Conditions: Triple Negative Breast Cancer TNBC - Triple-Negative Breast Cancer
Keywords: African ancestry African American CB-839 Glutaminase Inhibitor Glutaminase TNBC Tumor Metabolism Glutamine
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
CX-839-007 is an open-label Phase 2 study of the combination of CB-839 with paclitaxel in participants of African ancestry and non-African ancestry with advanced triple negative breast cancer. Multiple single-arm cohorts will be enrolled in which 800 mg twice daily (BID) CB-839 will be administered in combination with the full approved dose of paclitaxel.

Detailed description:
Participants will be enrolled into 4 cohorts, as follows:

* Cohort 1: patients of African ancestry with 2 or more lines of prior therapy for metastatic disease
* Cohort 2: patients of African ancestry with no prior lines of therapy for metastatic disease
* Cohort 3: same as cohort 1 but in patients of non-African ancestry
* Cohort 4: same as cohort 2 but in patients of non-African ancestry

Arms:
arm 1: Intervention = Paclitaxel- CB-839 (Pac-CB) combination

1. Participants must self-identify as African ancestry (includes African American).
2. At least 2 prior lines of systemic therapy for advanced/metastatic disease including a taxane.

   * Prior taxane (paclitaxel, docetaxel, or nab-paclitaxel) for advanced/metastatic disease is required but must not have been received in the immediate prior line of therapy.
   * Systemic neoadjuvant and/or adjuvant therapy is considered a line of therapy for advanced/metastatic disease if the time to recurrence from completion of treatment was ≤ 12 mo. arm 2: Intervention = Pac-CB combination

1. Participants must self-identify as African ancestry (includes African American).
2. No prior systemic therapy for advanced or metastatic disease.

   * Systemic neoadjuvant or adjuvant therapy, including taxane, is allowed if time to recurrence was \> 12 mo. arm 3: Intervention = Pac-CB combination

1. Participants do not self-identify as African ancestry.
2. Otherwise have the same criteria as Cohort 1. arm 4: Intervention = Pac-CB combination

1. Participants do not self-identify as African ancestry.
2. Otherwise have the same criteria as Cohort 2.

Interventions: intervention 1: Paclitaxel intervention 2: CB-839
Intervention descriptions: intervention 1: standard weekly paclitaxel in 28-day cycles intervention 2: CB-839 administered as oral tablets twice daily (BID)

Protocol document:
Prot_000.pdf: 
CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
1 
Title  
A Multicenter Phase 2 Study of the Glutaminase Inhibitor CB-839 in 
Combination with Paclitaxel in Patients with Advanced Triple Negative 
Breast Cancer (TNBC) Including Patients of African Ancestry and Non-
African Ancestry 
Protocol Number 
CX-839-007 
IND Number 
118397 
Sponsor 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Sponsor Contact  
 
Clinical Trial Manager 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Phone:  
 
Date/Version 
06 January 2017 / Original Protocol 
 
 
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. 
 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
2 
1.0 
TABLE OF CONTENTS 
1.0 
TABLE OF CONTENTS ..................................................................................................2 
2.0 
LIST OF TABLES .............................................................................................................5 
3.0 
LIST OF FIGURES ...........................................................................................................5 
4.0 
CONTACTS .......................................................................................................................6 
CORE PROTOCOL ......................................................................................................................7 
5.0 
OBJECTIVES AND ENDPOINTS ..................................................................................7 
6.0 
SAMPLE SIZE ...................................................................................................................8 
7.0 
STUDY DESIGN ................................................................................................................8 
8.0 
INCLUSION / EXCLUSION CRITERIA .......................................................................9 
8.1 
Inclusion Criteria .....................................................................................................9 
8.2 
Exclusion Criteria ..................................................................................................10 
PROTOCOL DETAILS ..............................................................................................................12 
9.0 
BACKGROUND AND RATIONALE ...........................................................................12 
9.1 
Introduction ............................................................................................................12 
9.2 
Triple-Negative Breast Cancer (TNBC) ................................................................13 
9.3 
Glutaminase Inhibitor CB-839 ...............................................................................13 
9.4 
Preclinical Activity of CB-839 ..............................................................................14 
9.5 
Previous Human Experience ..................................................................................15 
9.6 
Safety .....................................................................................................................16 
9.7 
Efficacy of CB-839 + Paclitaxel ............................................................................18 
10.0 
PROCEDURES ................................................................................................................21 
10.1 
Screening................................................................................................................21 
10.1.1 
Prior Treatment .....................................................................................21 
10.1.2 
Concomitant Treatment .........................................................................21 
10.1.3 
Screening Evaluation ............................................................................22 
10.2 
Other Schedules and Procedures ............................................................................23 
10.3 
End of Treatment (EOT) ........................................................................................24 
10.4 
Follow Up ..............................................................................................................25 
10.5 
Screen Failures .......................................................................................................25 
10.6 
Safety Evaluation ...................................................................................................25 
10.6.1 
Physical Examination ............................................................................25 
10.6.2 
Vital Signs .............................................................................................26 
10.6.3 
Electrocardiograms ...............................................................................26 
10.6.4 
Safety Laboratory Determinations ........................................................26 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
3 
10.7 
Biomarker Samples ................................................................................................26 
10.7.1 
Archival Tumor Biopsy Samples ..........................................................27 
10.7.2 
Other Tumor Biopsy Samples ...............................................................27 
10.7.3 
Saliva and Whole Blood Collection for Biomarker Analysis ...............27 
10.8 
Neuropathy Assessment .........................................................................................27 
10.9 
Pharmacokinetic Evaluation ..................................................................................27 
10.9.1 
Blood Collection ...................................................................................27 
10.9.2 
Bioanalytical Methodology ...................................................................28 
11.0 
DOSE MODIFICATION AND MANAGEMENT OF TOXICITIES ........................28 
11.1 
Potential Toxicities ................................................................................................28 
11.1.1 
CB-839 ..................................................................................................28 
11.1.2 
Paclitaxel ...............................................................................................28 
11.1.3 
Pac-CB Combination ............................................................................29 
11.2 
Dose Modifications and Toxicity Management .....................................................29 
11.2.1 
Dose Modification Guidelines ..............................................................29 
11.2.2 
Resumption of Study Treatment ...........................................................30 
11.3 
Dose Adjustments and Missed doses .....................................................................30 
11.4 
Discontinuation of Treatment and Withdrawal of Patients....................................30 
12.0 
TEST ARTICLE/STUDY DRUG ...................................................................................32 
12.1 
Test Article Administration ...................................................................................32 
12.2 
Packaging and Labeling .........................................................................................33 
12.3 
Storage and Stability ..............................................................................................33 
12.4 
CB-839 Accountability, Reconciliation, and Return .............................................33 
12.5 
Test Article Compliance ........................................................................................34 
13.0 
MEASURES TO MINIMIZE/AVOID BIAS ................................................................34 
14.0 
STATISTICAL ANALYSIS ...........................................................................................34 
14.1 
General Study Design ............................................................................................35 
14.1.1 
Determination of Sample Size ..............................................................35 
14.2 
Analysis Populations ..............................................................................................36 
14.2.1 
Efficacy Analysis Set ............................................................................36 
14.2.2 
Safety Analysis Set ...............................................................................37 
14.3 
Efficacy Analysis ...................................................................................................37 
14.4 
Treatment Exposure and Medication Compliance .................................................38 
14.5 
Safety Analysis ......................................................................................................39 
14.6 
Analyses and Effects of Genetic and other Background Factors ...........................39 
15.0 
ADVERSE EVENTS .......................................................................................................40 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
4 
15.1 
Definitions..............................................................................................................40 
15.2 
Recording and Reporting .......................................................................................44 
15.3 
Serious Adverse Event Reporting ..........................................................................45 
16.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION .............................46 
17.0 
INFORMED CONSENT .................................................................................................46 
18.0 
PROTOCOL AMENDMENTS ......................................................................................47 
19.0 
QUALITY CONTROL AND ASSURANCE.................................................................47 
20.0 
DIRECT ACCESS, DATA HANDLING, AND RECORD KEEPING ......................47 
20.1 
Investigator ............................................................................................................47 
20.2 
Sponsor ..................................................................................................................48 
21.0 
PRE-STUDY DOCUMENTATION ...............................................................................48 
22.0 
RECORDS RETENTION ...............................................................................................49 
23.0 
AUTHORSHIP AND ACCOUNTABILITY .................................................................49 
24.0 
LIST OF ABBREVIATIONS .........................................................................................51 
25.0 
REFERENCES .................................................................................................................53 
ATTACHMENT 1:  SCHEDULE OF STUDY ASSESSMENTS ...........................................54 
ATTACHMENT 2:  CLINICAL LABORATORY TESTS .....................................................56 
ATTACHMENT 3:  RECIST CRITERIA VERSION 1.1 .......................................................57 
ATTACHMENT 4:  CYP2C9 .....................................................................................................69 
 
 
 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
5 
2.0 
LIST OF TABLES 
Table 9.6-1: Adverse Events in ≥ 5 Patients on Monotherapy CB-839 (600-1000 mg BID) ........16 
Table 9.6-2: Adverse Events in ≥ 3 Patients Receiving CB-839 + Paclitaxel ...............................17 
Table 9.7-1: Efficacy of CB-839 + Paclitaxel in TNBC Patients in Phase 1.................................19 
Table 11.4-1: Dose Modifications Guidelines for Hematologic and Non-Hematologic 
Toxicity ............................................................................................................31 
Table 11.4-2: Dose Reductions for CB-839 ..................................................................................32 
Table 14.1-1: Design of the CX-839-007 Cohorts.........................................................................36 
 
 
 
 
3.0 
LIST OF FIGURES 
Figure 7.0-1.  Structure of CX-839-007...........................................................................................8 
Figure 9.4-1.  Antiproliferative and pro-apoptotic effects of CB-839 in breast cancer cell 
lines in vitro. ....................................................................................................14 
Figure 9.4-2.  Inhibition of human tumor xenografts in vivo. ........................................................15 
Figure 9.7-1.  Duration of treatment and tumor response for patients receiving CB-839 + 
paclitaxel in Phase 1.........................................................................................21 
 
 
 






CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
8 
6.0 
SAMPLE SIZE 
Approximately 112 patients are expected in total to be enrolled and treated across four cohorts.  
If a patient does not meet criteria for inclusion into the Efficacy Evaluable Population (Section 
14.2.1), the patient will be considered to be not evaluable for efficacy and will be replaced.   
7.0 
STUDY DESIGN 
Protocol CX-839-007 is a Phase 2 open-label study of the combination of CB-839 with paclitaxel 
with the design shown in Figure 7.0-1.  Multiple single-arm cohorts will be enrolled in which 
800 mg BID CB-839 will be administered in combination with the full approved dose of 
paclitaxel.  
 
Figure 7.0-1.  Structure of CX-839-007.  *TTR = Time to recurrence 
 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
9 
8.0 
INCLUSION / EXCLUSION CRITERIA 
8.1 Inclusion Criteria 
1. Informed Consent 
a. Ability to provide written informed consent in accordance with federal, local, and 
institutional guidelines. 
2. Target Population 
a. Female patients ≥ 18 years of age 
b. TNBC, defined as ER and PR negative (< 1% by immunohistochemistry) and 
HER2-negative (immunohistochemistry 0 to 1+ or fluorescence in situ 
hybridization [FISH] negative) 
c. Metastatic disease or locally-advanced disease not amenable to curative intent 
treatment 
d. ECOG Performance Score 0 - 1 
e. Estimated Life Expectancy of at least 3 mo 
f. Measurable Disease per RECIST 1.1 as determined by the Investigator (see 
Attachment 3) 
3. Laboratory Findings 
a. Calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation: 
CCr = {((l40 – age) x actual body weight)/(72 x SCr)} x 0.85 (if female)  
[Serum creatinine (SCr) in mg/dL; body weight in kg] 
b. ANC ≥ 1,200/mm3, Hb ≥ 9.0 g/dL, and platelet count ≥ 80,000/mm3.  Transfusions 
and growth factors must not be used within 2 weeks prior to C1D1 in order to meet 
these requirements.  
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × 
upper limit of normal [5x upper limit of normal (ULN) if liver metastases].  
d. Total bilirubin ≤ 1.5 x the ULN. For patients with Gilbert’s disease ≤ 3 mg/dL 
(≤ 51.3 μmol/L). 
4. Reproductive Status 
a. Patients of childbearing potential must have a negative serum or urine pregnancy 
test within 3 days prior to the first dose of study drug and agree to use dual methods 
of contraception during the study and for a minimum of 3 mo following the last 
dose of study drug.  Post-menopausal women (> 45 years old and without menses 
for > 1 year) and surgically sterilized women are exempt from these requirements.   


