Conditions: Advanced Renal Cell Carcinoma Metastatic Renal Cell Carcinoma
Keywords: Tumor Metabolism RCC Glutaminase Inhibitor CB-839 CANTATA TKI Tyrosine Kinase Inhibitor cabozantinib Cabometyx Cometriq glutaminase glutamine renal cell clear cell kidney cancer cMET MET HGFR telaglenastat
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 444
Healthy volunteers: no

Brief summary:
Tthe primary objective of this study is to compare blinded Independent Radiology Committee (IRC)-adjudicated progression free survival (PFS) of patients treated with CB-839 + cabozantinib (CB-Cabo) versus placebo + cabozantinib (Pbo-Cabo) for advanced or metastatic clear-cell RCC (ccRCC).

Detailed description:

Arms:
arm 1: Placebo twice daily (BID) + cabozantinib (60 mg once daily \[QD\]) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or unacceptable toxicity, whichever occurred first. arm 2: CB-839 800 mg BID + cabozantinib (60 mg QD) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per RECIST v1.1 or unacceptable toxicity, whichever occurred first.

Interventions: intervention 1: CB-839 intervention 2: Cabozantinib intervention 3: Placebo
Intervention descriptions: intervention 1: Oral glutaminase inhibitor intervention 2: Oral receptor tyrosine kinase inhibitor intervention 3: Placebo tablets

Protocol document:
Prot_000.pdf: 
CB-839 
Protocol CX-839-008 
 09 April 2020 Amendment 3.0 
 
CONFIDENTIAL 
1 
 
Title  
A Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial 
Comparing CB-839 in Combination with Cabozantinib (CB-Cabo) vs. 
Placebo with Cabozantinib (Pbo-Cabo) in Patients with Advanced or 
Metastatic Renal Cell Carcinoma (RCC) 
Protocol Number 
CX-839-008 
IND Number 
118397 
Sponsor 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Sponsor Contact  
 
 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Phone: 
 
EudraCT Number 2018-000363-91 
Date/Version 
09 April 2020/Amendment 3.0 
 
 
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. 
 
 
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1.0 
TABLE OF CONTENTS 
1.0 
TABLE OF CONTENTS ..................................................................................................2 
2.0 
LIST OF TABLES .............................................................................................................6 
3.0 
LIST OF FIGURES ...........................................................................................................7 
4.0 
CONTACTS .......................................................................................................................8 
5.0 
OBJECTIVES AND ENDPOINTS ..................................................................................9 
6.0 
SAMPLE SIZE ...................................................................................................................9 
7.0 
STUDY DESIGN ..............................................................................................................10 
7.1 
Study Duration and End of Study Definition .........................................................11 
8.0 
INCLUSION/ EXCLUSION CRITERIA ......................................................................12 
8.1 
Inclusion Criteria ...................................................................................................12 
8.2 
Exclusion Criteria ..................................................................................................13 
9.0 
BACKGROUND AND RATIONALE ...........................................................................16 
9.1 
Renal Cell Cancer ..................................................................................................16 
9.2 
Glutaminase Inhibitor CB-839 ...............................................................................17 
9.3 
Preclinical Activity of CB-839 ..............................................................................18 
9.4 
Previous Human Experience with CB-839 ............................................................22 
9.4.1 
Safety.....................................................................................................23 
9.4.2 
Efficacy of CB-839 plus Cabozantinib .................................................26 
9.5 
Rationale for CB-839 Dose Selection ....................................................................27 
10.0 
PROCEDURES ................................................................................................................28 
10.1 
Screening................................................................................................................28 
10.1.1 
Concomitant Treatment .........................................................................28 
10.1.2 
Screening Evaluation ............................................................................30 
10.2 
Randomization .......................................................................................................30 
10.3 
Study Treatment Procedures ..................................................................................31 
10.4 
Long Term Follow Up ...........................................................................................32 
10.5 
Screen Failures .......................................................................................................32 
10.6 
Procedure details ....................................................................................................32 
10.6.1 
Demographics, Medical, and Cancer History .......................................33 
10.6.2 
Physical Examination ............................................................................33 
10.6.3 
Vital Signs .............................................................................................33 
10.6.4 
Adverse Events......................................................................................33 
10.6.5 
Concomitant Medications .....................................................................33 
10.6.6 
Electrocardiograms ...............................................................................34 
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10.6.7 
Laboratory Assessments........................................................................34 
10.6.8 
Patient-Reported Quality of Life Assessment .......................................34 
10.6.9 
Tumor Assessments ..............................................................................35 
10.6.10 
Tumor Biopsies .....................................................................................36 
10.6.10.1 
Archival Tumor Biopsies ...............................................................36 
10.6.10.2 
Optional Fresh Tumor Biopsies .....................................................36 
10.6.11 
Pharmacokinetic Samples .....................................................................37 
10.6.12 
Pregnancy, Contraception and Nursing/Breast-feeding ........................38 
10.6.12.1 
Pregnancy Testing ..........................................................................38 
10.6.12.2 
Contraception .................................................................................38 
10.6.12.3 
Nursing/Breast-feeding ..................................................................40 
11.0 
POTENTIAL TOXICITIES, DOSE MODIFICATION AND MANAGEMENT 
OF TOXICITIES .............................................................................................................40 
11.1 
Potential Toxicities ................................................................................................40 
11.1.1 
CB-839 ..................................................................................................40 
11.1.2 
Cabozantinib .........................................................................................40 
11.1.3 
Dose Modification Guidelines ..............................................................41 
11.1.3.1 
Study Drug Dose Levels ................................................................41 
11.1.3.2 
Study Drug Dose Modifications ....................................................41 
11.1.4 
Cabozantinib Warnings, Precautions, and Guidelines for 
Management of Potential Adverse Events ............................................44 
11.1.4.1 
Gastrointestinal Disorders ..............................................................44 
11.1.4.2 
Hepatobiliary Disorders .................................................................45 
11.1.4.3 
Hematological Disorders ...............................................................46 
11.1.4.4 
Fatigue, Anorexia, and Weight Loss ..............................................46 
11.1.4.5 
Skin Disorders ................................................................................47 
11.1.4.6 
Hypertension ..................................................................................48 
11.1.4.7 
Thromboembolic Events ................................................................49 
11.1.4.8 
Proteinuria ......................................................................................50 
11.1.4.9 
Hypophosphatemia ........................................................................51 
11.1.4.10 
Thyroid Function Disorders ...........................................................51 
11.1.4.11 
Hemorrhagic Events.......................................................................52 
11.1.4.12 
GI Perforation/Fistula and Non-GI Fistula Formation...................52 
11.1.4.13 
Osteonecrosis of the Jaw ................................................................53 
11.2 
Resumption of Study Treatment ............................................................................54 
11.3 
Discontinuation of Treatment ................................................................................54 
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12.0 
TEST ARTICLES/STUDY DRUGS ..............................................................................56 
12.1 
Blinded Investigational Product .............................................................................56 
12.2 
Cabozantinib Study Drug .......................................................................................57 
12.3 
Missed or Vomited Doses ......................................................................................57 
12.4 
Packaging and Labeling .........................................................................................57 
12.5 
Storage and Stability ..............................................................................................57 
12.6 
CB-839 Accountability, Reconciliation, and Return .............................................58 
12.7 
Test Article/Study Drug Compliance.....................................................................58 
13.0 
MEASURES TO MINIMIZE/AVOID BIAS ................................................................58 
14.0 
STATISTICAL ANALYSIS ...........................................................................................58 
14.1 
General Study Design ............................................................................................59 
14.2 
Independent Radiology Committee (IRC) .............................................................59 
14.3 
Independent Data Monitoring Committee .............................................................59 
14.4 
Study Steering Committee .....................................................................................60 
14.5 
Analysis Patient Sets ..............................................................................................60 
14.5.1 
Efficacy Analysis Patient Set ................................................................60 
14.5.2 
Safety Analysis Set ...............................................................................60 
14.6 
Efficacy Analysis ...................................................................................................60 
14.6.1 
Primary Efficacy Endpoint: IRC-Adjudicated PFS ..............................60 
14.6.2 
Secondary Efficacy Endpoints ..............................................................61 
14.6.3 
Additional Endpoints ............................................................................62 
14.6.4 
Exploratory Analyses ............................................................................63 
14.7 
Safety Analysis ......................................................................................................63 
14.8 
Sample Size Estimation .........................................................................................63 
15.0 
ADVERSE EVENTS .......................................................................................................64 
15.1 
Definitions..............................................................................................................64 
15.2 
Recording and Reporting .......................................................................................69 
15.3 
Serious Adverse Event Reporting ..........................................................................70 
16.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION .............................71 
17.0 
INFORMED CONSENT .................................................................................................71 
18.0 
PROTOCOL AMENDMENTS ......................................................................................71 
19.0 
QUALITY CONTROL AND ASSURANCE.................................................................72 
20.0 
DIRECT ACCESS, DATA HANDLING, AND RECORD KEEPING ......................72 
20.1 
Ethical Considerations ...........................................................................................72 
20.2 
Investigator ............................................................................................................72 
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20.3 
Sponsor ..................................................................................................................73 
20.4 
Pre-Study Documentation ......................................................................................73 
20.5 
Records Retention ..................................................................................................74 
21.0 
PUBLICATION AND AUTHORSHIP ..........................................................................75 
22.0 
LIST OF ABBREVIATIONS .........................................................................................76 
23.0 
REFERENCES .................................................................................................................78 
ATTACHMENT 1: SCHEDULE OF STUDY ASSESSMENTS ............................................80 
ATTACHMENT 2: CLINICAL LABORATORY TESTS ......................................................83 
ATTACHMENT 3: IMDC PROGNOSTIC MODEL ..............................................................85 
ATTACHMENT 4: KARNOFSKY PERFORMANCE STATUS SCALE ............................86 
ATTACHMENT 5: RECIST CRITERIA VERSION 1.1 ........................................................87 
ATTACHMENT 6: DRUG INTERACTIONS .........................................................................96 
ATTACHMENT 7: NCCN-FACIT MEASUREMENT SYSTEM (FKSI-19) 
QUESTIONNAIRE/ SCALE ..........................................................................................98 
ATTACHMENT 8: EUROQOL QUESTIONNAIRE ED-5D-5L (US ENGLISH 
SAMPLE VERSION) ....................................................................................................100 
ATTACHMENT 9: SUMMARY OF CHANGES (AMENDMENT 3.0 VS. 2.0).................102 
 
 
 
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2.0 
LIST OF TABLES 
Table 9.5-1: CB-839 Related Adverse Events in ≥ 5% of Patients Treated with Monotherapy 
CB-839 on the BID Schedule on Study CX-839-001 ......................................23 
Table 9.5-2: CX-839-001 CB-839 + Cabozantinib Treatment-Related Adverse Events1 .............25 
Table 11.1-1: Dose Levels for CB-839/Placebo ............................................................................41 
Table 11.1-2: Dose Levels for Cabozantinib .................................................................................41 
Table 11.1-3: Treatment Modifications Guidelines for Treatment-Related AEs ..........................43 
Table 11.1-4: Management of Treatment-emergent PPE Syndrome .............................................48 
Table 11.1-5: Management of Treatment-emergent Hypertension................................................49 
Table 11.1-6: Management of Treatment-emergent Proteinuria ...................................................51 
Table A: Time Point Response: Patients with Targets (+/- Non-Target) Disease .........................95 
 
 
 
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3.0 
LIST OF FIGURES 
Figure 7.0-1  
Study Design Schema ......................................................................................11 
Figure 9.3-1 
Antiproliferative and pro-apoptotic activity of CB-839 in kidney tumor 
cell lines in vitro...............................................................................................19 
Figure 9.3-2 
Synergistic activity of CB-839 in combination with cabozantinib in the 
Caki-1 RCC cell line in vitro. ..........................................................................20 
Figure 9.3-3 
Inhibition of tumor growth by CB-839 in combination with other agents in 
the Caki-1 RCC cell line in vivo. .....................................................................21 
Figure 9.6-4 
Best tumor response for RCC patients receiving CB-839 + cabozantinib in 
Phase 1. ............................................................................................................27 
 
 
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7.0 
STUDY DESIGN 
Protocol CX-839-008 is a Phase 2 randomized, double-blind, placebo-controlled, multicenter 
study comparing two treatment regimens for patients with ccRCC (see Figure 7.0-1). Eligible 
patients will be randomized in a 1:1 ratio to the following study treatment arms: 
a) CB-Cabo – CB-839 (800 mg twice daily [BID]) + cabozantinib (60 mg once daily [QD])   
b) Pbo-Cabo – Placebo + cabozantinib (60 mg QD)  
Randomization will be stratified by the following variables: 
a) Prior treatment with PD-1/PD-L1 inhibitor therapy (yes vs. no) 
b) The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) 
Prognostic Risk Group (favorable vs. intermediate vs. poor; Attachment 3).  
The primary endpoint of this Phase 2 study is IRC-adjudicated PFS.  
Patients will receive study treatment determined by randomization in 28-day cycles until disease 
progression per RECIST v.1.1 or unacceptable toxicity, whichever occurs first (see Section 11.3 
for further details). Patients will be followed for safety for at least 28 days after the last dose of 
all study treatments (CB-839/placebo and cabozantinib), or until initiation of a new anticancer 
therapy, if earlier. Patients who discontinue study treatment for reasons other than disease 
progression by RECIST v.1.1 or death will also continue to be followed by radiographic tumor 
imaging until documentation of radiographic progressive disease per RECIST v.1.1, death, 
initiation of a new anticancer therapy, or withdrawal of consent as described in Section 10.6.9. 
Long-term follow up for survival will continue until death or withdrawal of consent for survival 
follow-up.  
A summary of the study design is presented in Figure 7.0-1. 
 
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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. Documented histological or cytological diagnosis of renal cell carcinoma with a 
clear-cell component 
b. Age ≥ 18 years 
c. Karnofsky Performance Score (KPS) ≥ 70% (Attachment 4) 
d. Estimated Life Expectancy of at least 3 mo 
e. Measurable Disease per RECIST 1.1 as determined by the Investigator (see 
Attachment 5) 
f. One and not more than two prior systemic lines of therapy (monotherapy or 
combination regimen) for advanced or metastatic RCC  
1) Must include either: 
i. one anti-angiogenic therapy (any VEGF pathway-targeted agent, used 
either as monotherapy or as a component of a combination regimen) 
– OR –  
ii. the combination regimen of nivolumab + ipilimumab 
2) Exposure to a prior treatment regimen for ≥4 weeks is considered a prior line 
of therapy, regardless of reason for its discontinuation (exception: high-dose 
IL2 will count as prior therapy if >3 doses administered) 
i. 4 weeks will be counted from first to last dose for regimens that are 
intended to be administered on daily schedules (e.g., sunitinib, 
pazopanib) and from first dose to end of cycle length after last dose for 
regimens that are intended to be administered in intervals of ≥ 1 week 
(e.g., one treatment of a Q2W regimen counts as 2 weeks of therapy)  
3) Rechallenge with the same agent or regimen will not be considered a new line 
of therapy, if the patient had not previously discontinued that agent or regimen 
because of disease progression  
4) Systemic adjuvant therapy is considered a prior line of therapy if the patient 
has disease recurrence on or within 1 year after the last dose of adjuvant 
therapy  
g. The patient must have had radiographic evidence of disease progression on or after 
the most recent systemic therapy and within 6 mo before randomization 
 
3. Laboratory Findings 
a. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance 
(CCr) ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation:  
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CCr = {((l40 – age) x actual body weight)/ (72 x SCr)} x 0.85 (if female)  
b. Adequate hematological function, defined as absolute neutrophil count ≥ 1,500/mm3, 
hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100,000/mm3. Transfusions and growth 
factors must not be used within 2 weeks prior to randomization to meet these 
requirements.  
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper 
limit of normal. 
d. Total bilirubin ≤ 1.5 × the upper limit of normal. For patients with Gilbert’s disease, 
≤ 3 mg/dL (≤ 51.3 μmol/L). 
e. Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) or 
24-hour urine protein < 1 g. 
4. Reproductive Status 
a. Female patients of childbearing potential must have a negative serum or urine 
pregnancy test and if sexually active must agree to contraceptive requirements 
outlined in Section 10.6.12.2. Male patients who are sexually active with heterosexual 
partners of childbearing potential must agree to contraceptive requirements and sperm 
donation restrictions outlined in Section 10.6.12.2.  
5. Other Inclusion Criteria 
a. Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior 
cancer therapy, unless after discussion with medical monitor adverse events (AEs) are 
deemed clinically non-significant and/or stable on supportive therapy. 
 
8.2 
Exclusion Criteria 
1. Medical History  
a. Prior treatment with cabozantinib (or other MET inhibitor) or CB-839 
b. Receipt of any anticancer therapy within the following windows before 
randomization: 
 Small molecule receptor tyrosine kinase inhibitor (TKI) therapy (including 
investigational) within 2 weeks or 5 half-lives, whichever is longer 
 Any type of anticancer antibody or cytotoxic chemotherapy within 
4 weeks 
 Radiation therapy for bone metastasis within 2 weeks, any other external 
radiation therapy within 4 weeks, or systemic treatment with radionuclides 
within 6 weeks before randomization. Patients with clinically relevant 
ongoing complications (per investigator assessment) from prior radiation 
therapy are not eligible. 
 Other investigational therapy within 4 weeks or 5 half-lives, whichever is 
longer. 
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c. Patients with active and/or untreated central nervous system (CNS) cancer are not 
eligible.  Patients with treated brain metastases (1) must have documented 
radiographic stability of at least 4 weeks duration demonstrated on baseline 
contrast-enhanced CNS imaging (e.g., contrast-enhanced MRI of the brain) prior 
to randomization and (2) must be symptomatically stable and off of steroids (for 
the purpose of treating symptoms of brain metastases) at least 2 weeks before 
randomization.  
d. Any other current or previous malignancy within the past three years except:  
 Adequately treated basal cell or squamous cell skin cancer,  
 Carcinoma in situ of the cervix,  
 Other neoplasm that, in the opinion of the Principal Investigator and with 
the agreement of the Medical Monitor, will not interfere with study-
specific endpoints 
e. Previously identified allergy or hypersensitivity to components of the study 
treatment formulations (Note: patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption 
should not take cabozantinib and are also excluded). 
f. Corrected QT interval (QTc) > 500 msec within 1 mo before randomization 
 Cabozantinib should be used with caution in patients with a history of QT 
interval prolongation, patients who are taking antiarrhythmics, or patients 
with clinically relevant pre-existing cardiac disease, bradycardia, or 
electrolyte disturbances. 
 
