Clinical trial NCT03163667
Conditions: Clear Cell Renal Cell Carcinoma
Keywords: advanced, metastatic RCC RCC CB-839 Everolimus CBE Glutaminase Inhibitor Glutaminase Tumor Metabolism Glutamine
Sponsor: Calithera Biosciences, Inc
Start date: 2017-09-06; Completion date: 2020-06-01
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to compare the progression-free survival (PFS) of participants treated with telaglenastat and everolimus versus placebo and everolimus for advanced or metastatic clear cell renal cell carcinoma (ccRCC) previously treated with the following:

* At least 2 lines of therapy, including at least 1 vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI)
* Radiographic progression of metastatic RCC must have occurred (per investigator assessment) on or after the most recent systemic therapy and within 6 months prior to cycle 1 day 1

Detailed description:

Arms: arm 1: CB-839 is administered as oral tablets twice daily (BID) in combination with standard daily (QD) everolimus in 28 day cycles. arm 2: Placebo is administered as oral tablets BID in combination with standard QD everolimus in 28 day cycles.
Interventions: intervention 1: Placebo intervention 2: CB-839 intervention 3: everolimus
Intervention descriptions: intervention 1: oral tablets intervention 2: oral tablets intervention 3: oral tablets

Protocol documents:
Prot_000.pdf: 
CB-839 
Protocol CX-839-005 
07 August 2018 
 
 
CONFIDENTIAL 
 
1 
Title  
A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study 
Comparing CB-839 in Combination with Everolimus (CBE) vs. Placebo 
with Everolimus (PboE) in Patients with Advanced or Metastatic Renal Cell 
Carcinoma (RCC) 
Protocol Number 
CX-839-005 
IND Number 
118397 
Sponsor 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Sponsor Contact  
 
Associate Director, Clinical Operations 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Phone:  
 
Date/Version 
07 August 2018/ Amendment 2 
 
 
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 .............................................................................................................5 
3.0 
LIST OF FIGURES ...........................................................................................................6 
4.0 
CONTACTS .......................................................................................................................7 
CORE PROTOCOL ......................................................................................................................8 
5.0 
OBJECTIVES AND ENDPOINTS ..................................................................................8 
6.0 
SAMPLE SIZE ...................................................................................................................9 
7.0 
STUDY DESIGN ................................................................................................................9 
8.0 
INCLUSION/ EXCLUSION CRITERIA ......................................................................11 
8.1 
Inclusion Criteria ...................................................................................................11 
8.2 
Exclusion Criteria ..................................................................................................12 
PROTOCOL DETAILS ..............................................................................................................14 
9.0 
BACKGROUND AND RATIONALE ...........................................................................14 
9.1 
Renal Cell Cancer (RCC).......................................................................................14 
9.2 
Glutaminase Inhibitor CB-839 ...............................................................................16 
9.3 
Preclinical Activity of CB-839 ..............................................................................17 
9.4 
Previous Human Experience ..................................................................................19 
9.5 
Safety .....................................................................................................................20 
9.6 
Efficacy of CB-839 + Everolimus .........................................................................25 
9.7 
Rationale for CB-839 Dose Selection ....................................................................26 
10.0 
PROCEDURES ................................................................................................................27 
10.1 
Screening................................................................................................................27 
10.1.1 
Concomitant Treatment .........................................................................27 
10.1.2 
Screening Evaluation ............................................................................28 
10.2 
Randomization .......................................................................................................30 
10.3 
Study Treatment Procedures ..................................................................................30 
10.4 
Long Term Follow Up ...........................................................................................31 
10.5 
Screen Failures .......................................................................................................31 
10.6 
Procedure Details ...................................................................................................31 
10.6.1 
Demographics, Medical, and Cancer History .......................................32 
10.6.2 
Physical Examination ............................................................................32 
10.6.3 
Vital Signs .............................................................................................32 
10.6.4 
Electrocardiograms ...............................................................................32 
10.6.5 
Laboratory Assessments........................................................................33 
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10.6.6 
Patient-Reported Quality of Life Assessment .......................................33 
10.6.7 
Tumor Assessments ..............................................................................34 
10.6.8 
Tumor Biopsies .....................................................................................34 
10.6.8.1 
Optional Fresh Tumor Biopsies .....................................................34 
10.6.8.2 
Archival Tumor Biopsies ...............................................................35 
10.6.9 
Pharmacokinetic Samples .....................................................................35 
11.0 
POTENTIAL TOXICITIES, DOSE MODIFICATION AND MANAGEMENT 
OF TOXICITIES .............................................................................................................36 
11.1 
Potential Toxicities ................................................................................................36 
11.1.1 
CB-839 ..................................................................................................36 
11.1.2 
Everolimus ............................................................................................36 
11.1.3 
CB-839 + Everolimus Combination .....................................................36 
11.2 
Dose Modifications and Toxicity Management .....................................................37 
11.2.1 
Dose Modification Guidelines ..............................................................37 
11.2.2 
Resumption of Study Treatment ...........................................................40 
11.3 
Missed Doses .........................................................................................................40 
11.4 
Discontinuation of Treatment and Withdrawal of Patients....................................41 
12.0 
TEST ARTICLE/STUDY DRUG ...................................................................................41 
12.1 
Blinded Investigational Product .............................................................................41 
12.2 
Packaging and Labeling .........................................................................................42 
12.3 
Storage and Stability ..............................................................................................42 
12.4 
CB-839 Accountability, Reconciliation, and Return .............................................43 
12.5 
Test Article Compliance ........................................................................................43 
13.0 
MEASURES TO MINIMIZE/AVOID BIAS ................................................................44 
14.0 
STATISTICAL ANALYSIS ...........................................................................................44 
14.1 
General Study Design ............................................................................................44 
14.2 
Analysis Patient Sets ..............................................................................................44 
14.2.1 
Efficacy Analysis Patient Set ................................................................44 
14.2.2 
Safety Analysis Set ...............................................................................45 
14.3 
Efficacy Analysis ...................................................................................................45 
14.3.1 
Primary Efficacy Endpoint: Investigator-Assessed PFS .......................45 
14.3.2 
Secondary Efficacy Endpoints ..............................................................46 
14.3.3 
Additional Endpoints ............................................................................46 
14.3.4 
Exploratory Analyses ............................................................................47 
14.4 
Safety Analysis ......................................................................................................47 
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14.5 
Sample Size Estimation .........................................................................................47 
15.0 
ADVERSE EVENTS .......................................................................................................48 
15.1 
Definitions..............................................................................................................48 
15.2 
Recording and Reporting .......................................................................................53 
15.3 
Serious Adverse Event Reporting ..........................................................................53 
16.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION .............................54 
17.0 
INFORMED CONSENT .................................................................................................55 
18.0 
PROTOCOL AMENDMENTS ......................................................................................55 
19.0 
QUALITY CONTROL AND ASSURANCE.................................................................55 
20.0 
DIRECT ACCESS, DATA HANDLING, AND RECORD KEEPING ......................55 
20.1 
Investigator ............................................................................................................55 
20.2 
Sponsor ..................................................................................................................56 
20.3 
Pre-Study Documentation ......................................................................................56 
20.4 
Records Retention ..................................................................................................57 
21.0 
AUTHORSHIP AND ACCOUNTABILITY .................................................................58 
22.0 
LIST OF ABBREVIATIONS .........................................................................................59 
23.0 
REFERENCES .................................................................................................................62 
ATTACHMENT 1: SCHEDULE OF STUDY ASSESSMENTS ............................................63 
ATTACHMENT 2: CLINICAL LABORATORY TESTS ......................................................65 
ATTACHMENT 3: MSKCC PROGNOSTIC SCORE............................................................66 
ATTACHMENT 4: KARNOFSKY PERFORMANCE STATUS SCALE ............................67 
ATTACHMENT 5: RECIST CRITERIA VERSION 1.1 ........................................................68 
ATTACHMENT 6: DRUG INTERACTIONS .........................................................................80 
ATTACHMENT 7: NCCN-FACIT MEASUREMENT SYSTEM (FKSI-19) 
QUESTIONNAIRE/SCALE ...........................................................................................82 
ATTACHMENT 8: EUROQOL QUESTIONNAIRE ED-5D-5L (US ENGLISH 
SAMPLE VERSION) ......................................................................................................84 
ATTACHMENT 9: AMENDMENT 2 SUMMARY OF CHANGES .....................................86 
 