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
10 
5. Other Inclusion Criteria 
a. Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior 
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive 
therapy.  
6. Cohort-specific Inclusion Criteria 
Cohort 1 – African ancestry with 3rd line+ Metastatic  
a. Patients must self-identify as African ancestry (AA; includes African American).  
b. At least 2 prior lines of systemic therapy for advanced/metastatic disease including 
a taxane. 
i. 
Prior taxane (paclitaxel, docetaxel, or nab-paclitaxel) for advanced/metastatic 
disease is required but must not have been received in the immediate prior line 
of therapy. 
ii. 
Systemic neoadjuvant and/or adjuvant therapy is considered a line of therapy 
for advanced/metastatic disease if the time to recurrence from completion of 
treatment was ≤ 12 mo. 
Cohort 2 – African ancestry 1st line Metastatic 
a. Patients must self-identify as African ancestry (includes African American). 
b. No prior systemic therapy for advanced or metastatic disease. 
i. 
Systemic neoadjuvant or adjuvant therapy, including taxane, is allowed if time 
to recurrence was > 12 mo.  
Cohort 3 – Non-African ancestry 3rd line+ Metastatic  
a. Patients do not self-identify as African ancestry. 
b. Otherwise have the same criteria as Cohort 1. 
Cohort 4 – Non-African ancestry 1st line Metastatic 
a. Patients do not self-identify as African ancestry.  
b. Otherwise have the same criteria as Cohort 2.  
8.2 Exclusion Criteria 
1. Cancer History 
a. Prior treatment with CB-839  
b. Receipt of any anticancer therapy within 4 weeks before C1D1 EXCEPT for the 
following: 
i. 
Targeted/small molecule or investigational therapy within 4 weeks or 5 half-
lives, whichever is shorter. 
ii. 
Radiation therapy for bone metastasis within 2 weeks, any other external 
radiation therapy within 4 weeks before C1D1 or systemic treatment with 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
11 
radionuclides within 6 weeks before 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 a) 
adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of 
the cervix, or c) 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 
d. Known brain metastases or CNS cancer unless adequately treated with radiotherapy 
and/or surgery and stable by symptoms and radiographic imaging and not requiring 
corticosteroids for at least 2 mo before C1D1. 
2. Concurrent Conditions 
a. Unable to receive medications PO or any condition that may prevent adequate 
absorption of oral study medication including refractory nausea and vomiting, 
uncontrolled diarrhea, malabsorption, significant small bowel resection or gastric 
bypass surgery, use of feeding tubes. 
b. Major surgery within 28 days prior to C1D1. 
c. Unstable/inadequate cardiac function: 
i. 
Symptomatic ischemia or myocardial infarction within the previous 6 mo 
ii. 
Uncontrolled or clinically significant conduction abnormalities (e.g., 
ventricular tachycardia on antiarrhythmics are excluded, 1st degree AV block 
or asymptomatic LAFB/RBBB are eligible) 
iii. 
Congestive heart failure (New York Heart Association class III to IV) 
d. Known active infection with HIV or Hepatitis B or C virus 
e. Any condition including social, psychiatric or medical (including uncontrolled 
significant concurrent illness) that in the opinion of the Investigator could interfere 
with treatment or protocol-related procedures 
f. Patients with a known hypersensitivity to Cremophor®-based agents 
g. Patients who are pregnant or lactating 
3. Cohort-specific Exclusion Criteria 
Cohorts 1 and 3: 
a. Taxane (paclitaxel, docetaxel or nab-paclitaxel) in the immediate prior metastatic 
line of therapy 
Cohorts 2 and 4:  
a. Prior metastatic therapy 
 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
12 
PROTOCOL DETAILS 
9.0 
BACKGROUND AND RATIONALE 
9.1 Introduction 
The glutaminase inhibitor CB-839 is highly active in preclinical studies in triple negative breast 
cancer (TNBC) (Gross 2014); strong anti-tumor activity correlates with high expression of the 
glutaminase 1 enzyme and high glutaminolytic activity in TNBC tumor cell lines.  In tumor 
xenografts, the combination of CB-839 and paclitaxel shows additive to synergistic activity in 
comparison to either agent as monotherapy.  In CX-839-001, an ongoing Phase 1 study, 28 
patients with advanced treatment-refractory TNBC have received CB-839 + paclitaxel as of the 
23 Nov 2016 data cut-off.  No maximum tolerated dose and no significant safety signals were 
identified, and the Recommended Phase 2 Dose (RP2D) and schedule were CB-839 at 800 mg 
PO BID continuously with paclitaxel at 80 mg/m2 IV on Days 1, 8, and 15 every 28 days.  The 
Phase 1 population received a median of 4.5 prior lines of therapy including 3 prior lines of 
therapy for advanced/metastatic disease.  Prior taxane had been received by 82% of patients and 
39% of patients had received taxane for advanced or metastatic disease.  In 23 response-
evaluable patients, the combination of CB-839 + paclitaxel had an overall response rate (ORR; 
RECIST 1.1) of 22% including 28% (n=5/18) in patients previously treated with a taxane and 
30% (n=3/10) in patients who had previously received a taxane for advanced or metastatic 
disease.  Additionally, in 8 patients with reported African ancestry, there was a 50% ORR to the 
combination regimen of CB-839 and paclitaxel.  
While these response data represent a small sample size and are subject to uncertainty, there are 
biologic mechanisms by which CB-839 could work to prevent or reverse taxane resistance in 
patients and by which CB-839 could be more active in patients with African ancestry in 
particular.  It has been reported that taxane-induced ER stress causes upregulation of the 
ubiquitin ligase RNF5 which, in turn, leads to degradation of the glutamine transporters SLC1A5 
and SLC38A2 and a decrease in intracellular availability of the critical amino acid glutamine and 
ultimately autophagy and cell death.  Taxane resistance has been demonstrated in vitro by RNF5 
depletion and overexpression of SLC1A5 and SLC38A2.  Interestingly, while not linked directly 
to taxane response, the prognostic significance of the RNF5-SLC1A5/38A2 axis in human breast 
cancer was demonstrated in a tissue microarray (TMA) of 538 breast cancer core biopsies, all of 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
13 
which had undergone pathological assessment and included annotated clinical outcomes 
(Jain 2015).  In this analysis, high SLC1A5 expression indicative of high glutamine uptake was 
associated with a significant decrease in disease free survival (p value of 7.5 x 10-5).  High 
glutamine utilization by TNBC tumors from patients of African ancestry is suggested by 
metabolomic results showing a high glutamate to glutamine ratio (the product and substrate of 
glutaminase, respectively) in comparison to TNBC tumors from patients of European ancestry 
(Terunuma 2014).  Furthermore, the GG genotype of a SNP within the non-coding RNA CCAT2 
that has a high prevalence in subjects of African ancestry has been shown to promote the 
expression of the more catalytically active GAC splice variant of GLS (Redis 2016). 
9.2 Triple-Negative Breast Cancer (TNBC) 
TNBC is an aggressive histological subtype with limited treatment options and very poor 
prognosis following progression after standard chemotherapeutic regimens.  Patients with a 
diagnosis of TNBC usually receive a combination of surgery with adjuvant or neoadjuvant 
chemotherapy and/or radiation therapy for primary sites of cancer.  One standard regimen is 
doxorubicin and cyclophosphamide followed by paclitaxel in the adjuvant or neoadjuvant 
setting, although other regimens are also used (Stover 2016).  Resistance to current standard 
therapies, such as anthracyclines or taxanes, limits the available options for previously-treated 
patients with metastatic TNBC to a small number of non-cross-resistant regimens, and there is 
currently no preferred standard chemotherapy.  Duration of response is usually short, with rapid 
relapse very common and median survival of just 13 mo.  The present study will evaluate the 
combination of CB-839 and paclitaxel in metastatic TNBC patients of African ancestry (AA) and 
non-AA patients who are heavily pretreated (3rd line and later) as well as patients who have 
received no prior therapy for advanced/metastatic disease (1st line). 
9.3 Glutaminase Inhibitor CB-839 
CB-839 is a potent and selective reversible inhibitor of glutaminase activity (Gross 2014).  It is 
an allosteric and noncompetitive inhibitor of glutaminase, but does not inhibit the liver isoform, 
glutaminase-2.  Incubation of recombinant human glutaminase with CB-839 results in time-
dependent and slowly reversible inhibition of glutaminase activity (IC50 = 34 nM with 1 hr pre-
incubation).  Glutaminase inhibition is associated with antiproliferative activity in human TNBC 






CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
16 
001.  An additional 59 patients received CB-839 dosed on the TID schedule ranging from 100 to 
1000 mg TID. 
A dose-related increase in exposure was observed and the half-life of CB-839 was approximately 
4 hr.  Robust inhibition of glutaminase (≥ 90%) was demonstrated in platelets at exposures that 
are maintained in most patients at interdose trough time points.  Tumor biopsies also 
demonstrated robust glutaminase inhibition (> 75% for most patients). Further information is 
available in the CB-839 Investigator’s Brochure.  
9.6 Safety 
CB-839 was well tolerated, with no maximum tolerated dose (MTD) identified.  On the 
recommended dosing regimen (BID with food) in the solid tumor CX-839-001 study, relatively 
few AEs ≥ Grade 3 were reported (Table 9.6-1).  A RP2D was established at 800 mg BID, based 
on the PK, PDn and safety profile of CB-839. 
Table 9.6-1: Adverse Events in ≥ 5 Patients on Monotherapy CB-839 (600-1000 mg BID) 
ADVERSE EVENTS (≥5 Patients) 
Number (%) of patients 
MedDRA Preferred Term 
All Grades 
≥ Grade 3 
 (N=88) 
 (N=88) 
Patients with Any TEAE  
82 (93) 
31 (35) 
FATIGUE 
27 (31) 
1 (1.1) 
NAUSEA 
26 (30) 
1 (1.1) 
ALANINE AMINOTRANSFERASE INCREASED 
15 (17) 
3 (3.4) 
PHOTOPHOBIA 
14 (16) 
0 
CONSTIPATION 
13 (15) 
0 
VOMITING 
13 (15) 
2 (2.3) 
ANAEMIA 
12 (14) 
5 (5.7) 
ASPARTATE AMINOTRANSFERASE 
INCREASED 
12 (14) 
2 (2.3) 
DECREASED APPETITE 
12 (14) 
0 
DYSPNOEA 
11 (13) 
2 (2.3) 
BLOOD ALKALINE PHOSPHATASE INCREASED 
10 (11) 
2 (2.3) 
BLOOD CREATININE INCREASED 
10 (11) 
0 
INSOMNIA 
9 (10) 
0 
GAMMA-GLUTAMYLTRANSFERASE 
INCREASED 
8 (9.1) 
2 (2.3) 
HYPERCALCAEMIA 
8 (9.1) 
1 (1.1) 
PAIN 
8 (9.1) 
0 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
17 
WEIGHT DECREASED 
8 (9.1) 
0 
HEADACHE 
7 (8.0) 
0 
HYPOMAGNESAEMIA 
7 (8.0) 
0 
THROMBOCYTOPENIA 
7 (8.0) 
0 
ABDOMINAL PAIN 
6 (6.8) 
1 (1.1) 
FALL 
6 (6.8) 
2 (2.3) 
BACK PAIN 
5 (5.7) 
0 
HYPONATRAEMIA 
5 (5.7) 
2 (2.3) 
OEDEMA PERIPHERAL 
5 (5.7) 
0 
PRURITUS 
5 (5.7) 
0 
 