2. Concurrent Conditions 
a. Unable to receive oral medications or any condition that may prevent adequate 
absorption of oral study medication including refractory nausea and vomiting, 
uncontrolled diarrhea, malabsorption, small bowel resection or gastric bypass 
surgery, use of feeding tubes 
b. Major surgery (e.g., GI surgery) within 6 weeks before first dose of study 
treatment or incomplete wound healing from any prior surgery. Patients with 
clinically relevant ongoing complications (per investigator assessment) from prior 
surgery are not eligible. 
c. The patient has uncontrolled, significant current or recent illness including, but 
not limited to, the following conditions: 
 Cardiovascular disorders: 
i. 
Symptomatic congestive heart failure, unstable angina pectoris, 
serious cardiac arrhythmias  
ii. 
Uncontrolled hypertension defined as sustained BP > 150 mm Hg 
systolic or > 100 mm Hg diastolic despite optimal antihypertensive 
treatment 
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 Stroke (including TIA), myocardial infarction, or other ischemic event 
within 6 mo before randomization 
 Gastrointestinal (GI) disorders including those associated with a high risk 
of perforation or fistula formation: 
i. 
Tumors invading the GI tract, active peptic ulcer disease, 
inflammatory bowel disease, diverticulitis, cholecystitis, 
symptomatic cholangitis or appendicitis, acute pancreatitis or acute 
obstruction of the pancreatic or biliary duct, or gastric outlet 
obstruction 
ii. 
Abdominal fistula, gastrointestinal perforation, bowel obstruction, 
or intraabdominal abscess within 6 mo before randomization 
iii. 
Complete healing of an intra-abdominal abscess must be confirmed 
before randomization  
 Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 
teaspoon (2.5 mL) of red blood, or other history of significant bleeding 
within 3 mo before randomization 
 Moderate to severe hepatic impairment (Child-Pugh B or C) 
 Lesions invading major pulmonary blood vessels 
d. Known active infection with HIV or Hepatitis B or C virus 
e. Anticoagulation with warfarin at therapeutic doses is prohibited.   
 Note: Anticoagulation with therapeutic doses of low molecular weight 
heparin (LMWH), direct thrombin inhibitors, factor Xa inhibitors, and 
platelet inhibitors (e.g., clopidogrel) is allowed in patients without brain 
metastases who are on stable doses for at least 4 weeks before 
randomization and have had no complications from the anticoagulation 
regimen.   
 Low-dose aspirin for cardioprotection, and low-dose (prophylactic) low 
molecular weight heparin (LMWH) are permitted.  
f. Inability to discontinue proton pump inhibitor use before randomization 
g. 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 
h. Patients who are pregnant or lactating 
 
 
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PROTOCOL DETAILS 
9.0 
BACKGROUND AND RATIONALE 
9.1 
Renal Cell Cancer 
Renal cell carcinoma represents approximately 3% of malignancies, with current worldwide 
diagnoses and deaths of approximately 295,000 and 134,000 respectively (Hsieh 2017). 
Approximately a third of patients diagnosed with RCC have curative partial or complete 
nephrectomy, a third of patients experience disease recurrence following nephrectomy, and a 
third of patients are diagnosed with de novo metastatic disease. Treatment of metastatic RCC 
(mRCC) is based on disease histology, patient overall health and performance status, and the 
number and type of prior systemic therapies. First-line patients with clear-cell mRCC typically 
receive vascular endothelial growth factor (VEGF)-targeted therapy, most commonly the TKIs 
sunitinib or pazopanib, although the anti-VEGF antibody bevacizumab in combination with 
low-dose gamma interferon is also an option. After failure of first-line anti-angiogenesis therapy, 
patients generally receive the anti-PD-1 antibody nivolumab or one of several TKIs (most 
commonly cabozantinib or axitinib). Patients may receive the mTOR inhibitor everolimus in 
second line, however this agent is now primarily used in the third-line and later settings. 
Despite the availability of multiple approved therapies for the treatment of mRCC in first and 
second line, these agents represent a limited number of anticancer mechanisms: angiogenesis 
targeting agents (TKIs or antibodies) or immune modulating agents (PD-1 inhibitor or 
cytokines). Most importantly, from the standpoint of unmet medical need, very few patients with 
mRCC are cured by therapy, and a substantial number receive little benefit from treatment. In the 
second-line setting, based on pivotal studies that lead to marketing approvals in the US and 
Europe, cabozantinib has an ORR of 17%, median PFS of 7.4 mo and median OS of 21.4 mo 
(Choueiri 2016), and nivolumab has an ORR of 25%, median PFS of 4.6 mo, and median OS of 
25 mo (Motzer 2015). Therefore, there is significant need for improved efficacy in the treatment 
of mRCC and for the development of therapies with novel and distinct mechanisms of action. 
Of importance for the first-line treatment of patients with mRCC, and therefore of importance for 
the design of second-line clinical studies, data were recently presented at the September 2017 
European Society of Medical Oncology Congress in Madrid (Escudier 2017). The Phase 3 
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randomized CheckMate 214 study compared the combination regimen of nivolumab + 
ipilimumab to the standard-of-care regimen of sunitinib for the first-line treatment of patients 
with mRCC. In the primary analysis of patients with intermediate and poor risk disease, the 
study demonstrated a 37% reduction in risk of death (hazard ratio 0.63, p<0.0001) for the 
experimental compared to control arm as well as an increased ORR (42% vs. 27%), an increased 
complete response (CR) rate (9% vs. 1%), and a 3.2-mo improvement in median PFS (p<0.03). 
In the intent-to-treat (ITT) analysis of all 1096 randomized patients, including favorable-risk 
patients, the median OS remained significantly improved for the nivolumab + ipilimumab 
combination compared to sunitinib, with a 32% reduction in risk of death (hazard ratio 0.68, 
p<0.0003). In addition, the exploratory endpoint of health-related QoL favored the nivolumab + 
ipilimumab arm over the sunitinib arm. Although these data are not yet reflected in regulatory 
approval, they are considered to represent a “paradigm shift” in the first-line treatment of mRCC 
and should be considered in the design of second-line mRCC trials.  
In addition, the Phase 2 randomized trial of cabozantinib compared with sunitinib in the first-line 
treatment of patients with mRCC demonstrated a 52% reduction in the risk of progression or 
death in patients with intermediate and poor risk disease (adjusted hazard ratio 0.48, p=0.0008; 
median PFS per IRC 8.6 mo vs. 5.3 mo) and increased ORR (20% vs. 9%) in favor of 
cabozantinib (Choueiri 2018). These data support the benefit of cabozantinib in patients without 
prior antiangiogenic therapy and the consideration that second-line mRCC trials including 
cabozantinib should not be restricted to patients with prior antiangiogenic therapy. 
9.2 
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 (GLS gene product), but does not inhibit 
the liver isoform, glutaminase-2 (GLS2 gene product). (Throughout this document, glutaminase 
refers to the GLS gene products only.) 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 a wide range of human tumor cell lines in vitro and in vivo when implanted in 
immunocompromised mice. The effect of glutaminase inhibition on tumor cell growth closely 
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correlates with a similar response to withdrawal of glutamine; the absolute requirement of most 
tumor cells for glutamine involves the production of glutamate by glutaminase. 
CB-839 is being developed for the treatment of RCC and other malignancies. Single-agent 
antitumor activity of CB-839 has been demonstrated in vitro in multiple RCC cell lines, and 
CB-839 has been shown to have antitumor activity in animal studies as a single agent and in 
combination with drugs such as everolimus, cabozantinib, and sunitinib, where additive or 
synergistic activity in immunocompromised mice was observed. CB-839 was also shown to 
enhance the activity of anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors, where there 
was a significant improvement in the incidence of syngeneic tumor regression in immuno-
competent mice. The mechanism of action of CB-839 may involve a combination of a) direct 
anti-tumor activity resulting from blockade of glutamine utilization and b) indirect stimulation of 
anti-tumor immune response due to the accumulation of glutamine in the tumor 
microenvironment. 
9.3 
Preclinical Activity of CB-839  
CB-839 has antiproliferative activity across a wide range of tumor cell types including solid 
tumors (ccRCC, non-small cell lung cancer, triple negative breast cancer [TNBC], etc.) and 
hematological tumors (multiple myeloma, acute myeloid leukemia, diffuse large B-cell 
lymphoma), with IC50 values ranging from 1 to 100 nM. When CB-839 was administered twice 
daily to immunocompromised mice bearing a variety of human tumor xenografts, including 
ccRCC and TNBC, a reduction of tumor growth rate was observed. CB-839 administration was 
well-tolerated up to 400 mg/kg BID and resulted in substantial inhibition of tumor growth.  
Incubation of cell lines with CB-839 leads to inhibition of glutaminase with a consequent 
increase in the cellular pools of the substrate glutamine and decrease in the product glutamate 
and metabolites derived from glutamate. Similar increases in glutamine and decreases in 
glutamate are observed in xenografted tumors from animals treated with CB-839. In the TNBC 
cell line HCC1806, inhibition of proliferation and metabolite changes were observed at similar 
CB-839 concentrations (Gross 2014), consistent with an on-target mechanism of action. 
Importantly, the antiproliferative activity of CB-839 across cancer cell lines from multiple 
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histological types (including ccRCC) is associated with inhibition of mTOR signaling, likely 
resulting from depletion of intracellular pools of nutrient amino acids. 
The antiproliferative and pro-apoptotic activity of CB-839 has been characterized in a panel of 
kidney cancer cell lines (Figure 9.3-1). Clear-cell RCC cell lines appear to be more sensitive to 
the effects of CB-839 as compared with other kidney cancer cell lines. 
 
 
Figure 9.3-1 
Antiproliferative and pro-apoptotic activity of CB-839 in kidney tumor cell lines in 
vitro.  
Kidney cancer cells were incubated with 1 µM CB-839 for 72 hr. Cell growth or cell loss 
(death) relative to vehicle control samples are shown for each cell line on the y-axis.  
 
The combination of CB-839 with the TKI cabozantinib was evaluated in vitro and included 
assessments of a) anti-proliferative activity, b) inhibition of signal transduction via the Ras/Raf 
pathway, and c) inhibition of oxidative phosphorylation as measured by reduced oxygen 
consumption. The activity of each drug individually and when given in combination is shown in 
Figure 9.3-2.  
CB-839 has strong synergistic activity in combination with cabozantinib with respect to the 
inhibition of cellular proliferation (Figure 9.3-2, Panel A). (Note: Combination Index values of 
1.0 indicate additivity, and values significantly lower than 1.0 indicate synergy in this assay 
[Chou 1984]). This may be, in part, due to the enhanced inhibition of VEGF signaling achieved 
with the combination (Figure 9.3-2, Panel B). Furthermore, there is a greater reduction in aerobic 
mitochondrial respiration (oxygen consumption) by the combination than either agent alone 
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9.4 
Previous Human Experience with CB-839 
Three separate Phase 1 studies were initiated in February 2014 to evaluate the safety, 
pharmacokinetics, and pharmacodynamics of orally administered CB-839 either as a single agent 
or in combination with approved agents in patients with solid tumors (CX-839-001), multiple 
myeloma and Non-Hodgkin’s Lymphoma (CX-839-002), or acute leukemia (CX-839-003). CX-
839-001 enrolled RCC patients for treatment with CB-839 + cabozantinib and CB-839 + 
everolimus, as well as TNBC patients for treatment with CB-839 + paclitaxel. In addition, the 
combination of CB-839 with nivolumab is being evaluated in the Phase 1/2 study, CX-839-004. 
During dose escalation in all three Phase 1 studies, single-agent CB-839 was administered 
initially three times daily (TID) without meals and was later changed to a BID schedule with 
breakfast and dinner.  
As of data cuts on 28 September 2017, a total of 102 patients received 600, 800, or 1000 mg BID 
CB-839 as a single agent; an additional 59 patients received single-agent CB-839 dosed on the 
TID schedule ranging from 100 to 1000 mg TID. More than 190 patients have received CB-839 
at doses ranging from 400 to 800 mg BID in combination with cabozantinib, erlotinib, 
everolimus, paclitaxel, nivolumab, dexamethasone, pomalidomide, or azacitidine. 
In pharmacokinetic studies, the half-life of CB-839 was approximately 4 hr. A dose-related 
increase in exposure was observed over doses ranging from 100 to 600 mg; exposures for 
600 mg and 800 mg doses were similar albeit with significant interpatient variability. In 
pharmacodynamic studies, robust inhibition of glutaminase was demonstrated in platelets at 
exposures maintained in most BID-dosed patients at 600 mg and 800 mg inter-dose troughs, with 
the 800 mg dose in particular showing ≥ 90% target inhibition. Patient tumor biopsies also 
demonstrated robust glutaminase inhibition (> 75% for most patients).  
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9.4.1 
Safety 
Please refer to the current CB-839 Investigator’s Brochure for the most recent safety information 
for CB-839 monotherapy and CB-839 in combination regimens.  
CB-839 Monotherapy 
Treatment-related AEs for patients enrolled on Study CX-839-001 who received monotherapy 
with CB-839 on the BID fed regimen are presented in Table 9.5-1. Of 88 safety-evaluable 
patients, 61 (69.3%) experienced AEs that were considered possibly or probably related to 
CB-839. The most frequent CB-839-related AEs were fatigue, gastrointestinal AEs (e.g., nausea, 
decreased appetite, and vomiting), liver function test (LFT) elevations (e.g., AST, ALT), and 
photophobia. These AEs were typically mild to moderate in intensity (Grade 1/2), reversible, and 
manageable without dose interruption or modification.  
The most frequent Grade 3 AEs were elevations in LFTs, including AST, ALT, and alkaline 
phosphatase. Gamma-glutamyltransferase elevations were also noted but are of unclear clinical 
significance. The frequency of Grade 3 elevations in LFTs was limited, with 2 of 88 patients 
experiencing a treatment-related Grade 3 AST or ALT elevation. One Grade 3 AE of anemia was 
also considered to be possibly related to CB-839 (not shown). There have been no reported 
Grade 4 or Grade 5 treatment-related adverse events.  
Table 9.5-1: CB-839 Related Adverse Events in ≥ 5% of Patients Treated with 
Monotherapy CB-839 on the BID Schedule on Study CX-839-001 
BID fed - Monotherapy (N=88) 
MedDRA Preferred Term 
Number (%) of patients 
All Grades 
Grade 3 
Patients with Any CB-839-Related AE 
61 (69.3) 
3 (3.4) 
Fatigue 
22 (25.0) 
0 
Nausea 
20 (22.7) 
0 
Alanine aminotransferase increased 
13 (14.8) 
2 (2.3) 
Photophobia 
12 (13.6) 
0 
Aspartate aminotransferase increased 
10 (11.4) 
1 (1.1) 
Decreased appetite 
7 (8.0) 
0 
Gamma-glutamyltransferase increased 
7 (8.0) 
2 (2.3) 
Blood alkaline phosphatase increased 
6 (6.8) 
1 (1.1) 
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Vomiting 
5 (5.7) 
0 
23July2017 data cut 
Photophobia and related ocular toxicities (e.g., photopsia) have been identified as 
CB-839-related events. In all but one case, these events have been Grade 1 and without impact 
on patients’ daily lives. One photophobia event was characterized as Grade 2. These events 
appear to occur around Cmax (1-4 hr after dosing) and resolve over a few hours. These events 
have been reported to become less frequent over extended dosing. Note: Photophobia/photopsia 
should be carefully distinguished from “photosensitivity”.  “Photosensitivity”, which refers to an 
adverse event of the skin such as an unexpected sunburn or dermatitis on sun-exposed skin, has 
not been observed with CB-839 monotherapy or in combination with cabozantinib. 
 
CB-839 in Combination  
CB-839 has been combined in Phase 1 studies with standard of care therapies in a number of 
different solid tumors, including everolimus (N = 27), cabozantinib (N = 12), paclitaxel (N = 49), 
nivolumab (N = 82), and erlotinib (N = 1). In all cases thus far, the Adverse Event profile of 
CB-839 administered at 600-800 mg BID together with the full dose of each partner agent has 
been similar to those previously reported for each agent alone. Additional details are available in 
the Investigator’s Brochure.  
CB-839 + Cabozantinib 
Based on the data cut on 23 October 2018 for patients enrolled on the phase 1 Study CX-839-
001, treatment-related AEs reported for ≥2 patients among 13 patients receiving CB-839 (6 at 
600 mg BID and 7 at 800 mg BID) with cabozantinib 60 mg QD are presented in Table 9.5-2. 
The combination was well tolerated at the 600 mg BID dose and the 800 mg BID dose of 
CB-839. The most frequently reported treatment-related AEs (assessed as possibly or probably 
related to either study drug) were diarrhea, elevations in alanine amino transferase and aspartate 
amino transferase, decreased appetite, nausea, fatigue, and rash. Grade 3 or Grade 4 events were 
one event each of Grade 3 diarrhea, Grade 3 hallucination, Grade 3 hypertension, and Grade 4 
decreased platelet count, the last of which was the sole dose limiting toxicity (DLT) reported 
during dose escalation (600 mg BID CB-839 cohort). As with other CB-839 combination 
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regimens, the recommended Phase 2 dose (RP2D) of CB-839 in combination with full dose 
cabozantinib was determined to be 800 mg BID. (See Section 11.1.2 for information about 
cabozantinib monotherapy safety). 
Table 9.5-2: CX-839-001 CB-839 + Cabozantinib Treatment-Related Adverse Events1 
CB-839 600 mg BID or 800 mg BID + Cabozantinib 60 mg (N=13) 
MedDRA Preferred Term 
Number (%) of patients 
All Grades 
≥Grade 32 
Patients with any treatment-related AEs1  
13 (100.0) 
 5 ( 38.5) 
DIARRHOEA 
 8 ( 61.5) 
 1 ( 7.7) 
ALANINE AMINOTRANSFERASE INCREASED 
 6 ( 46.2) 
 0 
DECREASED APPETITE  
 6 ( 46.2) 
 0 
ASPARTATE AMINOTRANSFERASE INCREASED 
 5 ( 38.5) 
 0 
FATIGUE  
5 ( 38.5) 
 0 
NAUSEA 
 4 ( 30.8) 
 0 
RASH 
4 ( 30.8) 
 0 
MUCOSAL INFLAMMATION 
 3 ( 23.1) 
 0 
PROTEINURIA 
 3 ( 23.1) 
 0 
VOMITING 
 3 ( 23.1) 
 0 
WEIGHT DECREASED 
3 ( 23.1) 
 0 
DEHYDRATION 
 2 ( 15.4) 
 0 
DYSGEUSIA 
2 ( 15.4) 
 0 
HYPERTENSION 
2 ( 15.4) 
1 ( 7.7) 
MUSCLE SPASMS 
2 ( 15.4) 
0 
PLATELET COUNT DECREASED 
2 ( 15.4) 
 1 ( 7.7) 
PRURITUS 
2 ( 15.4) 
 0 
STOMATITIS 
2 ( 15.4) 
0 
1 Adverse events assessed by investigator as possibly or probably related to either CB-839, cabozantinib or 
  both; preferred terms reported in ≥2 patients. 
2 Additional Grade 3 adverse event of hallucination reported in 1 patient.  
CB-839 + Everolimus  
As discussed in Section 9.3, the combinations of CB-839 with everolimus and with cabozantinib 
share a common mechanism of action. Inhibitors of the Ras/Raf and PI3K/mTOR pathways 
inhibit glucose utilization while CB-839 blocks glutamine utilization. The safety profile of these 
two combinations together with the preclinical data strongly suggest that this is a tumor-specific 
mechanism with little impact on normal cells and tissues. The combination of CB-839 with 
everolimus has been well tolerated to date. Of 27 patients who received CB-839 (400 mg, 
600 mg or 800 mg BID with food) in combination with everolimus, the most frequent AEs were 
anemia, decreased appetite, creatinine increase, fatigue, cough, diarrhea, nausea, and 
hyperglycemia. Grade 3 treatment-related adverse events were few in number, with the most 
common being decreased appetite, anemia, fatigue, and mucosal inflammation, and there have 
been no related Grade 4 events.  One event of Grade 3 pruritic rash occurred at the CB-839 
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400 mg BID dose level and was considered a DLT. The rash was considered related to 
everolimus and resolved upon a dose reduction of everolimus (CB-839 continued at full dose).   
9.4.2 
Efficacy of CB-839 plus Cabozantinib  
Please refer to the current CB-839 Investigator’s Brochure for the most recent efficacy 
information for CB-839 monotherapy and CB-839 in combination regimens.  
As of 24 September 2018, 13 patients have been enrolled and treated on Study CX-839-001, with 
the combination of cabozantinib and CB-839 (6 pts at 600 mg BID and 7 pts at 800 mg BID). 
Enrolled patients had received a median of 3 prior lines of therapy (range 0-7, including 1 patient 
with papillary RCC who had not received prior therapy). Among twelve response-evaluable 
patients treated with the combination, all have received clinical benefit, including 12 of 
12 patients with tumor shrinkage, and among evaluable clear cell RCC patients 5 of 10  (50%) 
had a partial response (PR) by RECIST 1.1.  
A waterfall plot of tumor response is shown in Figure 9.6-4.
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inhibition < 90%. In aggregate, these data support the risk:benefit ratio of the 800 mg BID 
CB-839 dose level when given alone or in the presence of a variety of standard of care agents. 
10.0 
PROCEDURES 
This section describes evaluations to be performed during the different periods of this study. All 
patients must sign an IRB/IEC-approved informed consent prior to starting any protocol-specific 
procedures, including screening procedures; however, evaluations performed as part of routine 
care prior to informed consent can be utilized as screening evaluations if permitted by the site’s 
IRB/IEC policies. During the consent process, the person obtaining consent must inform the 
patient of all elements of informed consent.  
10.1 
Screening 
An IRB/EC-approved Informed Consent Form (ICF) must be signed and dated before any study-
specific (i.e., non-standard of care) screening procedures are performed. The ICF must be signed 
and dated ≤42 days prior to randomization.  
To determine a patient’s eligibility, patients will undergo required screening evaluations as 
outlined in Attachment 1. Required screening assessments must be completed within 28 days 
prior to randomization, unless otherwise indicated. Patients must meet all inclusion criteria and 
none of the exclusion criteria in order to be deemed eligible and randomized into the study. The 
investigator is responsible for reviewing all screening data to confirm patient eligibility; a 
Medical Monitor representing the Sponsor will review a brief eligibility checklist with entries of 
select screening data to approve patient randomization. 
10.1.1 
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.  
Non-protocol systemic anticancer treatment, surgical resection of lesions, use of investigational 
therapeutic agents other than the study drugs, and palliative radiation to non-bone tumors are 
NOT permitted while the patient is on study. In general, palliative (limited field) radiation for 
bone metastasis pain should not be performed while on study. If palliative radiation to a bone 
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lesion is deemed clinically unavoidable for symptoms that in the opinion of the investigator are 
not due to progressive disease, the investigator must seek Sponsor approval prior to the 
procedure. Note that these patients may be considered non-evaluable or assigned an early 
censoring date or progression date at the date of first such therapy. Initiation of therapeutic 
anticoagulation is allowed on study, as clinically indicated, in consultation with the Sponsor’s 
medical monitor. Chronic use of immunosuppressive medication during study treatment is 
prohibited with the exceptions of inhaled or topical corticosteroids and corticosteroids with a 
daily dosage equivalent of ≤ 10 mg prednisone.  
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 6. 
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. Discontinuation of PPIs is required for patients on study. Alternative antacids such as 
H2 blockers (e.g., ranitidine, famotidine) and buffering agents (e.g., sodium bicarbonate, calcium 
carbonate, and sucralfate) may be substituted for PPIs; however to aid absorption, it is 
recommended to plan CB-839 dosing at the time of minimal exposure to the antacid (e.g., 10 hr 
after last dose of H2 blockers, or 2 hr before each dose of H2 blocker if administered BID). 
Please consult the medical monitor if a patient experiences significant difficulties with gastric 
symptoms during the study and requires a PPI based on the investigator’s assessment.  
Cabozantinib is a substrate of CYP3A4, and concomitant use of strong inhibitors or inducers of 
CYP3A4 may affect cabozantinib exposure. See Attachment 6 for a summary of related data and 
examples of strong CYP3A4 inhibitors or inducers. Refer to the most current cabozantinib 
prescribing information for additional details and guidance. 
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10.1.2 
Screening Evaluation 
Procedures listed below that are performed as part of the normal standard of care and within the 
required screening windows (≤ 28 days prior to randomization, unless otherwise specified) may 
be used for screening purposes: 
 Demographic information including date of birth, sex, race, and ethnic origin  
 Medical history including review of prior cancer treatments, procedures, and surgeries 
 Review of concomitant medications 
 Karnofsky performance evaluation 
 Complete physical examination including weight and height 
 Vital signs  
 Standard 12-lead ECG  
 Clinical laboratory evaluations; see Attachment 2. 
 Serum or urine pregnancy test for females of child-bearing potential  
 Radiographic evaluation of tumor burden meeting requirements described in 
Section 10.6.9  
 Brain MRI if history of brain metastases or suggestive symptoms 
 Bone scan if history of bone metastases or suggestive symptoms 
10.2 
Randomization 
Patients eligible after completing all screening evaluations will be randomly assigned by an 
interactive response technology (IRT) system in a 1:1 ratio to receive CB-Cabo or Pbo-Cabo. 
Randomization will be stratified by the following factors: 
 Prior treatment with PD-1/PD-L1 inhibitor therapy: Yes vs. No 
 IMDC Prognostic Risk Group: favorable vs. intermediate vs. poor (Attachment 3) 
 