 
 
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2.0 
LIST OF TABLES 
Table 9.5-1:  Adverse Events in > 10% of Patients Treated with Monotherapy CB-839 on the 
BID Schedule on Study CX-839-001 ..............................................................21 
Table 9.5-2:  CB-839 Related Adverse Events in ≥ 5% of Patients Treated with Monotherapy 
CB-839 on the BID Schedule on Study CX-839-001 ......................................22 
Table 9.5-3:  Adverse Events in ≥ 3 Patients Treated with CB-839 + Everolimus on Study 
CX-839-001 .....................................................................................................23 
Table 9.5-4:  Treatment-Related Adverse Events in ≥ 3 Patients Treated with CB-839 + 
Everolimus on Study CX-839-001...................................................................24 
Table 9.6-1:  Efficacy of the CB-839 + Everolimus Combination ................................................25 
Table 11.2-1: Dose Modifications Guidelines for Hematologic Toxicity .....................................38 
Table 11.2-2: Dose Modifications Guidelines for Non-Hematologic Toxicity .............................38 
Table 11.2-3: Dose Reductions for CB-839 (or Placebo) ..............................................................40 
Table A: Time Point Response:  Patients with Targets (+/- Non-Target) Disease ........................77 
Table B: Time Point Response:  Patients with Non-Target Disease Only ....................................77 
Table C: Best Overall Response when Confirmation of CR and PR Required .............................77 
 
 
 
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3.0 
LIST OF FIGURES 
Figure 7.0-1.  Study Design Schema: ............................................................................................10 
Figure 9.3-1.  Antiproliferative and pro-apoptotic activity of CB-839 in kidney tumor cell 
lines in vitro .....................................................................................................18 
Figure 9.3-2.  Synergistic activity of CB-839 in combination with everolimus in clear cell 
RCC..................................................................................................................19 
Figure 9.6-1.  Best tumor response, and duration of tumor response for ccRCC patients 
receiving CB-839 + everolimus in Phase 1......................................................26 
 
