Adverse Events and Serious Adverse Events 
....................................... 
55 
 
Pregnancy Reporting 
............................................................................ 
55 
 
Physical Examination 
........................................................................... 
56 
 
Vital Signs 
............................................................................................ 
56 
 
Electrocardiograms 
............................................................................... 
56 
 
Laboratory Assessments 
....................................................................... 
57 
 
Demographics and Patient Histories (Medical and Cancer Histories) 
.................. 
57 
 
Measures to Minimize/Avoid Bias 
........................................................................ 
57 
 
Statistical Analysis 
................................................................................................ 
57 
 
General Statistical Considerations 
........................................................ 
57 
 
Analysis Populations 
............................................................................ 
58 
 
Expansion Cohorts Efficacy Analysis 
.................................................. 
58 
 
Efficacy Endpoints ............................................................................... 
60 
 
Safety Analysis 
..................................................................................... 
61 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 7 of 104 
 
 
Identity, Administration, Preparation, Handling, Storage, and Accountability of 
Study Treatments 
................................................................................................... 
62 
 
Telaglenastat 
......................................................................................... 
62 
 
Talazoparib 
........................................................................................... 
64 
4.0 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
.. 
66 
 
Regulatory and Ethical Considerations 
................................................................. 
66 
 
Financial Disclosure 
.............................................................................................. 
67 
 
Data Protection 
...................................................................................................... 
67 
 
Publication Policy, Authorship, and Accountability 
............................ 
67 
 
Data Quality Control and Assurance 
..................................................................... 
68 
 
Protocol Amendments 
........................................................................................... 
69 
 
Source Documents 
................................................................................................. 
69 
 
Study Suspension, Termination, and Completion 
................................................. 
69 
 
Suspension and/or Termination 
............................................................ 
69 
 
Study Completion 
................................................................................. 
70 
 
Direct Access, Data Handling, and Record Keeping 
............................................ 
70 
 
Investigator 
........................................................................................... 
70 
 
Sponsor 
................................................................................................. 
71 
 
Pre-Study Documentation .................................................................... 
71 
 
Records Retention ................................................................................ 
72 
5.0 
REFERENCES 
................................................................................................................ 
73 
6.0 
ATTACHMENTS 
............................................................................................................ 
74 
Attachment 1.  List of Abbreviations and Definition of Terms 
.................................... 
75 
Attachment 2.   Eastern Cooperative Oncology Group Performance Status ................. 
78 
Attachment 3. Adverse Events: Definitions, Causality, Severity, and Reporting 
Procedures for SAES 
............................................................................................. 
79 
Attachment 4.  Clinical Laboratory Tests 
.................................................................... 
87 
Attachment 5. Response Criteria in Solid Tumors, Version 1.1 (RECIST, V1.1) 
....... 
88 
Attachment 6. Drug Interactions with TELAGLENASTAT 
..................................... 
101 
Attachment 7:  Drug Interactions with Talazoparib 
.................................................... 
103 
Attachment 8.  Protocol History 
................................................................................. 
104 
 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 8 of 104 
 
LIST OF TABLES 
Table 1 
Schedule of Study Assessments: Part 1, Dose Escalation ............................... 13 
Table 2  
Schedule of Study Assessments: Part 2, Dose Cohort Expansion .................. 15 
Table 3 
Collection Schedule for Pharmacokinetic Sampling: CX-839-011 ................ 17 
Table 4 
Part 1, Dose Escalation: Primary and Secondary Objectives and Endpoints .. 18 
Table 5 
Part 2, Cohort Expansion: Primary, Secondary, and Exploratory Objectives 
and Corresponding Endpoints ......................................................................... 20 
Table 6 
Dose Regimen for Part 1, Dose Escalation ..................................................... 25 
Table 7 
Dose Modification Guidelines for Hematologic Toxicity ............................... 28 
Table 8 
Dose Modification Guidelines for Nonhematologic Toxicity ......................... 30 
Table 9 
Dose Reduction Levels for Telaglenastat and Talazoparib ............................. 32 
Table 10 
List of Assessments for Determining Safety ................................................... 34 
Table 11 
CX-839-001 Treatment-Related AEs in ≥ 5% patients – BID Fed ................. 42 
Table 12 
Telaglenastat: Expected Serious Adverse Reactions ...................................... 43 
Table 13 
Simon 2-Stage Design ..................................................................................... 59 
Table 14 
Telaglenastat: Identity, Administration, Storage, Handling, Storage, and 
Accountability ................................................................................................. 62 
Table 15 
Talazoparib: Identity, Administration, Storage, Handling, Storage, and 
Accountability ................................................................................................. 64 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 9 of 104 
 
LIST OF FIGURES 
Figure 1 
Study Schema for CX-839-011 ....................................................................... 12 
Figure 2 
Structure of Telaglenastat ................................................................................ 38 
 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 10 of 104 
 
1.0 SUMMARY 
 Protocol Number and Title of Study  
Protocol CX-839-011 is a two-part, Phase 1b/2, open label, dose escalation and cohort expansion 
clinical study of the glutaminase inhibitor telaglenastat* (CB-839) in combination with the poly 
adenosine diphosphate ribose polymerase (PARP) inhibitor talazoparib in patients with advanced or 
metastatic solid tumors. 
*Telaglenastat is the non-proprietary name for CB-839. 
 Rationale Summary 
Calithera Biosciences, Inc. (Calithera), is investigating the combination of glutaminase inhibitor 
telaglenastat and PARP inhibitor talazoparib in patients with solid tumors (Dose Escalation part) 
and metastatic renal cell carcinoma (RCC) with a clear cell component (ccRCC), triple-negative 
breast cancer (TNBC), and colorectal cancer (CRC) (Cohort Expansion part), based on the 
following: 
• Calithera-sponsored Phase 1 clinical studies with the glutaminase inhibitor telaglenastat 
have shown encouraging single agent antitumor activity in indications including renal cell 
carcinoma (RCC) and triple-negative breast cancer (TNBC). 
• The combination of a PARP inhibitor and a glutaminase inhibitor has been shown to 
suppress the growth of ccRCC cell lines deficient in the Von Hippel Lindau (VHL) tumor 
suppressor gene, as is present in most cases of ccRCC in patients (Okazaki 2017).  
• Telaglenastat treatment decreases nucleotide pools and increases DNA replication stress via 
inhibition of glutaminase and reduction of glutamate and aspartate.  The combination of 
telaglenastat with PARP inhibitors has been evaluated in vitro with strong synergy seen 
across multiple tumor types including TNBC, ovarian, prostate, and CRC including in cell 
lines that are BRCA wild-type.  In vivo, the combination of telaglenastat with PARP 
inhibitors showed enhanced anti-tumor activity compared to either single agent alone in both 
prostate and CRC tumor xenograft models (Emberley 2018). 
• The PARP inhibitor TALZENNA™ (talazoparib), which will be investigated in this study 
protocol in combination with telaglenastat, was approved by FDA on 16 October 2018 for 
the treatment of adult patients with deleterious or suspected deleterious germline BRCA 
(gBRCA)-mutated, HER2-negative locally advanced or metastatic breast cancer (MBC) 
(based on the positive Phase 3 study results from EMBRACA-NCT01945775).  
• This study is designed to test the hypothesis that the combination of telaglenastat 
+talazoparib will be tolerable and active in indications beyond BRCA-mutated MBC. 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 11 of 104 
 
 Study Design Summary 
Study CX-839-011 is an open-label, multicenter, two-part, Phase 1b/2 study consisting of Part 1, 
Dose Escalation, which employs a 3+3 design, and Part 2, Cohort Expansion, (which employs a 
Simon 2-stage design).  The study will be conducted at approximately 10 sites in the United States 
(US). 
 Study Population Summary 
• Part 1, Dose Escalation: approximately 9 to 12 patients will be enrolled.  Patients with 
histologically or cytologically documented incurable, locally advanced/metastatic solid 
tumors refractory or intolerant to standard therapies of proven clinical benefit, or with no 
standard therapy available. 
• Part 2, Cohort Expansion:  Three cohorts with up to 25 patients in cohorts 1 and 2 and up to 
30 patients in cohort 3:  
o Cohort 1: Incurable/locally advanced or metastatic clear cell renal cell carcinoma  
(ccRCC), having received 2 or more prior systemic regimens, including at least one  
vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) 
therapy. 
o Cohort 2: Incurable/locally advanced or metastatic triple-negative breast cancer (TNBC), 
having received at least one prior line of cytotoxic chemotherapy for metastatic disease 
and not having received prior PARP inhibitor therapy for TNBC or platinum-based 
chemotherapy for TNBC in the metastatic setting. 
o Cohort 3: Incurable/locally advanced or metastatic CRC previously treated with 
oxaliplatin-, irinotecan- and 5-FU based chemotherapy (if appropriate) with or without 
bevacizumab. 
 Study Treatment Summary 
• Part 1, Dose Escalation: Escalating doses of telaglenastat starting at 600 mg twice daily 
(BID) on Days 1 to 28 in combination with talazoparib 1 mg once daily (QD) on a 28-day 
cycle.  The highest tested dose of telaglenastat in this study will be 800 mg BID, the 
recommended Phase 2 dose (RP2D) of telaglenastat when administered as a single-agent 
(based on efficacy, pharmacokinetic [PK], and safety data from CX-839-001; see the current 
CB-839 Investigator’s Brochure and Section 3.1.6.2 of this document).   
Telaglenastat will be administered with food, immediately following a meal, twice daily 
approximately 12 hours (hr) (± 2 hr) apart.  Talazoparib will be taken in the morning at 
approximately the same time each dosing day.  The morning dose of telaglenastat and 
talazoparib should be taken in the clinic for Cycle 1 Day 1 (C1D1) and C2D1 after the 
pre-dose PK collection. The dose of talazoparib in subsequent cohorts may also be reduced 


Calithera Biosciences, Inc. 
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
Confidential 
Page 12 of 104 
 
from the initial 1 mg dose in 0.25 mg increments as determined by safety and consensus of 
the Investigators and the Sponsor.  Alternative dosing schedules may also be evaluated. 
• Part 2, Cohort Expansion: Combination treatment of telaglenastat with talazoparib at the 
RP2D and schedule as determined in Part 1, Dose Escalation (or the maximum administered 
dose [MAD] and schedule if an RP2D is not identified).  Telaglenastat will be administered 
with food, immediately following a meal, twice daily approximately 12 hr (± 2 hr) apart. 
Talazoparib will be administered in the morning at approximately the same time each dosing 
day. The morning dose of telaglenastat and talazoparib should be taken in the clinic for 
Cycle 1 Day and C2D1 after the pre-dose P 
 Study Schema  
Figure 1 
Study Schema for CX-839-011 
 
 
 
 Schedule of Study Assessments 
The schedule of study assessments for Protocol CX-839-011 is provided in Table 1, Dose 
Escalation, and Table 2, Cohort Expansion. 


Calithera Biosciences, Inc.  
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
 
Confidential 
Page 13 of 104 
 
 
 
 
 
 
Table 1 
Schedule of Study Assessments: Part 1, Dose Escalation 
Visit 
Screening 
Cycle 1 
Cycle 2 
Cycle 3+ 
End of Treatment 
1 cycle = 28 days 
Day 
-28 to -1 
Day 15 
(-1 day) 
Days 8 and 22 
(± 2 days) 
Day 15 
(± 2 days) 
Days 1 and 15 
(± 5 days) 
Day 1  
(± 5 days) 
Within 28 Days Post 
Treatment DC (± 5 Days) 
Written informed consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
Physical examination1 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG with QTcF3 
X 
X4 
 
X4 
 
 
X 
Urinalysis6 
X 
 
 
 
 
 
 
Serum chemistry levels6 
X 
X 
X 
X 
X 
X 
X 
Coagulation tests6 
X 
 
 
 
 
 
 
Hematology6 
X 
X 
X 
X 
X 
X 
X 
Serum or urine pregnancy test7 
X 
 
 
 
 
 
X 
PK assay8 
 
See Table 3 for PK collection schedule 
 
 
Talazoparib dosing9 
 
Once daily (QD) of each 28-day cycle 
 
Telaglenastat (CB-839) dosing10 
 
Telaglenastat will be administered twice daily (BID) with food on Days 1 to 28 
 
Radiographic evaluation of tumor 
burden (diagnostic CT or MRI)11, 12 
X 
Tumor assessment to be performed per RECIST v1.1 every 8 weeks (+/- 5 days) 
and every 12 weeks (+/- 5 days)  beyond Cycle 12  
X 
MRI brain with contrast if h/o brain 
metastases13 
X 
 
 
 
 
 
 
Bone Scan (if h/o bone metastases)14 
X 
 
 
 
 
 
 
Whole blood for biomarker analysis15 
X 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X16 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 


Calithera Biosciences, Inc.  
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
 
Confidential 
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Table Notes to Table 1, Dose Escalation 
1. Complete physical exam is required at Screening and at End of Treatment. A symptom-directed physical exam can be done on all other visits. System 
exams are only required as clinically indicated. 
2. Vital sign measurements include temperature, pulse, respiratory rate and resting systolic and diastolic blood pressure.  
3. Duplicate ECGs are NOT required. 
4. ECG to be performed within approximately 2 to 4 hr after of telaglenastat administration.  
5. Does not need to be repeated if the Screening procedure was completed within 3 days prior to C1D1 unless a clinically significant change is suspected. 
6. Serum chemistry and hematology laboratory tests should be performed and reviewed before dosing. These laboratory evaluations may be performed up to 
72 hr prior to the planned dosing. Any new ≥ Grade 3 laboratory abnormality, such as liver function test elevations, electrolyte fluctuation, or 
hematologic deterioration should be assessed for potential risk to continue dosing. In the event of uncertainty, the medical monitor should be contacted. 
Coagulation assessments (PT, INR and aPTT) and urinalysis will be completed at Screening and as clinically indicated during the study. Note that 
coagulation assessments must be performed and reviewed within 24 hr prior of all biopsy procedures. 
7. Required of all females of child-bearing potential. Screen pregnancy test must occur within 7 days prior to C1D1. 
8. The schedule for collection of PK samples is provided in Table 3. 
9. Talazoparib is administered orally once a day at the same time every morning on dosing days. On the PK day (C2D1), patients will bring their dose of 
talazoparib to the clinic. Pre-dose procedures (including the pre-dose PK sample) must be completed, then the patient will eat breakfast and take their 
telaglenastat dose followed immediately by talazoparib. 
10. Telaglenastat is given BID with food approximately 12 hr apart. On the PK day (C2D1), patients will bring their morning dose of telaglenastat to clinic. 
Pre-dose procedures (including the pre-dose PK sample) must be completed, then the patient will eat breakfast and take their telaglenastat dose followed 
immediately by talazoparib. 
11. Whenever possible, imaging should be done at the same institution/ facility and with the same modality which will be used to measure response during the 
patient’s participation in the study.  
12. Completed approximately every 8 weeks per RECIST v1.1 for the first 12 cycles, every 12 weeks beyond Cycle 12. Should include chest/abdomen/pelvis 
and all other known areas of disease. Evaluations may occur more frequently as clinically indicated.  
13. Radiographic assessments should include baseline contrast-enhanced brain MRI for patients with history of brain metastases or suggestive symptoms  
14. Radiographic assessments should include baseline bone scan (bone scintigraphy) for patients with history of bone metastases or suggestive symptoms. 
15. 3 mL of blood will be collected from all patients during the screening period. 
16. After the EOT visit, the Investigator must follow up on all AEs and SAEs related to study medication and other reportable information until the events 
have subsided, returned to baseline, the patient has initiated any other anticancer treatment, or in case of permanent impairment, until the condition 
stabilizes. 


Calithera Biosciences, Inc.  
Protocol Number CX-839-011, Amendment 1 
 
Telaglenastat (CB-839) 
 
 
 
Confidential 
Page 15 of 104 
 
 
 
 
 
 
Table 2  
Schedule of Study Assessments: Part 2, Dose Cohort Expansion 
Visit 
Screening 
Cycle 1 
Cycle 2+ 
End of Treatment/  
1 cycle = 28 days 
Day 
-28 to -1 
Day 15 
(-1 day) 
Day 15 
(± 2 days) 
Days 1 
(± 5 days) 
Within 28 Days Post 
Treatment DC (± 5 Days)
Written informed consent 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
Physical examination1 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
12-lead ECG with QTcF3 
X 
X4 
X4 
X4 
X 
Urinalysis6 
X 
 
 
 
 
Serum chemistry levels6 
X 
X 
X 
X 
X 
Coagulation tests6 
X 
 
 
 
 
Hematology6 
X 
X 
X 
X 
X 
Serum or urine pregnancy test7 
X 
 
 
 
X 
PK assay8 
 
See Table 3 for PK collection schedule 
 
Talazoparib dosing9 
 
Once daily (QD) of each 28-day cycle 
 
Telaglenastat (CB-839) dosing10 
 
Administer telaglenastat (CB-839) twice daily (BID) with food 
on Days 1 to 28 
 
Radiographic evaluation of tumor burden 
(diagnostic CT or MRI)11, 12 
X 
Tumor assessment to be performed per RECIST v1.1 every 8 
weeks (+/- 5 days) and every 12 weeks (+/- 5 days)  beyond 
Cycle 12 
X 
MRI brain with contrast if h/o brain metastases13 
X 
 
 
 
 
Archival tumor tissue or fresh tumor biopsy14 
X 
 
 
 
 
Bone Scan (if h/o bone metastases)15 
X 
 
 
 
 
Whole blood for biomarker analysis16 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X17 
Concomitant medications 
X 
X 
X 
X 
X 


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Table Notes for Table 2, Cohort Expansion. 
1. Complete physical exam is required at Screening and at End of Treatment. A symptom-directed physical exam can be done on all other visits. System 
exams are only required as clinically indicated. 
2. Vital sign measurements include temperature, pulse, respiratory rate and resting systolic and diastolic blood pressure.  
3. Duplicate ECGs are NOT required. 
4. ECG to be performed within approximately 2 to 4 hr after of telaglenastat administration 
5. Does not need to be repeated if the Screening procedure was completed within 3 days prior to C1D1 unless a clinically significant change is suspected. 
6. Serum chemistry and hematology should be performed and reviewed before dosing. These laboratory evaluations may be performed up to 72 hr prior to the 
planned dosing. Any new ≥ Grade 3 laboratory abnormality, such as liver function test elevations, electrolyte fluctuation, or hematologic deterioration 
should be assessed for potential risk to continue dosing. In the event of uncertainty, the medical monitor should be contacted. Coagulation assessment (PT, 
INR and aPTT) and urinalysis will be completed at Screening and as clinically indicated during the study. Note that coagulation assessments must be 
performed and reviewed within 24 hr prior of all biopsy procedures 
7. Required of all females of child-bearing potential. Screen pregnancy test must occur within 7 days prior to C1D1.  
8. The schedule for collection of PK samples is provided in Table 3. 
9. Talazoparib is administered orally once a day at the same time every morning on dosing days. On the PK day (C2D1), patients will bring their dose of 
talazoparib to the clinic. Pre-dose procedures (including the pre-dose PK sample) must be completed, then the patient will eat breakfast and take their 
telaglenastat dose followed immediately by talazoparib. 
10. Telaglenastat is given BID with food approximately 12 hr apart. On the PK day (C2D1), patients will bring their morning dose of telaglenastat to clinic. 
Pre-dose procedures (including the pre-dose PK sample) must be completed, then the patient will eat breakfast and take their telaglenastat dose followed 
immediately by talazoparib. 
11. Whenever possible, imaging should be done at the same institution/ facility and with the same modality which will be used to measure response during the 
patient’s participation in the study. 
12. Completed approximately every 8 weeks per RECIST v1.1 for the first 12 cycles, every 12 weeks beyond Cycle 12. Should include chest/abdomen/pelvis 
and all other known areas of disease. Evaluations may occur more frequently as clinically indicated. Patients who discontinue study medication for reasons 
other than progressive disease or death should be followed by imaging per protocol until progressive disease, death, initiation of a new anti-cancer therapy, 
or withdrawal of consent for study follow-up.  
13. Radiographic assessments should include baseline contrast-enhanced brain MRI for patients with history of brain metastases or suggestive symptoms  
14. Availability of FFPE archival tumor tissue block or slides containing sufficient tissue for molecular profiling (see laboratory manual for details). De novo 
tumor biopsy is mandatory if archival tissue not available. 
15. Radiographic assessments should include baseline bone scan (bone scintigraphy) for patients with history of bone metastases or suggestive symptoms. 
16. 3 mL of blood will be collected from all patients during the screening period. 
17. After the EOT visit, the Investigator must follow up on all AEs and SAEs related to study medication and other reportable information until the events 
have subsided, returned to baseline, the patient has initiated any other anticancer treatment, or in case of permanent impairment, until the condition 
stabilizes. 


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 Collection Schedule for Pharmacokinetic Sampling 
The collection schedule for PK sampling is provided in Table 3. On PK sampling days, patients will 
arrive at the clinic prior to taking their morning study treatment and have blood samples drawn for 
PK analysis. They will take their morning dose of study treatment at the clinic after the blood draw. 
Table 3 
Collection Schedule for Pharmacokinetic Sampling: CX-839-011 
Protocol Part Cycle and Day 
Timepoint 
PK 
Telaglenastat 
/Talazoparib 
Part 1,  
Dose 
Escalation 
 
C2D1 
 
Predose 
3 mL 
0.5 hr post dose (± 10 minutes) 
3 mL 
1 hr post dose (± 10 minutes) 
3 mL 
2 hrs post dose (± 10 minutes) 
3 mL 
4 hrs post dose (±30 minutes) 
3 mL 
6 hrs post dose (± 30 minutes) 
3 mL 
8 hrs post dose (± 30 minutes) 
3 mL 
10-12 hrs post dose (±30 minutes) 
3 mL 
 
Part 2,  
Cohort 
Expansion 
C2D1 
Predose 
3 mL 
1 hr post dose (± 10 minutes) 
3 mL 
3-6 hrs post dose (± 30 minutes) 
3 mL 
Notes:   
1. Blood samples will be prepared into plasma and split into 4 aliquots (0.3 mL each).  
2. If the patient is holding either of both study drugs at C2D1, the PK draws may be rescheduled to C2D15 or 
C3D1 if dosing of both drugs has resumed. Patients will take telaglenastat and talazoparib morning dose in 
the clinic so patients should be instructed accordingly. This is not considered a protocol deviation. 
C = cycle; D = day; mL = milliliter. 