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Randomization should occur as close as possible to the planned start of treatment (i.e., within 
24 hr if practicable but no more than 3 days). Patients are defined as enrolled in the study if 
randomized.  
Crossover between treatment arms will not be allowed.  
10.3 
Study Treatment Procedures 
For the complete list of schedules of procedures, please refer to the Schedule of Assessments in 
Attachment 1.  
While the patient is receiving study treatment, the patient’s clinical status should be evaluated at 
each clinic visit to confirm that the patient is suitable for continuing study treatment and to make 
timely decisions regarding the interruption or restarting of study treatment.  
Assessments are based on 28-day cycles. Radiographic evaluation of tumor burden and QoL 
questionnaires will be performed as scheduled relative to the date of Cycle 1 Day 1 (C1D1) 
regardless of study treatment holds or delays. Additional assessments may occur, as clinically 
indicated, during unscheduled visits.  
After randomization, clinic visits for safety evaluations will occur Day 1 of every cycle 
(approximately every 4 weeks) for the first 12 cycles. Starting with Cycle 13, safety evaluations 
will occur every 3 cycles (approximately every 12 weeks). More frequent safety evaluations may 
be performed if clinically indicated. The final scheduled safety assessment will occur at the End 
of Treatment Visit. If the study treatment is held due to AEs, Investigators should perform 
additional safety assessments as clinically indicated.  
Radiographic evaluation of tumor burden (e.g., diagnostic computed tomography [CT] scan with 
intravenous contrast or MRI) will occur during Screening (within 28 days prior to 
randomization), every 8 weeks after C1D1 for the first 12 cycles, every 12 weeks beginning with 
Cycle 13, and at the End of Treatment Visit. Radiographic assessments may occur more 
frequently as clinically indicated. 
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Quality of life questionnaires will be completed before study drug dosing on C1D1, every 
4 weeks after C1D1 for the first 12 cycles, every 12 weeks beginning with Cycle 13, and at the 
End of Treatment Visit.  
Patients who hold or discontinue only one of the study drugs (either CB-839/placebo or 
cabozantinib) for any reason such as, but not limited to, an AE or surgery, should continue the 
other study drug on study and continue to have scheduled study visits and procedures per 
protocol.  
10.4 
Long Term Follow Up 
Patients who are in long-term survival follow-up should be contacted every 3 mo for the first 
12 mo following discontinuation of all study treatments (CB-839/placebo and cabozantinib) and 
every 6 mo thereafter. All reasonable efforts must be made to contact the patient and/or persons 
authorized by the patient to collect survival status and subsequent anticancer therapy.  
10.5 
Screen Failures 
Patients who sign an informed consent form but are not randomized into the study are defined as 
screen failures. For all screen failures, the following information will be captured in the 
electronic data capture (EDC) system: screening number, patient demographics, reason(s) for 
screen failure, and serious adverse events (SAEs) for study-related procedures through 30 days 
after the procedure, if applicable.  
10.6 Procedure details 
This section describes assessments to be performed and recorded in the EDC system.  
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, 12-lead ECGs, and 
clinical laboratory test results. 
Please refer to Attachment 1 for the schedule of study assessments. Unscheduled visits and 
additional assessments may be performed as clinically indicated at any time.  
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10.6.1 
Demographics, Medical, and Cancer History 
Demographics at screening will include date of birth (or age if date of birth is not allowed to be 
collected by local regulations), patient initials, race and ethnicity. Additional information such as 
medical and cancer history, surgical history, prior radiation history, and prior systemic anticancer 
treatment history will also be collected.  
10.6.2 
Physical Examination 
Complete physical examinations will be performed by a licensed physician (or physician’s 
assistant or nurse practitioner) at Screening and the End of Treatment Visit. Symptom-directed 
physical exams can be done on all other visits. System exams are only required as clinically 
indicated.  
The KPS score (Attachment 4) will be assessed during Screening to determine the patient’s 
eligibility and prognostic risk score according to IMDC criteria (Attachment 3). The KPS will 
also be used to evaluate the patient’s performance at scheduled clinic visits according to 
Attachment 1.  
10.6.3 
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 at least 3 min prior to obtaining vital signs.  
10.6.4 
Adverse Events  
Adverse event information will be collected at study visits and may also be collected via any 
other forms of communication any time during the study. See Section 15.0 for additional details 
on recording and reporting AEs and SAEs.  
10.6.5 
Concomitant Medications 
Concomitant medication information will be collected at study visits and may also be collected 
via any other forms of communication any time during the study. See Section 10.1.1 for details 
on permitted and protocol-restricted concomitant treatment. 
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10.6.6 
Electrocardiograms 
Patients should rest in the supine or semi-recumbent position for at least 5 min before the 12-lead 
ECG recording is started. ECG recordings must be performed using a standard, high-quality, 
high-fidelity electrocardiograph machine equipped with computer-based interval measurements.  
When performed, the ECG must be reviewed by a qualified physician (or qualified physician’s 
assistant or nurse practitioner), and any clinically important finding should be recorded on the 
appropriate electronic case report form (eCRF). ECG results will include heart rate, R-R interval, 
PR interval, QRS interval, QT interval, and QTc interval.  
10.6.7 
Laboratory Assessments 
Laboratory evaluations will be performed as noted in the Schedule of Study Assessments 
(Attachment 1). The laboratory analytes are listed in Attachment 2. All laboratory assessments 
will be completed by the site local laboratory and results entered in the EDC system.  
Any clinically significant results should be entered as medical history or adverse events in the 
EDC system.  
10.6.8 
Patient-Reported Quality of Life Assessment 
Quality of life assessments should be completed as scheduled relative to the date of C1D1 
regardless of study treatment holds or delay (see Attachment 1). 
Patients will be asked to complete two health related QoL assessments. The first is the NCCN-
Functional Assessment of Cancer Therapy - Kidney Symptom Index (FKSI-19) questionnaire, 
and the second is the EuroQol Health questionnaire (EQ-5D-5L).  
Patients should complete the questionnaires prior to receiving any information on their most 
recent medical results in order to ensure that their responses will not be influenced by their 
medical information when completing the questionnaires. If a clinic visit is not possible, patients 
should complete the questionnaires as per schedule at home and transmit their responses to the 
site (e.g., mail or email) or return it to the site during the next visit. Upon completion, the site 
should carefully review for completeness.  
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10.6.9 
Tumor Assessments 
Radiographic tumor assessments should be completed as scheduled relative to the date of 
C1D1 regardless of study treatment holds or delay (see Attachment 1). 
Radiographic tumor assessments will include diagnostic quality imaging (CT scan or MRI) of 
chest/abdomen/pelvis. For patients who have an MRI of the abdomen and pelvis, a CT scan of 
the chest is also required. An MRI or CT of the brain will also be performed at screening for 
patients with known or suspected brain metastases and continued post-baseline as clinically 
indicated. If a CT of the brain is performed, ambiguous results must be confirmed by MRI. For 
patients with symptoms of spinal compression, MRI of the spine and base of the skull should 
also be performed. Whole body bone scans will also be performed at screening for patients with 
known or suspected bone metastases and continued post-baseline as clinically indicated. 
The study-specific Imaging Manual should be followed. To ensure image consistency, the same 
imaging modality and acquisition protocols at the same institution/facility used at screening 
should be used for subsequent tumor assessments. Ideally contrast-enhanced imaging should be 
performed at screening and subsequent assessments, including at least post-contrast CT scan of 
the chest and post-contrast CT or MRI of the abdomen and pelvis. If CT contrast is 
contraindicated, a non-contrast CT scan of the chest together with contrast-enhanced MRI of the 
abdomen and pelvis is strongly recommended. If CT or MRI contrast is contraindicated in 
follow-up tumor assessments after contrast-enhanced imaging at baseline, the same modality 
without contrast should be performed. All imaging must be acquired and transmitted for central 
review in original Digital Imaging and Communications in Medicine (DICOM) format per 
guidelines in the study-specific imaging manual.  
For the purpose of patient management and treatment decisions during the course of the study, 
radiographic response and disease progression will be assessed locally by investigators using 
RECIST v1.1 (Attachment 5). For the purpose of robust documentation of radiographic 
progression per IRC: 
 If any doubt or ambiguities exist about radiographic progression, Investigators are 
encouraged to continue study therapy if the patient is tolerating treatment, repeat 
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radiographic studies at the next scheduled time, and delay determination of progression 
until the findings indicating radiographic progression are unequivocal.  
 Patients who discontinue study treatment for reasons other than progressive disease by 
RECIST v1.1 or death will continue to be followed by radiographic tumor imaging until 
documentation of radiographic progressive disease per RECIST v.1.1, death, initiation of 
a new anticancer therapy, or withdrawal of consent.  
 If study treatment continues beyond Investigator-assessed progression because the patient 
is receiving clinical benefit from continued treatment (see Section 11.3), radiographic 
tumor assessments will also continue until the patient discontinues study treatment. This 
practice has the benefit of providing radiographic studies for IRC review beyond 
Investigator-assessed progression, which may be helpful in the case of discordance 
between the Investigator and the IRC regarding the date of progression.  
10.6.10 
Tumor Biopsies  
10.6.10.1 
Archival Tumor Biopsies  
Archival tumor samples will be provided from all patients unless the archival sample is 
unavailable. Archival samples should be collected and shipped according to instructions 
provided in the laboratory manual. Archival tissue blocks or slides freshly cut from those blocks 
are strongly preferred, due to the concern of tissue stability after exposure. Archival tissue 
collected from recent time points before enrollment is preferred because it more accurately 
reflects the current state of the tumor/microenvironment at the time of study entry.  
10.6.10.2 
Optional Fresh Tumor Biopsies 
At North American sites only, optional tumor biopsies, collected as clinically indicated at any 
point on the study, may be shared with the Sponsor upon patient consent for exploratory 
biomarker assessment (e.g., predictive/prognostic biomarkers for response). Unless clinically 
indicated, biopsies should not be obtained from target lesions being followed for disease 
assessment prior to documentation of disease progression per RECIST v.1.1.  
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When obtained, tissue from optional tumor biopsies will be used for 1) the analysis of gene 
expression levels, 2) immunohistochemical/immunofluorescence analysis, and 3) mutation 
profiling. Tissue 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. 
10.6.11 
Pharmacokinetic Samples 
Pharmacokinetic samples will be collected from all patients. Plasma PK samples will be used to 
measure concentrations of CB-839, 110826 (the major metabolite of CB-839), and cabozantinib, 
and may be used to measure other associated analytes by using a validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) method of appropriate specificity and 
sensitivity according to GLP. Blood samples for PK analysis will be collected at the following 
time points: 
 Cycle 2 Day 1: Pre-dose and 2 hr post dose (± 30 min). Patients must take their morning 
dose of CB-839 in the clinic. 
 Cycle 3, Day 1: 4 hr and 6 hr post dose (± 1 hr). Patients can take their morning dose of 
CB-839 in the clinic or at home.  
The actual time of collection must be noted in the source documents and eCRFs. On Cycle 2 
Day 1, patients will have to arrive at the clinic to get their pre-dose PK sample drawn prior to 
taking their dose in the clinic. Patients must record the times they take their evening dose before 
Cycle 2 Day 1 and their morning dose on Cycle 3 Day 1 (if they take it at home). In the event 
that CB-839/placebo dosing is interrupted within 3 days before visits with PK sampling, PK 
samples should be collected during the next visit that the patient is in the clinic and has taken at 
least 3 consecutive days of CB-839/placebo. Please consult with the Medical Monitor to 
determine best options for making up missed PK samples. 
Refer to the laboratory manual for details on collection kits and sample processing. 
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10.6.12 
Pregnancy, Contraception and Nursing/Breast-feeding 
Patients should be informed that taking the study drugs may involve unknown risks to a fetus 
(unborn baby) if pregnancy were to occur during study treatment exposure. In order to 
participate in the study, patients must adhere to pregnancy testing and contraception 
requirements described below (Clinical Trial Facilitation Group 2014).  
10.6.12.1 Pregnancy Testing 
All women who are being considered for participation in the study, and who are not surgically 
sterilized or postmenopausal (defined as without menses for >1 year without an alternative 
medical cause), will have a serum or urine pregnancy test during screening, on C1D1 predose (if 
screening test >3 days before receiving the first dose of study treatment), and at the End of 
Treatment Visit. If a urine test is positive or borderline (unable to confirm as negative), a serum 
β-hCG test will be required. Patients must be excluded in the event of a positive or borderline 
test result that is not confirmed as negative. Patients who become pregnant on study will be 
required to discontinue study treatment. Pregnancies occurring during and up to 6 months after 
completion of study treatment will be reported and followed for outcomes (see Section 15.1). 
10.6.12.2 Contraception 
Sexually active patients with heterosexual partners must agree that they and their partners will 
use dual methods of contraception to prevent pregnancy during the course of study treatment and 
through 4 months after the last dose of all study treatment. Surgically sterilized or 
postmenopausal female patients (no menses for > 1 year without an alternative medical cause) or 
male patients with surgically sterilized or postmenopausal female partners are exempt from these 
requirements. Patients who choose abstinence are exempt from a second method of 
contraception. Male patients must include a barrier method of contraception (preferably male 
condom) if sexually active with a female partner of childbearing potential. 
Contraception must include at least one highly effective method. Highly effective methods of 
contraception include: 
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 combined (estrogen and progestogen containing) hormonal oral, intravaginal or 
transdermal contraception associated with inhibition of ovulation 
 progestogen-only hormonal oral, injectable, or implantable contraception associated with 
inhibition of ovulation  
 intrauterine device 
 intrauterine hormone-releasing system 
 vasectomised partner  
 sexual abstinence  
Additional acceptable methods of contraception that are not considered highly effective include: 
 progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action  
 male or female condom with or without spermicide  
 cap, diaphragm or sponge with spermicide 
The following birth control methods are considered unacceptable: 
 periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 withdrawal (coitus interruptus) 
 spermicides only 
 lactational amenorrhoea method 
Because the absence of pharmacokinetic interactions between hormonal contraception and study 
treatment cannot be guaranteed, patients should also be counselled that there is potential for 
hormonal contraception to be less effective. Therefore, if a hormonal contraception is chosen as 
the highly effective hormonal method, the second method of contraception should be a barrier 
method (preferably male condom).  
Male patients must also agree to refrain from donating sperm during the study and for a 
minimum of 4 mo following the last dose of all study treatment. 
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If there is any question that a patient will not reliably comply with the requirements for 
contraception, that patient should not be entered into the study. 
10.6.12.3 Nursing/Breast-feeding 
It is not known whether the study drugs and/or their metabolites are excreted in human milk. 
Because of the potential harm to the infant, mothers should discontinue nursing/breast-feeding 
during treatment with study all study drugs and for at least 4 months after completing therapy. 
11.0 
POTENTIAL TOXICITIES, DOSE MODIFICATION AND MANAGEMENT OF 
TOXICITIES 
11.1 Potential Toxicities 
11.1.1 
CB-839 
The most frequent AEs considered possibly or probably related to CB-839 monotherapy dosed 
on the BID schedule on the Phase 1 CX-839-001 study were fatigue, gastrointestinal events 
(nausea, vomiting, and constipation), photophobia, anemia, dyspnea, and elevations in liver 
function tests (see Table 9.5-1). 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 LFT elevations (see Table 9.5-1).  
11.1.2 
Cabozantinib 
The safety and tolerability profile of cabozantinib is well defined and outlined in the Cabometyx 
(cabozantinib) US Prescribing Information (or local equivalent). A summary is provided below:  
Adverse events most frequently observed with cabozantinib (≥25% of patients) are diarrhea, 
fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, hypertension, 
vomiting, weight decreased, and constipation. The majority of these AEs have been of mild to 
moderate severity (CTCAE Grade 1-2). Grade 3-4 adverse reactions and laboratory 
abnormalities which occurred in ≥ 5% of patients were hypertension, diarrhea, fatigue, palmar-
plantar erythrodysesthesia syndrome, hyponatremia, hypophosphatemia, hypomagnesemia, 
lymphocytes decreased, anemia, hypokalemia, and GGT increased. Cabozantinib has been 
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associated with a low incidence of severe and potentially lethal AEs, including hemorrhage, GI 
perforations and fistulas, thrombotic events, hypertension and hypertensive crisis, diarrhea, 
palmar-plantar erythrodysesthesia syndrome, reversible posterior leukoencephalopathy 
syndrome, and embryo-fetal toxicity (see Warnings and Precautions in the Cabometyx 
(cabozantinib) US Prescribing Information [or local equivalent]).  
11.1.3 
Dose Modification Guidelines 
11.1.3.1 
Study Drug Dose Levels 
The possible dose levels for CB-839/placebo and cabozantinib are provided in Table 11.1-1 and 
Table 11.1-2.  
Table 11.1-1: Dose Levels for CB-839/Placebo 
Dose Level 
CB-839/Placebo Dose 
Starting dose 
800 mg BID (1600 mg daily) 
First dose reduction 
600 mg BID (1200 mg daily) 
Second dose reduction 
400 mg BID (800 mg daily) 
Third dose reduction 
Discontinue  
 