 
 
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4.0 
CONTACTS 
Emergency Contacts 
Safety Physician and Medical Monitor 
Name:  
 
Address:  343 Oyster Point Blvd. Suite 200 
South San Francisco, CA  
Phone: 
 
Mobile: 
 
Email: 
  
Calithera Associate Director Clinical Operations  
Name:  
 
Address:  343 Oyster Point Blvd. Suite 200 
South San Francisco, CA  
Phone (Office): 
 
Email:  
 
 
United States Regional Project Manager  
Name:  
 
Phone (Mobile): 
 
Email:  
  
 
SAE Reporting Contact 
CRO Safety Lead 
Name: 
 
Address:  Oreskoviceva 20A, 10 000 Zagreb, Croatia 
 
Phone (Office): 
 
Central Safety Office: 
 
 
SAE Reporting Details (to be used for submitting the SAE forms): 
Central Safety Fax: 
 
Email: 
   
 
 
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CORE PROTOCOL 
5.0 
OBJECTIVES AND ENDPOINTS 
Primary Objectives 
Primary Endpoints 
To compare the progression free survival 
(PFS) of patients treated with CB-839 + 
everolimus (CBE) versus placebo + 
everolimus (PboE) for advanced or metastatic 
clear cell RCC (ccRCC)  previously treated 
with 
 At least 2 lines of therapy, including at 
least one vascular endothelial growth 
factor (VEGFR) tyrosine kinase inhibitor 
(TKI) 
 Radiographic progression of mRCC must 
have occurred (per investigator 
assessment) on or after the most recent 
systemic therapy and within 6 mo prior to 
C1D1.  
Investigator-assessed PFS per Response 
Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 
Secondary Objectives 
Secondary Endpoints 
To compare the  overall survival (OS) of 
study patients treated with CBE vs. PboE   
Assessed by time from randomization to death 
by any cause  
Additional Objectives 
Additional Endpoints 
To compare the objective response rate 
(ORR), Duration of Response (DOR), and 
Disease Control Rate (DCR) of CBE vs. PboE  
Per RECIST v1.1 
To compare the safety and tolerability of CBE 
vs. PboE 
 
Assessed by type, incidence, severity, 
seriousness, and study drug-relatedness of 
adverse events 
To investigate the population 
pharmacokinetics (PK) of CB-839 
Analysis of any potential relationship between 
drug exposure and various population 
parameters using sparse PK sampling 
To investigate the relationship of genetic 
variants and response to CBE vs. PboE 
Genetic variants and other biomarkers related to 
mTOR, angiogenesis, and metabolic pathways  
Change in kidney-cancer related symptoms 
Functional Assessment of Cancer Therapy-
Kidney Cancer Symptom Index (FKSI-19) 
Change in mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression, and 
global health 
EuroQol Health questionnaire instrument (EQ-
5D-5L) 
 
 
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6.0 
SAMPLE SIZE 
Approximately 63 evaluable patients are planned for recruitment to this study.  Eligible patients 
will be randomized in a 2:1 ratio to one of the following treatments:  
a) CBE - The glutaminase inhibitor CB-839 [4 x 200 mg tablets (800 mg) twice daily 
(BID)] and the mTOR inhibitor everolimus [10 mg once daily (QD)]   
b) PboE - Placebo tablets [4 tablets BID] and everolimus [10 mg QD]   
7.0 
STUDY DESIGN 
Protocol CX-839-005 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 2:1 ratio to receive CBE vs. PboE.  Randomization will be 
stratified by a) number of prior lines of TKI therapy (1 vs. >1) and b) Memorial Sloan Kettering 
Cancer Center (MSKCC) Prognostic Criteria (Attachment 3) for Previously Treated Metastatic 
RCC (favorable vs. intermediate/poor risk).  The estimated sample size is 63 patients.  The 
primary endpoint of this Phase 2 study is investigator-assessed PFS by RECIST 1.1.   
Patients will receive the treatment determined by randomization in 28-day cycles until disease 
progression or unacceptable toxicity (whichever occurs first).  Patients will be followed for 28 
additional days from last dose date or early discontinuation of treatment for safety follow-up.  
Patients who discontinue study treatment for reasons other than disease progression or death will 
remain in follow-up including protocol-defined imaging. Long-term follow up for survival will 
continue until death or withdrawal of consent for follow-up.  
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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. Age ≥ 18 years 
b. Karnofsky Performance Score (KPS) ≥ 70% (Attachment 4) 
c. Estimated Life Expectancy of at least 3 mo 
d. Documented histological or cytological diagnosis of renal cell carcinoma with a 
clear-cell component. 
e. Measurable Disease per RECIST 1.1 as determined by the Investigator (see 
Attachment 5) 
f. Must have received at least two prior lines of systemic therapy, including at least one 
VEGFR-targeting TKI (e.g., sunitinib, sorafenib, pazopanib, cabozantinib)  
 Radiographic progression of mRCC must have occurred (per investigator 
assessment) on or after the most recent systemic therapy and within 6 mo 
prior to C1D1.  
g. Prior treatment with other anti-cancer therapies including cytokines, monoclonal 
antibodies, immunotherapies, and cytotoxic chemotherapy is allowed (except for 
mTOR inhibitors, see Exclusion Criterion #1). 
3. Laboratory Findings 
a. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance 
≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation:  
CCr = {((l40 – age) x actual body weight)/ (72 x SCr)} x 0.85 (if female)   
b. Adequate hematological function, defined as ANC ≥ 1,500/mm3, Hb ≥ 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. HbA1c ≤ 8% 
f. Fasting serum triglycerides ≤ 2.5 × upper limit of normal AND total cholesterol 
≤ 300 mg/dL (≤ 7.75 mmol/L). Lipid-lowering medication is allowed. 
 