CB-839 has been administered with paclitaxel in a total of 27 safety-evaluable patients on the 
CX-839-001 clinical trial as of 25 Oct 2016.  The combination was well tolerated, with the 
majority of ≥ Grade 3 AEs similar to those seen previously with paclitaxel alone (Table 9.6-2). 
Table 9.6-2: Adverse Events in ≥ 3 Patients Receiving CB-839 + Paclitaxel 
ADVERSE EVENTS (≥ 3 Patients) 
Number (%) of patients 
MedDRA Preferred Term 
All Grades 
≥ Grade 3 
 (N=27) 
 (N=27) 
Patients with Any TEAE  
23 (85) 
12 (44) 
ALOPECIA 
7 (26) 
0 
FATIGUE 
7  (26) 
1  (3.7) 
NAUSEA 
5  (19) 
0 
VOMITING 
5  (19) 
0 
ANAEMIA 
4  (15) 
1  (3.7) 
BACK PAIN 
4  (15) 
0 
DYSPNOEA 
4  (15) 
1  (3.7) 
NEUTROPHIL COUNT DECREASED 
4  (15) 
3  (11) 
PHOTOPHOBIA 
4  (15) 
0 
ALANINE AMINOTRANSFERASE INCREASED 
3  (11) 
0 
ASPARTATE AMINOTRANSFERASE 
INCREASED 
3  (11) 
0 
CONSTIPATION 
3  (11) 
0 
DIARRHOEA 
3  (11) 
0 
HYPERGLYCAEMIA 
3  (11) 
0 
MYALGIA 
3  (11) 
0 
NEUTROPENIA 
3  (11) 
3  (11) 
OEDEMA PERIPHERAL 
3  (11) 
0 
OROPHARYNGEAL PAIN 
3  (11) 
0 
WHITE BLOOD CELL COUNT DECREASED 
3  (11) 
0 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
18 
Please refer to the most recent CB-839 Investigator’s Brochure for additional information from 
the Phase 1 studies. 
9.7 Efficacy of CB-839 + Paclitaxel 
The combination of CB-839 + paclitaxel is being evaluated in TNBC patients as part of the 
ongoing Phase 1 study CX-839-001.    
Five of 23 efficacy-evaluable patients, all with prior paclitaxel treatment, have shown PRs and an 
additional 9 have had stable disease (SD) for an overall Disease Control Rate (DCR = CR + PR 
+ SD) per RECIST v1.1 criteria of 61% (Table 9.7-1). All of the responding patients were treated 
at the 600 or 800 mg BID dose schedule and the DCR at these doses was 63 and 75%, 
respectively.   
Eighteen of 23 (78%) efficacy-evaluable patients on study received taxanes in the metastatic 
setting (10 patients) or in the neoadjuvant/adjuvant setting (8 patients).  Despite this prior 
treatment, 10 of 18 patients (56%) showed disease control from CB-839 + paclitaxel (Table 9.7-1 
and Figure 9.7-1, Panels B and C).   
Of particular interest, four of eight efficacy-evaluable patients of African ancestry treated with 
CB-839 + paclitaxel achieved PRs (50%) (Table 9.7-1).  These four patients had a median of 4 
prior treatments in the metastatic setting (range 1-7) and all four had experienced progressive 
disease on prior taxane therapy, three in the metastatic setting and one in the neoadjuvant setting.  
Patients with African ancestry also showed the deepest responses to the combination (Figure 9.7-
1, Panels D and E). 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
19 
   
Table 9.7-1: Efficacy of CB-839 + Paclitaxel in TNBC Patients in Phase 1 
 
 
By Dose 
By Prior Taxane 
By Ancestry 
Total 
400 mg 
600 mg 
800 mg 
Adv/Met 
Neo/Adj only 
None 
African 
Non-African 
Total Enrolled 
28 
7 
11 
10 
11 
12 
5 
8 
20 
RECIST Evaluable (N) 
23 
7 
8 
8 
10 
8 
5 
8 
15 
PR 
5 (22) 
0 
3 (38) 
2 (25) 
3 (30) 
2 (25) 
0 
4 (50) 
1 (6.7) 
SD 
9 (39) 
3 (43) 
2 (25) 
4 (50) 
2 (20) 
3 (38) 
4 (80) 
1 (13) 
8 (53) 
PD 
9 (39) 
4 (57) 
3 (38) 
2 (25) 
5 (50) 
3 (38) 
1 (20) 
3 (38) 
6 (40) 
 DCR (PR + SD) 
14 (61) 
3 (43) 
5 (63) 
6 (75) 
5 (50) 
5 (63) 
4 (80) 
5 (63) 
9 (60) 
Not evaluable (N) 
5 
0 
3 
2 
1 
4 
0 
0 
5 
Discontinued before scan 
2 
0 
1 
1 
0 
2 
0 
0 
2 
No scans: Too early 
3 
0 
2 
1 
1 
2 
0 
0 
3 
 
 




CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
21 
 
Figure 9.7-1.  Duration of treatment and tumor response for patients receiving CB-839 + paclitaxel 
in Phase 1. A) Swim lane plot for duration of treatment with best response, prior taxane treatment, and 
ancestry indicated, B) Waterfall plot of best response to therapy by prior taxane treatment, C) Spider plot 
of response duration by prior taxane treatment, C) Waterfall plot of best response to therapy by prior 
taxane therapy, D) Waterfall plot of best response to therapy by ancestry, and E) Spider plot of response 
duration by ancestry. 
10.0 
PROCEDURES 
This section describes evaluations to be performed during the different treatment periods of this 
study.  All patients must sign an IRB-approved informed consent prior to starting any protocol 
specific procedures, including screening procedures.  During the consent process, the person 
obtaining consent must inform the patient of all elements of informed consent.  Patients must 
also meet the inclusion and exclusion criteria to be enrolled in the study. 
10.1 
Screening 
To determine a patient’s eligibility patients will undergo required screening evaluations as 
outlined in Attachment 1. 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 also meet the inclusion and exclusion criteria to be enrolled in the study. 
10.1.1 Prior Treatment 
All previous cancer treatments, including systemic therapies, radiation and/or surgical 
procedures, must be recorded on the patients’ electronic case report forms (eCRF). 
10.1.2 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.  During the study, if the use of any 
concomitant treatment becomes necessary (e.g., for treatment of an adverse event), 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. 
Use of investigational therapeutic agents other than the study drugs, CB-839 and paclitaxel, is 
NOT permitted while the patient is on study. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
22 
 
CB-839 is metabolized by human hepatocytes primarily through amide hydrolysis.  CB-839 does 
not appear to induce CYP drug-metabolizing enzymes and only weakly inhibits CYP2C9 (~40-
50% inhibition at 5µM) in vitro.  Although CB-839 is not expected to inhibit CYP2C9 at the 
exposure levels planned, caution is warranted when administering CB-839 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 4. 
Preliminary PK data generated in single agent Phase 1 studies indicate that concomitant use of 
proton pump inhibitors (PPIs) may reduce absorption of CB-839, resulting in decreased systemic 
exposure.  Although patients are not required to discontinue their use of these agents, the strong 
preference is for patients to discontinue PPIs prior to joining the study.  Antagonists of the H2 
histamine receptor (e.g., ranitidine, famotidine, etc.) may be substituted for PPIs.  For patients 
unable to discontinue PPI therapy or that require restarting PPI therapy while on study, 
administration of CB-839 with an acidic beverage (e.g., orange juice) or supplement (e.g., citric 
acid) may be an option.  If an acidic beverage/oral supplement is approved by the Medical 
Monitor to be administered along with the CB-839 dose, it should be recorded on the appropriate 
eCRF, including the identity of the beverage/supplement, dosage, and start and stop dates of 
administration. 
10.1.3 Screening Evaluation 
The following screening assessments must be performed within 28 days before study drug 
administration on C1D1 according to the Attachment 1, Schedule of Study Assessments [with 
the exception of imaging (CT/MRI); scans must be performed within 21 days of study drug 
administration prior to C1D1].  Procedures listed below that are performed as part of the normal 
standard of care and within 28 days prior to C1D1 may be used for screening purposes (unless 
stated otherwise): 
 Demographic information including date of birth, sex, and ethnic origin (this self-
identification of ethnic origin will be used for placement into appropriate cohorts) 
 Medical history including review of prior cancer treatments 
 Review of concomitant medications 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
23 
 
 ECOG performance evaluation 
 Complete physical examination including weight (kg) and height (cm) 
 Vital signs  
 Standard duplicate 12-lead ECG with corrected QT interval by Fridericia’s Formula 
(QTcF) 
 Clinical laboratory evaluation (hematology, coagulation, serum chemistry, and 
urinalysis); see Attachment 2. 
 Serum or urine pregnancy test.  This is only required for patients of child-bearing 
potential and must be negative within 3 days prior to C1D1. 
 Radiographic evaluation of tumor burden (i.e., diagnostic CT or MRI).  Scans must be 
performed within 21 days prior to C1D1.  See additional details in Attachment 1. Note: 
For this study, evaluation of tumor burden must be based on a diagnostic CT or MRI.  
 Archival tumors (if available) or fresh tumor biopsy samples (if archival sample is 
unavailable) will be collected from all patients 
 Whole blood and saliva collection for biomarker and genetic variance analysis 
 Neuropathy assessment 
A patient who meets all of the inclusion criteria will enter the study.  Screen failures will be 
marked in the electronic data capture (EDC) system. 
10.2 
Other Schedules and Procedures 
For other schedules and procedures, please refer to the Schedule of Assessments in Attachment 
1.  Radiographic evaluation of tumor burden (e.g., diagnostic CT/MRI) will occur at Screening 
and approximately every 8 weeks (2 cycles) after study initiation for the first year, or more 
frequently as clinically indicated.  For patients with ≥ SD for at least 13 cycles who are on a 
steady dose for ≥ 2 cycles, study assessments may be reduced to every 3 cycles (i.e., 
approximately every 12 weeks, Cycles 16, 19, 22, etc.) or more frequently as clinically indicated.  
Scans are done locally but must be submitted for central review (please see CT/MRI Scanning 
Guide for additional details). Patients who come off of study for reasons other than progression 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
24 
 
of disease or death should continue to be followed with radiographic assessment until PD by 
RECIST 1.1, death, withdrawal of consent, or initiation of another systemic anti-cancer 
treatment.  Patients may receive study treatment as long as they continue to experience clinical 
benefit in the opinion of the Investigator, or until there is unacceptable toxicity or the need for 
subsequent systemic anticancer treatment.  Treatment may continue after radiographic 
progression of disease per RECIST 1.1 as long as the Investigator believes that the patient is still 
receiving clinical benefit from study treatment and that the potential benefit of continuing study 
treatment outweighs potential risks. 
10.3 
End of Treatment (EOT) 
The End of Treatment (EOT) visit must occur within 28 days of treatment discontinuation and 
prior to initiation of any new anti-cancer therapy/regimen.  All patients discontinuing study 
treatment for any reason should undergo the following EOT procedures: 
 AE monitoring 
 Recording of concomitant medications 
 Vital signs and weight 
 Complete physical examination  
 ECOG performance status evaluation 
 Clinical laboratory values (hematology and serum chemistry) 
 Serum or urine pregnancy test for women of child-bearing potential 
 Duplicate 12-lead ECG with QTcF 
 Neuropathy assessment 
 Radiographic evaluation (e.g., diagnostic CT or MRI) of tumor burden. Patients who 
discontinue from study due to objective findings of progressive disease during an on-
treatment evaluation do not need to have repeat scans.  CT or MRI is required for all 
patients who have not had at least 1 post-baseline image. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
25 
 