Table 11.1-2: Dose Levels for Cabozantinib 
Dose Level 
Cabozantinib Dose 
Starting dose 
60 mg oral QD 
First dose reduction 
40 mg oral QD 
Second dose reduction 
20 mg oral QD 
Third dose reduction 
Discontinue  
 
11.1.3.2 
Study Drug Dose Modifications 
Dose modifications may be considered for each study drug independently. Modifications, 
including dose interruption and resumption, dose reduction, dose re-escalation, and permanent 
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discontinuation of each study drug will be based on the investigator’s discretion, with the 
following exceptions: 
 The dose of each study drug cannot exceed the starting dose 
 Interruptions of study drug are allowed for up to 6 weeks (continuous) without Medical 
Monitor consultation, although it is strongly recommended that interruptions in dosing 
are as brief as possible. Resumption of study drug in a patient with a dose interruption 
lasting > 6 weeks requires discussion with and approval by the Medical Monitor (see 
Section 11.2) 
 Both study drugs should be interrupted for Grade ≥ 3 elevated ALT, AST, or bilirubin 
and restarted at reduced doses after ALT, AST, and bilirubin levels resolve to Grade ≤ 1 
or baseline 
 Suspected drug-induced liver injury should be reported to the Medical Monitor; both 
study drugs should be interrupted and then resumed only after discussion with and 
approval by the Medical Monitor (see Section 11.1.4.2) 
 Dose re-escalation is not allowed for a dose reduction triggered by study drug-related 
myelosuppression or Grade 4 life-threatening AEs affecting major organs 
 Permanently discontinue cabozantinib for any of the following: 
o Development of unmanageable fistula or GI perforation 
o Severe hemorrhage 
o Arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction) 
o Hypertensive crisis or severe hypertension despite optimal medical management 
o Nephrotic syndrome 
o Reversible posterior leukoencephalopathy syndrome 
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Additional guidelines for treatment modifications and AE management are provided below in 
Table 11.1-3 and in Section 11.1.4. These guidelines are based on the Cabometyx (cabozantinib) 
US Prescribing Information and the clinical experience with CB-839, cabozantinib, and the 
combination to date. Because cabozantinib prescribing information may change over time, the 
most up-to-date Cabometyx (cabozantinib) US Prescribing Information (or local equivalent) 
should also be consulted and followed.  
These guidelines are intended primarily for toxicities that investigators assess as related to study 
treatment (CB-839/placebo or cabozantinib) and that are not easily managed with routine 
supportive care. In general, all AEs should be managed with supportive care at the earliest signs. 
Dose interruptions of cabozantinib should be as brief as possible.  
Unless otherwise specified (see exceptions under Study Drug Dose Modifications above), dose 
modifications and AE management guidelines presented in this protocol are only 
recommendations and are not intended to supersede the clinical judgment of the treating 
physician.  
Table 11.1-3: Treatment Modifications Guidelines for Treatment-Related AEs 
Toxicity Grade 
(CTCAE v4) 
CB-839/Placebo 
Cabozantinib 
Grade 1-2 
If manageable and tolerable, continue current dose with supportive care. 
If not tolerable, interrupt dosing and resume at same dose level upon recovery. 
If Grade 2 toxicity recurs, interrupt and restart at next lower dose. 
Grade 3  
(except non-
clinically 
relevant 
laboratory 
abnormalities) 
Interrupt dosing and resume at the 
same dose level or next lower 
dose level upon recovery. 
Interrupt dosing, unless toxicity can be 
easily managed with a dose reduction, and 
resume at the next lower dose level upon 
recovery. 
Grade 4  
(except non-
clinically 
relevant 
laboratory 
abnormalities) 
Interrupt dosing immediately. Discontinue study drug unless the patient is 
deriving clear clinical benefit, as determined by the investigator and agreed by 
the Medical Monitor, and the toxicity can be managed with a dose reduction 
and optimal medical care. 
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11.1.4 
Cabozantinib Warnings, Precautions, and Guidelines for Management of 
Potential Adverse Events 
Below are guidelines for the treatment and/or prevention of certain treatment-emergent AEs of 
interest that have been associated with, or have a theoretical possibility of occurring with, 
cabozantinib treatment. 
11.1.4.1 Gastrointestinal Disorders 
The most common GI AEs reported in clinical studies with cabozantinib are diarrhea, oral pain, 
dyspepsia, stomatitis, and dysphagia.  
Diarrhea  
Patients should be instructed to notify their study doctor or site staff immediately at the first 
signs of poorly formed or loose stool or an increased frequency of bowel movements. 
Administration of antidiarrheal/ antimotility agents is recommended at the first sign of diarrhea 
as initial management. Some patients may require concomitant treatment with more than one 
antidiarrheal agent. When therapy with antidiarrheal agents does not control the diarrhea to 
tolerable levels, consider temporary dose interruption or reduction per Table 11.1-3. When the 
diarrhea is controlled, retreatment with study treatment may be acceptable per investigator 
decision. 
In addition, general supportive measures should be implemented including continuous oral 
hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and stopping 
lactose-containing products, high fat meals, and alcohol. 
Nausea and Vomiting 
Antiemetic agents are recommended as clinically appropriate at the first sign of nausea and 
vomiting or as prophylaxis to prevent emesis, along with supportive care according to clinical 
practice guidelines. The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 
receptor antagonists and dexamethasone (NK-1 receptor antagonists can induce or inhibit 
CYP3A4, and glucocorticoids induce CYP3A4 and thus could lower cabozantinib exposure). 
Caution is also recommended with the use of nabilone, which is a weak inhibitor of CYP3A4.  
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Stomatitis and Mucositis 
Preventive measures may include a comprehensive dental examination to identify any potential 
complications before study treatment is initiated. Removal of local factors should be instituted as 
indicated, such as modification of ill-fitting dentures and appropriate care of gingivitis. During 
treatment with cabozantinib good oral hygiene and standard local treatments such as 
nontraumatic cleansing and oral rinses (e.g., with a weak solution of salt and baking soda) should 
be maintained. The oral cavity should be rinsed and wiped after meals, and dentures should be 
cleaned and brushed often to remove plaque. Local treatment should be instituted at the earliest 
onset of symptoms. Obtain bacterial/viral culture if oral infection is suspected and treat infection 
as indicated by local guidelines. When stomatitis interferes with adequate nutrition and local 
therapy is not adequately effective, dose reduction or temporary withholding of cabozantinib 
should be considered. 
11.1.4.2 Hepatobiliary Disorders 
Elevations of ALT, AST, and bilirubin have been observed during treatment with cabozantinib. 
It is recommended that patients with elevation of ALT, AST, and/or bilirubin have more frequent 
laboratory monitoring of these parameters. If possible, hepatotoxic concomitant medications 
should be discontinued in patients who develop increased values of ALT, AST, or bilirubin. 
Patients on this study may enter with increased ALT/AST serum levels up to 3 × ULN. Dose 
reductions of study treatment should be considered in any patient who develops drug-related 
Grade 2 elevated ALT, AST, or bilirubin lasting longer than 1 week. A patient who develops 
Grade ≥ 3 elevated ALT, AST, or bilirubin should have study treatment held and restarted at a 
reduced dose (see Table 11.1-3) after ALT, AST, and bilirubin levels resolve to at least 
Grade ≤ 1 or baseline. In patients with recurrence of drug-related Grade ≥ 3 elevated ALT, AST, 
or bilirubin at the lowest dose level, study treatment should be discontinued. In patients who 
develop ALT/AST elevations > 3 × ULN in combination with a bilirubin elevation > 2 × ULN 
without reasonable other explanation, drug-induced liver injury should be suspected and study 
treatment interrupted. Reinstitution of study treatment after recovery of ALT, AST, and bilirubin 
to Grade 1 or baseline level must be discussed and approved with the Sponsor. 
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11.1.4.3 Hematological Disorders 
Hematological toxicities (i.e., neutropenia and thrombocytopenia) and associated complications 
have been observed after administration of cabozantinib and may be managed with dose 
interruptions and/or dose reductions. Use of granulocyte colony-stimulating factor support for 
neutrophil recovery is allowed per investigator discretion and in accordance with accepted 
guidelines after the first incidence of clinically relevant cytopenia.  
Complete blood counts with differentials and platelets should be performed regularly. Patients 
with hematologic toxicities may require additional or more frequent laboratory tests according to 
institutional guidelines.  
Febrile neutropenia or evidence of infection associated with neutropenia must be assessed 
immediately and treated appropriately and in a timely manner according to institutional 
guidelines. Dose reductions or dose interruptions for anemia are not mandated but can be applied 
as clinically indicated. Supportive care such as red blood cell transfusions may be managed 
according to institutional guidelines. 
11.1.4.4 Fatigue, Anorexia, and Weight Loss 
Fatigue has been reported during treatment with cabozantinib. Common causes of fatigue such as 
anemia, deconditioning, emotional distress (depression and/or anxiety), nutrition, sleep 
disturbance, and hypothyroidism should be ruled out and/or these causes treated according to 
standard of care. Individual non-pharmacological and/or pharmacologic interventions directed to 
the contributing and treatable factors should be given. Pharmacological management with 
psychostimulants such as methylphenidate should be considered after disease specific 
morbidities have been excluded. Note: Chronic use of modafinil should be avoided because of its 
potential to reduce cabozantinib exposure. 
Dose reduction of study treatment should be considered when general or pharmacological 
measures have not been successful in reducing symptoms. Dose interruption may be considered 
for Grade ≥ 3 fatigue despite optimal management, at the investigator’s discretion.  
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Anorexia and weight loss should be managed according to local standard of care including 
nutritional support. Pharmacologic therapy such as megestrol acetate should be considered for 
appetite enhancement. Should these interventions prove ineffective, dose hold and reductions 
may be considered for Grade ≥ 3 anorexia or weight loss. If anorexia and/or weight loss do not 
recur after a dose reduction, dose of cabozantinib may be re-escalated to the previous dose. 
11.1.4.5 Skin Disorders 
Palmar-plantar erythrodysesthesia syndrome  
Palmar-plantar erythrodysesthesia (PPE) syndrome (also known as hand-foot syndrome), skin 
rash (including blisters, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, 
and papular rash), pruritus, dry skin, and erythema have been reported in cabozantinib-treated 
patients. All patients on study should be advised on prophylactic skin care. This includes the use 
of hypoallergenic moisturizing creams, ointment for dry skin, and sunscreen with sun protection 
factor ≥ 30, avoidance of exposure of hands and feet to hot water, protection of pressure-
sensitive areas of hands and feet, and use of thick cotton gloves and socks to prevent injury and 
to keep the palms and soles dry. Patients with skin disorders should be carefully monitored for 
signs of infection (e.g., abscess, cellulitis, or impetigo). 
Early signs of hand-foot syndrome could be tingling, numbness, and slight redness or mild 
hyperkeratosis. Early manifestations include painful, symmetrical red and swollen areas on the 
palms and soles. The lateral sides of the fingers or peri-ungual zones may also be affected. 
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, 
desquamations, ulcerations, or necrosis of affected areas. Aggressive management of symptoms 
is recommended, including early dermatology referral. Treatment guidelines for PPE related to 
study treatment are presented in Table 11.1-4. 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the patient’s consent. 
These assessments may include digital photographs of the skin changes and/or a biopsy of the 
affected skin and may be repeated until the skin changes resolve. 
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Table 11.1-4: Management of Treatment-emergent PPE Syndrome 
CTCAE v.4.0 
Grade  
Action To Be Taken 
1 
Cabozantinib treatment may be continued at the current dose if PPE is clinically 
insignificant and tolerable. Otherwise, cabozantinib should be reduced to the next 
lower dose level. Start urea 20% cream twice daily and clobetasol 0.05% cream once 
daily. Reassess at least weekly; if PPE worsens at any time or does not improve after 
2 weeks, proceed to the intervention guidelines for Grade 2. 
2 
Cabozantinib treatment may be continued if PPE is tolerated. Cabozantinib should be 
dose reduced or interrupted if PPE is intolerable. Continue urea 20% cream twice 
daily and clobetasol 0.05% cream once daily and add analgesics (e.g., 
NSAIDs/GABA agonists) for pain control if needed. Reassess at least weekly; if 
PPE does not improve within 2 weeks or worsens or affects self-care, proceed to the 
intervention guidelines for Grade 3. 
3 
Interrupt cabozantinib treatment until severity decreases to Grade 1 or 0.  
Continue treatment of skin reaction with clobetasol 0.05% cream twice daily and 
analgesics. Resume cabozantinib at reduced dose if PPE recovers to Grade 1 or 0. 
Discontinue patient from study if intolerable PPE recurs after dose reduction or does 
not improve within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; GABA, gamma-amino butyric acid; 
NSAID, non-steroidal anti-inflammatory drug; PPE, palmar-plantar erythrodysethesia. 
 
Wound Healing and Surgery 
VEGF inhibitors can cause wound healing complications and wound dehiscence which may 
occur even long after a wound has been considered healed. Therefore, surgical and traumatic 
wounds must have completely healed prior to starting cabozantinib treatment and be monitored 
for wound dehiscence or wound infection while the patient is being treated with cabozantinib. 
11.1.4.6 Hypertension 
Hypertension is a common class effect of drugs that inhibit VEGF pathways and has been 
reported in patients treated with cabozantinib.  
Blood pressure should be monitored in a constant position at each visit (either sitting or supine). 
Treatment guidelines for hypertension deemed related to cabozantinib are presented in Table 
11.1-5. In general, patients with known hypertension should be optimally managed prior to study 
entry. Decisions to decrease or hold the dose of study treatment must be based on blood pressure 
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readings taken by a medical professional and must be confirmed with a second measurement at 
least 5 minutes following the first measurement. Other than for hypertension requiring 
immediate therapy, the presence of new or worsened hypertension should be confirmed at a 
second visit before taking therapeutic action. It is recommended that this second visit occurs 
within 1 week. 
Table 11.1-5: Management of Treatment-emergent Hypertension 
Criteria for Dose 
Modification 
Action To Be Taken 
> 150 to <160 mm Hg (systolic)  
OR 
> 100 to <110 mm Hg (diastolic)  
 Optimize antihypertensive treatment by adding new or 
additional antihypertensive medications and/or increase 
dose of existing medications. 
 Reduce cabozantinib treatment by one dose level if 
optimal antihypertensive therapy (usually to include 3 
agents) does not result in BP < 150 mm Hg systolic or < 
100 mm Hg diastolic. 
 If patient is symptomatic interrupt study treatment. 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
 Reduce cabozantinib treatment by one dose level and add 
new or additional antihypertensive medications and/or 
increase dose of existing medications and monitor patient 
closely for hypotension. If optimized antihypertensive 
therapy (usually to include 3 agents) does not result in BP 
< 150 mm Hg systolic or < 100 mm Hg diastolic, 
cabozantinib treatment should be dose reduced further or 
interrupted. 
 Interrupt cabozantinib treatment if upper limits of BP 
(≥ 160 mm Hg systolic or ≥ 110 mm Hg diastolic) are 
sustained and not adequately manageable or if BP is 
> 180 mm Hg systolic or > 120 mm Hg diastolic or if 
patient is symptomatic. 
 Restart cabozantinib treatment at the most tolerable dose 
and re-escalate cabozantinib dose only if BP falls to and is 
sustained at < 140 mm Hg systolic and < 90 mm Hg 
diastolic. 
Hypertensive crisis or 
hypertensive encephalopathy 
 Discontinue cabozantinib treatment 
BP, blood pressure. 
 
11.1.4.7 Thromboembolic Events 
Thromboembolic complications are frequent in cancer patients due to procoagulant changes 
induced by the malignancy or anti-cancer therapy including inhibitors of VEGF pathways. Deep 
vein thrombosis and PE have been observed in clinical studies with cabozantinib; including fatal 
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events. Patients who develop a PE or DVT should have cabozantinib treatment held until 
therapeutic anticoagulation with heparins (e.g., LMWH) is established. (Note: Initiation of 
therapeutic anticoagulation is allowed on study in consultation with the Sponsor’s medical 
monitor.) Cabozantinib treatment may be resumed in patients who are stable and have 
uncomplicated PE or DVT and are deriving clinical benefit from cabozantinib treatment. During 
anticoagulation treatment, patients need to be monitored on an ongoing basis for bleeding risk 
and signs of bleeding which may require additional or more frequent laboratory tests according 
to institutional guidelines. If there are any signs of clinically relevant bleedings, cabozantinib 
treatment should be interrupted immediately and the sponsor contacted to discuss further study 
participation. Patients with life-threatening PE or DVT should have study treatment discontinued 
unless toxicity can be managed and patient is deriving clear clinical benefit as determined by the 
investigator and agreed by the Sponsor. 
Arterial thrombotic events (e.g., transient ischemic attack, myocardial infarction) have been 
observed rarely in studies with cabozantinib. Patients should be evaluated for preexisting risk 
factors for arterial thrombotic events such as diabetes mellitus, hyperlipidemia, hypertension, 
coronary artery disease, history of tobacco use, and cardiac or thromboembolic events that 
occurred prior to initiation of study treatment. Cabozantinib treatment should be discontinued in 
patients who develop an acute myocardial infarction or any other clinically relevant arterial 
thromboembolic complication. 
11.1.4.8 Proteinuria 
Proteinuria is an anticipated AE with the inhibition of VEGF pathways and has been observed in 
cabozantinib clinical studies, and nephrotic syndrome has been reported with cabozantinib and 
other inhibitors of VEGF pathways. Urine protein should be monitored regularly during 
cabozantinib treatment. Guidelines for proteinuria management are described in Table 11.1-6. 
Cabozantinib should be discontinued in patients who develop nephrotic syndrome. 
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Table 11.1-6: Management of Treatment-emergent Proteinuria 
Severity of Proteinuria (UPCR) 
Action To Be Taken 
≤ 1 mg/mg (≤ 113.1 mg/mmol) 
No change in cabozantinib treatment or monitoring 
> 1 to < 3.5 mg/mg 
(> 113.1 to < 395.9 mg/mmol) 
 No change in cabozantinib treatment required 
 Consider confirming with a 24-hour protein assessment 
within 7 days 
 Repeat UPCR within 7 days and once per week. If UPCR < 1 
on 2 consecutive readings, UPCR monitoring can revert to 
protocol-specific times. (Second reading is confirmatory and 
can be done within 1 week of first reading.) 
≥ 3.5 mg/mg (≥ 395.9 mg/mmol) 
 Hold cabozantinib treatment pending repeat UPCR within 
7 days and/or 24-hour urine protein. 
 If ≥ 3.5 on repeat UPCR, continue to hold cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases 
to < 2, restart cabozantinib treatment at a reduced dose and 
monitoring of urine protein/creatinine should continue 
weekly until the UPCR decreases to < 1. 
Nephrotic syndrome 
Discontinue cabozantinib treatment 
UPCR, urine protein to creatinine ratio. 
 