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2.0 CORE PROTOCOL 
 Study Objectives and Endpoints 
The objectives and corresponding endpoints are provided in Table 4 for Part 1, Dose 
Escalation, and Table 5, for Part 2, Cohort Expansion. 
Table 4 
Part 1, Dose Escalation: Primary and Secondary Objectives and 
Endpoints 
Part 1: Dose Escalation ─  
Primary and Secondary Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
To evaluate the safety and tolerability of 
telaglenastat in combination with talazoparib  
Incidence, nature, and severity of adverse 
events and laboratory abnormalities graded 
per National Cancer Institute Common 
Terminology Criteria for Adverse Events 
(NCI CTCAE) v5.0 
To establish the maximum tolerated dose 
(MTD) and/or the Recommended Phase 2 
Dose (RP2D) of the regimen in patients with 
advanced solid tumors 
Incidence and nature of dose-limiting 
toxicities (DLTs) 
 
Secondary Objectives 
Secondary Endpoints 
To determine pharmacokinetics (PK) of 
telaglenastat in combination with talazoparib 
 
Total exposure (area under the curve) from 
Time 0 to the last measurable concentration 
(AUC
0–last) 
Time to maximum observed plasma 
concentration (t
max) and maximum observed 
plasma concentration (Cmax) 
Minimum observed plasma concentration 
(C
min, i.e., trough concentration) 
Clearance, volume of distribution, and half-
life, if data allow 
To determine pharmacokinetics (PK) of 
talazoparib in combination with telaglenastat 
Total exposure (area under the curve) from 
Time 0 to the last measurable concentration 
(AUC
0–last) 


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Part 1: Dose Escalation ─  
Primary and Secondary Objectives and Endpoints 
 
Time to maximum observed plasma 
concentration (tmax) and maximum observed 
plasma concentration (Cmax) 
Minimum observed plasma concentration 
(Cmin; i.e., trough concentration) 
To explore anti-tumor activity of 
telaglenastat in combination with talazoparib  
Overall response rate (ORR), confirmed 
ORR, clinical benefit rate (CBR) and 
progression-free survival (PFS) 
Exploratory Objectives 
Exploratory Endpoints 
To identify potential biomarkers associated 
with response and/or resistance to 
telaglenastat in combination with talazoparib 
Tumor DNA mutations and RNA expression 
profiles, including for BRCA, somatic vs. 
germline source 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
 


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Table 5 
Part 2, Cohort Expansion: Primary, Secondary, and Exploratory 
Objectives and Corresponding Endpoints 
Part 2: Cohort Expansion ─  
Primary and Secondary Objectives and Endpoints  
Primary Objectives 
Primary Endpoints 
To evaluate anti-tumor activity of 
telaglenastat in combination with talazoparib 
in patients with advanced or metastatic 
ccRCC, triple-negative breast cancer 
(TNBC), and colorectal cancer (CRC) 
Overall response rate (ORR), confirmed 
ORR, clinical benefit rate (CBR) and 
progression-free survival (PFS) 
To evaluate the safety and tolerability of 
telaglenastat in combination with talazoparib 
in patients with advanced or metastatic 
ccRCC, TNBC, and CRC 
 
Incidence, nature, and severity of adverse 
events and laboratory abnormalities graded 
per NCI CTCAE v5.0 
 
Secondary Objectives 
Secondary Endpoints 
To evaluate the population pharmacokinetics 
(Pop PK) of telaglenastat and talazoparib 
when used in combination 
Plasma concentrations are pre-dose and 
3 to 6 hours post dose on C2D1 
Exploratory Objectives 
Exploratory Endpoints 
To identify potential biomarkers associated 
with response and/or resistance to 
telaglenastat in combination with talazoparib 
Tumor DNA mutations and RNA expression 
profiles, including for BRCA, somatic vs. 
germline source 
BRCA = breast cancer gene; DNA = deoxyribonucleic acid; RNA = ribonucleic acid. NCI CTCAE = National 
Cancer Institute Common Terminology Criteria for Adverse Events. 


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 Study Population 
Patients will be enrolled according to the eligibility criteria specified below. 
 
Inclusion Criteria: Part 1, Dose Escalation 
a. Have histologically or cytologically documented incurable/locally advanced or 
metastatic solid tumors refractory or intolerant to standard therapies of proven clinical 
benefit, or with no therapy of clinically meaningful benefit (in the opinion of the 
investigator and patient).  
b. Have evaluable disease 
 
Disease-Specific Inclusion Criteria: Part 2, Cohort Expansion 
a. Cohort 1: Incurable/locally advanced or metastatic ccRCC having received 2 or more prior 
systemic regimens, including at least one vascular endothelial growth factor receptor 
tyrosine kinase inhibitor (VEGFR TKI) therapy  
OR  
b. Cohort 2: Incurable/locally advanced or metastatic TNBC defined as ER and PR negative 
(< 1% by immunohistochemistry) and HER2-negative (immunohistochemistry 0 to 1+ or 
fluorescence in situ hybridization [FISH] negative) having received at least one prior line of 
cytotoxic chemotherapy for metastatic disease.  The following inclusion criteria apply: 
i. Has not previously received therapy for TNBC with a PARP inhibitor 
ii. Has not previously received platinum therapy for TNBC in the metastatic setting 
iii. Prior platinum in the adjuvant or neoadjuvant setting is allowed if the first 
disease recurrence occurred > 6 months after the last dose of platinum therapy 
OR 
c. Cohort 3: Incurable/locally advanced or metastatic CRC treated with  prior systemic 
therapy, including oxaliplatin-, or irinotecan- and 5-FU-based chemotherapy (if 
appropriate) with or without bevacizumab 
 
 
Inclusion Criteria: All Patients (Part 1, Dose Escalation, and Part 2, 
Cohort Expansion) 
1. Target Population 
a. Age ≥18 years 


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b. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 
(Attachment 2) 
c. Estimated life expectancy of at least 3 months 
d. Evaluable disease (Part 1, Dose Escalation patients)  
or  
Measurable disease (Part 2, Cohort Expansion patients): at least one tumor 
lesion/lymph node that meets the Response Evaluation Criteria in Solid Tumors, 
version 1.1 (RECIST v1.1) specifications for measurability (Attachment 5) 
e. Part 2, Cohort Expansion patients only: Availability of formalin-fixed, paraffin-
embedded (FFPE) archival tumor tissue block or slides containing sufficient tissue 
for molecular profiling (see the laboratory manual for details) 
• Fresh tumor biopsy is mandatory if archival tissue is not available 
2. Laboratory Findings 
a. Dose Escalation: Serum creatinine ≤ 2.0 × upper limit of normal (ULN) or 
calculated creatinine clearance ≥ 60 mL/min (≥ 0.5 mL/sec) using the Cockcroft-
Gault equation 
Cohort Expansion: Serum creatinine ≤ 2.0 × upper limit of normal (ULN) or 
• For TNBC and CRC patients: calculated creatinine clearance ≥ 60 mL/min 
(≥ 0.5 mL/sec) using the Cockcroft-Gault equation  
• For RCC patients: calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) 
using the Cockcroft-Gault equation 
b. Adequate defined as absolute neutrophil count (ANC) ≥ 1,500/mm3, hemoglobin 
(Hgb) ≥ 9 g/dL, and platelet count ≥ 100,000/mm3  
Transfusions and growth factors must not be used within 2 weeks prior to C1D1 to 
meet these requirements. 
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
< 3.0 × ULN 
d. Total bilirubin ≤ 1.5 × ULN 
For patients with Gilbert’s disease, total bilirubin ≤ 3 mg/dL (≤ 51.3 µmol/L). 


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3. Reproductive Status 
Female Patients 
• Female patients may be enrolled if they are considered to be not of childbearing 
potential, or who are post-menopausal, or who are of childbearing potential and 
using a highly effective form of contraception. Female patients should not become 
pregnant or donate eggs from the time of first dose of either study treatment 
(telaglenastat or talazoparib) administration for at least 7 months after the last dose 
of either treatment. 
• Females of childbearing potential must have a negative serum or urine pregnancy 
test 7 days before the first dose of study treatment and must agree to serum or urine 
pregnancy tests at the end of treatment period.  
• Female patients may not be breastfeeding at the time of the first dose of study drug 
and must not breastfeed during study participation for at least 7 months after the last 
dose of either study treatment (either telaglenastat or talazoparib). 
Male Patients 
• Males with partners of childbearing potential may be enrolled if they use a condom 
when having sex with a pregnant woman or a condom and an additional highly 
effective form of contraception when having sex with a woman of childbearing 
potential from 21 days before the first dose of study drug through 4 months after the 
last dose of study drug. Males should not donate sperm from the time point of study 
treatment administration until at least 4 months after the last dose of study drug.  
Contraception should be considered for a nonpregnant female partner of 
childbearing potential. 
4. Recovery from Toxicities 
Recovery to baseline or ≤ Grade 1 CTCAE v.5.0 from toxicities related to the prior 
therapy, unless after discussion with the medical monitor the AE(s) are deemed 
clinically non-significant and/or stable on supportive therapy. 
 
Exclusion Criteria: All Patients (Part 1, Dose Escalation, and 
Part 2, Cohort Expansion) 
A patient who meets any one of the exclusion criteria listed below will not be eligible for the 
study. 
1. Medical History  
a. Prior treatment with telaglenastat or a PARP inhibitor 
b. Receipt of any anticancer therapy within the following windows: 


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• Small molecule tyrosine kinase inhibitor therapy (including investigational) 
within the prior 2 weeks or 5 half-lives prior to C1D1, whichever is longer 
• Any type of anti-cancer antibody or cytotoxic chemotherapy within 4 weeks prior 
to C1D1  
• Radiation therapy for bone metastasis within 2 weeks prior or any other external 
radiation therapy within 4 weeks prior to C1D1.  Patients with clinically relevant 
ongoing complications from prior radiation therapy are not eligible. 
c. Any other current or previous malignancy within the past three years except: 
Adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the 
cervix other neoplasm that, in the opinion of the Principal Investigator and with the 
agreement of the Medical Monitor, will not interfere with study-specific endpoints 
2. Concurrent Conditions 
a. Patients with symptomatic ascites or pleural effusion 
A patient who is clinically stable following treatment for these conditions (including 
therapeutic thoraco- or para-centesis) is eligible. 
b. Unable to receive oral medications  
3. Unstable/inadequate cardiac function, defined as: 
a. Myocardial infarction or symptomatic ischemia within the last 6 mo prior to C1D1 
b. Uncontrolled or clinically significant conduction abnormalities (e.g., ventricular 
tachycardia on arrhythmias is excluded; 1st degree atrioventricular (AV) block or 
asymptomatic LAFB/RBBB are eligible) 
c. Congestive heart failure (New York Heart Association class III to IV) 
4. Major surgery within 28 days prior to first dose of study drug 
5. Current or anticipated use of medications with potential drug-drug interaction (DDI) 
with talazoparib: P-glycoprotein (P-gp) inhibitors, P-gp inducers or breast cancer 
resistant protein (BCRP) inhibitors.  See Attachment 7, Drug-Drug Interactions with 
Talazoparib. 
6. Requirement for continued proton pump inhibitor use after C1D1 
7. Infection requiring more than 5 days of parenteral antibiotics, antivirals, or antifungals 
within two weeks prior to first dose of study drug 
8. Patient known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B, or 
Hepatitis C 
9. Refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, significant small 
bowel resection or gastric bypass surgery, use of feeding tubes or other situation that 
may preclude adequate absorption 


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10. Serious psychiatric or medical conditions that could interfere with treatment or 
protocol-related procedures 
11. Active and/or untreated central nervous system metastasis  
Patients with treated brain metastases must have (1) documented radiographic stability 
of at least 4 weeks duration demonstrated on baseline central nervous system (CNS) 
imaging prior to study treatment and (2) be symptomatically stable and off steroids for 
at least 2 weeks before administration of any study treatment. 
12. Patients in whom oral and/or intravenous (IV) fluid hydration are contraindicated 
13. Patients who are pregnant or lactating 
 
Part 1, Dose Escalation 
Part 1, Dose Escalation, will employ a 3+3 design and will enroll cohorts of 3 to 6 patients with 
advanced or metastatic cancer. Patients will receive telaglenastat and talazoparib as 
summarized in Table 6. During Part 1, patients will be assessed for DLT during Cycle 1 on 
Days 1 through 28, inclusive (see Section 2.2.5.1 for the definition of a DLT-evaluable patient). 
 Definition of Dose-Limiting-Toxicity (DLT) Evaluable Patients 
Patients who meet the criteria listed below will NOT be evaluable for DLT assessment and will 
be replaced.  All other patients will be considered DLT-evaluable. 
• Patients who withdraw or are withdrawn from the study prior to completing the DLT 
assessment window for any reason other than a DLT. 
• Patients who do not receive at least 75% of the assigned dose (depending on dose level) 
of telaglenastat and talazoparib, i.e., 42 doses of telaglenastat and 21 doses of 
talazoparib, in the first 28-day treatment cycle for any reason other than a DLT. 
 Dose Escalation Plan 
Cohorts of 3 to 6 patients will receive telaglenastat and talazoparib according to Table 6 and the 
dose escalation rules specified in Section 2.2.5.3. 
Table 6 
Dose Regimen for Part 1, Dose Escalation 
Dose Level 
Telaglenastat Dose 
(mg) BID 
Talazoparib Dose (mg) 
QD 
Number of 
Patients 
-1 
600 
0.75 
3-6 
1 (starting dose) 
600 
1 
3-6 
2 
800 
1 
3-6 


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Dose Level 
Telaglenastat Dose 
(mg) BID 
Talazoparib Dose (mg) 
QD 
Number of 
Patients 
Note: The dose of talazoparib in subsequent cohorts may also be reduced from the initial 1 mg dose in 0.25 mg 
increments as determined by safety and consensus of the Investigators and the Sponsor. Alternative dosing 
schedules may also be evaluated. 
QD = once daily. 
 Dose Escalation Rules 
Dose-limiting toxicity observed in Cycle 1 (first 28 days of dosing) of Part 1, Dose Escalation, 
will be used to determine escalation or de-escalation of telaglenastat and/or talazoparib to the 
next dose level.  The dose escalation rules are provided below 
An initial cohort of 3 patients will be enrolled at the starting dose level (Dose Level 1), as 
specified in Table 6.  For any given cohort: 
• If 0 of 3 patients develops a DLT, escalate to the next dose level. 
• If 1 of 3 patients develops a DLT: 
o Enroll another 3 patients at this dose level for a total of 6 patients. 
o If 0 of the 3 newly added patients develops a DLT (for a total of 1 of 6 patients with 
a DLT at this dose level), escalate to the next dose level. 
o If ≥ 1 of the 3 newly added patients develops a DLT (for a total of ≥ 2 of 6 patients 
with a DLT at this dose level), the dose directly below the current dose will be 
considered the MTD, if shown to be tolerable. 
• If ≥ 2 of 3 patients develop a DLT, the dose level one level below the current dose will 
be expanded to at least 6 patients, and no higher dose levels will be tested. 
• The MTD or RP2D is considered the highest dose at which ≤ 1 of 6 patients experiences 
a DLT. 
 
• The dose of talazoparib in subsequent cohorts may also be reduced from the initial 1 mg 
dose in 0.25 mg increments as determined by safety and consensus of the Investigators 
and the Sponsor. Alternative dosing schedules may also be evaluated. 
 Definitions of Dose-Limiting Toxicity 
The occurrence of any of the following toxicities during Cycle 1 of Part 1, Dose Escalation, 
will be considered a DLT, if judged by the Investigator to be related (possibly or probably) to 
administration of study treatment: 


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Non-Hematologic Dose-Limiting Toxicity 
• Any ≥ Grade 4 non-hematological toxicity 
• Grade 3 non-hematologic toxicity with the exception of the following: 
o Grade 3 fatigue 
o Grade 3 nausea/vomiting that responds within 24 hours after initiating maximal 
supportive care  
o Grade 3 rash or itching that resolves to ≤ Grade 1 within 2 weeks 
• Any clinically meaningful Grade 3 non-hematologic laboratory value if medical 
intervention (other than electrolyte repletion) is required to treat the patient, OR the 
abnormality leads to hospitalization, OR the abnormality persists for > 1 week except: 
o Grade 3/4 elevation in serum amylase and/or lipase not associated with clinical or 
radiological evidence of pancreatitis. 
Hematologic Dose-Limiting Toxicity 
• Grade ≥ 3 febrile neutropenia (as an oral temperature of > 38.3°C or two consecutive 
readings of > 38.0°C for 2 hours and an ANC of <0.5 × 10
9/L, or expected to fall below 
0.5 × 109/L) 
• Grade ≥ 4 anemia 
• Grade 
  4 neutropenia (absolute neutrophil count 
  500/L) lasting  7 days 
• Grade ≥ 4 thrombocytopenia  
• Grade 3 thrombocytopenia associated with: 
o A bleeding event that requires a platelet transfusion 
 
OR 
o A life-threatening bleeding event occurring due to low platelet count which results 
in urgent intervention  
 
Dose Modification Guidelines for Treatment-Related Hematological 
and Non-Hematological Toxicities 
Patients will be monitored continuously for AEs while on study.  Treatment modifications (e.g., 
dose delays or other dose modifications) will be based on specific laboratory and AE criteria, as 
summarized in Table 7 (hematologic criteria) and Table 8 (non-hematologic criteria). 


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Table 7 
Dose Modification Guidelines for Hematologic Toxicity 
Toxicity Grade  
(CTCAE v5) 
Telaglenastat 
Talazoparib 
Grade 3/4 Anemia 
(< 8.0 g/dL Hgb) 
Hold and resume at the same 
dose level upon resolution to 
≤ Grade 1 or baseline 
Hold talazoparib and implement supportive 
care per local guidelines.  Monitor weekly 
until Hgb returns to 9 g/dL or better; then 
resume talazoparib at a reduced dose at the 
initiation of the next cycle.  
• 
If anemia with Hgb < 8.0 g/dL recurs 
after dose reduction, hold talazoparib 
and implement supportive care per local 
guidelines.  Monitor weekly until 
hemoglobin returns to 9.0 g/dL (Day 1), 
then resume talazoparib at a further 
reduced dose at the initiation of the next 
cycle. 
• 
If anemia persists for > 4 weeks without 
recovery of Hgb to at least 9.0 g/dL 
despite supportive care measures at any 
dose level, discontinue talazoparib and 
consider referral to a hematologist. 
 
Transfusions and other supportive measures 
are permitted to support management of 
hematological toxicities at any occurrence. 
Grade 3/4 Neutropenia 
(ANC < 1000/µL) 
Hold and resume at the same 
dose level upon resolution to 
≤ Grade 1 or baseline. 
Hold talazoparib and implement supportive 
care per local guidelines.  Monitor weekly 
until ANC ≥ 1500/µL; then resume 
talazoparib at a reduced dose at the initiation 
of the next cycle  
• 
If neutropenia recurs after the dose 
reduction, hold talazoparib and 
implement supportive care per local 
guidelines.  Monitor weekly until ANC 
≥ 1500/µL, then resume talazoparib at 
a further reduced dose at the initiation 
of the next cycle. 
• 
If neutropenia persists for > 4 weeks 
without recovery to ≥ 1500/μL at any 
dose level despite supportive care 
measures, discontinue talazoparib and 
consider a referral to a hematologist. 


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Toxicity Grade  
(CTCAE v5) 
Telaglenastat 
Talazoparib 
G-CSF and GM-CSF may be used at 
Investigator’s discretion for the supportive 
treatment of neutropenia at any occurrence. 
Grade 3/4 
Thrombocytopenia 
(Platelets < 50,000/μL) 
Hold and resume at the same 
dose level upon resolution to 
≤ Grade 1 or baseline. 
Hold talazoparib and implement supportive 
care per local guidelines.  Monitor weekly 
until platelets ≥ 50,000/μL, then then resume 
talazoparib at a reduced dose at the initiation 
of the next cycle. 
• 
If thrombocytopenia (< 50,000/μL) 
recurs after one dose reduction, hold 
talazoparib and implement supportive 
care per local guidelines.  Monitor 
weekly until platelets ≥ 75,000/µL, 
then resume talazoparib at a further 
reduced dose at the initiation of the 
next cycle. 
• 
If thrombocytopenia persists for 
> 4 weeks without recovery to 
≥ 50,000/μL despite supportive care 
measures, discontinue talazoparib and 
consider a referral to a hematologist. 
Thrombopoietin analogues and/or platelet 
transfusions may be used at Investigator’s 
discretion for the supportive treatment of 
thrombocytopenia at any occurrence. 
ANC = absolute neutrophil count, Hgb = hemoglobin. 


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Table 8 
Dose Modification Guidelines for Nonhematologic Toxicity 
Toxicity Grade  
(CTCAE v5) 
Telaglenastat 
Talazoparib 
Nonhematologic 
laboratory 
Grade ≥ 3 
events 
determined to 
be clinically 
significant and 
attributable to 
study drug(s), 
except for 
abnormal liver 
tests 
If symptoms are not tolerable, 
hold and resume at the same 
dose level upon recovery to 
≤ Grade 1 or baseline.  If 
toxicity recurs, hold and 
restart at next lower dose. 
Hold talazoparib as follows: 
• 
For Grade 3 laboratory abnormalities, hold 
talazoparib until the laboratory abnormality 
resolves to Grade ≤ 2 (to baseline grade for 
creatinine increases).  Resume talazoparib at 
the same dose or reduce of one dose level at 
the initiation of the next cycle.    
• 
If a Grade 3 laboratory abnormality recurs, 
hold talazoparib until the laboratory 
abnormality resolves to Grade ≤ 2 (to baseline 
grade for creatinine increases).  Reduce 
talazoparib of one dose level if the dose was 
not previously reduced, or to further reduced 
dose level if subject was previously dose 
reduced at the initiation of the next cycle. 
• 
For Grade 4 laboratory abnormalities, hold 
talazoparib until the laboratory abnormality 
resolves to Grade ≤ 2 (to baseline grade for 
creatinine increases).  Reduce talazoparib of 
one dose level at the initiation of the next 
cycle.  
Talazoparib must be discontinued if a Grade 4 AE 
recurs after treatment resumes. 
Implement supportive care per local guidelines. 
Contact medical monitor to discuss potential dose 
modification. 
Discontinue talazoparib permanently for unresolved 
Grade 3 toxicity lasting longer than 14 days or for 
Grade 4 toxicity lasting longer than 3 days.  
Consider resuming talazoparib at a reduced dose 
level if clear clinical benefit from treatment is 
observed and after discussion with the Sponsor. 


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Toxicity Grade  
(CTCAE v5) 
Telaglenastat 
Talazoparib 
Abnormal liver 
function tests 
Dose reductions should be 
considered in any patient who 
develops drug-related ALT or 
AST >3-5x ULN or bilirubin 
>1.5-3 x ULN lasting longer 
than 1 week.  
A patient who develops 
elevated ALT or AST >5-10 x 
ULN or bilirubin >3-10 x 
ULN should have study 
treatment held and restarted at 
a reduced dose (dose-
reduction guidelines are 
provided in Table 9) after 
ALT and AST levels resolve 
to ≤ 3 x ULN or baseline, and 
bilirubin ≤ 1.5 x ULN or 
baseline.   
 
In patients with recurrence of 
drug-related elevated ALT or 
AST>5-10 x ULN or bilirubin 
>3-10 x ULN at the lowest 
telaglenastat dose level, 
treatment should be 
discontinued.  
 