10.4 
Follow Up 
Patients who discontinue from study treatment must continue to be followed for collection of 
survival data.  Patients who come off of study for reasons other than progression of disease or 
death should continue to be followed with radiographic assessment until PD by RECIST 1.1, 
initiation of another systemic anti-cancer treatment, death, or withdrawal of consent. Patients 
will be contacted every 3 mo for the first 12 mo after discontinuation and then once every 6 mo 
thereafter.  All reasonable efforts must be made to contact the patient and report their ongoing 
status.  This includes follow up with persons authorized by the patient.  
10.5 
Screen Failures 
Patients who sign an informed consent form and do not receive CB-839 or paclitaxel are defined 
as screen failures.  For all screen failures, the Investigator will enter the screening number, 
patient initials, and reason(s) for screen failure into the electronic data capture (EDC) system.  
These data will also be retained in the Investigator’s study files and can be printed by the site in 
log format at the end of the study.  
10.6 
Safety Evaluation 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, duplicate 12-lead 
electrocardiograms (ECGs; including QTcF intervals), and clinical laboratory test results. 
More frequent safety evaluations may be performed if clinically indicated or at the discretion of 
the Investigator.  All AEs will be recorded from the time of first dose until 28 days after the last 
dose of either study drug. 
10.6.1 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 
exams are required as clinically indicated. Please refer to the Schedule of Study Assessments 
(Attachment 1). 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
26 
 
10.6.2 Vital Signs 
Vital signs (blood pressure, respiratory rate, pulse rate, and temperature) will be obtained in the 
sitting position.  All patients should be sitting for 3-5 min prior to obtaining vital signs. 
10.6.3 Electrocardiograms 
Electrocardiograms will be performed as noted in the Schedule of Study Assessments 
(Attachment 1). Patients should rest in the supine position for at least 5 min before each 12-lead 
ECG recording is started.  Duplicate ECG recordings must be performed using a standard, high-
quality, high-fidelity electrocardiograph machine equipped with computer-based interval 
measurements. The average of values will used for Inclusion/Exclusion and AE reporting 
purposes. 
For safety monitoring purposes, the ECG must be reviewed, signed, and dated promptly by a 
qualified physician (or qualified physician’s assistant or nurse practitioner) and any clinically 
important finding recorded on the appropriate eCRF.  The Investigator is responsible for 
providing the interpretation of all ECGs.  The 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 
10.6.4 Safety Laboratory Determinations 
Laboratory evaluations will be performed as noted in the Schedule of Study Assessments 
(Attachment 1). See Attachment 2 for additional details. 
10.7 
Biomarker Samples 
The following biomarker samples may be used for genetic and genomic testing, and exploratory 
analysis to assess markers of response to treatment. They may also be used for the evaluation of 
additional exploratory biomarkers that are not pre-specified in this protocol based upon new 
scientific literature and/or preclinical data. Collection of any of the following biomarker samples 
may be discontinued by the Sponsor at any time during the study.  


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
27 
 
10.7.1 Archival Tumor Biopsy Samples 
Archival surgical samples or biopsy specimens must be provided from all patients on study who 
have archival tissue available.  Samples should be collected and shipped according to 
instructions provided in the Laboratory Manual.  
10.7.2 Other Tumor Biopsy Samples 
Fresh pre-dose biopsy samples must be provided by all patients on study unless an archival 
sample collected within 3 mo prior to C1D1 can be provided or if the tumor is deemed not safe 
to biopsy. 
Optional on-study and/or EOT tumor biopsies may be obtained for those patients who consent to 
providing samples (e.g., from progressing lesions or patient who is responding).  
Samples should be collected and shipped according to instructions provided in the Laboratory 
Manual. 
10.7.3 Saliva and Whole Blood Collection for Biomarker Analysis 
Saliva and whole blood (via peripheral venipuncture) will be collected at Screening and sent to a 
central lab. Refer to the laboratory manual and Attachment 1 for additional details.  
10.8 
Neuropathy Assessment 
Changes in chemotherapy-induced peripheral neuropathy will be assessed using a validated 
neuropathy assessment tool.  The assessments will occur at Screening, Cycle 3 Day 1, Cycle 6 
Day 1, and at EOT. Refer to the Study Reference Manual for detailed information. 
10.9 
Pharmacokinetic Evaluation 
10.9.1 Blood Collection 
Plasma PK samples will be used to measure concentrations of CB-839 for population 
pharmacokinetic analysis.  Blood samples for PK analysis should be collected at the requested 
time but must be obtained within a 30 min window of the requested time.  The exact actual time 
of collection must be noted in the source documents and eCRFs.  Samples will be collected 
predose and 4 hr postdose on Cycle 1 Day 15, Cycle 2 Day 1, and on Cycle 3 Day 1.  Time of the 
dose taken prior to the PK sample collection should also be noted in the source documents and 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
28 
 
eCRFs. Refer to the laboratory manual and Attachment 1 for additional details. Collection of PK 
samples may be discontinued by the Sponsor at any time during the study. 
10.9.2 Bioanalytical Methodology 
The plasma samples will be analyzed for CB-839 by using a validated liquid chromatography 
tandem mass spectrometry (LC-MS/MS) method of appropriate specificity and sensitivity 
according to Good Laboratory Practices (GLPs). 
11.0 
DOSE MODIFICATION AND MANAGEMENT OF TOXICITIES 
11.1 
Potential Toxicities 
11.1.1 CB-839 
The most frequent adverse events (AEs) considered possibly or probably related to CB-839 
monotherapy on the CX-839-001 were fatigue and nausea (Table 9.6-1).  These have been 
primarily Grade 1/2 AEs that have been manageable and reversible with minimal dose 
modifications or delays.  The most frequent Grade 3/4 AEs considered possibly or probably 
related to monotherapy CB-839 were anemia and LFT elevations.   
11.1.2 Paclitaxel 
Per paclitaxel warning label, anaphylaxis and severe hypersensitivity reactions characterized by 
dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have 
occurred in 2 to 4% of patients receiving TAXOL in clinical trials. Fatal reactions have occurred 
in patients despite premedication. All patients should be pretreated with corticosteroids, 
diphenhydramine, and H2 antagonists per product label or may be treated per local institutional 
guidelines.  Patients who experience severe hypersensitivity reactions to TAXOL should not be 
rechallenged with the drug.  The most frequent important adverse events observed with 
paclitaxel monotherapy are myelosuppression (most notably neutropenia, but also 
thrombocytopenia and anemia), peripheral neuropathy, hypersensitivity reactions (mostly low 
grade) and mild to moderate GI symptoms (nausea/vomiting, diarrhea, mucositis).   


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
29 
 
11.1.3 Pac-CB Combination 
In 17 safety-evaluable patients treated during the Phase 1 evaluation of CB-839 + paclitaxel, the 
most frequent adverse events (AEs) considered possibly or probably related to one or both drugs 
were alopecia, fatigue, neutropenia, vomiting and nausea, typically associated with monotherapy 
paclitaxel treatment (Table 9.6-2).  Low-grade photophobia or photopsia have previously been 
seen with monotherapy CB-839.  The most frequent Grade 3/4 AEs reported for the combination 
regimen were neutropenia and neutrophil count decreased (11% incidence for each). 
11.2 
Dose Modifications and Toxicity Management 
The safety and tolerability profile of CB-839 is summarized above (Section 9.6).  In general, 
management of AEs related to CB-839 and paclitaxel includes withholding the medication for 
moderate to severe toxicities and providing the appropriate supportive care. 
The safety and tolerability profile of paclitaxel is well defined and outlined in the Paclitaxel 
Package Insert.  
For patients with Gilbert’s Disease: toxicity grading and dose modifications should be based 
on liver transaminase levels and not bilirubin. 
11.2.1 Dose Modification Guidelines 
Patients will be monitored continuously for AEs while on study.  Treatment modifications (e.g., 
dose delay) will be based on specific laboratory and AE criteria.  Guidelines for dose 
modifications in CB-839 and paclitaxel due to hematological and non-hematological AEs are 
provided in Table 11.4-1.  The dose levels for dose reduction of CB-839 are provided in Table 
11.4-2.  These guidelines are based on the Package Insert for paclitaxel and the clinical 
experience with CB-839 and the combination to date.  These guidelines are intended primarily 
for toxicities that are not easily managed with routine supportive care.  For example, alopecia 
does not require dose modification, nor does Grade 2 nausea/vomiting that are easily managed 
with anti-emetics. 
These parameters are only guidelines and are not intended to supersede the clinical judgment of 
the treating physician.  Investigators should contact the Medical Monitor if 1) a dose 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
30 
 
modification is planned, or 2) there is a preference to deviate from the guidelines for the 
management of AEs or dose modifications.  Holding of the study drug and study discontinuation 
for both non-hematological and hematological toxicities will be based on the Principal 
Investigator’s judgment following discussion with the Medical Monitor. 
11.2.2 Resumption of Study Treatment 
For paclitaxel and CB-839, treatment may be delayed for up to 4 weeks from the last dose.  
Delays longer than 4 weeks may be allowed, however prior to re-initiating treatment in a patient 
with a dosing interruption lasting > 4 weeks, the Medical Monitor must be consulted.  Treatment 
compliance will be monitored by drug accountability as well as the patient’s medical record and 
eCRF. 
Upon withholding study drugs for adverse events, the study drugs may be restarted when the AE 
has returned to ≤ Grade 1.  In cases in which a particular toxicity is clearly related to CB-839 or 
paclitaxel, the study drug that is not involved in causing the AE may be restarted prior to a return 
to ≤ Grade 1.  If CB-839 is restarted after permanent discontinuation of paclitaxel, CB-839 
should be permanently discontinued for a ≥ Grade 3 recurrence of the AE that resulted in 
paclitaxel discontinuation. 
11.3 
Dose Adjustments and Missed doses 
Missed doses of CB-839 or paclitaxel should be skipped.  If a patient forgets to take a dose of 
CB-839 and he/she is outside of the allotted window period (± 6 hr), he/she should be instructed 
to skip that dose and NOT to take extra study drug at their next administration. 
11.4 
  Discontinuation of Treatment and Withdrawal of Patients 
The reasons a patient may discontinue or be withdrawn from the study include, but are not 
limited to, adverse events, disease progression, patient request, Investigator decision, protocol 
violation, patient noncompliance, and study termination by the Sponsor. 
When a patient discontinues or is withdrawn, the Investigator will notify the Sponsor (or 
designee) and should perform all End of Treatment and follow up procedures as indicated in the 
Schedule of Study Assessments after discontinuation of study drug. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
31 
 
 
Table 11.4-1: Dose Modifications Guidelines for Hematologic and Non-Hematologic 
Toxicity 
Toxicity Grade 
(CTCAE v4) 
CB-839 
Paclitaxel 
Non-hematologic: Grade 3  Hold CB-839 and provide 
supportive care. 
 
Resume CB-839 at the same 
dose level upon resolution to 
≤ Grade 1 or baseline 
Hold paclitaxel and provide 
supportive care. 
 
Upon recovery to baseline or ≤ 
Grade 1, resume paclitaxel 
treatment. No dose reduction 
necessary 
Hematologic: Grade 3  
Continue CB-839 and 
provide supportive care.  If 
recovery is delayed*, 
interrupt CB-839. 
 