11.1.4.9 Hypophosphatemia 
Hypophosphatemia has been reported during treatment with cabozantinib. Serum phosphorus 
should be monitored frequently while receiving cabozantinib. Mild hypophosphatemia is usually 
asymptomatic or symptoms can be non-specific such as weakness, bone pain, rhabdomyolysis, or 
altered mental status. Other causes of hypophosphatemia such as poor nutrition, chronic 
alcoholism, malabsorption, excessive antacid use, glucocorticoids use, kidney dysfunction, 
respiratory alkalosis, vitamin D deficiency should be ruled out and/or these causes treated 
according to standard of care. Mild to moderate hypophosphatemia should be managed by oral 
replacement including food that are high in phosphate (diary items, meats, beans) and/or oral 
phosphate supplements according to standard clinical practice guidelines. Clinically relevant 
hypophosphatemia should be managed according to the dose modification guidelines as outlined 
in Table 11.1-3 or as clinically indicated. 
11.1.4.10 Thyroid Function Disorders 
Changes in thyroid function tests (TFTs) and hypothyroidism have been reported with 
cabozantinib and other tyrosine kinase inhibitor treatment as a result of altered thyroid hormone 
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regulation by mechanisms that seem to be specific for each agent (Torino 2009). Preliminary 
data from ongoing studies indicate that treatment-emergent elevation of thyroid stimulating 
hormone (TSH) by cabozantinib may be dose-dependent in fashion. Currently available data are 
insufficient to determine the mechanism of TFT alterations and its clinical relevance. Monitor 
thyroid function as outlined in Attachment 1. Management of thyroid dysfunction (e.g., 
symptomatic hypothyroidism) should follow accepted clinical practice guidelines. 
11.1.4.11 Hemorrhagic Events 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways as well 
as with cabozantinib. In order to mitigate risk of severe hemorrhage, patients should be evaluated 
for potential bleeding risk factors prior to initiating cabozantinib treatment and monitored for 
bleeding events with serial complete blood counts and physical examination while on study. Risk 
factors for hemorrhagic events may include (but may not be limited to) the following: 
 Tumor of the lung with cavitary lesions or tumor lesions which invades, encases, or abuts 
major blood vessels. The anatomic location and characteristics of tumor as well as the 
medical history must be carefully reviewed in the selection of patients for treatment with 
cabozantinib. 
 Recent or concurrent radiation to the thoracic cavity 
 Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases 
 Underlying medical conditions which affect normal hemostasis (e.g., deficiencies in clotting 
factors and/or platelet function, or thrombocytopenia) 
 Concomitant medication with anticoagulants or other drugs which affect normal hemostasis 
 History of clinically significant hemoptysis 
Discontinue cabozantinib treatment in patients who have been diagnosed with a severe bleeding 
complication. 
11.1.4.12 GI Perforation/Fistula and Non-GI Fistula Formation 
GI perforation/fistula and non-GI fistula formation have been reported with approved drugs that 
inhibit VEGF pathways as well as with cabozantinib. Carefully monitor for episodes of 
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abdominal pain, especially in patients with known risk factors for developing GI 
perforation/fistula or non-GI fistula, to allow for early diagnosis. Such risk factors include (but 
may not be limited to) the following: 
GI perforation/fistula: 
 Intra-abdominal tumor/metastases invading GI mucosa 
 Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis or 
symptomatic cholangitis, or appendicitis 
 History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
 Prior GI surgery (particularly when associated with delayed or incomplete healing). 
Complete healing following abdominal surgery or resolution of intra-abdominal abscess must 
be confirmed prior to initiating treatment with cabozantinib. 
Additional risk factors include concurrent chronic use of steroid treatment or nonsteroidal anti-
inflammatory drugs. Constipation indicative of bowel obstruction should be monitored and 
effectively managed. 
Non-GI fistula: 
Complications from radiation therapy has been identified as a possible predisposing risk factor 
for non-GI fistula formation in patients undergoing treatment with VEGF pathway inhibitors 
(e.g., bevacizumab). Discontinue cabozantinib treatment in patients who have been diagnosed 
with GI or non-GI perforation/fistula. 
11.1.4.13 Osteonecrosis of the Jaw 
Osteonecrosis of the jaw (ONJ) has been reported with use of anti-angiogenic drugs and 
bisphosphonates and denosumab in cancer patients. Additional risk factors for ONJ have been 
identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, 
smoking, dental or orofacial surgery procedures, and cancer disease itself. Osteonecrosis has 
been reported in patients treated with cabozantinib. As a preventive measure, invasive dental 
procedures should be avoided if possible in patients who have previously been treated with or 
concomitantly receive bisphosphonates or denosumab. 
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In cases where dental procedures are unavoidable, the risks and benefits of a dental procedure 
and the extent of the procedure as well as the risk of developing osteonecrosis of the jaw need to 
be considered when deciding on the duration of a temporary treatment interruption of 
cabozantinib. If clinically possible, treatment with cabozantinib should be held for approximately 
4 weeks prior to a dental procedure and resumed after complete healing has occurred. 
Patients with any documented case of osteonecrosis should have study treatment interrupted, and 
appropriate clinical management should be initiated. Reinitiation of study treatment must be 
discussed with and approved by the Sponsor on a case-by-case basis. 
11.2 
Resumption of Study Treatment 
After withholding a study drug for an adverse event suspected to be related to that study drug, it 
is generally recommended that administration of the study drug is resumed when the AE has 
returned to ≤ Grade 1 or baseline; however, investigator discretion may be used to determine if 
resolution to Grade 1 is necessary prior to reintroducing study treatment.  If CB-839/placebo is 
restarted after permanent discontinuation of cabozantinib, it is also recommended that 
CB-839/placebo be permanently discontinued for a ≥ Grade 3 recurrence of the AE that resulted 
in cabozantinib discontinuation. Following a dose reduction of CB-839/placebo or cabozantinib, 
re-escalation to the previous dose may be allowed at the discretion of the investigator.  
11.3 Discontinuation of Treatment  
The reasons a patient may discontinue study treatment include, but are not limited to, the 
following: 
• 
Patient no longer experiences clinical benefit as determined by the investigator. If study 
treatment is withdrawn for this reason, the date this decision is to be recorded and every 
effort should be made to continue safety evaluations, tumor assessments, and collection 
of subsequent anticancer treatment information and follow-up information for survival. 
• 
Unacceptable side effects the investigator feels may be due to study treatment. 
• 
Investigator feels it is not in the best interest of the patient to continue on study. 
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• 
Patient participation in another clinical study using an investigational agent or 
investigational medical device 
• 
Necessity for treatment with other systemic anticancer therapy (non-protocol defined) 
• 
Necessity for withholding study drug for greater than 6 weeks (continuous) for study-
treatment related AEs 
• 
Refusal of sexually active fertile patients to use medically accepted highly effective 
methods of contraception 
• 
Female patient becomes pregnant 
• 
Patient request to discontinue study treatment (with or without concurrent withdrawal of 
consent) 
• 
Significant patient noncompliance with the protocol schedule in the opinion of the 
investigator or the Sponsor 
• 
Sponsor request 
The Sponsor should be notified of all patient withdrawals (from study treatment or from the 
study) as soon as possible. The reason for treatment discontinuation, the date of the decision to 
discontinue treatment, and the date of the last known dose of study treatment will be recorded in 
the end-of-treatment eCRFs.  For patients who withdraw or are withdrawn from study treatment, 
the investigator should perform all End of Treatment Visit and follow up procedures as indicated 
in the schedule of study assessments (Attachment 1), and continue protocol-specified evaluations 
and procedures unless consent to participate in the study is also withdrawn. All patients will be 
followed until death, unless consent to do so is specifically withdrawn by the patient or until a 
decision by the Sponsor is made to stop collection of these data.  Note that in order to maximize 
detection of progression events for the study primary endpoint patients who discontinue study 
treatment for reasons other than progressive disease or death will continue to be followed by 
radiographic tumor imaging as described in Section 10.6.9. 
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In cases where the investigator believes that a patient is clearly experiencing clinical benefit 
despite radiographic progression per RECIST 1.1, and that the potential benefit of continuing 
study treatment outweighs the potential risks, extension of study treatment beyond disease 
progression may be considered in consultation with the medical monitor. Patients who continue 
treatment beyond progression will continue to receive all scheduled protocol assessments, 
including continued radiographic tumor assessments, until study treatment is discontinued. 
12.0 
TEST ARTICLES/STUDY DRUGS 
12.1 Blinded Investigational Product 
CB-839 Tablets or Placebo Tablets 
Test article (CB-839, 200 mg/tablet) or placebo tablets that are identical in appearance will be 
administered orally. CB-839/placebo will be administered only to patients who have signed and 
dated an Informed Consent Form. Tablets should not be cut or crushed and only administered 
whole. Doses will be administered orally on Days 1 through 28 of each 28-day cycle. Dosing 
will not be adjusted for body weight or surface area. 
The first CB-839/placebo dose of the day will be administered in the morning immediately after 
breakfast. The evening/second dose should be taken immediately after a meal approximately 
12 hr (± 2 hr) after the morning dose. CB-839 ideally should be taken about 2 hr before antacid 
therapy (see Section 10.1.1). 
Guidelines for dose modifications are described in Section 11.1.3.  
In the rare event of medical emergency that requires unblinding of treatment assignment, 
Investigators will have the ability to independently unblind individual patients through the IRT 
system.  Unblinding of the study treatment assignment should be reserved for situations where 
knowledge of treatment assignment is necessary for critical medical decision-making. Please 
notify the Sponsor within 1 business day about any unblinding events. Please refer to the 
pharmacy manual for additional details regarding this process and procedures outlining how to 
unblind a patient using the IRT system. 
 
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12.2 Cabozantinib Study Drug 
Cabozantinib Tablets 
Cabozantinib (20, 40, or 60 mg/tablets) will be administered only to patients who have signed 
and dated an Informed Consent Form. Doses will be administered orally on Days 1 through 28 of 
each 28-day cycle. Patients should not eat for at least 2 hr before and at least 1 hr after taking 
cabozantinib, and the QD dose of cabozantinib should occur at around the same time every day, 
preferably at bedtime.  
Guidelines for dose modifications are described in Section 11.1.3.  
12.3 Missed or Vomited Doses 
If a patient does not take a dose of CB-839/placebo within 6 hr after the scheduled time or 
cabozantinib within 12 hr after the scheduled time, he/she should be instructed to skip that dose 
and NOT to take extra study drug at their next administration. Patients should be instructed NOT 
to make up vomited doses of CB-839/placebo or cabozantinib and to report the frequency of 
vomiting occurrences associated with study drug administration to the site.  
12.4 Packaging and Labeling 
CB-839 HCl tablets (200 mg) are manufactured, packaged, and labeled according to current 
GMP. For additional information, please refer to the Pharmacy Manual. 
Placebo tablets (200 mg equivalent) are manufactured, packaged, and labeled according to 
current GMP. For additional information, please refer to the Pharmacy Manual. 
Cabozantinib tablets are available as 20-, 40-, or 60-mg strengths. For additional information, 
please refer to the Pharmacy Manual. 
12.5 Storage and Stability 
For procedures for the proper handling, storage, preparation and administration of CB-839 
tablets or placebo tablets and cabozantinib tablets, please refer to the Pharmacy Manual. 
Patients will be requested to store all study treatment at the recommended storage conditions and 
out of reach and view of children. 
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12.6 CB-839 Accountability, Reconciliation, and Return 
Treatment compliance will be monitored by drug accountability as well as the patient’s medical 
record and eCRF. 
On Day 1 of Cycle 1, patients will be provided with enough study treatment (CB-839/placebo 
and cabozantinib [ex-US]) to last until their next clinic visit. Patients will return on Day 1 of 
each cycle thereafter and will receive enough supply until the next visit. The number of 
CB-839/placebo tablets and cabozantinib tablets remaining from the previous visit will be 
counted and recorded (as permitted at US sites). 
 
The Investigator or designee must maintain an accurate record of dispensing the study treatment 
in a drug accountability log, a copy of which must be given to the Sponsor at the end of the 
study.  
Please refer to the Pharmacy Manual for information about return or destruction of study drugs.  
12.7 Test Article/Study Drug Compliance 
At each clinic visit, patients will be asked to return any unused CB-839 test article/ placebo 
control article and cabozantinib (ex-US) and will be questioned about their compliance. The 
number of remaining tablets will be recorded in a drug accountability log. Significant non-
compliance (missing > 60% of the study drug for reasons other than documented AE) must be 
reported to the Medical Monitor. 
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. Additional 
details of the primary and key secondary analyses will be provided in the Statistical Analysis 
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Plan (SAP). If, after the study has begun but prior to the final analysis, important changes are 
made to the protocol that affect principal features of the primary or key secondary analyses, the 
protocol and/or SAP will be amended, as appropriate.   
14.1 
General Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled Phase 2 study comparing 
two treatment regimens for patients with advanced or metastatic ccRCC. Patients will be 
randomized to either CB-839 with cabozantinib or placebo with cabozantinib in a 1:1 ratio. The 
primary endpoint of this Phase 2 study is IRC-adjudicated PFS. The key secondary endpoint is 
OS. Patients will be stratified by: a) prior PD-1/PD-L1 inhibitor therapy (yes vs. no) and b) 
IMDC Prognostic Risk Group (favorable vs. intermediate vs. poor; Attachment 3). 
14.2 
Independent Radiology Committee (IRC)  
An IRC will be established to evaluate tumor scans and relevant history data of trial patients in a 
central, blinded, and independent fashion. The IRC will comprise board-certified radiologists 
who will use RECIST 1.1 to assess radiographic disease response and progression following 
randomization. The IRC will evaluate study data at designated interim (if applicable) and final 
analyses. Additional details regarding IRC member qualification, training, methods, procedures, 
and other issues relevant to committee operations will be described in the IRC Charter.  
14.3 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be established to monitor the safety 
and progress of the study on a regular basis. The committee will operate independently from the 
Sponsor and the clinical investigators. To minimize the potential introduction of bias, these 
individuals will not have any direct contact with the study site personnel or patients. IDMC 
members will be selected for their expertise in oncology. The IDMC will convene periodically 
and the start date will depend on patient accrual rates. Details of the composition, role, 
responsibilities, operational considerations, and trial stopping guidelines will be provided in the 
IDMC Charter.  
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14.4 
Study Steering Committee 
A study steering committee will comprise study investigators who are experts in the treatment of 
RCC who will provide ongoing guidance on issues including protocol design, implementation 
and interpretation of clinical study results. The steering committee duties and obligations will be 
outlined in the Study Steering Committee Charter.   
14.5 
Analysis Patient Sets 
14.5.1 
Efficacy Analysis Patient Set 
The ITT patient set will be the basis for the primary efficacy analysis for this study. The ITT 
patient set is composed of all randomized patients. Patients in the ITT set will be analyzed for 
treatment efficacy according to the treatment group to which they are randomized, regardless of 
post-randomization protocol deviations, including no protocol treatment received. 
14.5.2 
Safety Analysis Set 
All patients who receive any study-specific treatment (CB-839/ placebo or cabozantinib) after 
randomization will be included in the analysis of safety and analyzed according to the actual 
treatment received. Patients having taken any CB-839 tablet will be analyzed in the CB-839 with 
cabozantinib combination arm.  
14.6 
Efficacy Analysis 
14.6.1 
Primary Efficacy Endpoint: IRC-Adjudicated PFS 
The primary efficacy endpoint is PFS defined as the time from randomization to the earlier of 
IRC-adjudicated disease progression or death due to any cause. Radiographic disease progression 
will be assessed using the RECIST v.1.1 criteria. 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 evaluable radiographic disease assessment prior to the occurrence 
of any of the following scenarios: 
 Patient is alive and progression free at the time of analysis data cutoff 
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 Disease progression or death occurs after data are missing for two consecutive scheduled 
radiographic disease assessments, including [a] missing assessments, [b] insufficient data 
for the assessments, or [c] assessments resulting in a non-evaluable status for overall 
response per RECIST 1.1. 
 Prior to documentation of disease progression or death, patient receives non-protocol 
anticancer therapy, or any other treatment that in the opinion of the IRC interferes with 
assessment of disease per RECIST 1.1 (this includes the scenario when the IRC disagrees 
with the Investigator-judged progressive disease status but the patient received 
subsequent anticancer therapy). 
Patients missing baseline radiographic disease assessment will be censored at the date of 
randomization (i.e., PFS duration will be 0). 
The primary inferential PFS comparison between the two treatment arms will take place when a 
total of 262 events have been observed. Assuming exponential PFS distributions, patient accrual 
over a period of 15 months, a median PFS of 8 months for the control arm and a hazard ratio of 
0.69 in favor of the experimental arm (equivalent to a 45% increase of median PFS to 11.6 
months for the experimental arm), it is estimated that a total of 262 PFS events will occur with 
7 months of additional follow-up after accrual completion. The primary analysis will use the 
stratified log-rank test with the randomization stratification factors of prior PD-1/PD-L1 inhibitor 
therapy (yes vs. no) and IMDC Prognostic Risk Group (favorable vs. intermediate vs. poor). A 
2-sided p < 0.05 in favor of the CB-839 + cabozantinib experimental treatment will be regarded 
as a positive result for the study. The experimental over control hazard ratio will be estimated by 
a stratified Cox proportional hazards model with the same randomization stratification factors. 
Kaplan-Meier curves will be presented with median estimates to visually display the progression 
free survival percentages.  In addition, as a secondary analysis for the primary endpoint, the 
above analyses will be repeated with only two levels, i.e. favorable vs. intermediate/poor, for the 
IMDC Prognostic Risk grouping.  
14.6.2 
Secondary Efficacy Endpoints 
Overall Survival (OS) 
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OS is defined as the time from randomization to death due to any cause. For patients alive at the 
time of analysis, OS will be censored at the time when the patient is last known to be alive. OS 
analyses will be the similar to the PFS analyses. 
14.6.3 
Additional Endpoints 
Overall Response Rate (ORR) 
ORR is defined as the percentage of patients with CR or PR according to the RECIST 1.1 
criteria. Response will be adjudicated by the IRC, and response confirmation is not required to 
compare the two arms in this double-blind protocol.  Patients with no evaluable on-study 
response assessments will be regarded as non-responders. The ORR will be compared between 
treatment arms by both the Fisher’s exact test and a logistic regression analysis accounting for 
the randomization stratification factors. 
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. For patients achieving first a PR then a CR, the PR date will be the 
starting date for response duration calculation. For responders for whom a PD has not been 
documented yet, Section 14.6.1 conventions regarding PFS censoring will apply. Response 
duration will be descriptively presented for responders in each treatment arm.  
Disease Control Rate (DCR) 
DCR is defined as the summed percentage of patients with CR, PR or SD documented at least 8 
weeks (-5 day window) following randomization according to RECIST v1.1 criteria. 
Patient Reported Outcomes 
Patients will be assessed using the NCCN-Functional Assessment of Cancer Therapy (FACT) 
Kidney Symptom Index (FKSI-19) questionnaire and the EuroQoL 5D utility score (EQ-5D-5L) 
and compared between the two treatment arms. Details of the planned analyses for these 
outcomes will be provided in the SAP. 
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14.6.4 
Exploratory Analyses 
To explore the effects of the following baseline factors, a multivariate, stratified Cox model 
regression analysis will be conducted for PFS. The model will be stratified by the randomization 
stratification factors and include treatment arm as an independent variable, with the following 
variables as additional covariates:  
 Race (Caucasian vs. all others)  
 Sex (male vs. female) 
 Age (18–65 vs. > 65 years) 
 Number of previous anti-angiogenic therapies (1 vs. >1)  
The same analyses will be repeated with only two levels, i.e. favorable vs. intermediate/poor, for 
the IMDC Prognostic Risk grouping. 
Univariate plots will also be presented for descriptive purposes.  
14.7 
Safety Analysis 
Safety will be assessed by the patient incidence and severity of treatment-emergent adverse 
events (TEAEs).  TEAEs are adverse events (AEs) not present prior to protocol treatment, or an 
already present event that worsens either in intensity or frequency during or following protocol 
treatment initiation.  The analysis will be performed on the Safety Analysis Patient Set as defined 
in Section 14.5.2.  
TEAEs will be coded by System Organ Class and Preferred Term using the Medical Dictionary 
for Regulatory Activities (MedDRA). The number and proportion of patients reporting a given 
TEAE will be tabulated by treatment group according to the worst severity reported. Separate 
tables will be constructed for a) all reported TEAEs, b) serious TEAEs, and c) TEAEs leading to 
permanent discontinuation of study treatment. The above tables will also be presented for TEAEs 
judged to be related (probably or possibility) to the study treatment. 
14.8 
Sample Size Estimation 
The sample size of 416 patients, randomized 1:1 for CB-839 + cabozantinib vs. placebo + 
cabozantinib, is anticipated to provide sufficient efficacy data to demonstrate a clinically and 
statistically significant benefit for CB-839. For the purposes of study design, it is assumed that 
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the control arm's true median PFS will be approximately 8 months based upon recently published 
randomized Phase 3 study results with cabozantinib monotherapy (Choueiri 2015), and that the 
true hazard ratio (HR) favoring CB-839 + cabozantinib over placebo + cabozantinib will be 0.69, 
corresponding to a clinically significant increase of 45% or 3.6 months from 8 months to 
11.6 months.  
The proposed study will enroll patients with an accrual period of 15 months and additional 
follow-up of 7 months. If the control arm's median PFS is 8 months and the true PFS HR of 
experimental patients to control patients is 0.69, the study will require approximately 
208 experimental patients and 208 control patients in order to reject the null hypothesis of equal 
PFS between the two treatment arms with a power of 0.85.  This estimation assumes a 2-sided 
type I error rate of 0.05, uniform accrual, exponential PFS distributions and the log-rank test for 
PFS comparison. The expected total PFS event count is 262 under the above assumptions. 
15.0 
Adverse Events 
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 
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 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 
 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  
 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. 
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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.  In contrast, all deaths including those related to progression of 
disease and sudden and unexplained death should be reported as an SAE. If there is any 
uncertainty about a finding being due solely to progression of neoplasia, the finding should be 
reported as an AE or SAE as appropriate. 
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, had it 
occurred in a more severe form, which might have caused death, but as it actually occurred, did 
not create an immediate risk of death. For example, hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening, even though hepatitis of a more severe 
nature can be fatal. Similarly, an allergic reaction resulting in angioedema of the face would not 
be life-threatening, even though angioedema of the larynx, allergic bronchospasm, or 
anaphylaxis can be fatal. 
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 
an 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. 
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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. 
If there is any doubt about whether the information constitutes an SAE, the information is treated 
as an SAE. 
Causality Attribution Guidance: 
Adverse events 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 
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 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 
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 events, although not considered an SAE, must be 
recorded, reported, and followed up within the same timelines as for an SAE. These events 
include: 
 A case involving a pregnancy exposure to a test article, unless the product is indicated for 
use during pregnancy e.g., prenatal vitamins. Information about use in pregnancy 
encompasses the entire course of pregnancy and delivery and perinatal and neonatal 
outcomes, even if there were no abnormal findings. If a pregnancy is confirmed, test 
article must be discontinued immediately. All reports of pregnancy must be followed for 
information about the course of the pregnancy and delivery, as well as the condition of 
the newborn. When the newborn is healthy, additional follow-up is not needed. 
Pregnancies occurring up to 6 months after completion of the study treatment must also 
be reported to the Investigator. 
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 Overdose and abuse (e.g., a dose higher than that indicated in the protocol) with or 
without an AE. Overdose and/or abuse are not considered SAEs, but should be reported 
to the Sponsor expeditiously (within 24 hours of awareness). Overdose and/or abuse 
should be recorded as an AE in the eCRF and reported to Safety as a non-serious Grade 1 
AE using the SAE Report form (by checking the “not applicable” box in the seriousness 
criterion). If the overdose and/or abuse is/are associated with the following: 
o An AE: both the term overdose or abuse and the associated AE should be 
recorded in the eCRF as AEs 
o SAE: the term overdose or abuse should continue to be recorded as a non-serious 
AE in both the eCRF and the SAE report form. In addition, an SAE associated 
with the overdose/abuse should be reported as an SAE in the SAE Report Form. 
15.2 Recording and Reporting 
After informed consent, but prior to initiation of study drug, only SAEs caused by protocol- 
mandated interventions (e.g., a protocol-required blood test) will be collected. 
Patients will be followed for AEs or SAEs from the time the patient initiates treatment with the 
study regimen through at least 28 days after the last dose of all  study treatments (CB-
839/placebo and cabozantinib), or until initiation of a new anticancer therapy (if earlier). 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 
therapy, or in case of permanent impairment, until the condition stabilizes. 
All AEs and SAEs must be recorded on source documents and collected in EDC system. 
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. 
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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 24 hr 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 
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 IRB/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.  
PrimeVigilance, the pharmacovigilance vendor, has been contracted to provide drug safety and 
pharmacovigilance support, including EudraVigilance management and distribution of SUSAR 
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reports, in relation to CB-839 investigational medicinal product (IMP) clinical development 
program by Calithera Biosciences Inc. 
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 articles, 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. 
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 
 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. 
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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 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 Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
 Applicable ICH Good Clinical Practice (GCP) Guidelines 
 Applicable laws and regulations 
 The investigator will be responsible for the following: 
– Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
– Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
– Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
20.2 Investigator 
The Investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and documents. 
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All study-related information will be recorded on source documents. All required data will be 
recorded in the eCRFs. All eCRF data must be submitted to the Sponsor throughout and at the 
end of the study. 
If an Investigator retires, relocates, or otherwise withdraws from conducting the study, the 
Investigator must notify the Sponsor to agree upon an acceptable storage solution. Regulatory 
agencies will be notified with the appropriate documentation. 
All study-related laboratory and clinical data gathered in this protocol will be stored in a 
password-protected database. All patient information will be handled using anonymous 
identifiers. Linkage to patients’ study data is only possible after accessing a password-protected 
database. Access to the database is only available to individuals directly involved in the study. 
Patient personal health information that is accessed for this study will not be reused or disclosed 
to any other person or entity, or for other research. 
20.3 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. 
20.4 Pre-Study Documentation 
The Investigator must provide the Sponsor with the following documents BEFORE enrolling any 
patients: 
 Completed and signed form 1572 or (for sites outside the US) ICH GCP Statement 
 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. 
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 Copy of the IRB/IEC approval letter for the protocol and informed consent. All 
advertising, recruitment, and other written information provided to the patient must be 
approved by the IRB/IEC. Written assurance of continuing approval (at least annually) as 
well as a copy of the annual progress report submitted to the IRB/IEC must also be 
provided to the Sponsor.  
 Copy of the IRB/IEC-approved Informed Consent Form to be used 
 Where applicable, a list of the IRB/IEC members or a Federal-Wide Assurance/ 
Department of Health and Human Services (FWA/DHHS) number 
 Copy of the protocol sign-off page signed by the Investigator 
 Copy of the current medical license (online verification is also acceptable) of the 
Principal Investigator, any Sub-Investigators and any other individuals having significant 
responsibility as listed in the 1572 (or equivalent) 
 Fully executed Clinical Trial Agreement (CTA), if applicable 
 Financial disclosure form for the Principal Investigator and any other persons listed in the 
1572 (or equivalent) 
 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 (or equivalent). 
The Sponsor must be notified if the laboratory is changed or if any additional laboratory 
is to be used. 
 