In patients who develop ALT 
or AST elevations > 3 × ULN 
in combination with total 
bilirubin elevation > 2 × ULN 
without reasonable other 
explanation, drug-induced 
liver injury should be 
suspected and treatment 
interrupted.  Reinstitution of 
study treatment after recovery 
of ALT and AST to ≤ 3 x 
ULN and bilirubin to ≤ 1.5 x 
ULN must be discussed and 
approved by the Sponsor. 
Subjects who develop abnormal liver tests [AST, 
ALT, total bilirubin (TBili)], signs or symptoms 
consistent with hepatitis during study treatment may 
meet the criteria for temporarily withholding or 
permanently discontinuing talazoparib. 
Criteria for Temporary Withholding of Study 
Drug in Association with Liver Test 
Abnormalities if any of the following occur: 
• 
Subjects who develop AST or ALT > 5 x ULN 
(without TBili > 2 x ULN)  
OR 
• 
Subjects with baseline TBili ≤ 1.5 x ULN who 
subsequently present with > 3 x ULN OR 
• 
Subjects with baseline TBili > 1.5 x ULN and 
≤ 3 x ULN (e.g., Gilberts) who subsequently 
present with TBili > 5 x ULN 
If abnormalities resolve to baseline values within 2 
weeks, there are no signs of drug-induced liver 
injury (DILI), and none of the permanent 
discontinuation criteria are met, then upon 
discussion with the Sponsor, the Investigator may 
re-challenge at a reduced dose level.   
Criteria for Permanent Discontinuation of Study 
Drug in Association with Liver Test 
Abnormalities if any of the following occur: 
• 
Subjects who develop AST OR ALT values > 
3 × ULN AND a Tbili value > 2 × ULN  
• 
Subjects with AST/ALT > 5 × ULN that 
persists for more than 7 days (AST/ALT > 8 × 
ULN for subjects with hepatic involvement). 
• 
Subjects with AST/ALT > 20 × ULN that 
persists for longer than 3 days. 
• 
Subjects with TBili > 3 × ULN that persists for 
longer than 7 days (> 5 × ULN for subjects 
with Gilbert’s disease). 


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Toxicity Grade  
(CTCAE v5) 
Telaglenastat 
Talazoparib 
Non-laboratory 
Grade ≥3 AEs 
determined  to 
be clinically 
significant and 
attributable to 
the study drug 
For Grade 3 AEs: Hold and 
resume at the same dose level 
or the next lower dose level of 
telaglenastat upon recovery to 
≤ Grade 1 or baseline.  
For Grade 4 AEs: Permanently 
discontinue telaglenastat. 
• For Grade 3 AEs: Hold talazoparib until the 
AE resolves to Grade ≤ 1 or baseline.  Resume 
talazoparib at the same dose or reduce by 1 
dose level. 
• For Grade 4 AEs: Permanently discontinue 
talazoparib. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT=computerized tomography; Tbili=total 
bilirubin. 
 Guidelines for Dose Reductions 
Dose reductions for telaglenastat are allowed in decrements of 200 mg.  Dose reductions for 
talazoparib are allowed in increments of 0.25 mg (Table 9).  
Table 9 
Dose Reduction Levels for Telaglenastat and Talazoparib 
Telaglenastat (CB-839) 
Talazoparib 
800 mg 
1 mg 
600 mg 
0.75 mg 
400 mg 
0.50 mg 
Discontinue 
0.25 mg 
Not applicable 
Discontinue 
 Resumption of Study Treatment 
For talazoparib and telaglenastat, treatment may be delayed for up to 6 weeks from the last 
dose. Delays longer than 6 weeks are allowed only in cases where the delay was due to a non-
drug related cause.  
 
If study treatment (i.e., both telaglenastat and talazoparib) has been withheld due to an AE, 
treatment may be restarted when the AE has returned to ≤ Grade 1 or baseline.  In cases where 
a particular toxicity is clearly related to either telaglenastat or talazoparib, the study drug that is 
not involved in causing the AE may be restarted prior to a return to ≤ Grade 1 or baseline.  If 
telaglenastat is restarted after permanent discontinuation of talazoparib, telaglenastat should be 
permanently discontinued for a ≥ Grade 3 recurrence of the AE that resulted in talazoparib 
discontinuation. 


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Specific guidelines for dose modifications related to hematologic and nonhematologic toxicities 
occurring during Part 1, Dose Escalation, and Part 2, Cohort Expansion, are provided in 
Table 7 and Table 8, respectively. 
 Missed Doses 
Telaglenastat:  In the event a patient forgets a dose, it may be made up if it is not more than 6 
hours past the scheduled administration time for the missed dose.  The dose should be taken 
with food.  If more than six (6) hours have passed, the dose should not be taken, but instead 
recorded as a missed dose. Vomited doses should not be made up. 
Talazoparib: In the event a patient forgets a dose, it may be made up if it is not more than 2 
hours past the scheduled administration time for the missed dose.  The dose should be taken 
with food. If more than 2 hours have passed, the dose should not be taken, but instead recorded 
as a missed dose. Vomited doses should not be made up. 
 
Duration of Study and End of Study Definition 
The study will enroll patients over approximately a 12-month period.  The total duration of the 
study period is expected to be approximately 2 years.  
The end-of-study is defined as the date that the last patient completes the final scheduled safety 
assessments, performed at the End-of-Treatment (EOT)/Follow-up visit (see the respective 
Schedule of Study Assessments, Table 1, Dose Escalation, and Table 2, Cohort Expansion). 
 
Total Time on Study for Each Patient 
Patients will receive study treatment until disease progression or unacceptable toxicity or the 
need for subsequent systemic anticancer treatment.  Other criteria for discontinuation from 
study treatment are detailed in Section 3.2.8. 
 Study Assessments 
 
Overview 
Assessments are based on 28-day cycles, and patients will be closely monitored for safety and 
tolerability throughout the study.  All assessments must be performed and documented for each 
patient.   
Table 1 summarizes the schedule of study assessments for patients enrolled in Part 1, Dose 
Escalation, and Table 2 provides an analogous summary for patients enrolled in Part 2, 
Cohort Expansion. 


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The final scheduled safety assessment will occur at the EOT Visit. If the study treatment is held 
due to AEs, Investigators should perform additional safety assessments as clinically indicated. 
Radiographic evaluation of tumor burden (e.g., diagnostic computed tomography [CT] scan 
with intravenous contrast or magnetic resonance imaging [MRI]) will occur during Screening 
(within 28 days prior to Cycle 1 Day 1 [C1D1]), every 8 weeks (+/- 5 days) after C1D1, and at 
the EOT Visit.  
Plasma PK samples will be used to measure concentrations of telaglenastat and talazoparib for 
population PK analysis.  Blood samples for PK analysis should be collected at the requested 
time.  The actual time of collection must be noted in the source documents and electronic case 
report forms (eCRFs). See Table 3 for the schedule of sampling times for PK collection. 
Timepoints for assessment of tumor response are provided in Table 1, Dose Escalation, and 
Table 2, Cohort Expansion. 
The assessments used to determine the safety of telaglenastat in combination with talazoparib 
are listed in Table 10.   Details of collection procedures are provided in the Laboratory Manual 
for this study. 
Table 10 
List of Assessments for Determining Safety 
Safety Assessments 
Vital signs 
Physical examinations 
Assessments of AEa  
ECG  
Laboratory testsb  
AE = adverse event, aPTT = activated partial thromboplastin time; CBC = complete blood count; 
ECG = electrocardiogram; INR = International Normalized Ratio; NCI CTCAE = National 
Cancer Institute Common Terminology Criteria for Adverse Events; PT = prothrombin time. 
a. Severity of AEs will be graded and recorded according to NCI CTCAE, version 5.0.  
b. Routine laboratory tests comprise CBC, serum chemistry, urinalysis, pregnancy test (at 
screening), INR, PT/aPTT, (at screening and during the study when clinically indicated) 
 Summary of Statistical Analysis Plan 
Protocol CX-839-011 is a Phase 1b/2 multicenter, open-label, two-part study in patients with 
advanced and metastatic or refractory solid tumors. Part 1, Dose Escalation, will employ a 
3 + 3 design. Part 2, Cohort Expansion, will employ a Simon 2-stage design.  Descriptive 
statistics will be used to summarize the data.  Summary statistics for continuous variables will 
include the mean, standard deviation, median, and range (minimum/maximum).  Categorical 
variables will be presented by as frequency counts and percentages. Time-to-event data will be 


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summarized by Kaplan-Meier plots and median estimates. Additional details are provided in 
Section 3.6. 
3.0 PROTOCOL DETAILS 
 Background and Rationale 
 
Glutaminase and PARP Inhibitors  
There is strong biological rationale for targeting the mitochondrial enzyme glutaminase for the 
treatment of a variety of cancers.  Glutaminase catalyzes the first step in glutamine metabolism 
by converting glutamine to glutamate.  Many tumors become dependent upon glutamine 
metabolism because glucose is diverted from the tricarboxylic acid (TCA) cycle to the 
production of lactate by the Warburg effect (aerobic glycolysis).  Glutamine is used by tumor 
cells as a source of energy, to re-supply TCA cycle intermediates, and to synthesize amino 
acids, fatty acids and nucleotides.  Calithera has developed telaglenastat, an orally bioavailable, 
potent, highly selective, reversible, allosteric inhibitor of glutaminase with broad preclinical 
activity in vitro and in vivo against solid and hematologic malignancies.  Telaglenastat has been 
tested in Phase 1 and 2 studies as monotherapy and in combination with standard of care 
therapies in RCC, TNBC, and melanoma studies (see the current Investigators Brochure). 
Cellular deoxyribonucleic acid (DNA) is continually subject to damage from a variety of 
mechanisms, requiring coordinated pathways to repair and maintain genomic integrity and cell 
survival (Lindahl 1993; Hoeijmakers 2001).  Poly adenosine diphosphate ribose polymerases 
(PARPs) play a key role in the DNA damage response through the repair of DNA single-strand 
breaks (Amé 2004).  The inhibition of PARPs leads to the accumulation of DNA single-strand 
breaks, which if unrepaired, lead to DNA double-strand breaks at replication forks.  Normally, 
double-strand breaks are repaired by means of the error-free homologous-recombination (HR) 
repair pathway (McCabe 2006).  However, deficiency in HR repair by germline or somatic 
mutation of genes encoding repair proteins, such as BRCA1, BRCA2, or ATM, renders cells 
vulnerable to PARP inhibition.  
Telaglenastat treatment decreases nucleotide pools and increases DNA replication stress via 
inhibition of glutaminase and subsequent reduction of glutamate and aspartate, a precursor for 
nucleotide synthesis.  Talazoparib has been shown to have greater activity in tumors with 
impaired DNA damage response (e.g., tumors with mutations in homologous repair enzymes), 
these tumors have increased DNA replication stress.  The hypothesis tested in this protocol is 
that telaglenastat will increase DNA replication stress through depletion of nucleotide pools, 
thereby sensitizing tumors to talazoparib regardless of mutations in HRD enzymes.  The 
combination of telaglenastat with PARP inhibitors has shown synergistic activity in vitro and 
strong combination activity in vivo across multiple preclinical models (Emberley 2018).   


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Clear Cell Renal Cell Carcinoma (ccRCC) 
The most common type of renal cell carcinomas is clear cell. The ccRCC tumor harbors 
mutations or deletions of the Von Hippel Lindau (VHL) tumor suppressor gene, loss of which 
activates hypoxia-responsive gene transcription.  Importantly, VHL loss correlates with 
reduced HR gene expression and deficiency in the ability to repair double-strand DNA breaks, 
conferring a “BRCAness” phenotype to VHL-null RCC tumor cells (Scanlon 2018).  
Separately, VHL loss also is associated with increased dependence on glutamate and reductive 
carboxylation for biosynthesis of pyrimidine nucleotides and lipids, and upon glutamate for 
generation of glutathione for redox balance.  Inhibitors of glutaminase induce DNA replication 
stress by lowering the reductive transition of glutamine carbon atoms to aspartate resulting in 
reduced de novo synthesis of pyrimidines (Okazaki 2017).  Inhibitors of glutaminase also 
increase DNA replication stress through reduction in glutathione and the resulting increase in 
reactive oxygen species (ROS).  Consistent with these mechanisms and supporting the validity 
of combining PARP inhibitors and glutaminase inhibitors, single agent glutaminase inhibitor 
treatment led to activation of an intra-S phase checkpoint and suppressed the growth of VHL-/- 
RCC cells in vitro, while the combination of PARP inhibitor with glutaminase inhibitor 
synergistically suppressed the growth of VHL
-/- cells in vitro and in vivo (Okazaki 2017).  
 
Triple-Negative Breast Cancer 
Genetic analyses of breast and ovarian tumors have revealed similarities between two 
particularly aggressive and treatment-refractory tumor types: basal-like TNBC and high-grade 
serous ovarian cancer.  These similarities included inactivation of BRCA1 and BRCA2, high 
frequencies of ATM and TP53 mutations, high expression of AKT3 and MYC, RB1 loss, and 
cyclin E1 amplification.  From a therapeutic point of view, activity of PARP inhibitors 
demonstrated in patients with ovarian cancer may be recapitulated in at least a subset of 
patients with TNBC.  Consistent with this activity, the PARP inhibitor olaparib has recently 
been approved by the FDA for the treatment of patients with germline BRCA-positive, 
HER2-negative metastatic breast cancer who have previously received chemotherapy.  The 
PARP inhibitor talazoparib (TALZENNA®) was approved by FDA on 16 October 2018 for the 
treatment of adult patients with deleterious or suspected deleterious germline BRCA (gBRCA)-
mutated, HER2-negative locally advanced (LA) or metastatic breast cancer (MBC).  Given the 
ability of telaglenastat to decrease nucleotide pools and increase DNA replication stress via 
inhibition of glutaminase and reduction of glutamate, telaglenastat has been investigated in 
combination with PARP inhibitors in TNBC preclinical models as well as additional preclinical 
models.  Telaglenastat treatment in combination with the PARP inhibitors talazoparib and 
niraparib led to synergistic anti-proliferative activity in TNBC cell lines in vitro, as well as in 
non-small cell lung carcinoma (NSCLC), ovarian and prostate cancer cells in vitro 
(Emberley 2018).  In vivo, the combination of telaglenastat with PARP inhibitors showed 


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enhanced anti-tumor activity compared to either single agent alone in both prostate and CRC 
tumor xenograft models. 
 
Colorectal Cancer 
Telaglenastat treatment leads to a decrease nucleotide pools and increases DNA replication 
stress via inhibition of glutaminase and reduction of glutamate and aspartate.  This mechanism 
motivated preclinical evaluation of telaglenastat in combination with PARP inhibitors in 
multiple preclinical models including colorectal cancer.  Telaglenastat treatment in 
combination with the PARP inhibitors talazoparib and niraparib led to synergistic anti-
proliferative activity in CRC cell lines in vitro (Emberley 2018).  In vivo, the combination of 
telaglenastat with PARP inhibitors showed enhanced anti-tumor activity compared to either 
single agent alone in CRC tumor xenograft models.  This study is evaluating if the preclinical 
synergy seen between telaglenastat and talazoparib in CRC models translates into patients. 
 
Telaglenastat 
 Characterization of Telaglenastat and Effect of Glutaminase 
Inhibition on Antiproliferative Activity 
Telaglenastat is a potent and selective reversible inhibitor of glutaminase activity.  It is an 
allosteric and noncompetitive inhibitor of both splice variants of the broadly expressed gene for 
glutaminase but does not inhibit glutaminase-2, which is expressed predominantly in liver.  
Incubation of recombinant human glutaminase with CB 839 results in time-dependent and 
slowly reversible inhibition of glutaminase activity (half maximal inhibitory concentration 
(IC
50) = 34 nM with 1 hr pre-incubation).  In mice bearing human tumors, telaglenastat 
treatment leads to a significant increase in tumor concentration of glutamine and decreases in 
tumor glutamate and aspartate.  Profound reductions in the cellular pools of several TCA cycle 
intermediates, glutathione, and other metabolic intermediates downstream of glutaminase have 
been observed in tumor cells in vitro and in vivo following telaglenastat treatment.   
Glutaminase inhibition is associated with antiproliferative activity in a wide range of tumor cell 
lines.  Pro-apoptotic activity has been observed in TNBC, ccRCC, KRAS-mutant NSCLC, 
mesothelioma, as well as hematologic tumor cell lines including multiple myeloma (MM) and 
non-Hodgkin’s lymphoma (NHL).  Twice-daily administration of telaglenastat to 
immunocompromised mice bearing TNBC, RCC, NSCLC, and MM tumors has been shown to 
result in a significant reduction in tumor growth.  Synergistic activity in cell lines and additive 
or synergistic activity in vivo have been seen with CB 839 in combination with standard-of-care 
agents including paclitaxel in TNBC, tyrosine kinase and mechanistic target of rapamycin 
(mTOR) inhibitors in RCC, erlotinib in NSCLC, and immunomodulatory (IMiD) compounds in 
MM.  Following dosing with telaglenastat in mice and rats, there is a dose-dependent 


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suppression of systemic glutaminase activity reflected in an increase in plasma glutamine 
concentration.  Telaglenastat shows additive or synergistic activity in immunocompetent mice 
with the immuno-oncology antibodies anti-Programmed Death Protein-1 (anti-PD-1) and anti-
Programmed Death-Ligand 1 (anti-PD-L1), possibly due to indirect stimulation of T-cell 
proliferation resulting from accumulation of glutamine in the tumor microenvironment.  
The structure of telaglenastat is shown in Figure 2. 
Figure 2 
Structure of Telaglenastat  
 
 Telaglenastat Nonclinical Data 
A complete summary of nonclinical studies with telaglenastat is provided in the current 
telaglenastat Investigator’s Brochure.  A high-level summary of nonclinical studies with 
telaglenastat is provided below. 
Following dosing with telaglenastat in mice and rats, there is a dose-dependent suppression of 
glutaminase activity reflected by an increase in plasma glutamine concentration.  In 
immunocompromised mice bearing human tumors, a significant increase in tumor glutamine 
and a decrease in tumor glutamate and aspartate concentrations are observed.  When 
telaglenastat plasma concentrations of ≥ 0.3 µM are achieved, maximal glutaminase inhibition 
is achieved in tumors.  Twice-daily administration of CB 839 to immunocompromised mice 
bearing breast cancer (TNBC or basal-like), MM, and other tumors using regimens that 
maintain continuous plasma exposure of telaglenastat ≥ 0.3 µM, treatment has been shown to 
result in a significant reduction in tumor growth. 
The PK profile of telaglenastat has been examined in animals.  The terminal half-life (t
½) was 
44, 100, and 66 min in mice, rats, and marmoset monkeys, respectively. 
Good Laboratory Practice (GLP) toxicity studies were conducted in rats and marmoset 
monkeys.  Telaglenastat was administered BID to rats and marmoset monkeys for 13 weeks.  
Severe toxicity was not observed at the maximum feasible doses (limited by solubility and 
volume) in rats or marmoset monkeys using doses up to 500 mg/kg/day or 100 mg/kg/day, 
respectively.  Neither the severely toxic dose in 10% of rats (STD10) nor the highest non-
severely toxic dose (HNSTD) in marmoset monkeys was achieved using these doses.  A GLP 
Ames test for bacterial mutagenicity was negative.   


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The tolerability of telaglenastat has been evaluated in a variety of non-GLP studies.  The most 
extended treatment was conducted in immunocompromised mice, evaluating the nonclinical 
efficacy of telaglenastat in tumor-bearing xenograft studies at doses up to 800 mg/kg/day for 
3 weeks, and at doses up to 400 mg/kg/day for 4 months, each given on a BID schedule.  
Telaglenastat treatment in all species has been well tolerated despite Cmax of > 15 µM CB 839 
with no notable clinical observations or changes in body weight at any dose level or duration.  
 Telaglenastat Clinical Data 
3.1.5.3.1 Overview of Clinical Studies with Telaglenastat 
Telaglenastat is in clinical development with three Phase 1 dose escalation studies, a Phase 1/2 
combination study, three Phase 2 studies, and two single dose healthy volunteer studies (see the 
current CB-839 Investigator’s Brochure) 
3.1.5.3.2 Clinical Pharmacology 
A summary of studies that investigated the PK and PD of telaglenastat is provided in the 
current CB-839 Investigator’s Brochure.  High-level summaries of PK and PD findings are 
provided in the sections that follow.  
3.1.5.3.3 Pharmacokinetics and Drug Metabolism  
In PK studies, the half-life of telaglenastat was approximately 4 hours, and a dose-related 
increase in exposure was observed over doses ranging from 100 to 600 mg, with the 600 mg 
and 800 mg doses being similar due to interpatient variability. In PD studies, robust inhibition 
of glutaminase was demonstrated in platelets at exposures maintained in most patients at 
600 mg and 800 mg inter-dose troughs, with the 800 mg dose in particular showing ≥ 90% 
target inhibition. Patient tumor biopsies also demonstrated robust glutaminase inhibition 
(> 75% for most patients). 
3.1.5.3.4 Pharmacodynamics 
The pharmacodynamic response to telaglenastat was evaluated using an assay that directly 
measures glutaminase activity in platelets, PBMCs, or solid tumor biopsy samples.  
Glutaminase activity in peripheral blood cells (platelets or PBMCs) measured 4 hr after the first 
dose of telaglenastat on Cycle 1 Day 1 was inhibited to an extent that was clearly related to 
telaglenastat exposure measured at the same time point.  In the majority of patients, greater 
than 90% glutaminase inhibition in platelets was observed at plasma telaglenastat levels that 
exceeded 250 ng/mL.  In addition to the peripheral blood pharmacodynamic response, 
glutaminase inhibition of at least 75% was observed in solid tumor biopsies collected on Cycle 
2 Day 1 in early dose cohorts in the monotherapy phase 1 study. 