If interrupted, resume CB-
839 at the same dose level 
upon resolution to ≤ Grade 1 
or baseline.  Consider dose 
reduction for recurrent G3 
hematologic toxicity. 
 
Hold paclitaxel and provide 
supportive care. 
 
Upon recovery to baseline or ≤ 
Grade 1, resume paclitaxel 
treatment at a 25% dose reduction 
Grade 4 neutropenia or 
Grade ≥ 3 
thrombocytopenia with 
bleeding 
Interrupt CB-839 and provide 
supportive care. 
 
Resume CB-839 at the same 
dose level or reduce the dose 
upon resolution to ≤ Grade 1 
or baseline. Reduce the dose 
for recurrent G3 hematologic 
toxicity. 
Hold paclitaxel and provide 
supportive care. 
Upon recovery to baseline or ≤ 
Grade 1, resume paclitaxel 
treatment at a 25% dose reduction 
Grade 3 Neuropathy 
No modifications required 
Hold  paclitaxel and provide 
supportive care 
Upon recovery to baseline or ≤ 
Grade 1, resume paclitaxel 
treatment at a 25% dose reduction 
* dose modifications should be discussed with the Medical Monitor 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
32 
 
 
 
Table 11.4-2: Dose Reductions for CB-839 
Dose Level 
CB-839 Dose 
Number of Tablets 
Starting dose 
800 mg BID 
4 
First dose reduction 
600 mg BID 
3 
Second dose reduction 
400 mg BID 
2 
Third dose reduction 
Discontinue CB-839        
0 
 
12.0 
TEST ARTICLE/STUDY DRUG 
12.1 
Test Article Administration 
CB-839 Tablets 
Test article (CB-839) will be administered orally (PO) using a tablet (200 mg per tablet) 
formulation.  CB-839 will be administered only to patients who have signed and dated an 
Informed Consent Form.  CB-839 will be administered on Days 1 through 28 of each 28-day 
cycle and should be taken orally using the number of tablets directed in the Pharmacy Manual.  
CB-839 dosing will not be adjusted for body weight or surface area. 
The first CB-839 dose of the day will be administered immediately after breakfast.  The 
evening/second dose should be taken immediately after a meal approximately 12 hr (± 2 hr) after 
the morning dose. 
On PK collection days, patients should be instructed NOT to take their morning dose of CB-839 
at home. The morning dose must be administered the clinical site after all pre-dose procedures 
have been performed. The time of dosing will be collected in the clinic. The evening dose will be 
self-administered by the patient after all post-dose activities have been completed. 
On non-PK collection days, patients will administer CB-839 per their usual administrative 
schedule. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
33 
 
Patients who vomit their CB-839 dose should be instructed NOT to make up that dose and to 
report the frequency of vomiting occurrences associated with study drug administration to the 
site.   
 
CB-839 should be administered at least 1 hour prior to paclitaxel premedication administration. 
Paclitaxel infusion will be administered in the clinic after all safety evaluations have been 
performed and the appropriate premedication has been administered. 
 
Paclitaxel 
80 mg/m2 of paclitaxel will be administered as an IV infusion over 1- 3 hr on Days 1, 8, and 15 
of each 28-day cycle. Paclitaxel is supplied as a nonaqueous solution intended for dilution with a 
suitable parenteral fluid prior to intravenous infusion. Please refer to the paclitaxel package insert 
for specific instructions on paclitaxel premedication and administration. 
12.2 
Packaging and Labeling 
CB-839 HCl Tablets (200 mg) are manufactured, packaged, and labeled according to current 
Good Manufacturing Practices (cGMP).  For additional information, please refer to the 
Pharmacy Manual. 
12.3 
Storage and Stability 
CB-839 Tablets 
CB-839 HCl Tablets will be stored at the clinical site, as indicated on the study drug label, i.e., 
room temperature, between 15 - 30ºC (59 - 86ºF). 
Patients will be requested to store the test article at the recommended storage conditions noted on 
the label, out of the reach of children or other cohabitants. 
12.4 
CB-839 Accountability, Reconciliation, and Return 
On Day 1 of Cycle 1, patients will be provided with enough CB-839 tablets to last until their 
next clinic visit.  Patients will return on Day 1 of each cycle thereafter and will receive a 28-day 
supply of drug; the number of CB-839 tablets remaining from the previous visit will be counted 
and recorded. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
34 
 
 
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 drug received, dosage 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 tampering is observed, notify the Sponsor and return the questionable CB-839 
shipment with the appropriate label for to the contract distribution center.  Returned and unused 
CB-839 test article may also be destroyed and documented at the investigative site in accordance 
with approved site/institution standard operating procedures. 
12.5 
Test Article Compliance 
At each clinic visit, patients will be asked to return any unused CB-839 test and will be 
questioned about their compliance.  The number of remaining tablets will be recorded in the drug 
accountability log.  Significant non-compliance (missing > 60% of the study drug for reasons 
other than documented AE) must be reported to the monitor. 
Missed doses of CB-839 should be skipped.  If a patient forgets to take a dose of study drug and 
he/she is outside of the allotted window period (± 6 hr), he/she should be instructed NOT to take 
extra study drug at their next administration. 
13.0 
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. 
14.0 
STATISTICAL ANALYSIS 
This section outlines the statistical analysis strategy and procedures for the study.  Specific 
details of the primary and key secondary analyses will be provided in the Statistical Analysis 
Plan (SAP).  If, after the study has begun but prior to the final analysis, important changes are 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
35 
 
made to the protocol that affect principal features of the primary or key secondary analyses, then 
the protocol and/or SAP will be amended, as appropriate.  Any other changes made to the 
planned analyses after the protocol and SAP have been finalized, along with an explanation as to 
when and why they occurred, will be described in the Clinical Study Report, in which any post 
hoc exploratory analyses also will be clearly identified.   
14.1 
General Study Design 
Protocol CX-839-007 is a Phase 2 multicenter, open-label study in patients with metastatic 
TNBC. 
Since this is an open-label clinical trial, descriptive statistics will be employed to analyze the 
data.  Summary statistics for continuous variables will include the mean, standard deviation, 
median, and range (minimum/maximum).  Categorical variables will be presented as frequency 
counts and percentages, and time-to-event variables will be summarized by Kaplan-Meier plots, 
medians, and ranges. 
The data will be tabulated and analyzed with respect to patient enrollment and disposition, 
demographic and baseline characteristics, prior and concomitant medications, efficacy, and 
safety measures.  The efficacy analysis will be conducted on the Efficacy Evaluable Population, 
and the safety analysis will be performed on the Safety Population. 
All confidence intervals will be constructed at the 95% confidence level. Data listings will be 
created to support each table and to present all data collected. 
14.1.1 Determination of Sample Size 
Cohorts 1 and 3 – Taxane-treated patients with 3rd line+ advanced/metastatic disease 
Cohort 1 will enroll patients with African ancestry and Cohort 3 will enroll non-African ancestry 
patients.  Each cohort will enroll 28 response-evaluable patients (Table 14.1-1).  We assume that 
a baseline ORR to single agent paclitaxel would be < 10% in this 3rd line+ patient population.  
For the result to be acceptable, there must be ≥ 5/28 responses in the study with an ORR ≥ 18%. 
This design has a type I error rate of 0.14 if the true response rate is 10% and a power of 0.86 if 
the true response rate is 25%.   


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
36 
 
Cohorts 2 and 4 – Taxane-naïve patients with 1st line advanced/metastatic disease 
Cohort 2 will enroll patients with African ancestry and Cohort 4 will enroll non-African ancestry 
patients.  Simon's two-stage design (Simon, 1989) will be used.  The null hypothesis that the true 
response rate is ≤ 25% [p0] will be tested against the alternative hypothesis of ≥45% response 
rate.  In the first stage, 15 patients will be accrued to each cohort (Table 14.1-1).  If there are 3 or 
fewer responses in these 15 patients, accrual to this cohort will be stopped; otherwise, 13 
additional patients will be accrued for a total of 28 patients. The null hypothesis will be rejected 
if 10 or more responses are observed in 28 patients (objective response rate ≥36%). This design 
has a type I error rate of 0.13 when the true response rate is 25% and power of 0.87 when the 
true response rate is 45%. 
Table 14.1-1: Design of the CX-839-007 Cohorts 
Cohort 
Race 
Line 
Null 
ORR 
Alternative 
ORR 
Total 
Patients 
Req. for 
positive 
study 
Stage 
1 
Req. to 
advance 
1 
AA 
3rd 
≤ 10% 
≥ 25%, 
28 
5 
- 
- 
2 
AA 
1st 
≤ 25% 
≥ 45% 
28 
10 
15 
4 
3 
Non-
AA 
3rd 
≤ 10% 
≥ 25%, 
28 
5 
- 
- 
4 
Non-
AA 
1st 
≤ 25% 
≥ 45% 
28 
10 
15 
4 
 
14.2 
Analysis Populations 
14.2.1 Efficacy Analysis Set 
All patients who have measurable disease at baseline, receive at least one cycle of therapy 
(taking at least 75% of planned treatment), and complete at least one post-baseline tumor 
assessment will be considered evaluable for efficacy.  In addition, patients who discontinue study 
due objective disease progression prior to the completion of cycle 1 will be considered evaluable.  


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
37 
 
Patients who do not meet the aforementioned requirements will be considered non-evaluable for 
response and will be replaced. 
14.2.2 Safety Analysis Set 
All patients who receive at least 1 dose of any study-specific treatment (CB-839 or paclitaxel) 
will be included in the analysis of safety.  Patients will be included in the treatment group 
corresponding to the actual treatment received. 
14.3 
Efficacy Analysis 
Response to treatment will be evaluated using RECIST v1.1. 
The Kaplan-Meier method will be used to estimate the median Progression-Free Survival (PFS) 
for each treatment cohort. 
For each patient with objectively measurable disease, as defined by RECIST v1.1, response to 
therapy, duration of response, progression-free survival, and overall survival will be calculated.  
Overall Response Rate (ORR): ORR is defined as the percentage of patients with complete 
response (CR) or partial response (PR) according to the RECIST 1.1 criteria. To be assigned a 
status of CR or PR, changes in tumor measurements must be confirmed by repeat assessment 
performed no less than 4 weeks after the criteria for response were first met. 
Duration of Response (DOR):  For patients achieving a PR or a CR, the duration of response will 
be calculated as the time between the first documentation of a PR or a CR to the first 
documentation of PD or death, whichever occurs first, taking as reference for PD the smallest 
measurements recorded since baseline (i.e. radiographic assessment at screening).  For patients 
achieving first a PR then a CR, the PR date will be the starting date for response duration 
calculation.  
Stable Disease and Duration of Stable Disease:  for SD, follow-up measurements must have met 
the RECIST 1.1 SD criteria at least once at a minimum of 8 weeks.  The duration of stable 
disease is measured from enrollment date until the criteria for RECIST 1.1 progression are met, 
taking as reference the smallest measurements recorded since baseline.   


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
38 
 
Progression Free Survival:  PFS is defined as time from enrollment date to the earlier of either 
progression of disease per RECIST 1.1 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:  
 Patient is alive and progression free at the time of analysis data cutoff. 
 Disease progression or death occurs after missing data (including an inevaluable status 
for overall response assessment) for two consecutive radiographic disease assessments. 
 Patient receives non-protocol RCC treatment prior to documentation of disease 
progression.  
Patients missing baseline disease assessment will be censored at time 0. Patients who come off of 
study for reason other than PD or death should continue to be followed with radiographic 
assessment until PD by RECIST 1.1, death, withdrawal of consent, or initiation of another 
systemic anti-cancer treatment.  
Clinical Benefit Response (CBR): CBR is defined as the percentage of patients with best 
response of CR, PR, or SD according to the RECIST 1.1 criteria (SD defined as stable disease 
lasting ≥ 16 weeks for 3rd line+ patients and 24 weeks for 1st line patients).   
Overall Survival (OS): OS is defined as the time from enrollment date to death due to any cause.  
For patients alive at time of analysis, OS will be censored at the time when the patient is last 
known to be alive.  Patients who discontinue study for reason other than death should continue to 
be followed for survival status until death or withdrawal of consent. 
In addition, relationships between antitumor activity, PDn markers, exploratory biomarkers, and 
drug exposure levels will be explored.  
14.4 
Treatment Exposure and Medication Compliance 
Extent of exposure to both study treatments (CB-839 and paclitaxel) will be evaluated by 
summary statistics (N, mean, standard deviation, median, minimum and maximum).  Percent of 
patients and cycles with dose delays and reductions will be calculated by treatment group.   