20.5 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 
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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.  
21.0 
PUBLICATION AND AUTHORSHIP 
Results of the study, regardless of outcome, will be submitted for publication in peer-reviewed 
congresses and/or scientific journals. 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 approval of the version to be published, and 4) agreement to be 
accountable for all aspects of the work to ensure its accuracy and integrity. All four conditions 
should be met.
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22.0 
LIST OF ABBREVIATIONS 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
C1D1 
Cycle 1 Day 1 
CB-Cabo 
CB-839 plus cabozantinib combination treatment 
Ccr 
Creatinine Clearance 
ccRCC 
Clear Cell Renal Cell Carcinoma 
CFR 
Code of Federal Regulations 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CTA 
Clinical Trial Agreement 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DCR 
Disease Control Rate 
DICOM 
Digital Imaging and Communications in Medicine 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice  
GLS 
Glutaminase 
GMP 
Good Manufacturing Practice 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IC50 
Half maximal inhibitory concentration 
IDMC 
Independent Data Monitoring Committee 
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Abbreviation or Term1 
Definition/Explanation 
IEC 
Independent Ethics Committee 
IMDC 
International Metastatic Renal Cell Carcinoma Database 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRC 
Independent Radiology Committee 
IRT 
Interactive Response Technology 
ITT 
Intent-to-treat 
IV 
Intravenous 
KPS 
Karnofsky Performance Score 
LC-MS/MS 
Liquid chromatography-mass spectrometry/mass spectrometry 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
LMWH 
Low molecular weight heparins 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mRCC 
Metastatic Renal Cell Carcinoma 
MRI 
Magnetic Resonance Imaging 
ORR 
Overall response rate 
OS 
Overall Survival 
Pbo-Cabo 
Placebo tablets plus cabozantinib treatment 
PD-1 
Programmed Cell Death protein 1 
PD-L1 
Programmed Death Ligand 1 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PPI 
Proton Pump Inhibitors 
PR 
Partial response 
PSA 
Prostate Specific Antigen 
PT 
Prothrombin time 
QD 
Once daily 
QoL 
Quality of life 
QTc 
Corrected QT interval 
RP2D 
Recommended Phase 2 Dose 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
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Abbreviation or Term1 
Definition/Explanation 
SD 
Stable disease 
TKI 
Tyrosine kinase inhibitor 
TID 
Three times daily 
TNBC 
Triple negative breast cancer 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
VEGF 
Vascular Endothelial Growth Factor 
 
23.0 
REFERENCES 
Calithera Biosciences, Inc. CB-839 Investigator’s Brochure 
Chou TC and Talalay P. Quantitative analysis of dose-effect relationships: the combined effects 
of multiple drugs or enzyme inhibitors. Advances in Enzyme Regulation. Feb 1984:27-55. 
Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib 
versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814-1823. 
 
Choueiri TK, Escudier BJ, Powles T, Tannir NM, Mainwaring P, Rini BI, et al. Cabozantinib 
versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, 
open-label, phase 3 trial. Lancet Oncol 2016;17:917. 
Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, et al. Cabozantinib 
versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk 
(Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent 
review and overall survival update. Eur J Cancer 2018;94: 115–125. 
Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy 
testing in clinical trials. Sep 2014. Accessed at 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45:228-247. 
Escudier B, et al. CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v 
sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including 
IMDC risk and PD-L1 expression subgroups. European Society of Molecular Oncology 2017. 
 
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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.  
 
Heng DYC, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors 
for overall survival in patients with metastatic renal cell carcinoma treated with vascular 
endothelial growth factor–targeted agents: Results from a large, multicenter study. J Clin Oncol 
2009;27:5794-5799. 
 
Heng DYC, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, et al. 
External validation and comparison with other models of the International Metastatic Renal-Cell 
Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol 
2013;14:141–148. 
 
Hsieh JJ, Purdue MP, Signoretti S, et al. Renal Cell Carcinoma. Nature Reviews Disease Primers 
2017;3:1-19. 
 
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  
 
Ko JJ, Xie W, Kroeger N, Lee JL, Rini BI, Knox JJ, et al. International Metastatic Renal Cell 
Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell 
carcinoma previously treated with first-line targeted therapy: A population-based study. Lancet 
Oncol 2015;16:293-300. 
 
 
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al, Nivolumab 
versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-1813. 
 
 
Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to tyrosine 
kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol. 
2009;6:219-28. 
 
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12 PK samples are collected on C2D1: pre-dose and 2 hr post dose, and on C3D1: 4 hr and 6 hr post dose. Refer to the laboratory manual for detailed instructions on samples kits, 
 collection, and shipment to a central laboratory. Contact Sponsor for guidance on options for collecting missed samples. 
13 Optional tumor biopsies to be collected as clinically indicated from patients at North American sites only. 
14 Screening tumor assessments within 28 days prior to randomization accepted. Radiographic assessments should include brain MRI for patients with history of brain metastases or 
 suggestive symptoms and bone scan (bone scintigraphy) for patients with history of bone metastases or suggestive symptoms.  
15 Radiographic tumor assessments and QoL questionnaires will be performed at the scheduled intervals relative to the date of C1D1 regardless of study treatment holds or delays 
(note that treatment cycles are fixed and do not shift as a result of dose interruptions). 
16 Unless performed within the previous 4 weeks (Note: patients who discontinue study treatment for reasons other than progressive disease [PD] or death will continue to be 
 followed by radiographic tumor imaging until documentation of radiographic PD per RECIST v.1.1, death, initiation of a new anticancer therapy, or withdrawal of consent.) 
17 Patients will be contacted every 3 mo for the first 12 mo afterdiscontinuation of all study treatments (CB-839/placebo and cabozantinib) and every 6 mo thereafter for survival 
follow-up. 
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ATTACHMENT 2: CLINICAL LABORATORY TESTS 
Hematology (Peripheral Blood Sample): 
 Hemoglobin  
 Hematocrit 
 Red blood cell 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 
 Phosphate  
 Magnesium 
 Sodium 
 Potassium 
 Chloride 
 CO2  
 Calcium 
 Glucose 
 Blood urea nitrogen2 
 Total protein 
 Albumin 
 Total and direct bilirubin1 
 Aspartate aminotransferase (AST) 
 Alanine aminotransferase (ALT) 
 Alkaline phosphatase (ALP) 
 Lactate dehydrogenase (LDH) 
 Creatinine 
1 
Direct bilirubin is only required if Total Bilirubin is above the upper limit of normal.  
2 
Some sites, particularly in Europe, routinely measure blood urea instead of blood urea nitrogen in the 
standard of care chemistry panel. Because blood urea nitrogen and blood urea labs serve the same purpose 
and are interconvertible, either test is acceptable per protocol. The EDC system will allow for either blood 
urea nitrogen or urea levels to be collected.  
 
Thyroid function tests 
 TSH  
 Free T4 (required at screening; after screening only if TSH is outside normal range) 
 
Pregnancy test (urine or serum -HCG): Women of child-bearing potential 
Urinalysis 
Screening: 
 Protein 
 Leukocyte esterase 
 pH 
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 Glucose 
 Ketones 
 Hemoglobin 
 Nitrite 
 Urine protein:creatinine ratio 
(UPCR) or 24-hour urine protein  
 
Post-Screening: 
 Protein (to monitor for 
proteinuria; dipstick acceptable 
and if positive will be followed 
by UPCR) 
 
 
 Specific gravity 
 Urobilinogen 
 
 Microscopic evaluation performed at the 
discretion of the Investigator based on 
results of routine urinalysis or as clinically 
indicated 
 
 
 
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ATTACHMENT 3: IMDC PROGNOSTIC MODEL 
Source: Heng 2009, Heng 2013, Ko 2015 
 
Study patient prognosis will be evaluated using the International Metastatic Renal Cell 
Carcinoma Database Consortium (IMDC) model. The IMDC model was derived from 
multicenter data from the United States and Canada on 645 patients with no prior antiangiogenic 
therapy (Heng 2009), and was validated in large studies of patients from multiple international 
centers in both first-line antiangiogenic targeted therapy and second-line targeted therapy (with 
or without prior immunotherapy; Heng 2013 and Ko 2015). In the setting of second-line targeted 
therapy for metastatic RCC, median overall survival was 35 mo in the favorable risk group 
(0 risk factors), 16.6 mo in the intermediate risk group (1-2 risk factors), and 5.4 mo in the poor 
risk group (3-6 risk factors; Ko 2015). 
 
Worksheet for Determination of Prognostic Score in Previously Treated Patients 
Enter the patient’s assessment value in the Patient Value Column. If the patient value meets the 
criteria then enter “1”. To obtain the patient’s prognostic score, add up all the “1” entered in 
last column. The patient’s risk group is defined in the table below using the patient’s IMDC 
prognostic score.  
 
Parameter 
Risk Factor 
Criteria Value 
Patient 
Value 
If Patient Value 
meets criteria, enter 
1 
Time from 
diagnosis to 
initiation of 
systemic therapy 
Shorter time from diagnosis 
to systemic treatment for 
metastatic disease 
< 1 year 
 
 
KPS 
Low performance status 
˂ 80% 
 
 
Hemoglobin 
Low hemoglobin (anemia) 
Males: < LLN 
Females: < LLN  
 
 
Corrected calcium 
High calcium 
(hypercalcemia) 
> ULN 
 
 
Neutrophil 
High neutrophil count 
(neutrophilia) 
>ULN 
 
 
Platelets 
High platelet count 
(thrombocytosis) 
>ULN 
 
 
Sum total (IMDC Prognostic Score): 
 
KPS, Karnofsky performance status; LLN, lower limit of normal; ULN, upper limit of normal. 
Note: ULN and LLN lab results are according to institution/local lab reference ranges 
 
Use IMDC Prognostic Score to identify patient’s risk group in the table below. 
 
Risk Group Based on IMDC Prognostic Score 
 
IMDC Risk Group 
IMDC Prognostic Score 
Favorable Risk 
0 
Intermediate Risk 
1-2 
Poor Risk 
3-6 
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ATTACHMENT 4: KARNOFSKY PERFORMANCE STATUS SCALE 
Percent 
Description 
100 
Normal; no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self; unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of their personal 
needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated although death not 
imminent. 
20 
Very sick; hospital admission necessary; active supportive treatment 
necessary. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead 
 
 
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ATTACHMENT 5: RECIST CRITERIA VERSION 1.1 
(Adapted from Eisenhauer 2009) 
Sponsor’s Notes: 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 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: 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. 
 
 
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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 patiented 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 
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The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and  10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g., for body scans). 
If prior to enrollment it is known that a patient is not able to undergo CT scans with IV contrast 
due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (with 
or without IV contrast) will be used to evaluate the patient at baseline and follow-up, should be 
guided by the tumor type under investigation and the anatomic location of the disease (Note:  see 
Section 10.6.9 for protocol-specific requirements; contrast-enhanced MRI of the abdomen and 
pelvis along with non-contrast CT of the chest is strongly recommended if CT contrast is 
contraindicated). 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. 
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 
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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.  
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
This means in instances where patients have only one or two organ sites involved a maximum of 
two (one site) and four lesions (two sites), respectively, will be recorded. Other lesions in that 
organ will be recorded as non-measurable lesions (even if size is greater than 10 mm by CT 
scan). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, 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. 
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All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression.’ In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
Evaluation of target lesions 
 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
Special notes on the assessment of target lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. Case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis < 10 mm. For PR, SD, and 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 
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may not feel comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs it is important that a value be recorded on the case report form: 
 If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned 
and BML (below measurable limit) should be ticked (Note: It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when 
normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned in this circumstance as well and BML 
should also be ticked). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm and in that case BML should not be ticked. (BML is 
equivalent to a less than sign <) 
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
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). 
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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. 
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. 
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 No FDG-PET at baseline and a positive FDG-PET at follow-up: 
o If the positive FDG-PET at follow-up corresponds to a new sign of disease 
confirmed by CT, this is PD 
o If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal *CT scan). 
o If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
*reflects study-specific modification to RECIST v.1.1 
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. 
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. 
 