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Telaglenastat also increased plasma glutamine concentration levels compared to baseline in all 
dose groups by ~1.5-2.0-fold after multiple doses confirming glutaminase inhibition. 
3.1.5.3.5 
Safety and Tolerability of Telaglenastat 
The complete summary of the safety and tolerability of telaglenastat administered as 
monotherapy or in combination with other agents is provided in the current CB-839 
Investigator’s Brochure.  A high-level summary of safety findings is provided in the sections 
that follow. 
3.1.5.3.5.1 Overview of Safety 
The safety and tolerability of telaglenastat, both as a monotherapy and in selected 
combinations, has been studied in three Phase 1 clinical studies (CX-839-001, -002, and -003), 
a Phase 1/2 clinical study (CX-839-004), three Phase 2 studies (CX-839-005, -007, and -008) 
and two healthy volunteer studies (CX-839-006 and -009).  Combination cohorts are ongoing in 
studies CX-839-001, -004, -005, -007, and -008.  As of the cutoff date for the clinical database 
of January 23, 2018, 161 subjects were treated with telaglenastat monotherapy across all of the 
studies, at doses of 100 to 1000 mg orally three times daily (TID) fasted (59 patients) or 600 to 
1000 mg orally BID with food (102 patients).  Fourteen healthy subjects also received single 
600 mg doses of telaglenastat in CX-839-006.  An additional 250 patients have been treated 
with telaglenastat in combination with other agents at doses of 400-800 mg orally BID with 
food.  In the ongoing blinded Phase 2 study CX-839-005, known as ENTRATA, patients are 
being randomized to receive telaglenastat + everolimus or placebo + everolimus; in the ongoing 
blinded Phase 2 study CX-839-008, known as CANTATA, patients are being randomized to 
receive telaglenastat + cabozantinib or placebo + cabozantinib.  The limited amount of blinded 
data available from these studies precludes inclusion at this time.  
Monotherapy telaglenastat has been dosed either on a TID schedule in the fasting state or on a 
BID schedule with food.  All patients on combination therapy have received telaglenastat on 
the BID schedule.  During the dose escalation of telaglenastat monotherapy, two DLT events 
(Grade 3 elevated creatinine, Grade 3/4 elevated liver function tests [LFTs]) were reported for 
the monotherapy, both on the TID schedule.  DLTs reported for combination cohorts have been 
Gr4 neutropenia (400 mg dose on the paclitaxel combination and 400 mg dose on the 
pomalidomide/dexamethasone combination), Grade 3 pruritic rash (400 mg dose on the 
everolimus combination), Grade 3 ALT increased (800 mg dose on the nivolumab 
combination) and Grade 4 platelet count decreased (600 mg dose on the cabozantinib 
combination).  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.  The most frequent telaglenastat-related clinically significant Gr3/4 
toxicity has been reversible elevation in liver function tests (AST, ALT) reported at a frequency 


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of 2.3% in patients receiving BID dosing with food.  A complete summary of safety data is 
provided in the current CB-839 Investigator’s Brochure. 
3.1.5.3.5.2 Treatment-Related Adverse Events in ≥ 5% Patients Dosed BID 
with Food  
This study protocol is investigating treatment in patients with solid tumor indications with 
telaglenastat administered BID with food. Accordingly, TEAEs occurring in at least 5% of 
patients in the solid tumor clinical study CX-839-001 are described below and summarized in 
Table 11. 
Of the 88 patients treated, 72.7% experienced an AE that was considered possibly or probably 
related to CB 839.  The most frequent telaglenastat-related AEs were fatigue, LFT elevations 
(e.g., AST, ALT), gastrointestinal AEs (e.g., nausea, decreased appetite, and vomiting) and 
photophobia.  These AEs were typically mild to moderate in intensity (Grades 1/2), reversible 
and manageable without dose interruption or modification.   
The most frequent Grades 3/4 AEs were elevations in LFTs, including AST, ALT, and alkaline 
phosphatase.  GGT elevations were also noted but are of unclear clinical significance.  Of note, 
the frequency of Grades 3/4 elevations in LFTs was reduced with the BID fed regimen 
(compared to the TID fasted regimen), with only 2 of 88 patients experiencing a treatment-
related Grade 3 AST or ALT elevation.  One Grade 3 AE of anemia was also considered to be 
related to telaglenastat. 


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Table 11 
CX-839-001 Treatment-Related AEs in ≥ 5% patients – BID Fed 
BID Fed - Monotherapy (N = 88) 
MedDRA Preferred Term 
Number (%) of Patients 
All Grades 
≥ Grade 3 
Patients with Any Telaglenastat-Related AE 
64 (72.7) 
3 (3.4) 
Fatigue 
22 (25.0) 
0 
Nausea 
21 (23.9) 
0 
Alanine aminotransferase increased 
14 (15.9) 
2 (2.3) 
Photophobia 
13 (14.8) 
0 
Aspartate aminotransferase increased 
10 (11.4) 
1 (1.1) 
Decreased appetite 
8 (9.1) 
0 
Gamma-glutamyl transferase increased 
7 (8.0) 
2 (2.3) 
Blood alkaline phosphatase increased 
6 (6.8) 
1 (1.1) 
Anaemia 
5 (5.7) 
1 (1.1) 
Vomiting 
5 (5.7) 
0 
BID = twice daily; MedDRA = Medical Dictionary for Regulatory Activities; TEAE=treatment-emergent 
adverse event. 
3.1.5.3.5.3 Expected Adverse Reactions 
Overall, elevated transaminases (AST/ALT) are the only serious adverse drug reactions 
considered expected for regulatory reporting purposes (Table 12) for all subjects exposed to 
telaglenastat (as monotherapy or in any combination).  As of the 23 January 2018, there have 
been a total of 2 subjects with a reported serious event of elevated ALT and AST, 1 subject 
with a reported serious adverse event (SAE) of elevated ALT, and one subject with a reported 
SAE of hepatitis across all patients (monotherapy and combinations) that have received 
telaglenastat (n =411 patients).   
Adverse Reactions are listed below by Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class (SOC), Preferred Term and by frequency.  Frequencies are 
defined as very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥1/1,000 to 
<1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated 
from available data). 


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Table 12 
Telaglenastat: Expected Serious Adverse Reactions 
MedDRA SOC 
Preferred term 
Frequencya 
Toxicity Grade 
Investigations 
Alanine aminotransferase increased 
Very common 
Grade 1-3 
Aspartate aminotransferase increased 
Very common 
Grade 1-3 
Note: Based on data as of 23 January 2018; includes all subjects treated with the current recommended BID dose 
schedule on all telaglenastat studies. 
AE = adverse events; BID = twice daily; MedDRA = Medical Dictionary for Regulatory Activities; SOC = 
system organ class. 
a. Frequency of all AEs regardless of seriousness and causality for treatment population. 
3.1.5.3.5.4 Dose-Limiting Toxicities and Maximum Tolerated Doses 
Two DLTs have been reported for the telaglenastat dosed as a monotherapy and five DLTs 
have been reported for combination regimens. (Instructions regarding dose modifications, 
including management of DLT, are provided in Section 2.2.5) See the current CB-839 
Investigator’s Brochure for complete details.  
3.1.5.3.6 Antitumor Activity Telaglenastat 
Telaglenastat has shown anti-tumor activity Phase 1 clinical studies using single agent 
telaglenastat.  Combinations with standard-of-care agents used to treat RCC, TNBC, NSCLC, 
melanoma, MM, and AML have been evaluated as part of the Phase 1 program.  A full 
summary of the antitumor activity of telaglenastat is provided in the current CB-839 
Investigator’s Brochure. 
 
Talazoparib 
 Characterization of Talazoparib 
Talazoparib is a potent, orally available small molecule PARP inhibitor in development for the 
treatment of a variety of human cancers.  Talazoparib exerts cytotoxic effects via 2 
mechanisms: (1) inhibition of PARP1 and PARP2 catalytic activity, and (2) PARP trapping, a 
process in which PARP protein bound to a PARP inhibitor does not readily dissociate from 
DNA, thereby preventing DNA repair replication, and transcription (Murai 2012) through 
alternative mechanisms, resulting in higher potencies than other PARP inhibitors.  
In vitro pharmacology studies with talazoparib demonstrated potent and selective inhibition of 
PARP1 (IC50 = 0.7 nM) and PARP2 (IC50 = 0.3 nM) catalytic activity in a biochemical assay. 
Robust cytotoxicity following talazoparib treatment was observed in a panel of breast, prostate, 
pancreatic, and colorectal cancer cell lines with defects in deoxyribonucleic acid (DNA) 
damage repair pathways.  Evaluation of PARP trapping in breast and prostate cancer cell lines 
treated with talazoparib resulted in increased trapping in the presence of single-strand break 


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inducing agent methyl methane sulfonate (MMS).  The reduced population growth and 
cytotoxicity observed in the DNA Damage Response assays are consistent with the proposed 
mechanisms of action for talazoparib: inhibition of catalytic activity and PARP trapping.  
In vivo, antitumor efficacy of single agent talazoparib was better than carboplatin in a breast 
cancer patient-derived xenograft (PDX) model when dosed orally QD at 0.3 mg/kg.  Breast 
cancer PDX models (one each with mutated BRCA1 and mutated BRCA2, and 3 models with 
wild type BRCA1/2) evaluated with talazoparib dosed BID at 0.07 or 0.15 mg/kg showed that 
talazoparib elicited the strongest, statistically significant (compared to vehicle), dose dependent 
Tumor Growth Inhibition (TGI) response (100% tumor-free survival [TFS]) in the BRCA1-
mutated PDX model, but also elicited statistically significant TGI responses in the BRCA2-
mutated model and BRCA1/2 wild type models.  While activity was most robust in the BRCA1 
mutated model, talazoparib was also active in the BRCA2 mutant and in the presence of wild 
type BRCA1/2, possibly due to other unknown DDR-related mutations.  
The absorption, distribution, metabolism, and elimination (ADME) of talazoparib have been 
characterized in mice, rats, and dogs, as well as human tissues.  Talazoparib was orally 
bioavailable with low plasma clearance and moderate volume of distribution in rats and dogs. 
Talazoparib was highly bound to plasma proteins in rodent and moderately bound in dog, 
monkey, and human plasma.  Following oral administration of [14C]talazoparib to pigmented 
rats, drug-derived radioequivalents were widespread in most tissues including the bone marrow 
(BM) and were completely eliminated from all tissues by 168 hr, including melanin-containing 
tissues.  In several studies, talazoparib showed negligible brain distribution in mice and rats.  In 
vitro, talazoparib is metabolically stable in liver microsomes and hepatocytes of nonclinical 
species and humans.  In vivo, talazoparib mainly circulates as unchanged drug in rats, dogs and 
humans.  In rats and dogs, the majority of the [14C]talazoparib-derived radioactivity was 
eliminated as unchanged drug in the feces with excretion in the urine as a minor route, 
however, in humans [14C]talazoparib-derived radioactivity was mainly eliminated as unchanged 
drug in the urine, with excretion in the feces as a minor route of elimination.  The nonclinical 
toxicologic profile of talazoparib has been characterized through the conduct of studies 
including repeat-dose toxicity in rat and dog of ≤ 13-week duration, genetic toxicity (in vitro 
and in vivo), embryo-fetal development in rat, and phototoxicity, in accordance with the 
International Council for Harmonisation (ICH) S9 guidelines.  Based on the cumulative 
evaluation of the toxicology profile of talazoparib, the primary talazoparib-related target organ 
findings include effects on the hematolymphopoietic system, the male reproductive system and 
the gastrointestinal system in both rat and dog.  Additional target organ findings observed in rat 
only include findings in the female reproductive system and liver.  Talazoparib is clastogenic in 
vitro in human peripheral blood lymphocytes (HPBLs), in cancer cell lines and in vivo in rat. 
Talazoparib caused frank fetotoxicity in an embryo-fetal development study in rat.  The 
primary nonclinical toxicology profile of talazoparib following oral administration can be 
largely explained by the pharmacological effects of talazoparib on rapidly dividing cells 


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(talazoparib-induced PARP inhibition).  Talazoparib mechanism of action (cytotoxicity) is 
dependent on the inhibition of PARP1/2 enzyme activity (inhibition of catalytic activity) and its 
robust PARP trapping ability at the site of damaged DNA (causing S-phase-induced double-
stranded DNA [dsDNA] break leading to apoptosis and/or necrosis). Evaluation of the 
cumulative toxicological profile of talazoparib suggests that the hematolymphopoietic and 
testes toxicities occur at subtherapeutic clinical exposure margins, while the GI, liver and ovary 
findings occur in rat at higher clinical exposure margins and are potentially mediated by a 
combination of the catalytic activity inhibition and PARP trapping activity.  However, the 
clastogenic potential is considered to be mainly a result of talazoparib-induced inhibition of the 
PARP catalytic activity.  The frank embryo-fetal toxicity observed in pregnant female rat in the 
embryo-fetal development (EFD) study is considered to be a result of both the clastogenic and 
cytotoxic activities of talazoparib.  The nonclinical pharmacologic, PK, and toxicologic 
properties of talazoparib have been thoroughly evaluated and support the use of talazoparib in 
advanced cancer patients. 
 Talazoparib Clinical Data 
3.1.6.2.1 Pharmacokinetics 
The PK of talazoparib as a single agent has been evaluated in a total of 7 clinical studies.  The 
PK of talazoparib was similar in patients with hematological malignancies and patients with 
solid tumors, and no differences were apparent between males and females.  Oral absorption of 
talazoparib was rapid and independent of dose after administration of single or multiple doses. 
A food-effect study showed that food had no clinically meaningful effect on the extent of 
absorption; talazoparib can be administered without regard to food.  The plasma exposure of 
talazoparib is dose proportional in the dose range of 0.025 to 2 mg QD, suggesting linear PK. 
The mean terminal half-life (t½) was approximately 4 days.  Talazoparib accumulated after 
1-mg QD dosing with a median accumulation ratio ranging from 2.33 to 5.15, consistent with 
its t½.  Steady state was reached around 3 weeks after the start of talazoparib dosing. 
Talazoparib undergoes minimal hepatic metabolism in humans.  Renal excretion of unchanged 
talazoparib was the major elimination pathway of talazoparib.  Talazoparib is moderately 
bound to human plasma proteins (74%, in vitro) and is evenly distributed across human blood 
cells and plasma compartments.  In vitro, talazoparib did not significantly interact with any of 
the major cytochrome P450 (CYP) or uridine 5
'-diphospho-glucuronosyltransferase (UGT) 
drug metabolizing enzymes, nor was it an inhibitor of any ATP-binding cassette (ABC) or 
solute carrier (SLC) drug.  Talazoparib is a substrate for P-glycoprotein (P-gp) and breast 
cancer resistance protein (BCRP), and plasma talazoparib concentrations may increase or 
decrease when coadministered with P-gp or BCRP inhibitors or inducers, respectively.  Based 
on the high oral bioavailability observed in rats, dogs, and humans, absorption of talazoparib is 
not limited by these efflux transporters.  Additional ongoing Phase 1 company-sponsored 


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clinical studies are evaluating the PK of talazoparib in patients with renal impairment or hepatic 
impairment, and DDIs of talazoparib with itraconazole and rifampin. 
3.1.6.2.2 
Efficacy 
Efficacy data have been obtained from 3 Sponsor-initiated studies (PRP-001, Studies 673-201, 
and 673-301) evaluating talazoparib in patients with advanced or metastatic breast cancer.  
In the Phase 1 first-in-human study (Study PRP-001 [C3441007]) (de Bono 2017) in patients 
with advanced or recurrent solid tumors, a total of 110 patients were treated at a range of 
talazoparib doses (0.025-1.1 mg/day).  Data from this study demonstrated objective responses 
and/or clinical benefit in patients with breast, ovarian/peritoneal, and pancreatic cancer; small-
cell lung cancer (SCLC); and Ewing sarcoma.  
In an open-label Phase 2 study (Study 673-201, [C3441008, ABRAZO]) (Turner 2017) of 
talazoparib in patients with germline BRCA-mutated locally advanced or metastatic breast 
cancer, 83 patients were treated with talazoparib 1 mg/day across 2 cohorts.  Cohort 1 enrolled 
49 patients (48 treated) who had a partial response (PR) or complete response (CR) to a prior 
platinum-containing regimen for metastatic disease with disease progression > 8 weeks 
following the last dose of platinum.  Cohort 2 enrolled 35 patients who received 3 or more prior 
chemotherapy regimens and no prior platinum therapy for metastatic disease.  Cohort 1 had an 
ORR of 20.8% (95% CI: 10.5, 35.0) including 2 CRs (4.2%).  Cohort 2 had an ORR of 37.1% 
(95% CI: 21.5, 55.1).  Median duration of response (DOR) was 4.9 months (interquartile range 
[IQR]: 2.8, 7.1) in Cohort 1 and 4.2 months (IQR: 3.2, 5.6) in Cohort 2. 
In the pivotal randomized Phase 3 study (Study 673-301, [C3441009, EMBRACA]) 
(Litton 2018) of talazoparib versus physician’s choice treatment [PCT] in patients with 
germline BRCA-mutated human epidermal growth factor receptor 2 [HER2]-negative locally 
advanced or metastatic breast cancer, 431 patients overall were randomized in a 2:1 ratio to 
receive talazoparib 1 mg/day (n = 287) or 1 of 4 PCTs (n = 144).  In this study, talazoparib 
demonstrated significantly prolonged progression-free survival (PFS) by blinded independent 
central review (BICR) assessment when compared to PCT.  Median PFS by BICR in the 
talazoparib arm was 8.6 months (95% CI: 7.2, 9.3) compared to 5.6 month (95% CI: 4.2, 6.7) in 
the PCT arm. 
Talazoparib is currently being evaluated, both as single agent and in combination, in metastatic 
castration-resistant prostate cancer (mCRPC), for the neoadjuvant treatment of germline BRCA 
1/2 mutation patients with early TNBC, ovarian cancer, and SCLC. 


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3.1.6.2.3 
 Safety  
A comprehensive review of talazoparib may be found in the single reference safety document 
(SRSD), which for this study is the talazoparib and the CB-839 Investigator’s Brochures.  
Investigators are to review this document prior to initiating this study.                                                                
A total of 502 patients with solid tumors received 1 mg/day talazoparib through 31 January 
2018  in the Sponsor-initiated Study 673-301 (Phase 3 EMBRACA  pivotal, open-label 
randomized 2-Arm, Multicenter Study of Talazoparib [BMN 673] Versus Physician’s Choice 
in Patients With Germline BRCA Mutations and Locally Advanced and/or Metastatic Breast 
Cancer Who Had Prior Chemotherapy for Metastatic Disease study), Study 673-201 (Phase 2 
ABRAZO  open-label non randomized study in Patients With Germline BRCA Mutations and 
Locally Advanced and/or Metastatic Breast Cancer), Study MDV3800-13 (open label extension 
study), Study PRP-001 (Phase 1 dose escalation study in patients with advanced or recurrent 
solid tumors), and Study MDV3800-14 (Phase 1 Study MDV3800-14: cardiac repolarization 
study in patients with advanced solid tumors).  
The most common (≥ 20%) AEs related to talazoparib 1 mg/day, mostly with Grade 1 or 2 
severity, were anemia (45.8%), fatigue (36.1%), nausea (32.5%), neutropenia (21.9%), and 
alopecia (20.1%).  Grade 3 or 4 drug-related adverse events (AEs) occurring in ≥ 5% of 
patients were related to myelosuppression, namely anemia (34.1%), neutropenia (13.9%), 
thrombocytopenia (10.6%), and platelet count decreased (5.4%).  Most common serious AEs 
(≥ 3 patients) considered related to talazoparib were anemia (4.6%), thrombocytopenia/platelet 
count decreased (2.4), and neutropenia (0.6%). 
A total of 23 of 502 patients had an AE that led to death; of these, only an event of 
veno-occlusive liver disease was assessed by the Investigator as related to study drug. 
AEs leading to treatment discontinuation occurred in 4% of patients receiving talazoparib 
1 mg/day, the most common being anemia (in 3 patients) and increased ALT (in 2 patients). 
Among the 502 patients in the talazoparib 1 mg/day patient population, 63.9% had AEs that led 
to dose reduction and 61.2% had a TEAE that led to dosing interruption, most commonly 
associated with myelosuppression. 
In general, the AEs associated with talazoparib are detectable through routine laboratory and 
clinical monitoring and may be managed with supportive care or dose reductions or 
interruptions. 


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Justification of Doses Used in this Clinical Study 
Telaglenastat will be administered 600 or 800 mg BID; both of these doses were well tolerated 
when administered alone or in combination with paclitaxel, nivolumab, cabozantinib, 
everolimus, or azacitidine in Phase 1 studies.  The maximum dose in this study will be 800 mg 
BID, which is the RP2D of telaglenastat alone and in combination with all of these therapies.  
This dose was selected because, notably, no DLT was reported at this dose level, and the 
combination regimen was well tolerated with no MTD determined for telaglenastat alone or 
with other therapies.  In total, the 800 mg dose of telaglenastat has been administered with good 
tolerability as monotherapy to 22 patients with a variety of solid tumors and to an additional 
25 patients in combination therapy with SOC agents (everolimus, paclitaxel, nivolumab and 
azacitidine).  As noted above, in PK studies, exposures at the 800 mg RP2D and the 600 mg 
dose were similar with wide interpatient variability.  In pharmacodynamic studies in platelets, 
robust inhibition of glutaminase was demonstrated at telaglenastat inter-dose trough levels 
maintained in most patients at doses of 600 mg and 800 mg.  However, all patients treated at 
the 800 mg dose demonstrated ≥ 90% target inhibition in platelets whereas approximately 20% 
of patients treated at the 600 mg dose level showed target inhibition less than 90%.  In 
aggregate, these data support the benefit:risk ratio of the 800 mg BID dose level.  
The starting dose of talazoparib of 1 mg taken orally once daily (with or without food) is based 
on the approved dose and schedule.  
 General Study Procedures 
 
Informed Consent  
 Informed Consent Process 
The Investigator will provide for the protection of the patients by following all applicable 
regulations.  These regulations are available upon request from the Sponsor.  The Informed 
Consent form (ICF) used during the informed consent process must be reviewed by the Sponsor 
and approved by the Institutional Review Board/independent ethics committee (IRB/IEC). 
Before any procedures specified in the protocol are performed, a patient must: 
• Be informed of all pertinent aspects of the study and all elements of informed consent 
• Be given time to ask questions and time to consider the decision to participate 
• Voluntarily agree to participate in the study 
• Sign and date an IRB/IEC approved Informed Consent Form 
Study personnel must obtain documented consent from each potential patient prior to entering 
in a clinical study.  Consent must be documented by obtaining the dated signature of both the 


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patient and the person conducting the consent discussion on the consent form.  If local law does 
not allow written consent, then oral consent, attested to by the dated signature of an impartial 
witness (someone not involved with the conduct of the study), is the required alternative.  
If the patient is illiterate, an impartial witness should be present during the entire informed 
consent reading and discussion.  Afterward, the patient should sign and date the informed 
consent, if capable.  The impartial witness should also sign and date the informed consent along 
with the individual who read and discussed the informed consent (i.e., study staff personnel).  If 
the patient is legally incompetent (i.e., mentally incapacitated), the written consent of a parent, 
legal guardian or legal representative must be obtained.  Depending on local law or review 
committee requirements, such consent may also need to be signed by an impartial witness. 
The information from the consent form should be translated and communicated to the patient in 
language understandable to the patient.  When the study patient population includes non-
English speaking people, an accurately translated consent form should be provided with a 
written statement by the translator (whether the translator is the Investigator, the Clinical 
Monitor, or a professional translator), indicating that the consent form is an accurate translation 
of the accompanying English version. 
A copy of the signed and dated consent form should be given to the patient before participation 
in the study.  Patients may undergo study screening tests prior to giving written informed 
consent if these tests are considered part of standard care.  The initial informed consent 
form and any subsequent revised written informed consent form, and written information must 
receive the IRB/IEC’s approval/favorable opinion in advance of use.  The patient or his/her 
legally acceptable representative should be informed in a timely manner if new information 
becomes available that may be relevant to the patient’s willingness to continue participation in 
the study. The communication of this information should be documented. 
 