4. Reproductive Status 
a. Female patients of childbearing potential must have a negative serum or urine 
pregnancy test within 3 days prior to the first dose of study drug and agree to use dual 
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methods of contraception during the study and for a minimum of 3 mo following the 
last dose of study drug.  Post-menopausal females (> 45 years old and without menses 
for > 1 year) and surgically sterilized females are exempt from these requirements.  
Male patients must use an effective barrier method of contraception during the study 
and for a minimum of 3 mo following the last dose of study drug if sexually active 
with a female of childbearing potential. Male patients should not donate sperm for at 
least 3 months after the last dose of study drug.  
5. Other Inclusion Criteria 
a. Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior 
treatments, unless AE(s) are clinically non-significant and/or stable on supportive 
therapy. 
 
8.2 
Exclusion Criteria 
1. Medical History  
a. Prior treatment with mTOR inhibitors (everolimus or temsirolimus) or CB-839 
b. Receipt of any anticancer therapy within the following windows before 
randomization: 
 TKI therapy within 2 weeks or 5 half-lives, whichever is longer. 
 Any  type of anti-cancer antibody within 4 weeks 
 Cytotoxic chemotherapy within 4 weeks 
 Investigational therapy within 4 weeks or 5 half-lives whichever is longer 
 Radiation therapy for bone metastasis within 2 weeks, any other external 
radiation therapy within 4 weeks before randomization. Patients with 
clinically relevant ongoing complications from prior radiation therapy are 
not eligible. 
c. Any other current or previous malignancy within the past three years except a) 
adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of 
the cervix, c) prostate cancer with stable prostate specific antigen (PSA) levels for 
3 years, or d) other neoplasm that, in the opinion of the Principal Investigator and 
with the agreement of the Medical Monitor, will not interfere with study-specific 
endpoints 
 
2. Concurrent Conditions 
a. Unable to receive medications PO or any condition that may prevent adequate 
absorption of oral study medication including refractory nausea and vomiting, 
uncontrolled diarrhea, malabsorption, significant small bowel resection or gastric 
bypass surgery, use of feeding tubes 
b. Major surgery within 28 days prior to randomization 
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c. Patients with active and/or untreated central nervous system (CNS) cancer are not 
eligible. Patients with treated brain metastasis must have 1) documented 
radiographic stability of at least 4 weeks duration demonstrated on baseline 
contrast-enhanced CNS imaging (eg contrast-enhanced MRI of the brain) prior to 
randomization and 2) must be symptomatically stable and off steroids for at least 
2 weeks before randomization.   
d. Unstable/inadequate cardiac function: 
 Symptomatic ischemia or myocardial infarction within the previous 6 mo 
 Uncontrolled or clinically significant conduction abnormalities (e.g., 
ventricular tachycardia on antiarrhythmics are excluded, 1st degree AV 
block or asymptomatic LAFB/RBBB are eligible) 
 Congestive heart failure (New York Heart Association class III to IV) 
e. Known active infection with HIV or Hepatitis B or C virus 
f. Chronic treatment with corticosteroids or other immunosuppressive agents except 
(i) inhaled or topical steroids or replacement dose corticosteroids equivalent to 
≤ 10 mg prednisone and (ii) patients receiving physiological doses of 
hydrocortisone for adrenal insufficiency  
g. Requirement for continued proton pump inhibitor use after randomization 
h. 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 
i. Patients who are pregnant or lactating 
 
 
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PROTOCOL DETAILS 
9.0 
BACKGROUND AND RATIONALE 
9.1 
Renal Cell Cancer (RCC) 
The majority of newly diagnosed RCC patients are successfully treated with surgery (partial or 
complete nephrectomy) alone.  One-third of patients develop recurrence after surgery and 
another 25% present with metastatic disease, in both cases requiring systemic therapy for control 
of their disease.  While there is a growing list of approved agents to treat advanced RCC, 
including three recent approvals in second line therapy, the broadly applicable agents all fall into 
one of three mechanistic classes1:   
 Inhibitors of the vascular endothelial growth factor (VEGF) pathway, comprising small 
molecule TKIs (sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib) 
and a monoclonal antibody (bevacizumab) 
 Inhibitors of immune checkpoints (a single monoclonal antibody, nivolumab)  
 Inhibitors of the mechanistic target of rapamycin (mTOR) pathway (everolimus and 
temsirolimus) 
The current evidence-based treatment continuum employs a TKI in first line therapy, followed in 
second line by a checkpoint inhibitor or second TKI as monotherapy or lenvatinib paired with 
everolimus, and in third line by another TKI or nivolumab (depending upon 2nd line choice) or 
everolimus.  The need for effective and tolerable agents in third line and later RCC is driven by 
improved agents in early therapy and a steady increase in the proportion of patients surviving to 
receive multiple lines of therapy.  For example, a recent review from the International mRCC 
Database Consortium found that over 20% of patient starting 1st line therapy for metastatic RCC 
now go on to get 3rd line therapy (Heng 2015).   The most common regimens employed in 3rd 
                                                 