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
39 
 
For each patient, a compliance measure will be calculated based on the information provided in 
the CRFs.  Compliance will be defined as the percentage of the actual number of days with 
treatment intake over the expected number of days with treatment intake.  Summary statistics 
will be provided on percent compliance by treatment group.   
14.5 
Safety Analysis 
Safety will be assessed by the patient incidence and severity of adverse events (AEs); the 
analysis will be performed on the Safety Analysis Set as defined in Section 14.2.2.   
Adverse events will be coded by System Organ Class (SOC) and Preferred Term (PT) using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The number and proportion of 
patients reporting a given AE will be tabulated by treatment group according to the worst 
severity reported.  Separate tables will be constructed for a) all reported AE’s, b) serious AEs 
(SAEs), and c) AE’s leading to permanent discontinuation of study treatment.  The above tables 
will also be presented for treatment-emergent AEs (TEAEs) judged to be related to the study 
treatment. 
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 CB-839 or paclitaxel. 
ECG, weight, and vital signs will also be summarized by changes from baseline to scheduled 
time points using descriptive statistics. 
14.6 
Analyses and Effects of Genetic and other Background Factors 
To explore whether the treatment effect is consistent across various subgroups for hypotheses 
generation purposes, analyses will be conducted for the following baseline variables:   
 SNP rs6983267 (CCAT2) variants (GG, GT, TT) 
 TNBC subtypes 
 Multi-SNP analysis (genome-wide association studies)  
 Prior receipt of checkpoint inhibitor therapy such as inhibitors of the PD-1, PD-L1, and 
CTLA-4 pathways. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
40 
 
 
15.0 
ADVERSE EVENTS 
Single agent CB-839 has been well tolerated in three different Phase 1 clinical trials.  For safety 
information on single agent CB-839 and on the combination with paclitaxel, refer to Section 11.1 
and the most recent version of the CB-839 Investigator’s Brochure.  For safety information on 
paclitaxel, refer to the Product Label. 
15.1 
Definitions 
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: 
 Any 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 in the period prior to receiving the first dose of 
the test article that are related to the protocol-mandated intervention (e.g., medication 
wash out, 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 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., meeting 
one or more of the following conditions, should be recorded as a single diagnosis on the adverse 
event page in the eCRF: 
 Accompanied by clinical symptoms 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
41 
 
 Leading to a change in study medication (e.g., dose modification, interruption, or 
permanent discontinuation) 
 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) 
A serious adverse event (SAE) is an AE that: 
 Results in death (NOTE:  death is an outcome, not an event) 
 Is life-threatening (NOTE: see definition below) 
 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 
 Additionally, important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered SAEs when, based on 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  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. 
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).  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 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
42 
 
finding being due solely to progression of neoplasia, the finding should be reported as an AE or 
SAE as appropriate. 
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 
might have caused death had it occurred in a more severe form.  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. 
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. 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
43 
 
If there is any doubt about whether the information constitutes an SAE, the information is treated 
as an SAE. 
Causality Attribution Guidance: 
AEs should be considered (probably or possibly) treatment-related, unless they fulfill the 
following criteria (in which circumstances it 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 medication will be graded as either, “probably”, “possibly”, “unlikely”, or 
“unrelated” as follows: 
Probably Related – The adverse event 
 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 adverse event 
 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 adverse event 
 Is most likely to be explained by the patient’s clinical state or by other modes of therapy 
administered to the patient 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
44 
 
Unrelated – The adverse event 
 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 
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. 
Other Reportable Information:  certain information, although not considered an SAE, must be 
recorded, reported, and followed up as indicated for an SAE.  This includes: 
 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 mo after completion of the study treatment 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 
15.2 
Recording and Reporting 
After informed consent, but prior to initiation of study drug, only SAEs caused by protocol- 
mandated interventions (i.e., a protocol-related SAE such as a biopsy) will be collected. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
45 
 
Patients will be followed for AEs or SAEs from the time the patient initiates treatment with the 
study regimen up to 28 days after the last dose or until the start of a new treatment, whichever 
occurs first. The Investigator must follow up on all drug-related AEs, SAEs, 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. 
All AEs and SAEs must be recorded on source documents and collected in 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. 
15.3 
Serious Adverse Event Reporting 
All SAEs regardless of attribution, other reportable information, and follow-up information must 
be reported within 1 business day 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 FDA 
regulations 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 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
46 
 
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. 
16.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION 
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 CB-839 test article, containers, and other study materials to the 
Sponsor or designee, or destroy the materials at the investigative site.  Upon study completion, 
the Investigator will provide the Sponsor, IRB/IEC, and regulatory agency with final reports and 
summaries as required by regulations. 
Sites that do not enroll a single patient within the first 6 months of initiating the study may be 
closed at the discretion of the Sponsor. 
17.0 
INFORMED CONSENT 
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 used during the informed consent process must be reviewed by the Sponsor and 
approved by the 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 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
47 
 
 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 
18.0 
PROTOCOL AMENDMENTS 
Any significant change in the study 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. 
19.0 
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 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.  
20.0 
DIRECT ACCESS, DATA HANDLING, AND RECORD KEEPING 
20.1 
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. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
48 
 
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. 
20.2 
Sponsor 
The data will be checked for completeness and correctness in real-time online. 
Data are checked as they are entered into the EDC system.  Off-line checks will also be run to 
assess the need for additional data review. 
21.0 
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 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
49 
 
 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 the 1572 
 Fully executed Clinical Trial Agreement (CTA) 
 Financial disclosure form for the Principal Investigator and any other persons listed in the 
1572 
 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 the 1572. The Sponsor 
must be notified if the laboratory is changed or if any additional laboratory is to be used. 
22.0 
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 the longer 
of:  (i) 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 (ii) 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.  
23.0 
AUTHORSHIP AND ACCOUNTABILITY 
Per the International Committee of Medical Journal Editors (ICMJE) 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, 
and 2) drafting the article or revising it critically for important intellectual content, 3) final 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
50 
 
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.


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
51 
 
24.0 
LIST OF ABBREVIATIONS 
Abbreviation or Term1 
Definition/Explanation 
AA 
African Ancestry 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
CBR 
Clinical Benefit Rate 
CCr 
Creatinine clearance 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CTA 
Clinical Trial Agreement 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP2C9 
Cytochrome P450 2C9 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
g/dL 
Grams per deciliter 
GLP 
Good Laboratory Practice  
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HPLC 
High-performance liquid chromatography 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
IEC 
Independent Ethics Committee 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
52 
 
Abbreviation or Term1 
Definition/Explanation 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
LC-MS/MS 
Liquid chromatography-mass spectrometry/mass spectrometry 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mL 
Milliliter 
MTD 
Maximum tolerated dose  
ORR 
Overall response rate 
OS 
Overall Survival 
PDn 
Pharmacodynamic(s) 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
QTcF 
Corrected QT interval, Fridericia’s formula 
RP2D 
Recommended Phase 2 Dose 
RBC 
Red Blood Cell 
SAE 
Serious adverse event 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
TEAE 
Treatment-emergent adverse event 
TCA 
Tricarboxylic acid 
TID 
Three times daily 
TNBC 
Triple negative breast cancer 
TTR 
Time to recurrence 
ULN 
Upper limit of normal 
WBC 
White blood cell 
1 
All of these abbreviations may or may not be used in protocol. 
 
 
 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
CONFIDENTIAL 
53 
 
25.0 
REFERENCES 
 
Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, et al. Antitumor 
activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer 
Ther 2014;13:890-901.  
 
Jain YJ, Khelifa S, Ratnikov B, Scott BA, Feng Y, Parisi F et al.  Regulation of glutamine carrier 
proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies.  
Cancer Cell 2015;27: 354–369. 
 
ICMJE guidelines (2015) Recommendations for the Conduct, Reporting, Editing, and 
Publication of Scholarly Work in Medical Journals. Retrieved from http://www.icmje.org/icmje-
recommendations.pdf 
 
Redis RS, Vela LE, Lu W, Ferreira de Oliveira J, Ivan 5, Rodriguez-Aguayo C, et al. Allele-
Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2. Mol 
Cell 2016;61:520-34. 
 
Stover DG, Bell CF, and Tolaney SM. Neoadjuvant and adjuvant chemotherapy considerations 
for triple-negative breast cancer. Am J Hematol Oncol 2016;12:9-12. 
 
Terunuma A, Putluri N, Mishra P, Mathé EA, Dorsey TH, Yi M, et al. MYC-driven 
accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest. 
2014;124:398-412. 




CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
 
55 
Explanation of Superscripts: 
1. 
Informed consent must completed prior to any study-related screening procedures and may be completed before the 28-day screening window. 
2. 
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.  
3. 
Vital sign measurements include temperature, pulse, respiratory rate and resting systolic and diastolic blood pressure.  
4. 
On C1D1, duplicate ECGs to be performed 2-4 hr post CB-839 dose 
5. 
Assessments completed at screening. Investigators should monitor during the study if it is deemed necessary. 
6. 
Does not need to be repeated if the Screening sample was obtained within 3 days prior to C1D1 unless a clinically significant change is suspected 
7. 
Serum or urine pregnancy test is required of all patients of child-bearing potential. Screen pregnancy test must occur within 3 days prior to C1D1. 
8. 
PK sample (3 mL of whole blood) will be collected predose and 4 hours (± 30 min) post-dose on C1D15, C2D1, and C3D1. Refer to laboratory manual for further 
instructions. 
9. 
Biomarker analysis samples (3 mL of whole blood and saliva) will be taken at screening. Refer to laboratory manual for further instructions.  
10. Archival tumor tissue must be submitted, if available, for correlative studies.  
11. Fresh pre-dose tumor biopsies will be collected from all patients UNLESS an archival sample collected within 3 mo prior to C1D1 is provided or if the tumor is 
inaccessible. 
12. Optional fresh tumor biopsies may be collected from patients who consent to providing samples during the trial or at EOT (e.g., if patient is responding, progressing 
lesion, etc.). 
13. Tumor assessments for Screening must be done within 21 days prior to C1D1.  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.   
14. Completed approximately every 8 weeks (2 cycles) during the first 13 cycles per RECIST 1.1. For patients with ≥ SD for at least 13 cycles who are on a steady dose for 
≥ 2 cycles, radiographic evaluation of tumor burden may be reduced to every 3 cycles (i.e., at Cycles 16, 19, 22, etc.). Evaluations may occur more frequently as 
clinically indicated. Scans must be submitted for central review. 
15. Neuropathy assessment will be performed at Screening, C3D1, C6D1, and at EOT. Refer to Study Reference Manual for detailed information. 
16. Patients will be contacted every 3 mo for the first 12 mo after discontinuation and then every 6 months thereafter to confirm survival. 
17. For patients with ≥ SD for at least 13 cycles who are on a steady dose for ≥ 2 cycles, study assessments may be reduced to every 3 cycles (i.e., at Cycles 16, 19, 22, etc.). 
 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
56 
ATTACHMENT 2:  CLINICAL LABORATORY TESTS 
Hematology (Peripheral Blood Sample): 
 Hemoglobin and hematocrit 
 RBC count 
 White blood cell count with differential 
 Platelet count 
 
Coagulation Tests 
 PT, aPTT and INR 
Serum Chemistry-Full Metabolic Panel (Peripheral Blood Sample) with additional analytes 
 Sodium 
 Potassium 
 Chloride 
 CO2  
 Magnesium 
 Calcium 
 Phosphorus 
 Glucose 
 Blood urea nitrogen 
 Uric acid 
 Total protein 
 Albumin 
 Total and direct bilirubin1 
 Aspartate aminotransferase (AST or 
SGOT) 
 Alanine aminotransferase (ALT or SGPT) 
 Alkaline phosphatase (AP) 
 Lactate dehydrogenase (LDH) 
Creatinine 
1 
Direct bilirubin is only required if Total Bilirubin is above the upper limit of normal.  
 