Screen Failures 
Patients who sign an informed consent form and who are not assigned to a treatment or do not 
receive study treatment (telaglenastat or talazoparib) are defined as screen failures.  For all 
screen failures, the following information will be captured in the electronic data capture (EDC) 
system: screening number, patient demographics, and reason(s) for screen failure into the EDC 
system.    
A patient who has failed screen may be rescreened as a new patient (with new patient 
identification number assigned) after obtaining written reconsent: all screening procedures 
should be performed if applicable. The Sponsor should be notified and asked to provide 
approval, and if given, determine the screening procedures needed to be performed. 


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Methods of Treatment Assignment 
Patients will be assigned to treatment based on tumor type and study stage (Part 1, Dose 
Escalation, or Part 2, Cohort Expansion).  
 
Dispensation of Study Treatment and Returned Study Treatment 
Study treatment will be dispensed at the study visits summarized in Table 1, Dose Escalation, 
and Table 2, Cohort Expansion.  Returned study treatment should not be re-dispensed to the 
study patients.   
 
Concomitant Treatment 
Concomitant treatment is permitted if the medication is not expected to interfere with the 
evaluation of safety or efficacy of the study drugs and it is not an anti-cancer therapy.  During 
the study, if the use of any concomitant treatment becomes necessary (e.g., for treatment of an 
AE), the treatment must be recorded on the appropriate eCRF, including the reason for 
treatment, name of the drug, dosage, route, and start and stop dates of administration. 
Non-protocol systemic anti-cancer treatment, surgical resection of lesions, use of 
investigational therapeutic agents other than the study drugs, and palliative radiation to 
non-bone tumors are NOT permitted while the patient is on study.  In general, palliative 
(limited field) radiation for bone metastasis pain should not be performed while on study.  If 
palliative radiation to a bone lesion is deemed clinically unavoidable for symptoms that in the 
opinion of the Investigator are not due to progressive disease, the Investigator must seek 
Sponsor approval prior to the procedure.  Note that these patients may be considered 
unevaluable and assigned a censoring date or progression date. 
 Telaglenastat: Potential Drug-Drug Interactions 
Telaglenastat is metabolized by human hepatocytes primarily through amide hydrolysis.  
Telaglenastat does not appear to induce CYP drug-metabolizing enzymes and only weakly 
inhibits CYP2C9 (~40-50% inhibition at 5µM) in vitro.  Although telaglenastat is not expected 
to inhibit CYP2C9 at the exposure levels planned, caution is warranted when administering 
telaglenastat 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 Attachment 6. 
Preliminary PK data generated in single agent Phase 1 studies indicate that concomitant use of 
proton pump inhibitors (PPIs) may reduce absorption of telaglenastat, resulting in decreased 
systemic exposure.  Discontinuation of PPIs is required for patients on study.  Alternative 
antacids such as H2 receptor blockers (e.g., ranitidine, famotidine) and buffering agents (e.g., 


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sodium bicarbonate, calcium carbonate, and sucralfate) may be substituted for PPIs. 
Telaglenastat should be taken at least 2 hours before antacid therapy and two hours after 
buffering agents or 10 hours after H2 receptor blocking agents.    
 Talazoparib: Potential Drug-Drug Interactions 
Talazoparib is a P-gp/BCRP substrate; therefore, strong P-gp inhibitors should be avoided 
during concomitant treatment with talazoparib.  Strong P-gp inhibitors are defined as the P-gp 
inhibitors that result in ≥ 2-fold increase in the exposure of an in vivo probe P-gp substrate 
according to the University of Washington Drug-Drug Interaction database 
(https://www.druginteractioninfo.org/).  A list of P-gp inhibitors and inducers and BCRP 
inhibitors is provided in Attachment 7. 
 
Measurements of Treatment Compliance 
At each clinic visit, patients will be asked to return any unused telaglenastat tablets and 
talazoparib capsules and will be questioned about their compliance.  The number of remaining 
tablets and capsules will be recorded in the drug accountability log.  Significant noncompliance 
(missing > 60% of the study drug for reasons other than documented AE) must be reported to 
the monitor. 
 
Study Periods and Specific Procedures  
The study consists of three periods: Screening, Treatment, and End-of Treatment 
(EOT)/Follow-up.  The procedures and assessments during these periods are detailed in 
Table 1, Dose Escalation, and Table 2, Cohort Expansion. 
Procedures (assessments and treatments) should be performed as close to the scheduled time as 
possible and at the study center where the patient is treated.  The exact time at which a 
procedure is performed must be recorded in the patient’s study records or appropriate 
worksheet (if applicable).  Any nonscheduled procedures required for urgent evaluation of 
safety concerns take precedence over all routine scheduled procedures. 
Blood collections for safety evaluation take priority over other procedures.  Whenever possible, 
blood samples should be obtained by fresh peripheral venipuncture.  If a patient does not have 
peripheral access, the sample may be collected from a central catheter immediately after an 
initial withdrawal of at least 10 mL of blood; or preferably, after a series of other blood sample 
collections from the central catheter. 
PK blood sampling takes priority after blood sampling for safety evaluations.  The exact days 
and times at which PK sampling are performed must be recorded on the CRF.  The patient will 


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be assessed for adverse experiences per Table 1, Dose Escalation, and Table 2, Cohort 
Expansion, and at all unscheduled visits. 
 Screening (Days -28 to 1) 
To determine eligibility, patients will undergo required screening evaluations as outlined in 
Table 1, Dose Escalation, and Table 2, Cohort Expansion.  All previous cancer treatments, 
including systemic therapies, radiation and/or surgical procedures, should be recorded on the 
patients’ electronic case report forms (eCRF).  Patients must meet all inclusion and none of the 
exclusion criteria to be enrolled in the study. 
3.2.7.1.1 Screening Evaluation 
An IRB/IEC-approved ICF must be signed and dated before any study-specific (i.e., non-
standard of care) screening procedures are performed.  Procedures performed for standard of 
care before consent but within the screening window also may be used for screening purposes. 
The screening assessments presented below must be performed within 28 days (note exception 
of screening pregnancy test) before study drug administration on C1D1 and are also listed in 
Table 1, Dose Escalation, and Table 2, Cohort Expansion.  Note, screening assessments done 
within 3 days of C1D1 do not need to be repeated at the C1D1 visit.  
• Demographic information including date of birth, sex, race, and ethnic origin  
• Medical history including review of prior cancer treatments, procedures, and surgeries 
• Review of concomitant medications 
• ECOG performance status (Attachment 2) 
• Complete physical examination including weight and height 
• Vital signs  
• Standard 12-lead ECG with corrected QT interval by Fridericia’s Formula (QTcF) 
• Urinalysis and coagulation: these assessments should be repeated periodically during 
the course of the study if it is clinical indicated  
• Clinical laboratory evaluation (serum chemistry, and hematology) (Attachment 4) 
• Serum or urine pregnancy test.  This is only required for females of child-bearing 
potential and must be negative within 7 days prior to C1D1. 
• Radiographic evaluation of tumor burden comprising diagnostic quality CT with 
intravenous contrast or MRI with contrast that is appropriate for RECIST 1.1 
assessment (Attachment 5).  For patients who cannot receive intravenous CT contrast, 
non-contrast CT of the chest with contrast enhanced MRI of the abdomen and pelvis is 


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acceptable.  Scans performed within 28 days prior to C1D1 will be accepted and do not 
need to be repeated. 
• For Part 2, Cohort Expansion patients: Fresh tumor biopsy is mandatory for patients in 
dose expansion cohorts if archival tissue not available. 
3.2.7.1.2 Definition of Enrolled Patient 
A consented patient meeting all inclusion criteria and none of the exclusion criteria will be 
considered an eligible patient and is considered enrolled once the first dose of any study drug is 
administered.   
 Treatment Period (Day 1 to End of Study Treatment) 
The complete list of schedules and procedures, including administration of study treatment, 
please refer to Table 1, Dose escalation, and Table 2, Cohort Expansion. 
While the patient is receiving study treatment, the patient’s clinical status should be evaluated 
at each clinic visit to confirm that the patient is suitable for continuing study treatment and to 
make timely decisions regarding the interruption or restarting of study treatment.  If the study 
treatment is held due to AEs, Investigators should perform additional safety assessments as 
clinically indicated.  
 End-of Treatment/Follow-Up Period 
Perform the procedures detailed in the “End of Treatment/Follow-up Period” column in 
Table 1, Dose Escalation, and Table 2, Cohort Expansion. 
 
Discontinuation of Study Treatment 
 Criteria for Discontinuation of Study Treatment 
The reasons a patient may be discontinued from study treatment include, but are not limited to, 
the following: 
• Intolerable or unacceptable AEs  
• Disease progression 
• Patient request, including withdrawal of consent by patient 
• Investigator decision 
• Protocol violation 
• Patient noncompliance 


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• Termination of the study by the Sponsor (see Section 4.7) 
In unusual cases (e.g., a patient is clearly experiencing clinical benefit despite assessments to 
the  contrary and the potential benefit of continuing study medication outweighs the potential 
risks), extension of study medication may be considered after discussion with medical monitor. 
 Procedures for Patients Discontinued from Study Treatment 
If a patient is discontinued from study treatment, the Investigator will notify the Sponsor and 
perform all End-of-Treatment and follow up procedures as indicated in Table 1, Dose 
Escalation, and Table 2, Cohort Expansion, as soon as possible after discontinuation of study 
medication.  Note that cohort expansion patients who discontinue study medication for reasons 
other than progressive disease or death should be followed by imaging per protocol until 
progressive disease, death, initiation of a new anti-cancer therapy, or withdrawal of consent 
for study follow-up.   
 
Tumor Assessments 
Radiographic response and disease progression will be determined by using RECIST version 
1.1 and should employ diagnostic quality CT with intravenous contrast or MRI scans (see 
Attachment 5 for methods of assessment discussion of CT and MRI).   
Radiographic tumor assessments will include Chest/Abdomen/Pelvis (CAP).  Diagnostic-
quality CT (or MRI) of CAP with intravenous contrast will be performed in all patients at 
screening (within 28 days prior to C1D1), every 8 weeks (±5 days) from C1D1 for the first 12 
cycles, and every 12 weeks (± 7 days) beyond 12 cycles on study (Table 1, Dose Escalation, 
and Table 2, Cohort Expansion,). For patients deemed intolerant of intravenous CT contrast, a 
non-contrast CT of the chest may be obtained along with a contrast-enhanced MRI of the 
abdomen and pelvis.  For tumor and tissue resolution, a contrast-enhanced MRI of the abdomen 
and pelvis is preferred over a non-contrast CT of the abdomen and pelvis in this context.  
To ensure image consistency, the same imaging modality and acquisition protocols used at 
screening should be used for subsequent tumor assessments.   
Investigators are encouraged, if any doubt or ambiguities exist about radiographic progression, 
to continue study therapy if the patient is tolerating treatment, and repeat radiographic studies 
at the next scheduled time, and delay determination of progression until the findings indicating 
radiographic progression are unequivocal.  


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 Tumor Biopsies (Part 2, Cohort Expansion Patients Only) 
Archival tumor tissue samples will be provided from all cohort expansion patients.  Fresh 
tumor biopsy is mandatory if archival tissue is not available.  Archival samples should be 
collected and shipped according to instructions provided in the laboratory manual.  Archival 
tissue blocks or slides freshly cut from those blocks are strongly preferred, due to the concern 
of tissue stability after exposure.  Tissues collected from recent time points before enrollment is 
optimal because it more accurately reflects the current state of the tumor/microenvironment at 
the time of study entry.   
 Pharmacokinetics  
Pharmacokinetic samples will be collected from all patients (see Table 3 for the schedule of PK 
sampling times) and will be used to measure concentrations of telaglenastat and talazoparib.    
The actual time of collection must be noted in the source documents and eCRFs.  In the event 
of a delay in dosing on PK days, the PK sample should be collected at a later study visit (See 
Table 3, table note 2).   
 Biomarkers 
Whole blood will be collected during the screening period (see Table 1, Dose Escalation, and 
Table 2, Cohort Expansion) to identify potential biomarkers associated with response and/ or 
resistance to telaglenastat in combination with talazoparib.  
 Safety Assessments 
 
Adverse Events and Serious Adverse Events 
All AEs (including SAEs) occurring from the time the patient initiates treatment with the study 
regimen up to 28 days after the last dose of study treatment or until the start a new treatment, 
whichever occurs first, must be recorded. Definitions of and reporting procedures for AEs, 
including SAEs, are provided in Attachment 3. 
 
Pregnancy Reporting 
Pregnancy, although not considered an SAE, must be recorded, reported and follow up as 
indicated for an SAE.  
 Exposure to Investigational Product(s) During Pregnancy  
Patients should not become pregnant during the study.  If a patient becomes pregnant, study 
drug(s) must be discontinued immediately.  The investigator must report the pregnancy to 


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Sponsor or designated representative, within 24 hours of the study site staff becoming aware of 
the pregnancy.  The outcome of pregnancy (eg, spontaneous abortion, live birth, still-birth, 
congenital anomalies, and birth defects) must be reported within 24 hours.  If the pregnancy 
results in a live birth, a post-delivery follow-up must be reported to Calithera within 24 hours.  
Both maternal and paternal investigational product exposures are collected.  Pregnancy 
exposure information is collected even if the investigational product(s) is not contraindicated 
for us in pregnancy. 
 Pregnancy Reporting Procedures 
If a female subject becomes pregnant during the study, BOTH study drugs must be 
discontinued immediately and she must be followed through the pregnancy and delivery.  The 
investigator should report the event to the sponsor immediately (see contact information on the 
title page of this protocol.) and complete the Pregnancy Report Form.  The expected date of 
delivery or expected date of the end of the pregnancy should be included in this information.  
The investigator is also encouraged to submit to the Sponsor’s designated Safety CRO 
(PrimeVigilance) trimester follow up reports during the pregnancy and report the outcome.  
Details of the pregnancy, deliver and health of the infant should be recorded on the Pregnancy 
Report Form.   
The follow outcomes of pregnancy fall under the criteria for serious adverse events and should 
be reported as such:  delivery complications prolonging the hospitalization, spontaneous 
abortion, still-birth, death of newborn baby, congenital anomaly, and anomaly in a miscarried 
fetus. 
 
Physical Examination 
Complete physical examinations will be performed by a licensed physician (or physician’s 
assistant or nurse practitioner) at Screening and End of Treatment.  Symptom-directed physical 
examinations are required as clinically indicated.  
The ECOG performance status will be assessed during screening to determine the eligibility.   
 
Vital Signs 
Vital signs (blood pressure, respiratory rate, pulse rate, and temperature) will be obtained in the 
sitting position.   
 
Electrocardiograms 
Patients should rest in the supine or semi-recumbent position for at least 5 min before the 
12-lead ECG recording is started.  ECG recordings must be performed using a standard, 


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high-quality, high-fidelity electrocardiograph machine equipped with computer-based interval 
measurements.  ECGs may be performed periodically as clinically necessary.   
When performed, the ECG must be reviewed by a qualified physician (or qualified physician’s 
assistant or nurse practitioner) and any clinically important finding recorded on the appropriate 
eCRF.  ECG results will include heart rate (HR), R-R interval (RR), PR interval, QRS interval, 
QT interval, and QTcF interval.  The QT interval will be corrected for respiratory rate 
according to the following formula: 
Fridericia’s formula:  QTcF = QT/RR0.33 
 
Laboratory Assessments 
Laboratory evaluations will be performed as noted in Table 1, Dose Escalation, and Table 2, 
Cohort Expansion.  The laboratory tests are listed in Attachment 4.  All laboratory assessments 
will be completed by the sites’ local laboratory and results entered in the EDC.  
To confirm eligibility, urinalysis and coagulation, will be performed at screening.  These 
assessments should be repeated periodically during the course of the study if it is clinical 
indicated.   
Any clinically significant results should be entered in the EDC.  
 Demographics and Patient Histories (Medical and Cancer Histories) 
Demographics at screening will include date of birth (or age, if date of birth is not allowed to 
be collected by local regulations), patient initials, race and ethnicity. Additional information 
such as medical and cancer history, surgical history, prior radiation history, and prior systemic 
anti-cancer treatment history will also be collected.  
 Measures to Minimize/Avoid Bias 
Each patient will be assigned a unique number and will keep this number for the duration of the 
study.  Patient numbers will not be reassigned or reused for any reason.  Patients should be 
identified to the Sponsor only by their assigned number, initials, date of birth, and sex.  The 
Investigator must maintain a patient master log.  
 Statistical Analysis 
 
General Statistical Considerations 
Simon 2-stage designs will be employed to analyze the Phase 2, Cohort Expansion results.  
Otherwise descriptive statistics will be used to summarize the data.  Summary statistics for 


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continuous variables will include the mean, standard deviation, median, and range 
(minimum/maximum).  Categorical variables will be presented by as frequency counts and 
percentages. Time-to-event data will be summarized by Kaplan-Meier plots and median 
estimates. 
 
Analysis Populations        
The analysis populations for the study are as follows: 
• DLT-Evaluable Population: All patients enrolled to Part 1, Dose Escalation Part of 
the study with the following exclusions: 
o Patients who withdraw or are withdrawn from the study prior to completing 
the DLT assessment for any reason other than a DLT. 
o Patients who do not receive at least 75% the assigned doses of both telaglenastat and 
talazoparib, i.e. 42 doses of telaglenastat and 21 doses of talazoparib, in the first 28-
day treatment cycle for any reason other than a DLT. 
• Efficacy Evaluable Population: All enrolled patients who have measurable disease at 
baseline and receive at least one dose of study drug and complete at least one post 
baseline scan.  Patients who discontinued treatment for study-drug related toxicity or for 
disease-related death also are included in the efficacy evaluable population.. 
• Safety Analysis Population:  All enrolled patients who receive any amount of 
telaglenastat and/or talazoparib treatment. AE and laboratory data from all patients in 
the safety population will be evaluated for safety. Patients from dose escalation will be 
combined with patients from cohort expansion for safety evaluation. Data will be 
tabulated to examine the frequency, organ systems affected, and relationship to study 
drugs. No formal interim analysis is planned; however, safety data will be examined on 
an ongoing basis to ensure safety of the study patients and compliance with the trial 
dose escalation and expansion rules. Treatment-emergent adverse events (TEAEs) will 
be summarized by mapped term, appropriate thesaurus level, NCI CTCAE grade.  In 
addition, serious adverse events, severe adverse events (Grade ≥ 3), and adverse events 
leading to study drug discontinuation or interruption will be summarized.  Multiple 
occurrences of the same event will be counted once at the maximum grade.  
 
 
Expansion Cohorts Efficacy Analysis 
 Simon 2-stage 
All patients in the Efficacy Evaluable Population will be included in the Efficacy Analysis.  


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Expansion cohorts will employ a Simon 2-stage design to evaluate anti-tumor activity of the 
combination while minimizing the number of treated patients if the regimen is inactive 
(Table 13).   
The glutaminase inhibitor telaglenastat has demonstrated in multiple studies that clinical 
benefit via prolongation of disease control may occur irrespective of objective response.  In 
order not to miss clinical benefit due to disease control in late line cancer patients, the primary 
efficacy endpoint for expansion cohorts is a composite endpoint of responders plus disease 
controlled patients termed clinical benefit rate (CBR) for this protocol. CBR is defined as SD 
per RECIST 1.1 for at least 2 consecutive post-baseline scans per protocol (every 8 weeks +/- 5 
days, minimum 102 days from C1D1) or a best response of CR/PR per RECIST 1.1 at any 
time. 
For each of the mRCC and TNBC expansion cohorts, the null hypothesis that the true CBR is 
< 30% [H0] will be tested against a one-sided alternative that the CBR is ≥ 60% [H1].  In the 
first stage, 15 patients will be accrued.  If 4 or fewer patients achieve CBR in these 15 patients, 
accrual to the applicable cohort will be stopped and the treatment regimen will be deemed not 
of interest for further pursuit in the cohort.  Otherwise, 10 additional patients will be accrued to 
stage 2 for a total of 25 patients.  The null hypothesis will be rejected and the treatment 
regimen deemed of interest for further investigation if 12 or more CBRs are observed in 25 
patients.  This design has a type I error rate of 0.042 when the true CBR rate is 30% and a 
power of 0.92 when the true CBR rate is 60%.    
For the CRC expansion cohort, the null hypothesis that the true CBR is < 25% [H0] will be 
tested against a one-sided alternative that the CBR is ≥ 50% [H1].  In the first stage, 13 patients 
will be accrued.  If 3 or fewer patients achieve CBR in these 13 patients, accrual to the cohort 
will be stopped and the treatment regimen deemed not of interest for further pursuit for CRC.  
Otherwise, 17 additional patients will be accrued for a total of 30 patients.  The null hypothesis 
will be rejected and the treatment regimen deemed of interest for further pursuit if 12 or more 
CBRs are observed in 30 patients.  This design has a type I error rate of 0.047 when the true 
CBR is 25% and a power of 0.88 when the true CBR is 50%.    
Table 13 
Simon 2-Stage Design 
Cohort 
H0 
CBR 4 mo 
(%) 
H1 
CBR 4 mo (%) 
Actual α - 
one sided 
Actual 
Power  
n1 for 
Stage 1 
(r1) 
n2 for 
Stage 2 
Total n 
(r2) 
mRCC 
30% 
60% 
0.044 
0.92 
15 (4) 
10 
25 (12) 
TNBC 
30% 
60% 
0.044 
0.92 
15 (4) 
10 
25 (12) 
CRC 
25% 
50% 
0.047 
0.88 
13 (3) 
17 
30 (12) 
Notes:  


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Cohort 
H0 
CBR 4 mo 
(%) 
H1 
CBR 4 mo (%) 
Actual α - 
one sided 
Actual 
Power  
n1 for 
Stage 1 
(r1) 
n2 for 
Stage 2 
Total n 
(r2) 
H0 (null hypothesis) is the outcome of no interest. 
H1 (alternative hypothesis) is the outcome of interest  
n1 is the number of subjects accrued during Stage 1. 
n2 is the number of subjects accrued during Stage 2, if opened. 
If ≤ r1 responses are observed during Stage 1, the trial study is stopped for futility; otherwise, Stage 2 will be opened. 
If ≥ r2 two-stage total responses are observed by the end of Stage 2, then further investigation is warranted. 
In addition, the overall response rate (i.e. CR or PR), ≥4-week confirmed overall response rate, and progression free 
survival will be descriptively summarized for each cohort. Progression free survival is defined as time from initiation of 
study therapy to the earlier date of documented disease progression or death.  Details of the PFS definition will be 
included in Statistical Analysis Plan (SAP) document. Kaplan-Meir plots will be presented for PFS along with the 
estimated median PFS. 
CR = complete response; PFS = progression-free survival; PR = partial response; SAP = Statistical Analysis Plan. 
 Efficacy Endpoints 
 Clinical Benefit Rate (CBR)   
CBR is defined as SD per RECIST 1.1 for at least 2 consecutive post-baseline scans per 
protocol (every 8 weeks +/- 5 days, minimum 102 days from C1D1) or a best response of 
CR/PR per RECIST 1.1 at any time.    
 Objective Response Rate (ORR) 
Objective Response Rate (ORR) is defined as the proportion of patients who had an objective 
response per RECIST 1.1. An objective response is defined as either complete response (CR) or 
partial response (PR), as determined by the investigator with use of RECIST v1.1.  The efficacy 
evaluable ORR population will be the same as CBR.  An estimate of the ORR and its 95% CI 
will be calculated with the Clopper-Pearson method.   
 Progression Free Survival (PFS) 
Progression free survival (PFS) is defined as the time from randomization to the first 
occurrence of disease progression as determined by the investigator using RECIST v1.1 or 
death from any cause, whichever occurs first. Patients who have not experienced disease 
progression or death at the time of analysis will be censored at the time of the last tumor 
assessment. The efficacy evaluable PFS population is defined in the Analysis Population 
Section.  Kaplan-Meier methodology will be used to estimate median PFS and construct 


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survival curves for the visual description. The Brookmeyer-Crowley methodology will be used 
to construct the 95% CI for the median PFS.   
 