 
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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 
Note: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
 
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). 
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. 
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.  
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected
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ATTACHMENT 6: DRUG INTERACTIONS 
Drug Interactions with CB-839 
CYP2C9 Substrates with a 
narrow therapeutic index 
Other CYP2C9 Substrates 
 
S-Warfarin (anticoagulant) 
 
Phenytoin (antiepileptic) 
 
 
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 
 
irbesartanlosartan 
 
sildenafil (in erectile dysfunction) 
 
terbinafine (antifungal) 
 
amitriptyline (tricyclic antidepressant) 
 
fluoxetine (SSRI antidepressant) 
 
nateglinide (antidiabetic) 
 
rosiglitazone (antidiabetic) 
 
tamoxifen (SERM) 
 
torasemide (loop diuretic) ketamine 
*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 
 
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Drug Interactions with Cabozantinib 
CYP3A4 Inhibition on Cabozantinib 
Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to 
healthy patients increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. 
Concomitant use of cabozantinib with a strong CYP3A4 inhibitor increased the exposure of 
cabozantinib compared to the use of cabozantinib alone. Reduce the dosage of cabozantinib if 
concomitant use with strong CYP3A4 inhibitors cannot be avoided. 
Examples include: boceprevir, clarithromycin, conivaptan, erythromycin, grapefruit juice, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telithromycin, verapamil, and voriconazole 
CYP3A4 Induction on Cabozantinib 
Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy 
patients decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Concomitant 
use of cabozantinib with a strong CYP3A4 inducer decreased the exposure of cabozantinib 
compared to the use of cabozantinib alone. Increase the dosage of cabozantinib if concomitant 
use with strong CYP3A4 inducers cannot be avoided. 
Examples include: rifampin, phenytoin, carbamazepine, phenobarbital, rifabutin, rifapentine, and 
St. John’s Wort   
 
 
 
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ATTACHMENT 8: EUROQOL QUESTIONNAIRE ED-5D-5L (US ENGLISH SAMPLE 
VERSION) 
 
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ATTACHMENT 9: SUMMARY OF CHANGES (AMENDMENT 3.0 VS. 2.0) 
Section 
Change 
Rationale 
4.0  
Updated emergency contacts and 
SAE reporting contact 
Result of staff changes 
5.0  
Additional objectives for PK 
updated  
Included PK analysis of cabozantinib, 
and the major CB-839 metabolite 
110826 using sparse PK sampling.  
The Population PK analysis will be the 
subject of a separate report. Clarified 
that the purpose of the PK analyses are 
to evaluate the relationship between 
drug and metabolite exposure and the 
efficacy and safety, as well as evaluate  
the possible effect of CB-839 on 
cabozantinib exposure 
8.1  
Clarified inclusion criteria 3e  
Removed creatinine (typo) as 
described in the protocol clarification 
letter previously submitted to sites and 
IRBs/ECs 
9.4.1  
Added phase 1 study CX-839-001 
for the CB-839 + cabozantinib 
data 
Clarified that the CB-839 + 
cabozantinib data was based on the 
phase 1 study CX-839-001 
9.4.2  
Added phase 1 study CX-839-001 
for the efficacy of CB-839 plus 
cabozantinib data 
Clarified that the efficacy data of CB-
839 + cabozantinib was based on the 
phase 1 study CX-839-001 
10.3  
Added instructions for patients 
who discontinue either CB-
839/placebo or cabozantinib 
Added language that patients should 
continue with their scheduled study 
visits and procedures per protocol if 
they discontinue either CB-
839/placebo or cabozantinib for any 
reason such as an AE or surgery 
10.4 
Clarified language for survival 
follow-up  
Clarified that patients will be contacted 
every 3 months for the first 12 months 
and every 6 months thereafter after 
discontinuing CB-839/placebo and 
cabozantinib for survival follow-up 
10.6.11  
Included 110826 (major 
metabolite of CB-839) and 
cabozantinib for PK analysis 
Updated due to revised additional 
objectives for PK 
15.1  
Updated other reportable 
information language 
Clarified that other reportable 
information should be recorded, 
reported, and followed up within the 
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same expedited timelines as for an 
SAE 
15.1  
Updated overdose and abuse 
definition 
Added instructions on how to record 
and report overdoses and abuses 
depending on whether they are an AE 
or SAE 
15.2 
Updated safety follow-up 
language 
Clarified that patients will be followed 
for AEs or SAEs from initiation of 
study treatment through at least 28 
days after the last dose of all study 
treatments (CB-839/placebo and 
cabozantinib) or until initiation of a 
new anticancer therapy (if earlier) 
Attachment 1 
Updated window for end of 
treatment/follow up visit 
Included +7 day window per protocol 
clarification letter previously submitted 
to sites and IRBs/ECs 
Attachment 1 
Updated footnote 4  
Revised language to match language in 
section 15.2 
Attachment 1 
Updated footnote 17 
Clarified that patients will be contacted 
every 3 months for the first 12 months 
and every 6 months thereafter after 
discontinuing CB-839/placebo and 
cabozantinib for survival follow-up 
Attachment 2 
Added footnote 2 to serum 
chemistry panel for blood urea 
nitrogen 
Updated per protocol clarification 
letter previously submitted to sites and 
IRBs/ECs. Blood BUN and blood urea 
results will be accepted for blood urea 
nitrogen tests. 
 
 
 
 
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SAP_001.pdf: 
Calithera Biosciences, Inc. 
Statistical Analysis Plan
CX-839-008
Version 1.0; 10 June, 2020
 
 
Confidential
Page 1 of 24
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Calithera Biosciences, Inc. 
CX-839-008 
 
 
 
 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Phase 2 
Clinical Trial Comparing CB-839 in Combination with 
Cabozantinib (CB-Cabo) vs. Placebo with Cabozantinib (Pbo-
Cabo) in Patients with Advanced or Metastatic Renal Cell 
Carcinoma (RCC)
 
Sponsor: 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080
Prepared By: 
 
Document Version 
and Date: 
Version 1.0; 10 June, 2020 
 
 
 






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1 
TABLE OF CONTENTS 
 
1 
Table of Contents ..................................................................................................................................4 
2 
List of Abbreviations ............................................................................................................................5 
3 
Introduction ...........................................................................................................................................7 
4 
Study Design ..........................................................................................................................................7 
4.1 
Study Endpoints ..............................................................................................................................9 
4.1.1 
Efficacy Endpoints ...................................................................................................................9 
4.1.2 
Pharmacokinetic (PK) Endpoints ......................................................................................... 10 
4.1.3 
Safety Endpoints..................................................................................................................... 10 
4.2 
Determination of Sample Size ...................................................................................................... 10 
4.3 
Analysis Timing ............................................................................................................................. 11 
5 
Study Conduct ..................................................................................................................................... 12 
5.1 
Independent Radiology Committee (IRC) .................................................................................. 12 
5.2 
Data Monitoring ............................................................................................................................ 13 
6 
Statistical Methods .............................................................................................................................. 13 
6.1 
Analysis Populations ..................................................................................................................... 13 
6.2 
General Statistical Methods ......................................................................................................... 13 
6.3 
Analysis of Study Conduct ............................................................................................................ 14 
6.4 
Analysis of Treatment Group Comparability ............................................................................. 14 
6.5 
Efficacy Analysis ........................................................................................................................... 14 
6.5.1 
Primary Analysis of Progression-Free Survival .................................................................. 14 
6.5.2 
Secondary Analysis ................................................................................................................ 16 
6.5.3 
Additional Analyses ............................................................................................................... 17 
6.6 
Pharmacokinetic Analyses ............................................................................................................ 20 
6.7 
Safety Analyses .............................................................................................................................. 20 
6.7.1 
Exposure of Study Medication .............................................................................................. 20 
6.7.2 
Adverse Events ....................................................................................................................... 20 
6.7.3 
Laboratory Data ..................................................................................................................... 21 
6.7.4 
Vital Signs ............................................................................................................................... 21 
6.8 
Missing Data .................................................................................................................................. 21 
6.9 
Analyses Related to COVID-19 .................................................................................................... 21 
6.9.1 
General .................................................................................................................................... 22 
6.9.2 
Efficacy .................................................................................................................................... 22 
6.9.3 
Safety ....................................................................................................................................... 23 
7 
References ............................................................................................................................................ 23 
 
TABLE OF TABLES 
Table 1 
List of Abbreviations ........................................................................................................5 
Table 2:  
The Expected Analysis Timing for Progression -Free Survival in the Intent-to-Treat 
Population ........................................................................................................................ 12 
Table 3:  
The Expected Analysis Timing for Overall Survival in the Intent-to-Treat 
Population ........................................................................................................................ 12 
Table 4 
Censoring Rules for Progression Free Survival ........................................................... 16 
 
 
 


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2 
LIST OF ABBREVIATIONS  
Table 1 
List of Abbreviations  
Abbreviation
Definition 
AE
adverse event 
ATC
Anatomical Therapeutic Chemical
BID 
twice daily
BMI
body mass index
CB-Cabo
CB-839 in combination with Cabozantinib 
ccRCC
clear cell renal cell carcinoma
CR
complete response
CRF
case report form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR 
disease control rate
DOR 
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EQ 5D-5L
EuroQol 5D
FA
final analysis
FACT 
Functional Assessment of Cancer Therapy
FKSI-19 
Functional Assessment of Cancer Therapy Kidney Cancer 
Symptom Index
IA 
interim analysis
IDMC 
Independent Data Monitoring Committee
INV
Investigator
IRC 
Independent Radiology Committee
IWRS
interactive web response system
IxRS 
interactive voice/web response system
KPS
Karnofsky Performance Status
MedDRA
Medical Dictionary for Regulatory Activities
mRCC
metastatic renal cell carcinoma
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI 
National Cancer Institute
ORR 
overall response rate
OS
overall survival
Pbo-Cabo
placebo in combination with Cabozantinib
PD
progressive disease
PDn
pharmacodynamics
PD-1 
programmed cell death protein 1
PD-L1
programmed death ligand 1


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Abbreviation
Definition 
PFS 
progression-free survival
PK
pharmacokinetics
PR 
partial response
QD
once daily
RCC
renal cell carcinoma
RECIST
response evaluation criteria in solid tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease 
SI
Système International
TEAE
treatment-emergent adverse event
TKI 
tyrosine kinase inhibitor
 
 


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3 
INTRODUCTION  
The statistical analysis plan (SAP) provides details of the planned analyses and statistical 
methods for the study CX-839-008 (A Randomized, Double-Blind, Placebo-Controlled 
Phase 2 Clinical Trial Comparing CB-839 (Telaglenastat) in Combination with 
Cabozantinib [CB-Cabo] vs. Placebo with Cabozantinib [Pbo-Cabo] in Patients with 
Advanced or Metastatic Renal Cell Carcinoma [RCC]).  The background and rationale 
for the study can be found in the study protocol.  Statistical analyses including endpoints 
in the SAP supersedes the protocol.   
4 
STUDY DESIGN 
Protocol CX-839-008 is a Phase 2 randomized, double-blind, placebo-controlled, 
multicenter study comparing two treatment regimens for patients with clear cell RCC 
(ccRCC). Figure 1: Study Design SchemaEligible patients were randomized in a 1:1 ratio 
to the following study treatment arms:  
 CB-Cabo - telaglenastat (800 mg twice daily [BID]) + cabozantinib (60 mg once 
daily [QD]) 
 Pbo-Cabo - Placebo + cabozantinib (60 mg QD) 
Randomization will be stratified by the following variables: 
 Prior treatment with PD-1/PD-L1 inhibitor therapy (yes vs. no) 
 The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) 
Prognostic Risk Group (favorable vs. intermediate vs. poor)  
Treatment administrations are per the instructions and schedule of events outlined in the 
protocol.  Crossover between treatment arms will not be allowed. 
Radiographic evaluation of tumor burden (e.g., diagnostic computed tomography [CT] 
scan with intravenous contrast or MRI) will occur during Screening (within 28 days prior 
to randomization), every 8 weeks after C1D1 for the first 12 cycles, every 12 weeks 
beginning with cycle 13, and at the End of Treatment Visit. Radiographic assessments 
may occur more frequently as clinically indicated.  
 
Patients will receive study treatment determined by randomization in 28-day cycles until 
disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 or 
unacceptable toxicity, whichever occurs first. Patients will be followed for safety for at 
least 28 days after the last dose of all study treatments (telaglenastat/placebo and 
cabozantinib), or until initiation of a new anticancer therapy, if earlier. Patients who 
discontinue study treatment for reasons other than disease progression by RECIST v.1.1 
or death will also continue to be followed by radiographic tumor imaging until 
documentation of radiographic progressive disease per RECIST v.1.1, death, initiation of 
a new anticancer therapy, or withdrawal of consent. Long-term follow up for survival 


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will continue until death or withdrawal of consent for survival follow-up. Patients who 
continue treatment beyond progression will continue to receive all scheduled protocol 
assessments, including continued radiographic tumor assessments, until study treatment 
is discontinued. 
An independent Data Monitoring Committee (IDMC) monitors safety data. See Section 
5.2 for more information.  
Figure 1 illustrates the study design. 
Figure 1: Study Design Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 


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4.1 
Study Endpoints  
4.1.1 
Efficacy Endpoints 
4.1.1.1 
Primary Efficacy Endpoint 
Independent Radiology Committee (IRC)-assessed progression-free survival (PFS) per 
RECIST v1.1, defined as the time from randomization to documented disease progression 
or death due to any cause, whichever occurs first.  
4.1.1.2 
Secondary Efficacy Endpoints 
Overall Survival (OS) is defined as the time from randomization to death due to any 
cause.  
Investigator (INV)-assessed PFS per RECIST v1.1, defined as the time from 
randomization to documented disease progression or death due to any cause, whichever 
occurs first. 
4.1.1.3 
Additional Efficacy Endpoints 
The additional efficacy endpoints are: 
 Overall response rate (ORR), defined as the percentage of patients with complete 
response (CR) or partial response (PR) according to the RECIST 1.1 criteria per 
IRC   
 Duration of response (DOR), defined as the time between the first documentation 
of a PR or a CR to the first documentation of progressive disease (PD) or death, 
whichever occurs first as determined by RECIST 1.1 criteria per IRC  
 Disease control rate (DCR), defined as the summed percentage of patients with 
CR, PR and stable disease (SD) following treatment initiation according to 
RECIST 1.1 criteria per IRC.  
 PFS rates according to RECIST v1.1 criteria per IRC at 6-month, 9-month and at 
1-year landmark timepoints 
 OS rate at 1-year, 2-year, and 3-year landmark timepoints 
 PFS according to RECIST v1.1 criteria per IRC and OS in subgroups based on 
demographics and baseline characteristics  
 Patient reported outcomes using the NCCN-Functional Assessment of Cancer 
Therapy (FACT) Kidney Symptom Index (FKSI-19) questionnaire and the 
EuroQoL 5D utility score (EQ-5D-5L). 


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 Genetic variants and other biomarkers related to angiogenesis and metabolic 
pathways 
4.1.2 
Pharmacokinetic (PK) Endpoints 
 Potential relationship between drug  and metabolite exposure  and the efficacy 
and safety as well as evaluate the possible effect of telaglenastat on cabozantinib 
exposure  
Additional PK may be summarized in a separate report and may be outside the scope of 
the CSR. 
4.1.3 
Safety Endpoints 
The safety endpoints are the following: 
 Type, incidence, severity, seriousness, and study drug-relatedness of adverse 
events graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.03 (NCI CTCAE v4.03) 
 Changes in vital signs, ECGs, physical findings, and clinical laboratory test 
results and following study treatment administration 
4.2 
Determination of Sample Size 
The study anticipated approximately 416 patients, with 1:1 for CB-Cabo vs. Pbo-Cabo, 
and is anticipated to provide sufficient efficacy data to demonstrate a clinically and 
statistically significant benefit for telaglenastat for the primary endpoint of PFS per IRC.  
For the purposes of study design, it is assumed that the control arm's true median PFS 
will be approximately 8 months based upon recently published randomized Phase 3 study 
results with cabozantinib monotherapy (Choueiri 2015), and that the assumed true hazard 
ratio (HR) favoring CB-Cabo over Pbo-Cabo will be 0.69, corresponding to an increase 
of 3.6 months from 8 months to 11.6 months. 
The proposed study enrolled patients with an accrual period of 16 months and additional 
follow-up of at least 8 months. With the control arm's median PFS being 8 months and 
the true PFS HR of experimental patients to control patients is 0.69, the study will require 
approximately 262 PFS events in order to reject the null hypothesis of equal PFS between 
the two treatment arms with a power of 0.85. This estimation assumes a 2-sided type I 
error rate of 0.05, uniform accrual, exponential PFS distributions and the log-rank test for 
PFS comparison.  The estimate of the number of events required to demonstrate efficacy 
with regard to PFS is shown in Table 2.   
 
To control the overall type I error rate for treatment comparisons at 2-sided test at 0.05, 
when PFS per IRC is statistically positive, all of the α will be passed to the secondary 
endpoint of OS, which will be tested at a 2-sided α level of 0.05 (see Figure 2).   


Calithera Biosciences, Inc. 
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OS will be tested using the group sequential method at the interim (when PFS is assessed 
as described above) and final analyses based on the 2-sided  level of 0.05.  Statistical 
significance at the interim analysis of OS will be tested as described in Table 3, which 
also shows estimated number of OS events.  The stopping boundaries for the interim and 
final OS analyses will be calculated using the Lan-DeMets approximation to the O’Brien-
Fleming boundary.       Table 3 
Figure 2: 
Progression-Free Survival and Overall Survival Analysis Testing 
Strategy, Alpha Allocation  
 
IRC, independent radiology committee; OS, overall survival; PFS, progression-free survival. 
4.3 
Analysis Timing 
No interim analyses are planned for PFS in this study; one interim analysis is planned for 
OS.  Because the cabozantinib median PFS is expected to be 8 months, the sponsor 
anticipates that having a minimum follow-up period of 8 months will provide sufficient 
maturity of the PFS data.  The PFS primary analysis will be conducted when 
approximately 262 IRC-determined PFS events have occurred in the ITT population 
(analysis populations are defined in Section 6.1) and at least 8 months elapse after the last 
patient is enrolled, whichever occurs later. The expected timing for the IRC-determined 
PFS analysis is shown in Table 2.  
At the time of the PFS primary analysis, the interim analysis of OS will be performed.  
The expected timing of the final analysis of OS will be determined by the number of OS 
events that are observed in the ITT population as shown in Table 3. The estimated 
number of events for the OS at the interim analysis is also shown in Table 3.  
For OS analyses (IA and FA), actual boundaries will be adjusted according to the true 
number of OS events observed at the data cuts.   
   
 
 
 
 
 
 
 


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Table 2:  The Expected Analysis Timing for Progression -Free Survival in the 
Intent-to-Treat Population 
Type of Analysis 
Months from FPI 
Criteria 
 
PFS Primary 
~25 
Number of 
Events/Event Ratio 
262/63% 
 
 
MDD in HR 
<0.784 
 
 
p-value stopping 
boundary 
<0.05 
 
 
Power 
85% 
~, approximately; FPI, first patient initiated screening; PFS, progression-free survival; HR, hazard ratio; 
MDD, minimum detectable differences. Target HR assumption is 0.69.  p-values are 2-sided
 
Table 3:  The Expected Analysis Timing for Overall Survival in the Intent-to-Treat 
Population 
Type of Analysis 
Months from 
FPI 
Percent 
Information 
Criteria 
 
OS  IA 
~25 
45% 
Estimated 
Events/Event Ratio 
135/32% 
 
 
 
MDD in HR 
<0.582 
 
 
 
p-value stopping 
boundary 
0.002 
 
 
 
Power 
10.4% 
OS FA 
~53 
100% 
Events/Event Ratio 
300/72% 
 
 
 
MDD in HR 
<0.797 
 
 
 
p-value stopping 
boundary 
0.049 
 
 
 
Total power 
80% 
~, approximately; FPI, first patient initiated screening; IA, Interim analysis; FA, final analysis; HR, 
hazard ratio; MDD, minimum detectable differences; target HR assumption is0.723.  OS interim 
boundary is determined by O’Brien-Fleming Method;  p-values are 2-sided
 
5 
STUDY CONDUCT 
5.1 
Independent Radiology Committee (IRC) 
An IRC has been established to evaluate tumor scans and relevant history data of trial 
patients in a central, blinded, and independent fashion. The IRC is comprised of board-
certified radiologists who use RECIST v1.1 to assess radiographic disease response and 
progression following randomization. The IRC will evaluate study data at the designated 
primary analysis. Additional details regarding IRC member qualification, training, 
methods, procedures, and other issues relevant to committee operations is described in 
the IRC Charter.  


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5.2 
Data Monitoring 
An Independent Data Monitoring Committee (IDMC) has been established to monitor the 
unblinded safety and progress of the study on a regular basis. The committee operates 
independently from the Sponsor and the clinical investigators. To minimize the potential 
introduction of bias, these individuals do not have any direct contact with the study site 
personnel or patients. The IDMC convenes periodically (approximately every 3 -6 
months depending on the progress of the study).  Details of the composition, role, 
responsibilities and operational considerations are provided in the IDMC Charter.  
In addition to real time medical review of emergent serious adverse events (SAEs), a 
cross functional sponsor safety review team performs regular periodic aggregate data 
reviews across all telaglenastat studies.  
6 
STATISTICAL METHODS 
6.1 
Analysis Populations 
The analysis populations are defined as follows:  
 The ITT population is defined as all randomized patients, whether or not the 
patients receive the assigned treatment per the interactive web response system 
(IWRS). Patients in the ITT set will be analyzed according to the treatment group 
to which they are randomized regardless of post randomization protocol 
deviations. The ITT patient set will be the basis for the efficacy analysis for this 
study unless otherwise specified. 
 Safety analysis population includes all patients who receive any study-specific 
treatment (telaglenastat/placebo or cabozantinib) after randomization and will be 
analyzed according to the actual treatment received.  Patients having taken any 
telaglenastat tablet will be analyzed in the telaglenastat with cabozantinib 
combination arm.  Similarly, patients randomized to the telaglenastat with 
cabozantinib combination arm without receiving any telaglenastat will be 
analyzed in the placebo plus cabozantinib arm.  
 
PK analyses will be based on PK observations from all patients who receive 
telaglenastat or cabozantinib treatment and who provide at least one evaluable PK 
sample.  
 
 
PRO-evaluable population is defined as ITT with a non-missing baseline assessment and 
at least one non-missing post-baseline assessment until treatment discontinuation 
6.2 
General Statistical Methods 
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. Descriptive statistics (mean, median, SD, range) will be presented for continuous 
variables, and frequencies and percentages will be presented for categorical variables. 