Pregnancy test (urine -HCG):  Women of child-bearing potential 
Urinalysis 
 Protein 
 Glucose 
 Ketones 
 Hemoglobin/myoglobin 
 Nitrite 
 
 Leukocyte esterase 
 pH 
 Specific gravity 
 Urobilinogen 
 Microscopic evaluation (only when 
protein, esterase or hemoglobin dipstick is 
positive)  
 
 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
57 
ATTACHMENT 3:  RECIST CRITERIA VERSION 1.1 
Source: Eisenhauer et al, 2009 
Sponsor’s Note: CB-839, 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 CB-839. 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:  leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, peritoneal spread, abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
 
 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
58 
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. 
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 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
59 
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 enrolment 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 subject 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 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. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
60 
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 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 
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 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
61 
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, saggital 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. 
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 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
62 
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 PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
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 <) 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
63 
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). 
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 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
64 
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 
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, CB-839, 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 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
65 
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 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment 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 are 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. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
66 
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 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 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. 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 
2. 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. 
 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
67 
 
 
 
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 
3. 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. 


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
68 
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


CB-839 
Protocol CX-839-007 
 
06 January 2017 
 
 
CONFIDENTIAL 
 
69 
ATTACHMENT 4:  CYP2C9 
CYP2C9 Substrates with a narrow therapeutic index* 
 
S-Warfarin (anticoagulant) 
 
Phenytoin (antiepileptic) 
*Narrow therapeutic index is defined as “CYP substrates with narrow therapeutic range refers 
to drugs whose exposure-response relationship indicates that small increases in their exposure 
levels by the concomitant use of CYP inhibitors may lead to serious safety concerns (e.g., 
Torsades de Pointes).” 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm 
Other CYP2C9 Substrates 
 
NSAIDs (analgesic, antipyretic, anti-inflammatory)  
o celecoxib 
o lornoxicam 
o diclofenac 
o ibuprofen  
o naproxen 
o ketoprofen 
o piroxicam 
o meloxicam 
o suprofen 
 
fluvastatin (statin) 
 
sulfonylureas (antidiabetic)  
o glipizide 
o glibenclamide 
o glimepiride 
o tolbutamide 
o glyburide 
 
irbesartan (to treat hypertension) 
 
losartan (to treat hypertension) 
 
sildenafil (in erectile dysfunction) 
 
terbinafine (antifungal) 
 
amitriptyline (tricyclic antidepressant) 
 
fluoxetine (SSRI antidepressant) 
 
nateglinide (antidiabetic) 
 
rosiglitazone (antidiabetic) 
 
tamoxifen (SERM) 
 
torasemide (loop diuretic) ketamine
 


Signature Page for VV-TMF-02366 v1.0
Signature Page for VV-TMF-02366 v1.0
Reason for signing: Approved
Name: 
Role: C
opment
Date of signature: 09-Jan-2017 05:23:18 GMT+0000

SAP_001.pdf: 
Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 1 of 15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Calithera Biosciences, Inc. 
 
CX-839-007 
 
 
 
 
 
 
 
Protocol Title: 
A Multicenter Phase 2 Study of the Glutaminase Inhibitor 
CB-839 in Combination with Paclitaxel in Patients with 
Advanced Triple Negative Breast Cancer (TNBC) Including 
Patients of African Ancestry and Non-African Ancestry 
 
Protocol Version 
and Date: 
Original / 06 Jan 2017 
 
 
 
Sponsor: 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
 
Prepared By: 
 
Biostatistician Contracted to Calithera 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
 
 
Document Version 
and Date: 
Draft Version 1.0; 8 Oct 2019 




Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 3 of 15 
 
 
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 
Efficacy Endpoints ...................................................................................................................... 7 
5.2.2 
Safety Endpoints ......................................................................................................................... 8 
5.3 
Determination of Sample Size ....................................................................................... 8 
6 
STUDY CONDUCT ....................................................................................................... 8 
6.1 
Safety Data Monitoring ................................................................................................. 8 
7 
STATISTICAL METHODS ......................................................................................... 9 
7.1 
Analysis Sets ................................................................................................................... 9 
7.1.1 
Efficacy Evaluable Population for ORR and CBR – Response Evaluable Analysis Set ...... 9 
7.1.2 
Efficacy Evaluable Population for PFS – PFS Evaluable Analysis Set .................................. 9 
7.1.3 
Safety Analysis Set ...................................................................................................................... 9 
7.2 
Analysis of Study Conduct ............................................................................................ 9 
7.3 
Analysis of Treatment Group Comparability ............................................................. 9 
7.4 
Efficacy Analysis ............................................................................................................. 9 
7.4.1 
Primary Analysis of Overall Response Rate .......................................................................... 10 
7.4.2 
Secondary Analyses .................................................................................................................. 10 
7.3 
Safety .............................................................................................................................. 12 
7.3.1 Treatment Exposure ..................................................................................................... 12 
7.3.2 
Adverse Events ............................................................................................................. 12 
7.3.3 
Laboratory Data ........................................................................................................... 12 
7.3.4 
ECG and Vital Signs .................................................................................................... 12 
7.4 
Missing Data ................................................................................................................. 12 
8 
REFERENCES ............................................................................................................. 13 
APPENDIX A:  SCHEDULE OF STUDY ASSESSMENTS ............................................... 14 


Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 4 of 15 
 
 
TABLE OF TABLES 
Table 1: Primary Analysis: The Censor/Event Rules for Progression Free Survival and Duration of 
Responsea ............................................................................................................................................................ 11 


Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 5 of 15 
 
 
3 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AA 
African Ancestry 
AE 
Adverse event 
BID 
Twice daily 
CBR 
Clinical Benefit Rate 
CI 
Confidence interval 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
hr 
Hour or hours 
IV 
Intravenous, intravenously 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mL 
Milliliter 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
QTcF 
Corrected QT interval, Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
TEAE 
Treatment-emergent adverse event 
TNBC 
Triple negative breast cancer 
TTR 
Time to recurrence 
 


Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 6 of 15 
 
 
4 
INTRODUCTION 
The statistical analysis plan (SAP) provides details of the planned analyses and statistical 
methods for the study CX-839-007 (A Multicenter Phase 2 Study of the Glutaminase Inhibitor 
CB-839 in Combination with Paclitaxel in Patients with Advanced Triple Negative Breast 
Cancer (TNBC) Including Patients of African Ancestry and Non-African Ancestry). The 
background and rationale for the study can be found in the study protocol. 
 
5 
STUDY DESIGN 
 
Protocol CX-839-007 is a Phase 2 open-label study of the combination of CB-839 with 
paclitaxel. Multiple single-arm cohorts will be enrolled in which 800 mg twice daily (BID) CB- 
839 will be administered in combination with the full approved dose of paclitaxel. Figure 1 
illustrates the study design. 
 
Patients eligible after completing all screening evaluations will be enrolled into one of four 
cohorts: 
 
Cohort 1 – African ancestry with 3rd line+ Metastatic  
a. Patients must self-identify as African ancestry (AA; includes African American). 
b. At least 2 prior lines of systemic therapy for advanced/metastatic disease including a 
taxane. 
i. Prior taxane (paclitaxel, docetaxel, or nab-paclitaxel) for advanced/metastatic disease is 
required but must not have been received in the immediate prior line of therapy. 
ii. Systemic neoadjuvant and/or adjuvant therapy is considered a line of therapy for 
advanced/metastatic disease if the time to recurrence from completion of treatment was 
≤ 12 months. 
 
Cohort 2 – African ancestry 1st line Metastatic 
a. Patients must self-identify as African ancestry (includes African American). 
b. No prior systemic therapy for advanced or metastatic disease. 
i. Systemic neoadjuvant or adjuvant therapy, including taxane, is allowed if time to 
recurrence was > 12 mo. 
 
Cohort 3 – Non-African ancestry 3rd line+ Metastatic  
a. Patients do not self-identify as African ancestry. 
b. Otherwise have the same criteria as Cohort 1. 
 
Cohort 4 – Non-African ancestry 1st line Metastatic 
a. Patients do not self-identify as African ancestry. 
b. Otherwise have the same criteria as Cohort 2. 
 
Treatment administrations are per the instructions and schedule of events outlined in the 
protocol. 
 
CB-839 will be administered orally 800 mg BID with food, on days 1 through 28 of each 28-day 
cycle. Paclitaxel (80 mg/m2) will be administered as an IV infusion over 1- 3 hr on Days 1, 8, 
and 15 of each 28-day cycle. Patients will receive the treatment in 28-day cycles until disease 
progression or unacceptable toxicity (whichever occurs first). Patients will be followed within 28 


Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 7 of 15 
 
 
days of last dose date or early discontinuation of treatment for safety follow up. Patients who 
discontinue study treatment for reasons other than disease progression or death will remain in 
follow up including protocol-defined imaging. Long-term follow up for survival will continue 
until death or withdrawal of consent to follow up. 
 
Figure 1: Study Design Schema 
* TTR = Time to recurrence 
 
5.1 
Protocol Synopsis 
Please refer to protocol synopsis in the original protocol dated 06 Jan 2017 (13). The Schedule of 
Assessments is in Appendix A: Schedule of Study Assessments. 
 
5.2 
Study Endpoints 
 
5.2.1 
Efficacy Endpoints 
5.2.1.1 Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the overall response rate (ORR) of patients treated with CB-839 
plus paclitaxel (Pac-CB) for metastatic TNBC. Overall Response Rate is defined as the 
percentage of patients with complete response (CR) or partial response (PR) per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1. To be assigned a status of CR or PR, 
changes in tumor measurements must be confirmed by repeat assessment performed no less than 
4 weeks after the criteria for response were first met. 


Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 8 of 15 
 
 
5.2.1.2 Secondary Efficacy Endpoints 
 
The secondary efficacy endpoints are as follows: 
 
 Progression free survival (PFS) of patients treated with CB-839 plus paclitaxel (Pac-CB) for 
metastatic TNBC. PFS is defined as time from first dose date to the earlier of either 
progression of disease per RECIST v1.1 or death from any cause.
 Overall survival (OS) of patients treated with CB-839 plus paclitaxel (Pac-CB) for metastatic 
TNBC. Overall Survival is assessed by time from first dose date to death due to any cause.
 Duration of response (DOR) of patients treated with CB-839 plus paclitaxel (Pac-CB) for 
metastatic TNBC. DOR is defined as the time between the first documentation of a confirmed 
PR or a CR per RECIST v1.1 to the first documentation of PD or death.
 Clinical benefit rate (CBR) of patients treated with CB-839 plus paclitaxel (Pac-CB) for 
metastatic TNBC. Clinical Benefit Rate is defined as the percentage of patients with best 
response of CR, PR, or SD per RECIST v1.1 criteria. SD is defined as stable disease lasting ≥ 
16 weeks for 3rd line + patients and ≥ 24 weeks for 1st line patients.
5.2.2 
Safety Endpoints 
The safety endpoints are: 
 
 Type, incidence, seriousness, nature, severity, and drug-relatedness of adverse events graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.0 (NCI CTCAE v4.0).
 