 
Safety Analysis   
Safety analysis will be performed for both parts of the study, i.e. Dose Escalation Part and  
Cohort Expansion Part. Analysis will be performed by dose group tested for the Dose 
Escalation Part and by tumor cohort (ccRCC, TNBC, CRC) for the Expansion Cohort Part.   
 Treatment-Emergent Adverse Events  
Adverse event (AE) descriptions will be mapped to system organ classes (SOC) and preferred 
terms (PT) using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-
Emergent Adverse Events (TEAEs) are defined as AEs with onset on or after the date of first 
study treatment or procedure, or pre-existing events that worsened after the first study treatment 
or procedure.  
For any reported TEAE, patient incidence and proportion will be tabulated by SOC and PT 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) severity 
grade; each patient will be counted only once according to the highest CTCAE severity grade 
reported.  Separate tables will be presented for (a) all reported events, (b) telaglenastat related 
events, (c) Talazoparib related events.  The same tables will also be presented for serious 
adverse events (SAEs).  In additional, dose limiting toxicities (DLTs) will be reported as a by 
patient listing for each telaglenastat and talazoparib combination tested. 
 Laboratory Measurements 
Laboratory measurements, including serum chemistry, hematology, urinalysis and coagulation 
will be summarized as mean, standard deviation, median, minimum and maximum for observed 
values at each scheduled assessment and for changes from baseline at each post-baseline 
assessment visit. Where applicable, parameter values will be mapped to a toxicity grade based 
on the CTCAE.  Shift tables will be presented for shifts from baseline grade to worst post-
baseline grade. 
 Vital Signs 
Vital sign measurements (temperature, pulse, respiratory rate, resting systolic and diastolic 
blood pressures) will be summarized similarly as for laboratory measurements with the 
exception that shift tables will not be constructed. All efficacy-evaluable patients will be 
included in the analysis. 


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 Identity, Administration, Preparation, Handling, Storage, and 
Accountability of Study Treatments 
 
Telaglenastat  
Details regarding the identity, formulation, administration, preparation, and storage of 
telaglenastat are provided in Table 14. 
Table 14 
Telaglenastat: Identity, Administration, Storage, Handling, Storage, 
and Accountability 
Details 
Telaglenastat 
Product name or identifier 
Telaglenastat 
Chemical name 
2-(pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl) 
acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide 
hydrochloride 
Drug substance 
HCl salt of telaglenastat 
Dosage formulation 
200 mg tablets 
Route of administration 
Oral  
Telaglenastat will be administered with food, immediately 
following a meal, twice daily 12 hr (± 2 hr) apart.   
Vomited doses 
 
Patients should not make up vomited doses; dosing should 
resume at the next scheduled dosing unless otherwise 
instructed. 
Missed doses 
 
In the event a patient forgets a dose, it may be made up if it is 
not more than 6 hours past the scheduled administration time 
for the missed dose. 
Preparation  
Not applicable 
Storage  
Clinical Site: telaglenastat HCl Tablets will be stored as 
indicated on the study drug label; i.e., room temperature, 
between 15 - 30ºC (59 - 86ºF). 
Home: Patients will be instructed to store telaglenastat at the 
recommended storage conditions noted on the label, out of 
the reach of children or other cohabitants. 
Handling 
Precautions regarding appropriate secure storage and 
handling must be used by healthcare professionals, including 
personal protective clothing, disposable gloves, and 
equipment. 
Stability 
Stable for at least 24 mo 
Packaging and labelling 
Telaglenastat HCl Tablets (200 mg) are manufactured, 
packaged, and labeled according to current Good 


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Details 
Telaglenastat 
Manufacturing Practices (GMP).  For additional information, 
please refer to the Pharmacy Manual. 
Accountability, Reconciliation, and 
Return 
On Day 1 of Cycle 1, patients will be provided with enough 
telaglenastat tablets to last until their next clinic visit.  
Patients will return on Day 1 of each cycle thereafter and will 
receive enough supply until the next visit.  The number of 
telaglenastat tablets remaining from the previous visit will be 
counted and recorded. 
The Investigator or designee must maintain an accurate 
record of dispensing the study drug in a Drug Accountability 
Log, a copy of which must be given to the Sponsor at the end 
of the study.  The Drug Accountability Log will record the 
study drugs received, dosages prepared, time prepared, doses 
dispensed, and doses and/ or bottles destroyed.  The Drug 
Accountability Log will be reviewed by the field monitor 
during site visits and at the completion of the study. 
If evidence of damage or tampering is observed, notify the 
Sponsor and return the questionable telaglenastat shipment 
with the appropriate form to the contract distribution center.   
Returned/ partially used, and unused telaglenastat test article 
may also be destroyed and documented at the investigative 
site in accordance with approved site/institution standard 
operating procedures.  If the investigative site does not have 
an approved standard operating procedure, investigative 
product may be returned to the distribution center for 
destruction. 
Additional details 
See the Pharmacy Binder. 


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Talazoparib 
Details regarding the identity, drug substance, drug product, administration, preparation, 
handling, and storage of talazoparib are provided in Table 15. 
Table 15 
Talazoparib: Identity, Administration, Storage, Handling, Storage, and 
Accountability 
Details 
Talazoparib 
Product name or identifier 
Talazoparib (also known as MDV3800, BMN 673) 
Chemical name 
(8S,9R) 5-fluoro-8-(4-fluorophenyl)-2,7,8,9-tetrahydro-9-(1-
methyl-1H-1,2,4-triazol-5-yl)-3H-pyrido[4,3,2-de]phthalazin-3-
one (provided as the 4 methylbenzenesulfonate [tosylate] salt). 
Drug substance 
Formulated with silicified microcrystalline cellulose 
Dosage formulation 
Powder-filled, hard gelatin capsule in strengths of 1 mg and 
0.25 mg , with capsules for each dose strength provided in 
specific colors 
Route of administration 
Oral 
Talazoparib will be administered as a 1 mg once-daily starting 
dose, to be taken at the same time as one of the doses of 
telaglenastat, at approximately the same time each day.  
Patients should self-administer talazoparib orally once daily, 
with or without food.  The capsules should be swallowed whole 
with a glass of water and should not be chewed, dissolved, or 
opened.  
Vomited doses 
Patients should not make up vomited doses; dosing should 
resume on the next calendar day unless otherwise instructed. 
Missed doses 
 
In the event a patient forgets a dose, it may be made up if it is 
not more than 2 hours past the scheduled administration time 
for the missed dose. 
Preparation 
Not applicable. 
Storage 
Talazoparib capsules should be stored at room temperature 
(between temperature 15º to 30ºC or 59º to 86ºF).  Capsules 
should be protected from light and not frozen. 
Handling 
Talazoparib is considered a cytotoxic and clastogenic agent; 
precautions regarding appropriate secure storage and handling 
must be used by healthcare professionals, including personal 
protective clothing, disposable gloves, and equipment (Godin 
2011). Patients should be advised that oral anticancer agents are 
toxic substances and that other caregivers should always use 
gloves when handling the capsules. 
 


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Accountability, Reconciliation, 
and Return 
On Day 1 of Cycle 1, patients will be provided with enough 
talazoparib capsules to last until their next clinic visit.  Patients 
will return on Day 1 of each cycle thereafter and will receive 
enough supply until the next visit.  The number of talazoparib 
capsules remaining from the previous visit will be counted and 
recorded. 
The Investigator or designee must maintain an accurate record 
of dispensing the study drug in a Drug Accountability Log, a 
copy of which must be given to the Sponsor at the end of the 
study.  The Drug Accountability Log will record the study 
drugs received, dosages prepared, time prepared, doses 
dispensed, and doses and/ or bottles destroyed.  The Drug 
Accountability Log will be reviewed by the field monitor 
during site visits and at the completion of the study. 
If evidence of damage or tampering is observed, notify the 
Sponsor and return the questionable talazoparib shipment with 
the appropriate form to the contract distribution center.   
Returned/partially used, and unused talazoparib may also be 
destroyed and documented at the investigative site in 
accordance with approved site/institution standard operating 
procedures.  If the investigative site does not have an approved 
standard operating procedure, investigative product may be 
returned to the distribution center for destruction. 
Additional details 
See the Pharmacy Binder. 
   


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4.0 REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• The protocol, protocol amendments, ICF, CB-839 Investigator’s Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 


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 Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators are 
responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study. 
 Data Protection 
Each patient will be assigned a unique number and will keep this number for the duration of the 
study.  Patient numbers will not be reassigned or reused for any reason.  Patients should be 
identified to the Sponsor only by their assigned number, initials, date of birth, and sex.  The 
Investigator must maintain a patient master log.  
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
 
Publication Policy, Authorship, and Accountability 
Per the International Committee of Medical Journal Editors recommendations, an author is 
generally considered to be anyone who provides substantive intellectual contributions to a 
published study.  Specifically, authorship credit should be based on 1) substantial contributions 
to study conception and design, or acquisition, analysis and interpretation of data 2) drafting the 
article or revising it critically for important intellectual content, 3) final approval of the version 
to be published, and 4) agreement to be accountable for all aspects of the work to ensure its 
accuracy and integrity.  All four conditions should be met.


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 Data Quality Control and Assurance 
The Sponsor or designee performs quality control and assurance checks on all clinical studies 
that it sponsors.  Before enrolling any patients in this study, Sponsor personnel and the 
Investigator review the protocol, the current CB-839 Investigator’s Brochure, the eCRFs and 
instructions for their completion, the procedure for obtaining informed consent, and the 
procedure for reporting AEs and SAEs.  A qualified representative of the Sponsor will monitor 
the conduct of the study. During these site visits, information recorded in the eCRFs is verified 
against source documents.  
The following policies will be implemented to assure integrity of the data: 
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data).  The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the study Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 


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• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 2 years after study completion unless local 
regulations or institutional policies require a longer retention period.  No records may 
be destroyed during the retention period without the written approval of the Sponsor.  
No records may be transferred to another location or party without written notification 
to the Sponsor. 
 Protocol Amendments 
Any significant change in to the conduct of the study or the analysis of data requires a protocol 
amendment.  An Investigator must not make any changes to the study without IRB/IEC and 
Sponsor approval.  All protocol amendments must be reviewed and approved following the 
same process as the original protocol. 
 Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the eCRF will be traceable to the source documents. 
The Investigator may need to request previous medical records or transfer records, depending 
on the study.  Also, current medical records must be available. 
Source data may contain the following: 
• Demographic and medical information 
• Laboratory data, ECGs, etc… 
• Signed Informed consent/ HIPAA authorization 
• Medical records 
• Hospital records 
 
 Study Suspension, Termination, and Completion 
 
Suspension and/or Termination 
The Sponsor may suspend or terminate the study or any part of the study at any time for any 
reason.  If the Investigator suspends or terminates the study, the Investigator will promptly 
inform the Sponsor and the IRB/IEC and provide a detailed written explanation.  The 
Investigator will also return all telaglenastat and talazoparib containers, as well as any other 
study materials, to the Sponsor or designee, or will destroy the materials at the investigative 


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site.  Upon study completion, the Investigator will provide the Sponsor, IRB/IEC, and 
regulatory agency with final reports and summaries as required by regulations. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor
's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
 
Study Completion 
The study will be considered complete when the last patient has completed his or her last visit. 
 Direct Access, Data Handling, and Record Keeping 
 
Investigator 
The Investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and documents. 
All study-related information will be recorded on source documents.  All required data will be 
recorded in the eCRFs.  All eCRF data must be submitted to the Sponsor throughout and at the 
end of the study. 
If an Investigator retires, relocates, or otherwise withdraws from conducting the study, the 
Investigator must notify the Sponsor to agree upon an acceptable storage solution.  Regulatory 
agencies will be notified with the appropriate documentation. 
All study-related laboratory and clinical data gathered in this protocol will be stored in a 
password-protected database.  All patient information will be handled using anonymous 
identifiers.  Linkage to patients’ study data is only possible after accessing a password-
protected database.  Access to the database is only available to individuals directly involved in 
the study. 
Patient personal health information that is accessed for this study will not be reused or 
disclosed to any other person or entity, or for other research. 


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Sponsor 
During the study, the sponsor study monitor, or designee, will visit the site regularly to check 
the completeness of subject records, accuracy of entries on the eCRFs, adherence to the 
protocol and to GCP, progress of enrollment, and also the ensure that study drug is stored, 
dispensed, and accounted for according to specifications. Data may also be checked remotely 
via the EDC system.  
Representatives of the sponsor must be allowed to visit all study site locations periodically to 
assess the data quality and study integrity.  
 
Pre-Study Documentation 
The Investigator must provide the Sponsor with the following documents BEFORE enrolling 
any patients: 
• Completed and signed Form 1572 
• All applicable country-specific regulatory forms 
• Current, dated curricula vitae for the Investigator, Sub-Investigators, and other 
individuals having significant Investigator responsibility who are listed on the Form 
1572 or equivalent, or the clinical study information form. 
• Copy of the IRB/IEC approval letter for the protocol and informed consent.  All 
advertising, recruitment, and other written information provided to the patient must be 
approved by the IRB/IEC.  Written assurance of continuing approval (at least annually) 
as well as a copy of the annual progress report submitted to the IRB/IEC must also be 
provided to the Sponsor.  
• Copy of the IRB/IEC-approved Informed Consent Form to be used 
• Where applicable, a list of the IRB/IEC members or a Federal-Wide Assurance/ 
Department of Health and Human Services (FWA/DHHS) number 
• Copy of the protocol sign-off page signed by the Investigator 
• Copy of the current medical license (online verification is also acceptable) of the 
Principal Investigator, any Sub-Investigators and any other individuals having 
significant responsibility as listed in Form 1572 
• Fully executed Clinical Trial Agreement (CTA) 
• Financial disclosure form for the Principal Investigator and any other persons listed in 
Form 1572 


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• A written document containing the name, location, certification number, and date of 
certification of the laboratory to be used for laboratory assays and those of other 
facilities conducting tests.  This document should be returned along with Form 1572. 
The Sponsor must be notified if the laboratory is changed or if any additional laboratory 
is to be used. 
 
Records Retention 
The Investigator shall retain and preserve one copy of all data generated in the course of the 
study, specifically including but not limited to those defined by GCP as essential, for whatever 
period is longer:   
• 2 years after the last marketing authorization for the study drug has been approved or 
the Sponsor has discontinued its research with respect to such drug  
 
or  
• Such longer period as required by applicable global regulatory requirements.  At the end 
of such period, the Investigator shall notify the Sponsor in writing of its intent to 
destroy all such material.  The Sponsor shall have 30 days to respond to the 
Investigator’s notice, and the Sponsor shall have a further opportunity to retain such 
materials at the Sponsor’s expense.  


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5.0 
REFERENCES 
Amé JC, Spenlehauer C, de Murcia G.  The PARP superfamily. Bioessays. 2004;26:882-893. 
de Bono J, Ramanathan, RK, Mina, L, Chugh R., Glaspy J, Rafii S, Kaye S, Sachdev, J, 
Heymach J., Smith DC, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor 
talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic 
cancers. Cancer Discov. 2017;7:620-629. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45 (2):228-47. 
Emberley E, Bennett M, Bhupathi D, Chen J, Gross M, Huang T, Makkouk A, Mackinnon A 
The Glutaminase Inhibitor CB-839 Synergizes with CDK4/6 and PARP Inhibitors in Pre-
Clinical Tumor Models. Poster presented at: Annual Meeting of American Association for 
Cancer Research (AACR): April 14-18, 2018; Chicago, Illinois. 
Goodin S, Griffith N, Chen B, Chuk K, Daouphars M, Doreau C, et al. Safe handling of oral 
chemotherapeutic agents in clinical practice: recommendations from an international 
pharmacy panel. J Oncol Pract. 2011;7(1):7-12. 
Hoeijmakers T.  Genome maintenance mechanisms for preventing cancer.  Nature. 
2001;17:366-374. 
Lindahl T.  Instability and decay of the primary structure of DNA.  Nature. 1993;362:709-715. 
Litton J, Rugo HS, Ettl J, Hurvitz S, Gonçalves A, Lee K-H, Fehrenbacher L, Yerushalmi R, 
Mina LA, Martin M, Roché H, Im Y-H, Quek RGW, Tudor IC, Hannah AL, Eiermann W, 
Blum JL. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA 
Mutation. N Engl J Med. 2018;379, 753-763. 
McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift SD, et al.  Deficiency in the 
repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) 
polymerase inhibition.  Cancer Res 2006;66:8109-8115. 
Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1and 
PARP2 by clinical PARP inhibitors. Cancer Res. 2012; Nov 1;72(21):5588-99. 
Okazaki A, Gameiro PA, Christodoulou D, Laviollette L, Schneider M, Chaves F, et al., 
Glutaminase and poly (ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis 
and VHL-deficient renal cancers. J Clin Invest. 2017;127:1631-16. 
Scanlon SE, Hgnen DC, Sulkowski PL and Glazer PM. Suppression of homology-dependent 
DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient 
human renal cell carcinoma. Oncotarget. 2018; 9(4);4647. 
Turner NC, Telli ML, Rugo HS, Mailliez A, Ettl J, Grischke E-M, Mina LA, Gelpi JB, 
Fasching PA, Hurvitz SA, et al. Final results of a phase 2 study of talazoparib (TALA) 
following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) 
with germline BRCA1/2 mutations (ABRAZO). J Clin Oncol. 2017; 35,1007-1007. 


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6.0 
ATTACHMENTS 
This section contains the following attachments: 
Attachment 1 
List of Abbreviations and Definitions of Terms 
Attachment 2 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Attachment 3 
Adverse Events: Definitions, Causality, Severity, and Reporting 
Procedures for SAEs 
Attachment 4 
Clinical Laboratory Tests 
Attachment 5 
RECIST Version 1.1 
Attachment 6 
Drug Interactions with Telaglenastat 
Attachment 7 
Drug Interactions with Talazoparib 
Attachment 8 
Protocol History 


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ATTACHMENT 1.  
LIST OF ABBREVIATIONS AND DEFINITION 
OF TERMS 
Abbreviation or Term 
Expansion/Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BCRP 
Breast cancer resistant protein 
BID 
Twice daily 
CBR 
Clinical benefit rate 
ccRCC 
Clear Cell Renal Cell Carcinoma 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
cm 
Centimeters 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
CR 
Complete response  
CTA 
Clinical Trial Agreement 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP, CYP450 
Cytochrome P450 
DLT 
 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 


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Abbreviation or Term 
Expansion/Definition 
FFPE 
Formalin-fixed, paraffin-embedded 
GCP 
Good Clinical Practice 
g/dL 
Grams per deciliter 
GLP 
Good Laboratory Practice  
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hr 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous, intravenously 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
LC-MS/MS 
Liquid chromatography-mass spectrometry/mass spectrometry 
mCRPC 
metastatic castration resistant prostate cancer 
mcL or µL 
Microliter  
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
mRCC 
Metastatic renal cell carcinoma 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose  
mTOR 
Mechanistic target of rapamycin 
NHL 
Non-Hodgkin’s Lymphoma 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Overall response rate 


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Abbreviation or Term 
Expansion/Definition 
PARP 
Poly adenosine diphosphate ribose polymerase 
PD-1 
Programmed Cell Death protein 1 
PD-L1 
Programmed Death Ligand 1 
P-gp 
P-Glycoprotein 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PPI 
Proton Pump Inhibitors 
PR 
Partial response 
PSA 
Prostate Specific Antigen 
PT 
Prothrombin time of partial response (depending on the context) 
QD 
Once-daily 
QTcF 
Corrected QT interval, Fridericia’s formula 
RP2D 
Recommended Phase 2 Dose 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SD 
Stable disease or standard deviation, depending on context 
TKI 
Tyrosine kinase inhibitor 
Tmax 
Time of maximum observed concentration 
TEAE 
Treatment-emergent adverse event 
TID 
Three times daily 
TNBC 
Triple negative breast cancer 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
 


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ATTACHMENT 2.   
EASTERN COOPERATIVE ONCOLOGY 
GROUP PERFORMANCE STATUS 
Grade 
ECOG Performance Statusa 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair 
5 
Dead 
ECOG = Eastern Cooperative Oncology Group. 
a. 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649-655. 


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ATTACHMENT 3. 
ADVERSE EVENTS: DEFINITIONS, 
CAUSALITY, SEVERITY, AND REPORTING 
PROCEDURES FOR SAES 
A. Definitions 
1. Adverse event 
An adverse event (AE) is any untoward, undesired, or unplanned event in the form of signs, 
symptoms, disease, or laboratory or physiologic observations occurring in a person given a test 
article or associated with other protocol interventions in a clinical study.  The event does not 
need to be causally related to the test article.  An AE includes, but is not limited to, the 
following: 
• An AE not previously observed in the patient that emerges during the 
protocol-specified AE reporting period 
• Any clinically significant worsening of a preexisting condition 
• Complications occurring as a result of protocol-mandated interventions (e.g., 
invasive procedure such as biopsies), including events that occur in the period prior 
to receiving the first dose of the test article and are related to the protocol-mandated 
intervention (e.g., pretreatment medication wash-out procedures, biopsies) 
• An AE occurring from overdose (i.e., a dose higher than that indicated in the 
protocol) of a test article, whether accidental or intentional 
• An AE occurring from abuse (e.g., use for nonclinical reasons) of a test article 
• An AE that has been associated with the discontinuation of the use of a test article 
• Note:  Clear progression of neoplasia should not be reported as an AE (or SAE) 
unless the Investigator considers the progression of underlying neoplasia to be atypical 
in its nature, presentation or severity from the normal course of the disease in a 
particular patient. 