 
 
1 High dose interleukin 2 (HD IL-2) falls into a fourth class, cytokine therapy, and is a 1st line therapy with durable 
benefit but high toxicity in a small proportion of carefully selected patients.  Typically HD IL-2 is reserved for a 
small subset of 1st line patients. 
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line therapy were everolimus (26%), sorafenib (13%), sunitinib (13%), temsirolimus (11%) and 
pazopanib (11%).  Among 920 pts, the median PFS from the start of 3rd line treatment was 3.4 
mo (range 3.2 – 4.4 mo) and median OS 12.4 mo (range 9.9 - 15.5 mo) with overlapping 
confidence intervals between the various drugs.  Everolimus, the most-used drug in 3rd line 
therapy, had a median PFS of 3.4 mo and median OS of 12.1 mo.  The authors concluded from 
this analysis that third line therapy has demonstrated activity in mRCC, is prevalent in use, and 
should be offered to clinically eligible patients with mRCC. 
Therapy of mRCC in late line (3rd line plus) remains minimally tested in randomized trials and 
represents an unmet medical need.  Many 2nd line drug trials include a small proportion of 3rd 
line patients, but typically less than 25%.  The lack of novel mechanisms, particularly outside of 
the VEGF TKI realm is also an impediment in the late line setting.  It is unclear how many 
agents with overlapping MOAs and toxicities can be employed in serial fashion before either 
toxicity or resistance becomes prohibitive. 
The mTOR inhibitor everolimus was initially approved for 2nd and 3rd line patients with 
advanced RCC based upon the results of a pivotal Phase 3 study (Motzer 2010) demonstrating an 
improvement in median PFS compared to placebo of ~ 2 mo in patients who had previously 
progressed on either sunitinib or sorafenib or both TKIs (74% of patients being 2nd line and 26% 
3rd line).  Everolimus has been the dominant agent employed in 2nd line therapy until the past 
year when it has been surpassed in head-to-head randomized trials in primarily 2nd line patients 
by the checkpoint inhibitor nivolumab (Motzer 2015a), the TKI cabozantinib (Choueiri 2015), 
and the combination regimen of the TKI lenvatinib with everolimus (Motzer 2015b); this latter 
study was entirely 2nd line.  As a result of these studies and the resulting new drug approvals, in 
the US everolimus is now considered primarily in the 3rd line or later setting in mRCC.  
However, it retains an important place in the treatment continuum due to its distinct mechanism 
of action compared to the multiple VEGF TKIs and checkpoint inhibitors that are approved in 
2nd line or are (in the case of checkpoint inhibitors) being tested in 1st line.  Everolimus is 
generally well tolerated and has a relatively low rate of adverse events, making it an appealing 
single agent for patients who have already experienced disease progression on 2 or more 
additional therapies.   
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The current protocol will evaluate in a randomized, blinded, placebo-controlled setting single 
agent everolimus as standard of care control arm against the combination of the glutaminase 
inhibitor CB-839 with everolimus in patients with advanced RCC after prior treatment with at 
least 2 lines of therapy including at least one TKI.  Patients must be demonstrating radiographic 
progression of mRCC (per investigator assessment) on or after the most recent systemic therapy 
and within 6 mo prior to C1D1.  
9.2 
Glutaminase Inhibitor CB-839 
CB-839 is an inhibitor of glutaminase 1 that is being developed for the treatment of renal cell 
cancer and other malignancies.  Single agent antitumor activity of CB-839 has been 
demonstrated in vitro in multiple RCC cell lines.  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.  Recently, CB-839 was shown to enhance the activity of anti-PD-1 and anti-PD-
L1, immune checkpoint inhibitor, 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 immune response due to the accumulation of glutamine 
in the tumor microenvironment. 
CB-839 is a potent and selective reversible inhibitor of glutaminase activity (Gross 2014).  It is 
an allosteric and noncompetitive inhibitor of glutaminase, but does not inhibit the liver isoform, 
glutaminase-2.  Incubation of recombinant human glutaminase with CB-839 results in time-
dependent and slowly reversible inhibition of glutaminase activity (IC50 = 34 nM with 1 hr pre-
incubation).  Glutaminase inhibition is associated with antiproliferative activity in 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 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. 
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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 (NSCLC), 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 cell lines from multiple histotypes 
(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. 
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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.   
CB-839 in combination with the mTOR inhibitor everolimus displays enhanced anti-tumor 
activity in clear cell RCC models both in vitro and in vivo in comparison to either agent as 
monotherapy (Figure 9.3-2).  With the ACHN cell line in vitro, CB-839 blocks glutamine 
utilization and everolimus suppresses glucose consumption while the combination inhibits both 
major nutrient pathways.  These metabolic effects with the combination regimen translate into 
synergistic antiproliferative activity.   With the Caki-1 cell line grown as a subcutaneous tumor 
in vivo, the combination of CB-839 and everolimus results in nearly complete arrest of tumor 
growth whereas each agent individually only partially suppresses tumor growth.  These 
preclinical data provided the rationale for investigating the combination of CB-839 plus 
everolimus in RCC patients.  
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0 . 4
0 . 6
0 . 8
1 . 0
A C H N  c e l l  l i n e
i n  v i t r o
C e l l  S u r v i v a l
( r e a l t i v e  t o  D M S O )
CB-839 (nM)
Everolimus (nM)
Mixture (Comb. Index)
300
100
0.38
18.8
1.6
0.19
150
50
0.33
75
25
0.20
37.5
3.1
0.36
P la t in g
d e n is t y
E v e r o lim u s
C o m b o
C B 8 3 9
G lu t a m in e
V e h ic le
C B 8 3 9
E v e r o lim u s
C o m b o
G lu c o s e
0 . 0
0 . 5
1 . 0
N u t r i e n t   C o n s u m p t i o n
( r e l a t i v e  t o  v e h i c l e )
C a k i - 1  X e n o g r a f t
D a y  P o s t  I m p l a n t
T u m o r  V o l u m e  ( m m
3 )
1 6
2 0
2 4
2 8
3 2
3 0 0
6 0 0
9 0 0
1 2 0 0
1 5 0 0
V e h ic le
C B - 8 3 9
C o m b o
E v e r o lim u s
D o s in g
  s t a r t
* * *
A
B
C
 