 Changes in vital signs, physical findings, and clinical laboratory test results following study 
treatment administration.
 
5.3 
Determination of Sample Size 
Approximately 112 response evaluable patients are expected in total to be enrolled and treated 
across four cohorts. If a patient does not meet criteria for inclusion into the Efficacy Analysis 
Set, the patient will be considered to be not evaluable for efficacy and will be replaced. 
 
Cohorts 1 and 3: We assume that the ORR from single agent paclitaxel will be < 10% in this 3rd 
line+ patient population. With a sample size of 28 patients this design has a type I error rate of 
0.14 if the true response rate is 10% and a power of 0.86 if the true response rate is 25%. 
 
Cohorts 2 and 4: Simon's two-stage design (Simon, 1989) will be used. The null hypothesis that 
the true response rate is < 25% will be tested against the alternative hypothesis of ≥ 45% 
response rate. In the first stage, 15 patients will be accrued to each cohort. If there are 3 or fewer 
responses in these 15 patients, accrual to this cohort will be stopped. Otherwise, 13 additional 
patients will be accrued for a total of 28 patients. The null hypothesis will be rejected if 10 or 
more responses are observed in 28 patients (ORR ≥ 36%). This design has a type I error rate of 
0.13 when the true response rate is 25% and power of 0.87 when the true response rate is 45%. 
 
6 
STUDY CONDUCT 
 
6.1 
Safety Data Monitoring 


Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 9 of 15 
 
 
 
Safety data from the study is monitored on an ongoing basis via routine PrimeVigilance 
activities. In addition to real time medical review of emergent SAEs, a cross functional sponsor 
safety review team performs regular periodic aggregate data reviews across all CB-839 studies. 
 
7 
STATISTICAL METHODS 
 
7.1 
Analysis Sets 
7.1.1 
Efficacy Evaluable Population for ORR and CBR – Response Evaluable Analysis 
Set 
All patients who have measurable disease at baseline, receive at least one dose of study drug 
(CB-839 or paclitaxel), and complete at least one post-baseline tumor assessment, will be 
considered evaluable for efficacy. In addition, patients who discontinue treatment for study-drug 
related toxicity or for disease-related death also are included in the efficacy evaluable population 
for ORR and CBR. 
All response efficacy analyses will be performed by cohort. 
 
7.1.2 
Efficacy Evaluable Population for PFS – PFS Evaluable Analysis Set 
All patients who receive at least one dose of any study-specific treatment (CB-839 or paclitaxel) 
will be included in the PFS evaluable analysis set. The PFS analysis will be performed by cohort. 
 
7.1.3 
Safety Analysis Set 
All patients who receive at least 1 dose of any study-specific treatment (CB-839 or paclitaxel) 
will be included in the analysis of safety. All safety analyses will be performed by cohort. 
 
7.2 
Analysis of Study Conduct 
Subject disposition, including enrollment, analysis populations, major protocol deviations 
(including major deviations of inclusion and/or exclusion criteria), reason for discontinuation 
from the study, and on-study status will be summarized by cohort and overall for the safety 
analysis set. 
 
7.3 
Analysis of Treatment Group Comparability 
Demographic and baseline characteristics, including age, sex, race, ethnicity, and disease 
characteristics will be summarized by 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 Cycle 1 Day 1 visits unless otherwise noted. 
 
7.4 
Efficacy Analysis 
Efficacy analyses will be performed by cohort. Response to treatment will be evaluated using 
RECIST v1.1. 
 
The four cohorts are based on patient’s demographics and treatment history instead of 
randomization, therefore formal hypothesis testing among cohorts will not be performed. 


Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 10 of 15 
 
 
7.4.1 
Primary Analysis of Overall Response Rate 
Overall Response Rate (ORR) will be assessed by cohort where ORR is defined as the 
percentage of patients with complete response (CR) or partial response (PR) per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1. To be assigned a status of CR or PR, 
changes in tumor measurements must be confirmed by repeat assessment performed no less than 
4 weeks after the criteria for response were first met. Patients without assessed response will be 
treated as non-responders. 
 
The analysis set for ORR will be the response evaluable analysis set. An estimate of ORR and its 
95% confidence interval (CI) will be calculated with the Clopper-Pearson method. Best of 
Response (BOR) Rate is defined as the percentage of patients with their best of response being 
CR, PR, SD or PD, and will be estimated in the same approach as for ORR. 
 
In Cohorts 1 and 3 respectively, the observed ORR will be compared to 10%. If stage I and II are 
both completed, in Cohorts 2 and 4 respectively, the observed ORR will be compared to 25%. 
One-sample binomial tests will be performed in the comparisons. The resultant p-values are 
descriptive in nature. 
 
7.4.2 
Secondary Analyses 
Progression Free Survival: PFS is defined as time from the first dose date to the earlier of either 
progression of disease per RECIST 1.1 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: 
 
 Patient is alive and progression free at the time of analysis data cutoff.
 Disease progression or death occurs after missing data (including a non-evaluable status for 
overall response assessment) for two consecutive radiographic disease assessments.
 Patient receives non-protocol TNBC treatment prior to documentation of disease progression.
 
Patients missing baseline disease assessment will be censored at the first dose date (day 1). 
Patients who come off of study for reason other than PD or death should continue to be followed 
with radiographic assessment 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 PFS evaluable analysis set. 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). 
 
Overall Survival (OS): OS is defined as the time from the first dose date to death due to any 
cause. For patients alive at time of analysis, OS will be censored at the time when the patient is 
last known to be alive. Patients who discontinue study for reason other than death should 
continue to be followed for survival status until death or withdrawal of consent. Because OS may 
require longer follow up than the primary PFS analysis, additional OS analyses may be 
performed after the time of PFS primary analysis. OS will be analyzed with the same 
methodologies and analysis set as PFS. 


Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 11 of 15 
 
 
 
Duration of Response (DOR): For patients achieving a PR or a CR, the duration of response will 
be calculated as the time between the first documentation of a PR or a CR to the first 
documentation of PD or death, whichever occurs first, taking as reference for PD the smallest 
measurements recorded on study (including baseline, i.e. radiographic assessment at screening). 
For patients achieving first a PR then a CR, the PR date will be the starting date for response 
duration calculation. Patients who are alive and have not experienced disease progression at the 
time of the analysis will follow the censoring rules in Table 2 where only assessments after first 
response will be included. The determination of DOR is based on responders only. DOR will be 
analyzed with the same methodologies as PFS using response evaluable analysis set. 
 
DOR will be reported for patients with confirmed OR. 
 
Table 1: Primary Analysis: The Censor/Event Rules for Progression Free Survival and Duration 
of Responsea 
 
 
Situation 
Date of Event or 
Censoring 
Outcome 
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 of 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. 


Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 12 of 15 
 
 
7.3 
Safety 
Unless specified otherwise, safety analyses described in this section will be conducted for the 
Safety analysis set. 
 
7.3.1 Treatment Exposure 
Extent of exposure to both study treatments (CB-839 and paclitaxel), including treatment 
duration, total dose received (mg for CB-839 and mg/m2 for paclitaxel), number of cycles, will 
be evaluated by summary statistics (N, mean, standard deviation, median, minimum and 
maximum). Percent of patients and cycles with dose delays and reductions will be calculated. 
 
Exposures will be summarized by cohort for CB-839 and paclitaxel separately. 
 
7.3.2 
Adverse Events 
Verbatim description of adverse events will be coded to System Organ Class (SOC) and 
Preferred Term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) and 
graded by the investigator according to NCI CTCAE v4.03. Treatment-emergent AEs (TEAEs) 
are defined as AEs started or worsened on or after first dose 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 a) all reported TEAE’s, b) 
serious TEAEs (SAEs), c) severe TEAEs (Grade ≥ 3), and d) TEAE’s leading to permanent 
discontinuation or interruption of study treatments. The above tables will also be presented for 
TEAEs judged to be related to either study treatment. 
 
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 and the follow up period after treatment 
completion/discontinuation will be listed and summarized by cause. 
 
7.3.3 
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 CB-839 or paclitaxel. Proportion of patients with laboratory 
measurement outside the normal range and by NCI CTCAE v4.03 grade will be summarized. 
 
7.3.4 
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. 
 
7.4 
Missing Data 
Patients with missing response assessment will be treated as non-responders in analyzing ORR 
and CBR. Tables 2 will be followed to censor these patients in analyzing PFS and DOR. Missing 
laboratory, ECG and vital sign measurements will not be imputed and included in the analysis. 


Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 13 of 15 
 
 
AEs with missing or partial start date that cannot be definitely determined to be earlier than first 
dose will be treated as TEAE. AEs with missing relationship to study treatments will be treated 
as related. 
 
8 
REFERENCES 
1. Protocol CX-839-007, dated 16 Jan 2017 
 
2. Brookmeyer, R. and Crowley, J. (1982) A confidence interval for the median survival time. 
Biometrics, 38, 29-41. doi:10.2307/2530286 
 
3. 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. 
 
4. 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 
 
5. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.03. 14 June 2010. Available 
from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 
14_QuickReference_8.5x11.pdf. 




Calithera Biosciences, Inc. 
CX-839-007 
Statistical Analysis Plan Draft 
Version 1.0; 08 October 2019 
Page 15 of 15 
 
 
 
Explanation of Superscripts: 
1. 
Informed consent must completed prior to any study-related screening procedures and may be completed before the 28-day screening window. 
2. 
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. 
3. 
Vital sign measurements include temperature, pulse, respiratory rate and resting systolic and diastolic blood pressure. 
4. 
On C1D1, duplicate ECGs to be performed 2-4 hr post CB-839 dose 
5. 
Assessments completed at screening. Investigators should monitor during the study if it is deemed necessary. 
6. 
Does not need to be repeated if the Screening sample was obtained within 3 days prior to C1D1 unless a clinically significant change is suspected 
7. 
Serum or urine pregnancy test is required of all patients of child-bearing potential. Screen pregnancy test must occur within 3 days prior to C1D1. 
8. 
PK sample (3 mL of whole blood) will be collected predose and 4 hours (± 30 min) post-dose on C1D15, C2D1, and C3D1. Refer to laboratory manual for further 
instructions. 
9. 
Biomarker analysis samples (3 mL of whole blood and saliva) will be taken at screening. Refer to laboratory manual for further instructions. 
10. Archival tumor tissue must be submitted, if available, for correlative studies. 
11. Fresh pre-dose tumor biopsies will be collected from all patients UNLESS an archival sample collected within 3 months prior to C1D1 is provided or if the tumor is 
inaccessible. 
12. Optional fresh tumor biopsies may be collected from patients who consent to providing samples during the trial or at EOT (e.g., if patient is responding, progressing lesion, 
etc.). 
13. Tumor assessments for Screening must be done within 21 days prior to C1D1. 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. 
14. Completed approximately every 8 weeks (2 cycles) during the first 13 cycles per RECIST 1.1. For patients with ≥ SD for at least 13 cycles who are on a steady dose for ≥ 2 
cycles, radiographic evaluation of tumor burden may be reduced to every 3 cycles (i.e., at Cycles 16, 19, 22, etc.). Evaluations may occur more frequently as clinically 
indicated. Scans must be submitted for central review. 
15. Neuropathy assessment will be performed at Screening, C3D1, C6D1, and at EOT. Refer to Study Reference Manual for detailed information. 
16. Patients will be contacted every 3 months for the first 12 months after discontinuation and then every 6 months thereafter to confirm survival. 
17. For patients with ≥ SD for at least 13 cycles who are on a steady dose for ≥ 2 cycles, study assessments may be reduced to every 3 cycles (i.e., at Cycles 16, 19, 22, etc.).