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2. Serious Adverse Event 
A serious adverse event (SAE) is an AE that meets at least one of the following conditions 
described below. 
• Results in death (Note:  death is an outcome, not an event) 
• Is life-threatening  
Life-threatening, in the context of an SAE, refers to immediate risk of death as the event 
occurred per the reporter.  A life-threatening experience does not include an experience 
that, had it occurred in a more severe form, might have caused death, but rather an 
experience as it occurred that created an immediate risk of death.  For example, hepatitis 
that resolved without evidence of hepatic failure would not be considered life-
threatening, even though hepatitis of a more severe nature can be fatal.  Similarly, an 
allergic reaction resulting in angioedema of the face would not be life-threatening, even 
though angioedema of the larynx, allergic bronchospasm, or anaphylaxis can be fatal.  
• Requires inpatient hospitalization or prolongation of an existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• Results in a congenital anomaly or birth defect 
• Is an important medical event 
An important medical event is an event that  may not result in death, be life-threatening, 
or require hospitalization that may be considered  an SAE when, based on appropriate 
medical judgment, the event may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed above.  Examples of such 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 


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2a. Clarifications to Definitions of Serious Adverse Event  
An SAE can be treatment-emergent or can occur before treatment with study medication 
has begun. 
Clear progression of neoplasia should not be reported as an SAE (unless the Investigator 
considers the progression of underlying neoplasia to be atypical in its nature, presentation or 
severity from the normal course of the disease in a particular patient).  Findings that are clearly 
consistent with the expected progression of the underlying cancer should not be reported as 
an adverse event, and hospitalizations due to the progression of cancer do not necessarily 
qualify for an SAE.  All deaths including those related to progression of disease and sudden 
and unexplained death should be reported as an SAE. If there is any uncertainty about a 
finding being due solely to progression of neoplasia, the finding should be reported as an AE 
or SAE as appropriate. 
Death is an outcome of an event.  The events that resulted in death and/or caused the death 
should be recorded and reported as SAEs as described in Section 2, above).  The investigator 
should make every effort to obtain and send death certificates and autopsy reports to 
Calithera, or designee. 
Hospitalization is official admission to a hospital.  Hospitalization or prolongation of a 
hospitalization constitutes criteria for an AE to be serious; however, it is not in itself 
considered a serious adverse event (SAE).  In the absence of an AE, a hospitalization or 
prolongation of a hospitalization should not be reported as an SAE.  This is the case in the 
following situations: 
• The hospitalization or prolongation of hospitalization is needed for a procedure 
required by the protocol.  Day or night survey visits for biopsy or surgery required by 
the protocol are not considered serious. 
• The hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (e.g., stent removal after surgery).  This should be recorded in 
the study file. 
• Hospitalization for survey visits or annual physicals falls into the same category. 
In addition, hospitalizations planned before the start of the study, for a preexisting 
condition that has not worsened, do not constitute an SAE.  Visits to the Emergency 
Room that do not result in hospital admission are not considered hospitalizations but may 
constitute a medically important event. 


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Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt about whether an AE constitutes an SAE, the AE is to be treated 
as an SAE. 
2b. Other Events Reportable as SAEs  
Certain information, although not meeting one of the definitions of an SAE, must be recorded, 
reported, and followed up as is performed for an SAE.  This includes, but is not limited to the 
following: 
• A case involving a pregnancy exposure to a test article, unless the product is indicated for 
use during pregnancy e.g., prenatal vitamins.  Information about use in pregnancy 
encompasses the entire course of pregnancy and delivery and perinatal and neonatal 
outcomes even if there were no abnormal findings.  If a pregnancy is confirmed test 
article must be discontinued immediately.  All reports of pregnancy must be followed for 
information about the course of the pregnancy and delivery as well as the condition of the 
newborn.  When the newborn is healthy, additional follow-up is not needed. Pregnancies 
occurring up to 6 months after completion of the study medication must also be reported 
to the Investigator. 
• Overdose (e.g., a dose higher than that indicated in the protocol) with or without an AE 
• Abuse (e.g., use for nonclinical reasons) with or without an AE 
 
3. Treatment-Emergent Adverse Event, Including an Abnormal Laboratory 
Result 
A treatment-emergent adverse event (TEAE) is an AE that occurs from the time of the first 
dose of study medication until up to 28 days after the last dose of the study medication. TEAEs 
can be classified as either serious or nonserious. 
 A treatment-emergent abnormal laboratory result that is clinically significant, i.e., meets one or 
more of the following conditions, should be considered a TEAE and recorded as a single 
diagnosis on the AE page in the eCRF: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g., dose modification, interruption, or 
permanent discontinuation) 


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• Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 


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4. Protocol-Related Adverse Event 
A protocol-related adverse event is an AE occurring during a clinical study that is not related to 
the test article but is considered by the Investigator or the  Medical Monitor (or designee) to be 
related to the research conditions, i.e., related to the fact that a patient is participating in the 
study.  For example, a protocol-related AE may be an untoward event occurring during a 
washout period or an event related to a medical procedure required by the protocol. 
B. Causality (“Relatedness”) Guidance for All AEs (Including TEAEs, SAEs, 
Unexpected AEs, AESIs) 
An AE should be considered probably or possibly related to treatment, unless the AE fulfills 
the following criteria (in which circumstances the AE should be considered unlikely related or 
unrelated): 
• Evidence exists that the AE has an etiology other than the investigational product (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication), and/or 
• The AE has no plausible temporal relationship to administration of the investigational 
product (e.g., a new cancer diagnosed 2 days after first dose of study drug). 
Relatedness to study treatment will be graded as either, “probably related,” “possibly related,” 
“unlikely related,” or “unrelated,” as shown below: 
Classification 
Description 
Probably 
Related  
The AE: 
• Follows a reasonable temporal sequence from drug administration 
• Abates upon discontinuation of the drug 
• Cannot be reasonably explained by the known characteristics of the 
patient’s clinical state 
Possibly 
Related  
The AE: 
• Follows a reasonable temporal sequence from drug administration 
• Could have been produced by the patient’s clinical state or by other 
modes of therapy administered to the patient 
Unlikely 
Related  
The AE: 
• Is most likely to be explained by the patient’s clinical state or by other 
modes of therapy administered to the patient 


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Classification 
Description 
Unrelated  
The AE: 
• Does not follow a reasonable sequence from drug administration 
• Is readily explained by and considered by the Principal Investigator to 
be an expected complication of the patient’s primary malignancy, 
clinical state, concurrent medical conditions, or by other modes of 
therapy administered to the patient 
C. Assessment of Adverse Event Severity 
The severity of AEs will be assessed and recorded according to NCI CTCAE, version 5.0: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf#search=%22CTCAE%22  .    
D. Recording and Reporting of Adverse Events, Including Serious Adverse 
Events 
1. Documentation, Diagnosis, and Elicitation 
All AEs and SAEs must be recorded on source documents and collected in the EDC. 
Although AEs should be based on the signs or symptoms detected during the physical 
examination and on clinical evaluation of the patient, a specific diagnosis should be reported as 
the AE whenever feasible. In addition to the information obtained from those sources, the 
patient should be asked the following nonspecific question:  “How have you been feeling since 
your last visit?” Signs and symptoms should be recorded using standard medical terminology. 
Any unanticipated risks to the patients must be reported by the Investigator promptly to the 
Sponsor and IRB/IEC. 
2. Adverse Events Occurring Prior to Initiation of Study Treatment 
After informed consent but prior to initiation of study medication, only SAEs caused by 
protocol- mandated interventions (i.e., a protocol-related procedure such as a biopsy) will be 
collected. All AEs (including SAEs) occurring during the Treatment period up to 28 days after 
the last dose of study medication or until the start a new treatment, whichever occurs first, will 
be recorded and considered to be TEAEs.   


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3. Follow-up of  Adverse Events, Serious Adverse Events, and Other 
Reportable Information 
The Investigator must follow up on all AEs and SAEs related to study medication and other 
reportable information until the events have subsided, returned to baseline, the patient has 
initiated any other anticancer treatment, or in case of permanent impairment, until the condition 
stabilizes. 
4. Serious Adverse Event Reporting 
All SAEs regardless of attribution, other reportable information, and follow-up information 
must be reported within 24 hours of learning of the event by completing the SAE form and 
either emailing or faxing the form to the SAE Reporting Contact.  Calithera Biosciences (or 
designee) will process and evaluate all SAEs as soon as the reports are received.  For each SAE 
received, Calithera Biosciences will make a determination as to whether the criteria for 
expedited reporting have been met.  The Medical Monitor should also be contacted for any fatal 
or life-threatening SAE that is considered possibly or probably related to study drug. 
Calithera Biosciences, Inc. (or designee) is responsible for reporting relevant SAEs to the 
relevant regulatory authorities and participating Investigators, in accordance with Food and 
Drug Administration (FDA) Code of Federal Regulation (CFR) 21 CFR 312.32, ICH 
Guidelines, European Clinical Trials Directive (Directive 2001/20/EC), and/or local regulatory 
requirements and monitoring the safety profile of the study drug.  To meet this requirement, 
Calithera Biosciences, Inc. (or designee) may request additional information from the sites 
including, but not limited to, hospitalization records.  Any requests for such information should 
be addressed in a timely manner.  Additionally, any SAE considered by an Investigator to be 
possibly or probably  related to the study therapy that is brought to the attention of the 
Investigator at any time outside of the time period specified for SAE reporting also must be 
reported immediately to one of the individuals listed on the Sponsor contact information page. 
Reporting of SAEs by the Investigator to the Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC) will be done in accordance with the standard operation procedures and 
policies of the IRB/IEC.  Adequate documentation must be maintained showing that the 
IRB/IEC was properly notified. 


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ATTACHMENT 4. 
 CLINICAL LABORATORY TESTS 
Hematology (Peripheral Blood Sample): 
• Hemoglobin  
• Hematocrit 
• Red blood cell count 
• White blood cell count with differential 
• Platelet count 
• Mean corpuscular volume 
Coagulation Tests 
• PT, activated partial thromboplastin time (aPTT) and international normalized ratio 
(INR) 
Serum Chemistry-Full Metabolic Panel (Peripheral Blood Sample) with Additional 
Analytes 
• Sodium 
• Potassium 
• Chloride 
• CO2  
• Calcium 
• Glucose 
• Blood urea nitrogen 
• Total protein 
• Albumin 
• Total and direct bilirubina 
• Aspartate aminotransferase (AST) 
• Alanine aminotransferase (ALT) 
• Alkaline phosphatase (AP) 
• Lactate dehydrogenase (LDH) 
Creatinine 
a. 
Direct bilirubin is only required if Total Bilirubin is above the upper limit of normal.  
 
Pregnancy test (urine or serum -HCG):  Women of child-bearing potential 
Urinalysis 
• Protein 
• Glucose 
• Ketones 
• Hemoglobin 
• Nitrite 
 
• Leukocyte esterase 
• pH 
• Specific gravity 
• Urobilinogen 
• Microscopic evaluation(performed at the 
discretion of the Investigator based on 
results of routine urinalysis or as clinically 
indicated) 
 
 


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ATTACHMENT 5. 
RESPONSE CRITERIA IN SOLID TUMORS, 
VERSION 1.1 (RECIST, V1.1) 
Source: Eisenhauer 2009 
Sponsor’s Note: telaglenastat, may affect glucose metabolism in both normal and tumor tissues. 
Preclinical data suggest that glucose uptake may increase with glutaminase inhibition in 
sensitive tissues, reflecting the pharmacodynamics effects of telaglenastat. False positive 
interpretations of progressive disease with FDG-PET scans may occur. Therefore, all FDG-
PET findings suggestive of progressive disease should be confirmed by dedicated anatomic 
imaging (CT or MRI) for this study. 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions will be categorized measurable or non-measurable as follows. 
Measurable tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:   
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10 mm by caliper measurement (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be  15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed.  See also section below on ‘Baseline documentation of target 
and non-target lesions’ for information on lymph node measurement. 
Non-measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter <10 mm or 
pathological lymph nodes with  10 to < 15 mm short axis) as well as truly non-measurable 
lesions.  Lesions considered truly non-measurable include the following:  leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 


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involvement of skin or lung, peritoneal spread, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions.  However, these techniques can be used to confirm the presence 
or disappearance of bone lesions.  
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT or 
MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above. 
• Blastic bone lesions are non-measurable.  
Cystic lesions: 
• 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. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  For this protocol, these tumor lesions will be 
considered non-measurable lesions. 


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Specifications by methods of measurements 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
Method of assessment 
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 
should always be done rather than 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 
and  10 mm diameter as assessed using calipers (e.g., skin nodules).  For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion 
is suggested.  As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. Still, non-contrast CT is preferred over chest X-ray. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g., for body scans). 
If prior to enrollment it is known that a patient is not able to undergo CT scans with IV contrast 
due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (with 
or without IV contrast) will be used to evaluate the patient at baseline and follow-up, should be 
guided by the tumor type under investigation and the anatomic location of the disease.  For 
patients who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed, 
should also be based on the tumor type, anatomic location of the disease and should be 
optimized to allow for comparison to the prior studies if possible.  Each case should be 


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discussed with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward. 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess objective tumor response.  If 
markers are initially above the upper normal limit, however, they must normalize for a patient 
to be considered in complete response.  Because tumor markers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease specific 
basis.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
prostate-specific androgen (PSA) response (in recurrent prostate cancer), have been published.  
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. 
Cytology, histology:  These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain).  When effusions are known to be a 
potential adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
Tumor response evaluation 
Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements.  Only patients 
with measurable disease at baseline should be included in protocols where objective tumor 


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response is the primary endpoint.  Measurable disease is defined by the presence of at least one 
measurable lesion.  In studies where the primary endpoint is tumor progression (either time to 
progression or proportion with progression at a fixed date), the protocol must specify if entry is 
restricted to those with measurable disease or whether patients having non-measurable disease 
only are also eligible.  
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
This means in instances where patients have only one or two organ sites involved a maximum 
of two (one site) and four lesions (two sites), respectively, will be recorded.  Other lesions in 
that organ will be recorded as non-measurable lesions (even if size is greater than 10 mm by 
CT scan). 
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. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor.  Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, sagittal or coronal).  The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm x 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with short 
axis  10 mm but < 15 mm) should be considered non-target lesions.  Nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or followed. 
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 as noted above, 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. 


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All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline.  Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression.’  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
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. 
• Partial Response (PR):  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
• Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progression). 
• 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. 
Special notes on the assessment of target lesions 
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short axis 
of < 10 mm. Case report forms or other data collection methods may therefore be designed to 
have target nodal lesions recorded in a separate section where, in order to qualify for CR, each 
node must achieve a short axis < 10 mm.  For PR, SD, and progressive disease (PD), the actual 
short axis measurement of the nodes is to be included in the sum of target lesions. 


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Target lesions that become ‘too small to measure’:  While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small 
to measure’.  When this occurs, it is important that a value be recorded on the case report form: 
• If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned and BML (below measurable limit) should be ticked (Note:  It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned in this circumstance as well 
and BML should also be ticked). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness).  The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. 
To reiterate:  However, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm and, in that case, BML should not be ticked.  (BML 
is equivalent to a less than sign <) 
Lesions that split or coalesce on treatment:  When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
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 short axis). 


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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):  Unequivocal progression of existing non-target lesions. (Note:  the 
appearance of one or more new lesions is also considered progression). 
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease:  In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease in a magnitude that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status.  The designation of 
overall progression solely on the basis of change in non-target disease in the face of SD or PR 
of target disease will therefore be extremely rare. 
When the patient has only non-measurable disease:  This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease.  The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition:  if all 
lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease:  i.e., an increase in tumor burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’.  If ‘unequivocal progression’ is seen, 
the patient should be considered to have had overall PD at that point.  While it would be ideal 
to have objective criteria to apply to non-measurable disease, the very nature of that disease 
makes it impossible to do so; therefore, the increase must be substantial. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal:  i.e., not attributable to differences in scanning technique, change in imaging 


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modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the patient’s baseline lesions show partial or complete response.  For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it 
is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is 
the patient who has visceral disease at baseline and while on study has a brain CT or MRI 
ordered which reveals metastases.  The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)For the purposes of 
this study, progressive disease should not be made solely on FDG-PET findings because the 
mechanism of the study drug telaglenastat may affect glucose metabolism in both normal and 
tumor tissues. All FDG-PET findings suggestive of progressive disease should be confirmed by 
dedicated anatomic imaging (CT or MRI). The following modifications to RECIST v1.1. will 
be applied to this study: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.  *Confirmation of the new lesion by CT or MRI scan is 
required per protocol. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: 
o If the positive FDG-PET at follow-up corresponds to a new sign of disease 
confirmed by CT, this is PD 
o 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 *CT scan). 
o 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. 
*reflects study-specific modification to RECIST v.1.1 


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Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study medication 
until the end of treatment taking into account any requirement for confirmation.  On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation.  The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions.  Furthermore, depending on the nature of the study and the protocol 
requirements, it may also require confirmatory measurement.  Specifically, in nonrandomized 
trials where response is the primary endpoint, confirmation of PR or CR is needed to deem 
either one the ‘best overall response’.  This is described further below. 
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs.  Table A 
provides a summary of the overall response status calculation at each time point for patients 
who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table B is to be used.  
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point.  If only a subset of lesion measurements is made at an assessment, 
usually the case is also considered not evaluable at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response.  This would be most likely to happen in the case of 
PD. 
For example, if a patient had a baseline sum of 50 mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved PD status, regardless of the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done or could 
not be assessed because of poor image quality or obstructed view, the Response for Target 
Lesions should be “Unable to Assess” since the patient is not evaluable.  Similarly, if one or 
more non-target lesions are indicated as ‘not assessed’, the response for non-target lesions 
should be “Unable to Assess” (except where there is clear progression).  Overall response 
would be “Unable to Assess” if either the target response or the non-target response is “Unable 


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to Assess” (except where this is clear evidence of progression) as this equates with the case 
being not evaluable at that time point. 
Best overall response:  All time points 
The best overall response (Table C) will be determined by statistical programming once all the 
data for the patient are known. 
Table A: Time Point Response:  Patients with Targets (+/- Non-Target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
Unequivocal PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Note:  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
 
Table B: Time Point Response:  Patients with Non-Target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Note:  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
a = ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
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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Table C: Best Overall Response when Confirmation of CR and PR Required 
Overall Response  
First Time Point 
Overall Response  
Subsequent Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
Note:  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
a = If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement 
should be recorded even though the nodes are normal in order not to overstate progression 
should it be based on increase in size of the nodes.  As noted earlier, this means that patients 
with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination.  The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression.  For 
example, in most trials it is reasonable to consider a patient with time point responses of PR-
NE-PR as a confirmed response. 


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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 objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response:  it is a reason for stopping study therapy.  The objective response 
status of such patients is to be determined by evaluation of target and non-target disease. 
Conditions that define ‘early progression, early death, and non-evaluability are study specific 
and should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response.  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. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected


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ATTACHMENT 6. 
DRUG INTERACTIONS WITH 
TELAGLENASTAT 
Substrate Type 
Identification 
CYP2C9 Substrates with a 
Narrow Therapeutic Indexa 
• 
S-Warfarin (anticoagulant) 
• 
Phenytoin (antiepileptic 
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 
• 
losartan 
• 
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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Substrate Type 
Identification 
CYP = cytochrome. 
a. 
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).” 
 


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ATTACHMENT 7:  
DRUG INTERACTIONS WITH TALAZOPARIB 
The table below contains a list of strong P-Glycoprotein (P-gp) inhibitors that should be 
avoided during concomitant treatment with talazoparib.  Strong P-gp inhibitors were defined as 
the P-gp inhibitors that result in ≥ 2-fold increase in the exposure of an in vivo probe P-gp 
substrate according to the University of Washington Drug-Drug Interaction database 
(https://www.druginteractioninfo.org/). 
 
Prohibited: Strong P-gp Inhibitors 
Including but not limited to: 
• 
amiodarone 
• 
carvedilol 
• 
clarithromycin 
• 
cobicistat 
• 
darunavir 
• 
dronedarone 
• 
erythromycin 
• 
indinavir 
• 
itraconazole 
• 
ketoconazole 
• 
lapatinib 
• 
lopinavir 
• 
propafenone 
• 
quinidine 
• 
ranolazine 
• 
ritonavir 
• 
saquinavir 
• 
telaprevir 
• 
tipranavir 
• 
valspodar 
• 
verapamil 
The following P-gp inhibitors that may be taken with caution at the Investigator’s discretion: 
Atorvastatin, azithromycin, conivaptan, diltiazem, diosmin, eliglustat, felodipine, flibanserin, 
fluvoxamine, piperine, quercetin, and schisandra chinesis extract. 
 
 


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ATTACHMENT 8. 
 PROTOCOL HISTORY 
Version 
Date 
Original protocol 
21 December 2018 
Amendment 1 
10 April 2019 
 

SAP_001.pdf: 
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Statistical Analysis Plan 
Version 1.0; 10 September 2020 
 
Page 1 of 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Calithera Biosciences, Inc. 
 
CX-839-011 
 
 
 
 
 
 
 
Protocol Title: 
A Phase 1b/2 open label, Dose Escalation and Expansion 
Study of the Glutaminase Inhibitor Telaglenastat (CB-839) 
in Combination with the PARP inhibitor Talazoparib in 
Patients with Advanced or Metastatic Solid Tumors 
 
Protocol Version 
and Date: 
Amendment 1 / 10 April 2019 
Sponsor: 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
 
Prepared By: 
Yongmei Zhou 
Biostatistician Contracted to Calithera  
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
 
 
Document Version 
and Date: 
Version 1.0; 10 September 2020 




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2 
TABLE OF CONTENTS 
Contents 
1 
STATISTICAL ANALYSIS PLAN APPROVAL ......................................... 2 
2 
TABLE OF CONTENTS ................................................................................. 3 
3 
LIST OF ABBREVIATIONS .......................................................................... 5 
4 
INTRODUCTION ............................................................................................ 6 
5 
STUDY DESIGN .............................................................................................. 6 
5.1 
Protocol Synopsis .............................................................................................. 7 
5.2 
Study Endpoints ................................................................................................ 7 
5.2.1 
Primary Endpoints ........................................................................................................ 7 
5.2.2 
Secondary Endpoints .................................................................................................... 8 
5.2.3 
Exploratory Endpoints .................................................................................................. 8 
5.3 
Sample Size and Power .................................................................................... 8 
6 
STUDY CONDUCT ......................................................................................... 9 
6.1 
Safety Data Monitoring .................................................................................... 9 
7 
STATISTICAL METHODS ............................................................................ 9 
7.1 
Analysis Sets ...................................................................................................... 9 
7.1.1 
Efficacy Evaluable Population ..................................................................................... 9 
7.1.2 
Safety Analysis Set ...................................................................................................... 10 
7.1.3 
DLT-Evaluable Population in Dose Escalation ......................................................... 10 
7.2 
Analysis of Study Conduct ............................................................................. 10 
7.3 
Analysis of Group Comparability ................................................................. 10 
7.4 
Efficacy Analysis ............................................................................................. 10 
7.4.1 
Clinical Benefit Rate (CBR) ....................................................................................... 10 
7.4.2 
Objective Response Rate (ORR) ................................................................................. 11 
7.4.3 
Progression Free Survival (PFS) ............................................................................... 11 
7.5 
Dose-Limiting Toxicity ................................................................................... 12 
7.6 
Safety................................................................................................................ 13 
7.6.1 
Treatment Exposure .................................................................................................... 13 
7.6.2 
Prior and Concomitant Medications .......................................................................... 13 
7.6.2 
Prior Systemic Therapies ............................................................................................ 13 
7.6.3 
Adverse Events ............................................................................................................ 13 
7.6.4 
Laboratory Data .......................................................................................................... 14 
7.6.5 
ECG and Vital Signs ................................................................................................... 14 
7.7 
Change of Planned Analyses .......................................................................... 14 
7.8 
Missing Data .................................................................................................... 14 
8 
REFERENCES ............................................................................................... 15 
ATTACHMENT 1:  SCHEDULE OF STUDY ASSESSMENTS .......................... 16 
 


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TABLE OF TABLES 
 
Table 1 
Summary of Sample Size and Power for Expansion Cohorts (Simon 2-Stage Design) ............. 9 
Table 2 
The Censor/Event Rules for Progression Free Survival and Duration of Responsea .............. 11 


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3 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition________________________________________ 
AE 
Adverse event 
ANC 
Absolute Neutrophil Count 
AUC 
Area under the concentration-time curve 
BID 
Twice daily 
CBR 
Clinical benefit rate 
ccRCC 
Clear Cell Renal Cell Carcinoma 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
CI 
Confidence interval 
CR 
Complete response 
CRC 
Colorectal Cancer 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicities 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
hr 
Hour or hours 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mg 
Milligram 
mRCC 
Metastatic renal cell carcinoma 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
PARP 
Poly adenosine diphosphate ribose polymerase 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PT 
Preferred term 
QD 
Once-daily 
QTcF 
Corrected QT interval, Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOC 
System organ class 
TKI 
tyrosine kinase inhibitor 
Tmax 
Time of maximum observed concentration 
TEAE 
Treatment-emergent adverse event 
TNBC 
Triple-negative breast cancer 
VEGFR 
Vascular endothelial growth factor receptor 
US 
United States 
 


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4 INTRODUCTION 
The statistical analysis plan (SAP) provides details of the planned analyses and statistical 
methods for study CX-839-011 (A Phase 1b/2 Open Label, Dose Escalation and 
Expansion Study of the Glutaminase Inhibitor Telaglenastat (CB-839) in Combination 
with the PARP inhibitor Talazoparib in Patients with Advanced or Metastatic Solid 
Tumors – Amendment 1 dated 10 Apr 2019). The background and rationale for the study 
can be found in the study protocol. 
 