Figure 9.3-2.  Synergistic activity of CB-839 in combination with everolimus in clear cell RCC A) 
Antiproliferative activity in ACHN cells treated with CB-839, everolimus, or CB-839 + everolimus.  
Following a72 hr incubation, cell viability was normalized to the DMSO-treated control.  Representative 
dose-response profiles and average calculated Chou-Talalay Combination Index (C.I.) values from 
multiple experiments are shown.  B) The consumption of glucose and glutamine from the medium by 
ACHN cells treated for 24 hr with vehicle, 75 nM CB-839, 25 nM everolimus, or CB-839 + everolimus. 
C) Inhibition of tumor growth in the Caki-1 RCC cell line in vivo. Tumors were implanted 
subcutaneously in immunocompromised mice.  Animals received CB-839 (200 mg BID), everolimus (1 
mg/kg QD), or the two agents in combination.   *** p<0.001 by ANOVA. 
9.4 
Previous Human Experience 
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 NHL (CX-839-002), or acute leukemia (CX-839-003).  CX-839-001 is currently 
enrolling ccRCC patients for treatment with CB-839 + everolimus and CB-839 + cabozantinib 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 twice daily (BID) with breakfast and dinner.  
As of data cuts on 23 January 2017, a total of 102 patients received 600, 800, or 1000 mg BID 
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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.  A total of 66 patients have received CB-839 at 
doses ranging from 400 to 800 mg BID in combination with everolimus (19), paclitaxel (31), or 
azacitidine (16). 
In pharmacokinetic studies, the half-life of CB-839 was approximately 4 hr and a dose-related 
increase in exposure was observed over doses ranging from 100 to 600 mg, with the 600 mg and 
800 mg doses being similar due to interpatient variability.  In pharmacodynamic studies, robust 
inhibition of glutaminase was demonstrated in platelets at exposures maintained in most patients 
at 600 mg and 800 mg inter-dose troughs, with the 800 mg dose in particular showing ≥ 90% 
target inhibition.  Patient tumor biopsies also demonstrated robust glutaminase inhibition (> 75% 
for most patients).   
9.5 
Safety 
Monotherapy 
CB-839 has been well tolerated across all dose levels tested.  This section provides a brief 
summary of the safety and tolerability data for monotherapy CB-839 dosed on the recommended 
Phase 2 schedule of BID dosing with food in solid tumor patients on study CX-839-001; in total 
88 patients received doses between 600 mg and 1000 mg BID for a median of approximately 2 
mo.  A more complete description of the safety of monotherapy CB-839 is included in the 
Investigator’s Brochure.   
The frequency of adverse events in patients receiving monotherapy CB-839 on the BID regimen 
are provided in Table 9.5-1 (all adverse events) and Table 9.5-2 (CB-839 related adverse events).  
The large majority of toxicities that have been observed have been Grades 1 and 2 and 
manageable with supportive care (Table 9.5-1).  The primary adverse events that have been 
observed to date include fatigue, gastrointestinal events (nausea, vomiting, and constipation), 
photophobia, anemia, dyspnea, and elevations in liver function tests.   
The few treatment-related Grade 3/4 toxicities on the BID schedule have included elevations in 
liver function tests (LFTs), primarily the transaminases ALT and AST (Table 9.5-2).  There have 
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been no treatment-related Grade 4 or Grade 5 adverse events.  Although somewhat more 
frequent on the original TID schedule, Grade 3/4 elevations in LFTs have been relatively 
infrequent on the BID schedule (3.4% of patients, Table 9.5-1).  When they have occurred, these 
events have been asymptomatic and rapidly reversible upon holding study treatment.  In most 
cases, the patient is able to continue on study following a minus-1 dose reduction of CB-839. 
 