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6.3 
Analysis of Study Conduct 
Enrollment, major protocol deviations (including major deviations of inclusion and/or 
exclusion criteria), and reason for discontinuation from the study will be summarized by 
treatment arm for the ITT population.   Study treatment administration and reasons for 
discontinuation from either component of the study treatment will be summarized by 
treatment arm for the safety population.  
6.4 
Analysis of Treatment Group Comparability  
Demographic and baseline characteristics, including age, sex, race, ethnicity, baseline 
medical history, prior medications, disease characteristics including previous treatment, 
histologic subtype, current disease status, and stratification factors will be summarized by 
treatment arm and overall subjects combined for the ITT and safety populations.  
6.5 
Efficacy Analysis 
6.5.1 
Primary Analysis of Progression-Free Survival 
Progression-free survival is defined as the time from randomization to the occurrence of 
disease progression as assessed by the IRC using RECIST v1.1 or death from any cause, 
whichever occurs first. Patients who have not experienced disease progression or death at 
the time of analysis of PFS will be censored at the date of the last evaluable radiographic 
disease assessment. The duration of primary analysis of PFS will be censored as outlined 
in Table 4.  The sensitivity analysis will be performed if > 5% of patients have a PFS 
event immediately after missing at least two scans consecutively before the data cutoff,  
by considering such as event at the first date of documented progression or death.    
Treatment comparisons will be based on the stratified log-rank test in the ITT population.  
The stratification factors will be those used for randomization and will be obtained from 
the IWRS (prior PD-1/PD-L1 inhibitor therapy [yes vs. no] and IMDC prognostic risk 
group [favorable vs. intermediate vs. poor]).  A 2-sided p < 0.05 in favor of the CB-Cabo 
experimental treatment will be regarded as a positive result for the study. The null and 
alternative hypotheses can be phrased in terms of the survival functions SPFS_CB-Cabo (t) 
and SPFS_Pbo-Cabo (t) in arm CB-Cabo and arm Pbo-Cabo, respectively:  
H0: SPFS_CB-Cabo (t)=SPFS_Pbo-Cabo (t) versus H1: SPFS_CB-Cabo (t)≠SPFS_Pbo-Cabo (t) 
Kaplan-Meier methodology will be used to estimate median PFS for each treatment arm 
and construct survival curves for the visual description of the difference between the 
treatment arms. The Brookmeyer-Crowley methodology will be used to construct the 
95% CI for the median PFS for each treatment arm (1). 
The hazard ratio (HR), λPFS_CB-Cabo/λPFS_Pbo-Cabo, where λPFS_CB-Cabo and λPFS_Pbo-Cabo, 
represents the hazard of PFS in arm CB-Cabo and arm Pbo-Cabo, respectively.  HR will 
be estimated with a stratified Cox proportional hazards regression model and the same 
stratification variables used for the stratified log-rank test.  In addition, as a sensitivity 


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analysis for the primary endpoint, the above analyses will be repeated with only two 
levels, i.e., favorable vs. intermediate/poor, for the IMDC Prognostic Risk grouping. 
To prevent a stratification cell having too few events, if a stratification cell has less than 
10 PFS events (two arms combined), the stratification factor that contributes the least 
number of events for that cell will be removed.  Stratification factors for the analyses will 
be removed until all stratification cells have at least 10 PFS events in two arms combined. 
As a sensitivity analysis, the above analyses will be performed using the number of prior 
TKI cancer therapy (0 vs. ≥ 1) and IMDC prognostic risk group (favorable vs. 
intermediate vs. poor) and prior PD-1/PD-L1 inhibitor therapy as the stratification 
factors.   
If there is notable imbalance in number of prior lines of anti-cancer therapy between the 
two treatment arms and if sample size permits, sensitivity analysis will be performed 
using number of prior lines of anti-cancer therapy (1 vs. 2) and IMDC prognostic risk 
group (favorable vs. intermediate vs. poor) and prior PD-1/PD-L1 inhibitor therapy as the 
stratification factors. 
Similarly to the primary analysis, to prevent a stratification cell having too few events, if 
a stratification cell has less than 10 PFS events (two arms combined), the stratification 
factor of prior PD-1/PD-L1 inhibitor therapy will be removed.   
Results from an unstratified analysis will also be provided. 


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Situation 
Date of PFS Event or 
Censoring 
Outcome 
No baseline disease assessment 
Date of randomization 
Censored 
No post-baseline assessments and no death 
Date of randomization 
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 before initiation of 
additional cancer therapy  
Censored 
Documented RECIST v1.1 progression or death 
between scheduled visits [1] 
First date of documented 
progression or death  
PFS event 
RECIST v1.1 progression or death documented 
to occur following missing at least 2 
consecutive scheduled radiographic disease 
assessments (including missing assessments, 
insufficient data for the assessments, and an 
overall response of non-evaluable) following 
previous evaluable radiologic tumor assessment 
Date of last tumor assessment 
with no 
documented progression [2]  
Censored [2] 
 
RECIST v1.1, Response Evaluation Criteria in Solid Tumors Version 1.1 
[1]  RECIST v1.1 progression or death can occur either on treatment or during the survival follow up 
period.  
[2] Sensitivity analysis with status  of PFS event at the first date of documented progression or death.
 
PFS (month) = (date of event / censor – date of randomization + 1) / 30.4375 
6.5.2 
Secondary Analyses 
6.5.2.1 
Overall Survival 
Overall Survival (OS) is defined as the time from randomization to death from any cause.  
Patients who are not reported as having died at the date of analysis will be censored at the 
date when they were last known to be alive.  Patients who do not have post-baseline 
information will be censored at the date of randomization.   
OS will be analyzed with the same methodologies as PFS.  Treatment comparisons will 
be based on the stratified log-rank test in the ITT population. The null and alternative 
hypotheses can be phrased in terms of the survival functions SOS_CB-Cabo (t) and SOS_Pbo-
Cabo (t) in arm CB-Cabo and arm Pbo-Cabo, respectively:  
H0: SOS_CB-Cabo (t)=SOS_Pbo-Cabo (t) versus H1: SOS_CB-Cabo (t)≠SOS_Pbo-Cabo (t) 
OS will be tested with a total of two-sided alpha of 0.05 if PFS crosses the efficacy 
boundary.  P-value boundaries of OS are provided in Table 3.   
Table 4 
Censoring Rules for Progression Free Survival 


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As a sensitivity analysis, the above analyses will be performed using the number of prior 
TKI cancer therapy (0 vs. ≥ 1) and IMDC prognostic risk group (favorable vs. 
intermediate vs. poor) and prior PD-1/PD-L1 inhibitor therapy as the stratification 
factors.   
 If there is notable imbalance in number of prior lines of anti-cancer therapy between the 
two treatment arms and if sample size permits, sensitivity analysis will be performed 
using number of prior lines of anti-cancer therapy (1 vs. 2) and IMDC prognostic risk 
group (favorable vs. intermediate vs. poor) and prior PD-1/PD-L1 inhibitor therapy as the 
stratification factors.   
Similarly to the primary analysis, to prevent a stratification cell having too few events, if 
a stratification cell has less than 10 PFS events (two arms combined), the stratification 
factor of prior PD-1/PD-L1 inhibitor therapy will be removed.   
Results from an unstratified analysis will also be provided. 
6.5.2.2 
Investigator-assessed PFS 
Investigator-assessed PFS will be defined and analyzed the same way as the primary 
efficacy endpoint of IRC-assessed PFS. Disease progression status and date will be 
determined by investigators instead of IRC.   
6.5.3 
Additional Analyses 
6.5.3.1 
Overall Response Rate 
Overall response rate (ORR) is defined as the percentage of patients who had an overall 
response (unconfirmed). An overall response is defined as either complete response (CR) 
or partial response (PR), as assessed by the IRC according to RECIST v1.1. Patients not 
meeting these criteria, including patients without any post-baseline evaluable response 
assessments, will be considered non-responders.  Confirmation is not required in this 
double-blind protocol, but for exploratory purposes ORR with confirmation by IRC will 
also be summarized. Two CR and PR assessments must be at least 28 days apart without 
non-response in between, when confirmation is reported.  
The analysis population for ORR will be the ITT population.  An estimate of ORR and its 
95% CI will be calculated with the Clopper-Pearson method for each treatment arm.  The 
difference in ORRs between the two treatment arms and its 95% CI will be computed and 
compared by Fisher’s exact test. The ORR will also be compared between the two arms 
using the stratified Cochran-Mantel-Haenszel test, stratified by the same factors used in 
the primary PFS and OS analyses (see Section 6.5.1).  
6.5.3.2 
Duration of Response 
Duration of Response (DOR) is defined for patients achieving a PR or a CR as the time 
from the first documented overall response (PR or CR) to the first documented PD as 
assessed by the IRC according to RECIST v1.1 or death from any cause, whichever 


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occurs first.  Patients who are alive and who have not experienced disease progression at 
the time of the analysis will be censored at the date of the last evaluable tumor 
assessment.  If no tumor assessments were performed after the date of the first occurrence 
of the overall response (CR or PR), DOR will be censored at the date of the first 
occurrence of the overall response.  Censoring rules for DOR will follow those in Table 
4.  The determination of DOR is based on a non-randomized subset of patients 
(confirmed responders only), and formal hypothesis testing will not be performed.  The 
subset of responders are defined based on post randomization outcomes therefore the 
responder population is not balanced across the two treatment arms. DOR will be 
estimated using Kaplan Meier (KM) methodology.  Comparisons between treatment arms 
will be made using the stratified and unstratified log-rank test for descriptive purposes 
only. 
DOR will be reported for patients with confirmed ORR. 
6.5.3.3 
Disease Control Rate 
Disease Control Rate (DCR) is defined as the summed percentage of patients with CR, 
PR or stable disease (SD) documented following randomization according to RECIST 
v1.1 per IRC.. DCR will be analyzed the same way as ORR.  
6.5.3.4 
PFS and OS Rates at Landmark Timepoints    
The PFS rates (according to RECIST 1.1 criteria per IRC) at 6-month, 9-month, and 1-
year timepoints are defined as the probabilities the patients are alive and progression free  
at those timepoints after randomization.   The OS rates at 1- and 2- and 3-year landmark 
timepoints are defined as the probabilities that patients are alive at those time points after 
randomization.  The PFS and OS rate at the  landmark timepoints after randomization 
within the ITT population will be estimated for each treatment arm using Kaplan-Meier 
methodology, along with 95% CI calculated with the standard error derived from the 
Greenwood formula.  
6.5.3.5 
Patient Reported Outcomes 
Patient-reported outcomes (PRO) for the NCCN-FACT FKSI-19 (Version 2) will be 
summarized by treatment group.  Summary statistics (mean, SD, median, range) of the 
change from baseline will be provided at each time point.  Mean score for each endpoint 
will be displayed graphically.  The analysis will be performed for patients in the PRO-
evaluable population, which is defined as ITT with a non-missing baseline assessment 
and at least one non-missing post-baseline assessment until treatment discontinuation.    
With the exception of the visual analog scale (VAS) score and index score for EQ-5D-5L 
questionnaire, descriptive statistics summarizing the proportions of patients who reported 
having “no,” “slight,” “moderate,” “severe,” or “extreme/unable” problems at each time 
point will be reported.  The VAS score and the US-specific Index score for EQ-5D-5L 
questionnaire will be summarized and analyzed as continuous measures.  Patients without 
post-baseline assessments will be excluded from this analysis.   


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6.5.3.6 
Additional Sensitivity Analyses  
Missing Tumor Assessment 
 
The impact of missing scheduled tumor assessments on PFS may be assessed depending 
on the number of patients who missed assessments scheduled immediately prior to the 
date of disease progression per RECIST v1.1.  If  5% of patients missed two or more 
scheduled assessments consecutively immediately prior to the date of disease progression 
per RECIST v1.1 in any treatment arm, the following sensitivity analyses will be 
performed: 
Patients who missed two or more scheduled assessments immediately prior to the date of 
disease progression per RECIST v1.1 or the data cutoff or death will be censored at the 
last tumor assessment prior to the missed visits. 
 
Statistical methodologies analogous to those used in the primary analysis of PFS as 
specified in Section 6.5.1 will be used for this sensitivity analysis. 
 
Loss to Follow-up 
The impact of loss to follow-up on OS may be assessed depending on the number of 
patients who are lost to follow-up.  If  5% of patients are lost to follow-up for OS in 
either treatment arm, a sensitivity analysis will be performed for the comparisons 
between two treatment arms in which patients who are lost to follow-up will be 
considered as having died on the date they are lost to follow-up. 
 
6.5.3.7 
Subgroup Analyses  
The consistency of the primary PFS and secondary OS results in subgroups will be 
examined.  The subgroups are defined by the following 
1) demographics (age [<75 vs ≥ 75], sex [F vs M], and race/ethnicity) 
2) baseline prognostic characteristics (KPS performance status [70-80, 90-100], 
IMDC prognostic risk grouping [EDC version], number of organs with metastases 
[1, 2, ≥3], prior nephrectomy, and prior radiotherapy, time from metastatic 
diagnosis  [>1 and <= 1 year] ) 
3) Prior therapies (previous anti-angiogenic therapies [yes/no], number of prior TKI 
[1, 2, ≥3], prior PD-1/PD-L1 [yes, no], prior nivo/ipi [yes, no], number of prior 
line of therapy [2, 3]) 
4) Metastatic Sites (lung, lymph node, bone, liver, brain, other as categories) 


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5) Geographic region (US/ex US)  
Summaries of PFS and OS, including unstratified HRs estimated from Cox proportional 
hazards models and Kaplan-Meier estimates of median PFS and OS, will be produced 
separately for each level of the categorical variables for the comparisons between 
treatment arms and displayed in a forest plot (Lewis 2001).  
Summaries of ORR by subgroup defined above will also be provided. 
Analyses of subgroups with sample size too small  may not be performed.   
 
6.6 
Pharmacokinetic Analyses 
Population PK analysis of telaglenastat will be performed for the PK-evaluable 
population, defined as all CB-Cabo patients who have received at least one dose of 
telaglenastat and have at least one evaluable PK sample.  Individual PK concentrations 
will be tabulated and summarized.  Descriptive statistics will include means, medians, 
ranges, and SDs, as appropriate. 
The impact of telaglenastat on the PK exposure of cabozantinib will be evaluated by 
comparing the CB-Cabo arm with that of the Pbo-Cabo arm.   
Additional PK analyses will be conducted as appropriate, on the basis of the availability 
of data.  A separate report will include these additional analyses as well as details of 
population PK analyses.    
6.7 
Safety Analyses 
Unless specified otherwise, safety analyses described in this section will be conducted for 
the Safety population, with patients grouped according to whether they received any 
telaglenastat treatment.   
6.7.1 
Exposure of Study Medication 
Study drug exposure status for each component of the study drug, which include 
treatment duration, total dose received (mg), number of cycles, number of patients with 
dose adjustment and the reasons will be summarized for each treatment arm for the 
Safety population.  
6.7.2 
Adverse Events 
Verbatim description of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) preferred terms and system organ classes, and graded by the 
investigator according to NCI CTCAE v4.03.  Treatment-emergent adverse events 
(TEAEs) will be summarized by mapped term, appropriate thesaurus level, NCI CTCAE 
grade, and treatment arm.  In addition, serious adverse events, severe adverse events 


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(Grade ≥ 3), and adverse events leading to study drug discontinuation or interruption will 
be summarized accordingly. These tables will also be presented for TEAEs judged to be 
related (probably or possibility) to the study treatment. Multiple occurrences of the same 
event in a given patient will be counted once at the maximum grade. All deaths are 
reported as SAEs per study conduct. In order to accurately summarize the true SAE rate, 
all SAE summaries will not count Grade 5 events for patients who died due to 
progressive disease.    
Per protocol and study conduct, safety follow-up is 28 days from date of last study drug 
administration or until initiation of a new anti-cancer therapy if earlier.  For reporting 
purposes, “treatment emergent” is defined as new adverse events occurring on or after the 
first dose of study drug is administered until the clinical cutoff date, or existing events 
that worsened after the first dose during the study.   
All listings of adverse events will also include all adverse events. 
Deaths reported during the study treatment period and the follow-up period after 
treatment discontinuation will be listed by treatment arm. 
6.7.3 
Laboratory Data 
Laboratory data will be summarized by treatment arm at each assessment time point.  
Values outside the normal ranges will be summarized by treatment arm.  In addition, 
selected laboratory data will be summarized by treatment arm and NCI CTCAE v4.0 
grade at each assessment time point. 
6.7.4 
Vital Signs 
Changes in selected vital signs will be summarized by treatment arm and by change over 
time, which includes change from baseline at each visit where parameters are scheduled 
to be collected.  Baseline is defined as the measurement obtained on Cycle 1, Day 1 
before the first dose of study drug is administered.  
6.8 
Missing Data 
See Section 6.5 for methods for handling missing data for primary and secondary efficacy 
endpoints.  Missing data will not be imputed for safety analyses except for the purpose of 
identification of TEAEs and prior or concomitant medications with missing start or end 
date. Imputation rules for the partial or missing dates will be pre-specified in a separate 
document. All available data will be presented on the data listings as collected (no 
imputation).  
6.9 
Analyses Related to COVID-19  
This section describes the pre-specified analyses to assess the potential impact of the 
COVID-19 pandemic on the study conduct and the evaluation of efficacy and safety of 
the drug.  


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Two populations defined: 
COVID-19 impacted: Any patients with important protocol deviations due to COVID-19 
including missed important visits, missed data and changes in methods of important 
assessments or those who are infected with COVID-19 
COVID-19 infected: any patient with a reported infection (a subgroup of COVID-19 
impacted)  
6.9.1 
General 
Important protocol deviations due to COVID-19 including missed important visits, 
missed data and changes in methods of important assessments will be summarized by 
treatment groups.  
Number and percent of patients who are COVID-19 infected and impacted will be 
summarized by treatment groups. The demographic and baseline disease characteristics 
and extent of exposure to study drug will be summarized for these patients.  
Potential additional analyses with COVID-19 infected and COVID-19 impacted may be 
done for any of the endpoints including patient reported outcomes etc.   
Listing of all patients that are COVID-19 impacted and infected will be reported. 
6.9.2 
Efficacy  
6.9.2.1 
Progression Free Survival  
Two kinds of events due to COVID-19 can impact the PFS endpoint: deaths and missing 
tumor assessments.  
The first one is missing tumor assessment due to COVID-19 (COVID-19 impacted).  
Since primary analysis  will handle missing tumor assessment due to  cause including 
COVID-19 (described in Table 4),  this scenario is covered by the primary analysis 
missing tumor assessment handling.  
The second one is if there are a total of 10 or more patients who die due to COVID-19 
(COVID-19 infected) without a documented disease progression or starting a new anti-
cancer therapy or missing at least 2 consecutive scheduled radiographic disease 
assessments for reasons not related to COVID-19, the following sensitivity analyses will 
be performed: 
a.
These patient will be considered as censored at the date of death due to
COVID-19. The primary analyses described in section 6.5.1 (log-rank test
and Cox proportional hazard model) will be repeated using this adjusted
censoring rule.


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b. Inverse probability of censoring weighting (IPCW) approach will be used
to adjust for potential bias of the planned primary analysis introduced by
COVID-19 death. With this approach, COVID-19 death will be modeled
using a Cox model with treatment group and factors specified in section
6.5.3.7 as covariates. Hazard for COVID-19 death will be estimated for
each subject based on which weights will be obtained. The analyses
described in section 6.5.1 (Cox regression model and KM estimates) will
be performed using these weights.
6.9.2.2 
Overall Survival
If there are a total of 10 or more patients who die due to COVID-19, similar sensitivity 
analyses described for the PFS (a and b) above will be performed for the OS endpoint.  
6.9.3 
Safety 
Treatment-emergent AEs and SAEs due to COVID-19 infection will be summarized by 
treatment groups, preferred terms, and severities. All AEs for subjects diagnosed with a 
COVID-19 infection will be summarized by treatment groups, preferred terms, severities 
and the relatedness to the study drug.  
7 
REFERENCES 
1. Brookmeyer, R. and Crowley, J. (1982) A confidence interval for the median 
survival time. Biometrics, 38, 29-41. doi:10.2307/2530286
2. 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.
3. M2 eCTD: Electronic Common Technical Document Specification Appendix 7, 
provided by the International Conference on Harmonization. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio 
n/Guidances/ucm073240.pdf
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/ucm372553. 
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.
6. Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 
2001;322:1479-80.


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