5 
STUDY DESIGN 
 
Study CX-839-011 is an open-label, multicenter, two-part, Phase 1b/2 study consisting of 
Part 1, Dose Escalation, which employs a 3+3 design, and Part 2, Cohort Expansion, 
which employs a Simon 2-stage design. The study will be conducted at approximately 10 
sites in the United States (US). 
Telaglenastat will be administered with food, immediately following a meal, twice daily 
approximately 12 hr (± 2 hr) apart. Talazoparib will be administered in the morning at 
approximately the same time each dosing day. The morning dose of telaglenastat and 
talazoparib should be taken in the clinic for Cycle 1 Day 1 (C1D1) and C2D1 after the 
pre-dose PK collection. The dose of talazoparib in subsequent cohorts may also be 
reduced from the initial 1 mg dose in 0.25 mg increments as determined by safety and 
consensus of the Investigators and the Sponsor. Alternative dosing schedules may also be 
evaluated. 
The study design is illustrated in the following schematic: 
 
 
 
Part 1. Dose Escalation 


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Approximately 9 to 12 patients will be enrolled. Patients with histologically or 
cytologically documented incurable, locally advanced/metastatic solid tumors 
refractory or intolerant to standard therapies of proven clinical benefit, or with no 
standard therapy available.  
Escalating doses of telaglenastat starting at 600 mg twice daily (BID) on Days 1 to 
28 in combination with talazoparib 1 mg once daily (QD) on a 28-day cycle. The 
highest tested dose of telaglenastat in this study will be 800 mg BID, the 
recommended Phase 2 dose (RP2D) of telaglenastat when administered as a single-
agent. 
Part 2. Cohort Expansion 
Three cohorts with up to 25 patients in cohorts 1 and 2 and up to 30 patients in 
cohort 3. Combination treatment of telaglenastat with talazoparib at the RP2D 
(identified as 800 mg telaglenastat and 1 mg talazoparib) and schedule as determined 
in Part 1, Dose Escalation.  
• Cohort 1: Incurable/locally advanced or metastatic clear cell renal cell 
carcinoma (ccRCC), having received 2 or more prior systemic regimens, 
including at least one vascular endothelial growth factor receptor tyrosine 
kinase inhibitor (VEGFR TKI) therapy. 
• Cohort 2: Incurable/locally advanced or metastatic triple-negative breast 
cancer (TNBC), having received at least one prior line of cytotoxic 
chemotherapy for metastatic disease and not having received prior PARP 
inhibitor therapy for TNBC or platinum-based chemotherapy for TNBC in the 
metastatic setting. 
• Cohort 3: Incurable/locally advanced or metastatic CRC previously treated 
with oxaliplatin-, irinotecan- and 5-FU based chemotherapy (if appropriate) 
with or without bevacizumab. 
5.1 
Protocol Synopsis 
 
Please refer to protocol amendment 1 dated 10 Apr 2019 (1). The Schedule of 
Assessments for this study is also provided in ATTACHMENT 1 of this SAP. 
 
5.2 
Study Endpoints 
 
5.2.1 
Primary Endpoints 
Part 1, Dose Escalation: 
• 
Incidence, nature, and severity of adverse events  
• 
Laboratory abnormalities graded per National Cancer Institute Common 
Terminology Criteria for Adverse Events(NCI CTCAE) v5.0 
• 
Incidence and nature of dose-limiting toxicities (DLTs) 
Part 2, Dose Expansion: 
• 
Overall response rate (ORR), confirmed ORR, clinical benefit rate (CBR) 


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and progression-free survival (PFS) 
• 
Incidence, nature, and severity of adverse events  
• 
Laboratory abnormalities graded per National Cancer Institute Common 
Terminology Criteria for Adverse Events(NCI CTCAE) v5.0 
 
5.2.2 
Secondary Endpoints 
Part 1, Dose Escalation: 
• 
Total exposure (area under the curve) of telaglenastat/talazoparib from 
Time 0 to the last measurable concentration (AUC0–last)  
• 
Time to maximum observed plasma concentration (tmax) and maximum 
observed plasma concentration (Cmax) of telaglenastat/talazoparib 
• 
Minimum observed plasma concentration (Cmin, i.e., trough concentration) 
of telaglenastat/talazoparib 
• 
Clearance, volume of distribution, and half-life of telaglenastat, if data 
allow 
• 
ORR, confirmed ORR, CBR, and PFS 
Part 2, Dose Expansion: 
• 
Population PK of telaglenastat and talazoparib when used in combination 
– plasma concentrations are pre-dose and 3 to 6 hours post dose on C2D1 
 
5.2.3 
Exploratory Endpoints 
Part 1, Dose Escalation: 
• 
Tumor DNA mutations and RNA expression profiles, including for 
BRCA, somatic vs. germline source 
Part 2, Dose Expansion: 
• 
Tumor DNA mutations and RNA expression profiles, including for 
BRCA, somatic vs. germline source 
 
5.3 
Sample Size and Power 
Sample size and power calculations are as specified in the protocol. During dose escalation 
(Part 1) a 3 + 3 design will be employed to determine the RP2D for use during Dose 
Expansion (Part 2). Expansion cohorts will employ a Simon 2-stage design (3) to evaluate 
anti-tumor activity of the combination while minimizing the number of treated patients if 
the regimen is inactive (Table 1).   
For each of the mRCC and TNBC expansion cohorts, the null hypothesis that the true CBR 
is ≤ 30% [H0] will be tested against a one-sided alternative that the CBR is ≥ 60% [H1]. In 
the first stage, 15 patients will be accrued. If 4 or fewer patients achieve CBR in these 15 
patients, accrual to the applicable cohort will be stopped and the treatment regimen will be 
deemed not of interest for further pursuit in the cohort. Otherwise, 10 additional patients 
will be accrued to stage 2 for a total of 25 patients. The null hypothesis will be rejected and 


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the treatment regimen deemed of interest for further investigation if 12 or more CBRs are 
observed in 25 patients. This design has a type I error rate of 0.042 when the true CBR rate 
is 30% and a power of 0.92 when the true CBR rate is 60%. 
For the CRC expansion cohort, the null hypothesis that the true CBR is ≤25% [H0] will be 
tested against a one-sided alternative that the CBR is ≥ 50% [H1]. In the first stage, 13 
patients will be accrued. If 3 or fewer patients achieve CBR in these 13 patients, accrual to 
the cohort will be stopped and the treatment regimen deemed not of interest for further 
pursuit for CRC. Otherwise, 17 additional patients will be accrued for a total of 30 patients. 
The null hypothesis will be rejected and the treatment regimen deemed of interest for further 
pursuit if 12 or more CBRs are observed in 30 patients. This design has a type I error rate of 
0.047 when the true CBR is 25% and a power of 0.88 when the true CBR is 50%. 
Table 1 
Summary of Sample Size and Power for Expansion Cohorts (Simon 2-
Stage Design) 
Cohort 
H0 
CBR 4 mo 
(%) 
H1 
CBR 4 mo 
(%) 
Actual α – 
one sided 
Actual 
Power 
n1 for 
Stage 1 
(r1) 
n2 (n - n1) 
for Stage 2 
Total n 
(r2) 
mRCC 
30% 
60% 
0.044 
0.92 
15 (4) 
10 
25 (12) 
TNBC 
30% 
60% 
0.044 
0.92 
15 (4) 
10 
25 (12) 
CRC 
25% 
50% 
0.047 
0.88 
13 (3) 
17 
30 (12) 
H0 (null hypothesis) is the outcome of no interest.  
H1 (alternative hypothesis) is the outcome of interest  
n1 is the number of subjects accrued during Stage 1.  
n2 is the number of subjects accrued during Stage 2, if opened.  
If ≤ r1 responses are observed during Stage 1, the trial study is stopped for futility; otherwise, Stage 2 will 
be opened.  
If ≥ r2 two-stage total responses are observed by the end of Stage 2, then further investigation is warranted.  
 
6 
STUDY CONDUCT 
 
6.1 
Safety Data Monitoring 
 
Safety data from the study is monitored on an ongoing basis via routine pharmacovigilance 
activities. In addition to real time medical review of emergent serious adverse events 
(SAEs), a cross functional sponsor safety review team performs regular periodic aggregate 
data reviews. 
 
7 
STATISTICAL METHODS 
7.1 
Analysis Sets 
7.1.1 
Efficacy Evaluable Population  
All enrolled patients who have measurable disease at baseline, receive at least one dose of 
study drug (telaglenastat or talazoparib), and complete at least one post-baseline tumor 
assessment, will be considered evaluable for efficacy.  In addition, patients who 
discontinued treatment for study-drug related toxicity or for disease-related death also are 


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included in the efficacy evaluable population.  
7.1.2 
Safety Analysis Set 
All patients who receive at least 1 dose of any study-specific treatment (telaglenastat or 
talazoparib) will be included in the analysis of safety.   
7.1.3 
DLT-Evaluable Population in Dose Escalation 
All patients enrolled in the Dose Escalation Part of the study will be DLT evaluable 
excluding the following: 1) Patients who withdraw or are withdrawn from the study prior to 
completing the DLT assessment for any reason other than a DLT; 2) Patients who do not 
receive at least 75% the assigned doses of both telaglenastat and talazoparib, (i.e., 42 doses 
of telaglenastat and 21 doses of talazoparib) in the first 28- day treatment cycle for any 
reason other than a DLT.  
7.2 
Analysis of Study Conduct 
Patient disposition, including analysis populations, major protocol deviations (including 
major deviations of inclusion and/or exclusion criteria), reason for discontinuation from the 
study, reason for telaglenastat discontinuation, reason for talazoparib, expected to continue 
in survival follow-up, and patient survival follow-up status will be summarized by dose 
level, cohort, and overall. 
7.3 
Analysis of Group Comparability 
Demographic and baseline characteristics, including age, sex, race, ethnicity, baseline 
ECOG, and disease characteristics will be summarized by dose level and cohort, and overall 
for the safety analysis set. 
Baseline values are defined as the last available data obtained prior to the patient receiving 
the first dose of any study treatments on C1D1 visit unless otherwise noted. 
Medical history will be presented in by-patient listing. 
7.4 
Efficacy Analysis 
Efficacy analyses will be performed by dose and cohort. Response to treatment will be 
assessed by the Investigator using RECIST v1.1. 
The cohorts are based on patient’s tumor type. Dose escalation patients of the same 
histology that received treatment at the RP2D will be included in the corresponding cohort. 
All efficacy analyses will be based on the Efficacy Evaluable Population. 
The following efficacy endpoints will be analyzed. 
7.4.1 
Clinical Benefit Rate (CBR) 
Clinical Benefit Rate (CBR) will be assessed by dose and cohort where unconfirmed CBR is 
defined as stable disease (SD) per RECIST 1.1 for at least 2 consecutive post-baseline scans 


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per protocol (every 8 weeks +/- 5 days, minimum 102 days from C1D1) or a best response 
of CR/PR per RECIST 1.1 at any time. 
The analysis set for CBR will be the efficacy evaluable population. An estimate of CBR and 
its 95% CI will be calculated with the Clopper-Pearson method.  
7.4.2 
Objective Response Rate (ORR) 
Objective Response Rate (ORR) is defined as the proportion of patients who had an 
objective response per RECIST 1.1. An objective response is defined as either complete 
response (CR) or partial response (PR), as determined by the investigator with use of 
RECIST v1.1.  
The analysis set for ORR (both confirmed and unconfirmed) will be the same as CBR (the 
efficacy evaluable population). An estimate of ORR and its 95% CI will be calculated with 
the Clopper-Pearson method. 
7.4.3 
Progression Free Survival (PFS) 
Progression Free Survival (PFS):  PFS is defined as the time from the first dose date to the 
earlier of either progression of disease per RECIST v1.1 or death from any cause. If the 
disease progression assessment involves more than one date, the earliest date will be used as 
the event date.   
The duration of PFS will be censored at the date of the last radiographic disease assessment 
if any of the following occurs:  
• Patient is alive and progression free at the time of analysis data cutoff. 
• Disease progression or death occurs after missing data (including an 
unevaluable status for overall response assessment) for two consecutive 
radiographic disease assessments. 
• Patient receives non-protocol treatment prior to documentation of disease 
progression.  
Patients missing baseline disease assessment will be censored at the first dose date (C1D1). 
Patients who come off of study for reason other than PD or death should continue to be 
followed up with radiographic assessments until PD by RECIST 1.1, death, withdrawal of 
consent, or initiation of another systemic anti-cancer treatment. Censoring rules are 
summarized in Table 2 
The analysis set for PFS will be the efficacy evaluable population. Kaplan-Meier 
methodology will be used to estimate median PFS for each cohort and construct survival 
curves for visual description. The Brookmeyer-Crowley methodology will be used to 
construct the 95% CI for the median PFS for each cohort (2).  
 
Table 2 The Censor/Event Rules for Progression Free Survival and Duration of 
Responsea 
 
Situation 
Date of Event or  
Censoring 
Outcome 


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No baseline disease assessment 
Date of first dose 
Censored 
No post-baseline assessments and no death 
Date of first dose 
Censored 
No progression and no death 
Date of last evaluable  
tumor assessment 
Censored 
Additional cancer therapy prior to documentation o
disease progression or death 
Date of last evaluable  
tumor assessment  
prior to first new  
cancer therapy 
Censored 
Documented RECIST progression per  
investigator or death within 2 scheduled scan  
intervals following previous evaluable  
radiological tumor assessment 
First date of evaluation  
of overall response of PD  
or death is determined 
Event 
RECIST progression or death documented to  
occur after missing 2 scheduled disease 
assessments (including an overall response of  
non-evaluable) following previous evaluable 
radiological tumor assessment 
Date of last evaluable  
tumor assessment  
with no progression  
prior to the first of  
these missed visits 
Censored 
PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors  
aRECIST progression or death can occur either on study or during the survival follow up period after 
treatment discontinuation for symptomatic deterioration, adverse event, or other reason not related to disease 
and prior to the initiation of new cancer therapy. 
 
7.5 
Dose-Limiting Toxicity 
DLT incident rate will be analyzed by dose level for the DLT-Evaluable population. 
Definition of DLT: The occurrence of any of the following toxicities during Cycle 1 of Part 
1, Dose Escalation, will be considered a DLT, if judged by the Investigator to be related 
(possibly or probably) to administration of study treatment: 
Non-Hematologic Dose-Limiting Toxicity 
• Any ≥ Grade 4 non-hematologic toxicity 
• Grade 3 non-hematologic toxicity with the exception of the following: 
o Grade 3 fatigue 
o Grade 3 nausea/vomiting that responds within 24 hours after initiating 
maximal supportive care 
o Grade 3 rash or itching that resolves to ≤ Grade 1 within 2 weeks 
• Any clinically meaningful Grade 3 non-hematologic laboratory value if medical 
intervention (other than electrolyte repletion) is required to treat the patient, OR the 
abnormality leads to hospitalization, OR the abnormality persists for > 1 week 
except: 
o Grade 3/4 elevation in serum amylase and/or lipase not associated with 
clinical or radiological evidence of pancreatitis 
Hematologic Dose-Limiting Toxicity 
• Grade ≥ 3 febrile neutropenia (as an oral temperature of > 38.3°C or two consecutive 


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readings of > 38.0°C for 2 hours and an ANC of <0.5 × 109/L, or expected to fall 
below 0.5 × 109/L) 
• Grade ≥ 4 anemia 
• Grade ≥ 4 neutropenia (absolute neutrophil count < 500/µL) lasting > 7 days 
• Grade ≥ 4 thrombocytopenia 
• Grade 3 thrombocytopenia associated with: 
o A bleeding event that requires a platelet transfusion 
OR 
o A life-threatening bleeding event occurring due to low platelet count which 
results in urgent intervention 
 
7.6 
Safety 
Unless specified otherwise, the safety analyses described in this section will be conducted 
for the safety analysis set and all safety variables will be analyzed by dose level and cohort. 
Dose escalation patients of the same histology that received treatment at the RP2D will be 
included in the corresponding cohort. 
 
7.6.1 
Treatment Exposure 
Extent of exposure to both study treatments (telaglenastat and talazoparib), including 
treatment duration, total dose received, number of cycles, dose intensity, relative dose 
intensity, and absolute dose intensity will be evaluated by summary statistics (N, mean, 
standard deviation, median, minimum and maximum) for safety analysis set.  Percent of 
patients with dose delays and reductions will be calculated.   
Exposures will be summarized by dose and cohort for telaglenastat and talazoparib 
separately. 
7.6.2 
Prior and Concomitant Medications 
Prior and on-study concomitant medications will be listed and summarized by Anatomical 
Therapeutic Chemical (ATC) Level 1 and Preferred Name using the WHODDE, Version 
March 1, 2019 for the safety analysis set.    
7.6.2 
Prior Systemic Therapies 
Prior systemic therapies will be listed and summarized by Anatomical Therapeutic 
Chemical (ATC) Level 1 and Preferred Name using the WHODDE, Version March 1, 2019 
for the safety analysis set.    
7.6.3 
Adverse Events 
Verbatim description of adverse events will be coded to Preferred Term (PT) and grouped 
according to System Organ Class (SOC) using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 22.0 and graded by the investigator according to NCI CTCAE 
v5.0 (National Cancer Institute Common Terminology Criteria for Adverse Events, Version 
5.0). Treatment-emergent AEs (TEAEs) are defined as AEs started or worsened on or after 
first dose of either telaglenastat or talazoparib and will be tabulated. The number and 
proportion of patients reporting a given TEAE will be tabulated according to the worst 
severity grade reported.  Separate tables will be constructed for the following: 


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a) 
all reported TEAE’s,  
b) 
serious TEAEs (treatment-emergent SAEs) 
c) 
Grade >3 TEAEs,  
d) 
Grade 5 TEAEs 
e) 
TEAE’s leading to permanent discontinuation of study treatments.  
The above tables will also be presented for TEAEs judged to be related to either study 
treatment. In addition, TEAEs leading to interruption or reduction of study treatment might 
also be summarized if needed. 
Multiple occurrences of the same event will be counted once at the maximum grade. In 
order to accurately summarize the true TEAE rate, all TEAE summaries will not count 
grade 5 events for patients who died due to progressive disease. 
All listings of adverse events will include both TEAEs and non-TEAEs. 
Deaths reported during the study treatment period will be listed and summarized by cause. 
7.6.4 
Laboratory Data 
Laboratory variables will be examined using mean change in value from baseline to 
scheduled time points. The baseline value of a variable is defined as the last value obtained 
on or before the date and time of the first dose of telaglenastat and talazoparib. Proportion 
of patients with laboratory measurement outside the normal range and by NCI CTCAE 
v5.0 grade will be summarized. Shift tables will be presented for shifts from baseline to worst 
post-baseline by NCI CTCAE v5.0 grade. Coagulation will be summarized at baseline only. 
Urinalysis will be listed only. 
7.6.5 
ECG and Vital Signs 
Electrocardiogram (ECG), weight, and vital signs will be summarized by changes from 
baseline to scheduled time points using descriptive statistics. Baseline is defined the same 
way as for laboratory measurements. 
7.7 
Change of Planned Analyses 
Sparse sampling was used to collect PK plasma samples in this trial. Since we have not 
build a population PK model for telaglenastat, PK parameters which are listed as secondary 
endpoints in section 5.2.2 will not be calculated or reported.   
Since an abbreviated report with a focus on safety is planned, exploratory endpoints in 
Section 5.2.3 will not be performed as well. 
7.8 
Missing Data 
Patients with missing response assessment will be treated as non-responders in analyzing 
ORR and CBR. Table 2 will be followed to censor these patients in analyzing PFS. 
Missing laboratory, ECG and vital sign measurements will not be imputed and included in 
the analysis. AEs with missing or partial start date that cannot be definitively determined to 
be earlier than first dose will be treated as TEAE. AEs with missing relationship to study 
treatments will be treated as related.


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8 
REFERENCES 
 
1. 
Protocol CX-839-011 Amendment 1, dated 10 Apr 2019 
2. 
Brookmeyer, R. and Crowley, J. (1982) A confidence interval for the median 
survival time. Biometrics, 38, 29-41. doi:10.2307/2530286 
3. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 
1989;10:1-10. 
 
4. 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. Statistical principles for clinical trials 
(E9). International Conference on Harmonization; 1998. 
 
5. 
Data Standards: Position on Use of SI Units for Lab Tests. U.S Food and Drug 
Administration; 25 October 2013. Available 
from: http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/ucm37 
2553.htm 
 
6. 
U.S. Department of Health and Human Services. Common Terminology Criteria 
for Adverse Events (CTCAE), Version 5.0. 05 January 2018.  
 


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ATTACHMENT 1:  SCHEDULE OF STUDY ASSESSMENTS  
 
 


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