Table 9.5-1:  Adverse Events in > 10% of Patients Treated with Monotherapy CB-839 on 
the BID Schedule on Study CX-839-001 
BID Schedule - Monotherapy (N=88): All TEAEs 
MedDRA Preferred Term 
Number (%) of patients 
All Events 
≥ Grade 3 
Patients with Any TEAE 
 83 (94.3) 
 32 (36.4) 
FATIGUE 
 27 (30.7) 
  1 (1.1) 
NAUSEA 
 27 (30.7) 
  1 (1.1) 
ALANINE AMINOTRANSFERASE INCREASED 
 15 (17.0) 
  3 (3.4) 
PHOTOPHOBIA 
 14 (15.9) 
0 
CONSTIPATION 
 13 (14.8) 
0 
VOMITING 
 13 (14.8) 
  2 (2.3) 
ANAEMIA 
 12 (13.6) 
  5 (5.7) 
ASPARTATE AMINOTRANSFERASE INCREASED 
 12 (13.6) 
  2 (2.3) 
DECREASED APPETITE 
 12 (13.6) 
0 
DYSPNOEA 
 11 (12.5) 
  2 (2.3) 
BLOOD ALKALINE PHOSPHATASE INCREASED 
 10 (11.4) 
  2 (2.3) 
BLOOD CREATININE INCREASED 
 10 (11.4) 
0 
INSOMNIA 
  9 (10.2) 
0 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 9.5-2:  CB-839 Related Adverse Events in ≥ 5% of Patients Treated with 
Monotherapy CB-839 on the BID Schedule on Study CX-839-001 
BID Schedule - Monotherapy (N=88): CB-839 Related TEAEs 
MedDRA Preferred Term 
Number (%) of patients 
All Events 
≥ Grade 3^ 
Patients with Any CB-839-Related TEAE 
 61 (69.3) 
  3 (3.4) 
FATIGUE 
 21 (23.9) 
  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) 
VOMITING 
  5 (5.7) 
  0 
^no Grade 4 or Grade 5 events 
 
 
 
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 and required the 
patient rest for 1-2 hr in a dark room.  These events appear to occur around Cmax (1-4 hr after 
dosing) and resolve with time.  Anecdotal reports suggest that these events tend to become less 
frequent over extended dosing.  The AE profile of monotherapy CB-839 using the original 
schedule (TID without food) as well as the final schedule (BID with food) are described more 
completely in the Investigator’s Brochure. 
 
CB-839 + Everolimus  
The combination of CB-839 with everolimus has been well tolerated to date.  The frequency of 
adverse events (reported as of the safety data cut of 23 January 2017) in patients receiving CB-
839 on the BID regimen in combination with standard dose everolimus (10 mg QD orally) are 
provided in Table 9.5-3 (all adverse events) and Table 9.5-4 (treatment related adverse events).  
Of the first 19 patients who have received escalating doses of CB-839 (7 at 400 mg, 9 at 600 mg 
and 3 at 800 mg orally BID with food) in combination with everolimus, the most frequent AEs 
were anemia, decreased appetite, creatinine increase and hyperglycemia; with anemia, 
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hyperglycemia and fatigue being the most frequent Grade 3/4 AEs.  Of note, both patients with 
G3 hyperglycemia had preexisting diabetes (Table 9.5-3).   
Table 9.5-3:  Adverse Events in ≥ 3 Patients Treated with CB-839 + Everolimus on Study 
CX-839-001 
CB-839 + Everolimus (N=19): All TEAEs 
MedDRA Preferred Term 
Number (%) of patients 
All Events 
≥ Grade 3 
Patients with Any TEAE in CBE Cohort 
 19 (100.0) 
 13 (68.4) 
ANAEMIA 
 13 (68.4) 
  5 (26.3) 
DECREASED APPETITE 
  9 (47.4) 
0 
BLOOD CREATININE INCREASED 
  7 (36.8) 
0 
HYPERGLYCAEMIA 
  7 (36.8) 
  2 (10.5)* 
COUGH 
  6 (31.6) 
0 
NAUSEA 
  6 (31.6) 
0 
DIARRHOEA 
  5 (26.3) 
  1 (5.3) 
HEADACHE 
  5 (26.3) 
  1 (5.3) 
PROTEINURIA 
  5 (26.3) 
0 
VOMITING 
  5 (26.3) 
0 
ASPARTATE AMINOTRANSFERASE INCREASED 
  4 (21.1) 
0 
FATIGUE 
  4 (21.1) 
  2 (10.5) 
STOMATITIS 
  4 (21.1) 
0 
ABDOMINAL PAIN 
  3 (15.8) 
  1 (5.3) 
ALANINE AMINOTRANSFERASE INCREASED 
  3 (15.8) 
0 
CHILLS 
  3 (15.8) 
0 
DERMATITIS ACNEIFORM 
  3 (15.8) 
0 
DYSGEUSIA 
  3 (15.8) 
0 
DYSPNOEA 
  3 (15.8) 
0 
HYPOMAGNESAEMIA 
  3 (15.8) 
0 
HYPOPHOSPHATAEMIA 
  3 (15.8) 
  1 (5.3) 
INSOMNIA 
  3 (15.8) 
0 
MUCOSAL INFLAMMATION 
  3 (15.8) 
0 
MYALGIA 
  3 (15.8) 
  1 (5.3) 
PAIN 
  3 (15.8) 
  1 (5.3) 
PLATELET COUNT DECREASED 
  3 (15.8) 
0 
PYREXIA 
  3 (15.8) 
0 
THROMBOCYTOPENIA 
  3 (15.8) 
0 
WEIGHT DECREASED 
  3 (15.8) 
0 
*preexisting diabetes 
        
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Treatment-related adverse events that were Grade 3 were few in number and there have been no 
Grade 4 events (Table 9.5-4).   One event of Grade 3 rash occurred at the 400 mg BID dose 
level, which was considered a dose limiting toxicity (DLT).  The rash was considered related to 
everolimus and resolved upon a dose reduction of everolimus (CB-839 continued at full dose).   
No additional DLTs have been reported in subsequent patients treated at 400, 600 or 800 mg 
BID and a maximum tolerated dose has not been identified.   
 
Table 9.5-4:  Treatment-Related Adverse Events in ≥ 3 Patients Treated with CB-839 + 
Everolimus on Study CX-839-001  
CB-839 + Everolimus (N=19): Treatment-related TEAEs* 
MedDRA Preferred Term 
Number (%) of patients 
All Events 
≥ Grade 3^ 
Patients with Any Treatment-related TEAE in CBE cohort 
19 (100) 
9 (47.4) 
DECREASED APPETITE 
  7 (36.8) 
0 
ANAEMIA 
  5 (26.3) 
  1 (5.3) 
DIARRHOEA 
  5 (26.3) 
0 
HYPERGLYCAEMIA 
  5 (26.3) 
  2 (10.5) 
PROTEINURIA 
  5 (26.3) 
0 
ASPARTATE AMINOTRANSFERASE INCREASED 
  4 (21.1) 
0 
BLOOD CREATININE INCREASED 
  4 (21.1) 
0 
FATIGUE 
  4 (21.1) 
  2 (10.5) 
NAUSEA 
  4 (21.1) 
0 
STOMATITIS 
  4 (21.1) 
0 
ALANINE AMINOTRANSFERASE INCREASED 
  3 (15.8) 
0 
DERMATITIS ACNEIFORM 
  3 (15.8) 
0 
DYSGEUSIA 
  3 (15.8) 
0 
MUCOSAL INFLAMMATION 
  3 (15.8) 
0 
MYALGIA 
  3 (15.8) 
0 
THROMBOCYTOPENIA 
  3 (15.8) 
0 
VOMITING 
  3 (15.8) 
0 
^no Grade 4 or Grade 5 events  
*considered to be at least possibly related to either CB-839 or everolimus 
 
Please refer to the most recent CB-839 Investigator’s Brochure for additional safety information 
from the Phase 1 studies. 
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9.6 
Efficacy of CB-839 + Everolimus 
As of the efficacy data cut of 25 October 2016, the CB-839 plus everolimus portion of Phase 1 
clinical trial CX-839-001 had enrolled patients with ccRCC (N=14), papillary RCC (N=3), 
chromophobe RCC (N=1) and FH-mutant RCC (N=1). The CX-839-005 study will enroll only 
ccRCC patients; therefore this efficacy summary will focus on only the ccRCC patients.  For the 
14 ccRCC patients that have received the combination of CB-839 and everolimus, all patients 
had received 2 or more prior lines of therapy with 6 (43%) having received at least 3 prior lines 
of therapy.  Prior therapies included mTOR inhibitors (2 patients), PD-1 inhibitors (9 patients), 
and at least one TKI (all patients), and 29% of patients had received at least 2 prior TKIs.     
Of the 14 ccRCC patients enrolled, 12 were evaluable for efficacy as of the data cut (one patient 
discontinued prior to the first tumor assessment and one patient was on study prior to first scan).  
Among the 12 evaluable ccRCC patients, one achieved a partial response (PR) and no patient 
had disease progression at their first scan at 8 weeks, resulting in a disease control rate (DCR = 
CR + PR + SD) of 100% (Table 9.6-1).  Seven of eight patients that had reached the second scan 
timepoint at 16 weeks continued to show disease control (an additional four patients remained on 
study between the first and second scans).  Although small numbers, these data are notable for 
the low rate of progression in patients at the first two time points, since monotherapy everolimus 
in 2nd line RCC has shown 30-40% progressive disease (PD) at the first scan (8 weeks) and 
approximately 50%  PD at the second scan (16 weeks). 
Table 9.6-1:  Efficacy of the CB-839 + Everolimus Combination 
 
Clear cell RCC 
Response Evaluable (N) 
12 
PR 
1 (8.3%) 
SD 
11 (92%) 
DCR at 8 weeks 
12 (100%) 
PD 
0 
Not evaluable (N) 
2 
 
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Large randomized Phase 3 studies of a) everolimus vs. placebo (Motzer 2010), b) nivolumab vs. 
everolimus (Motzer 2015a), and c) cabozantinib vs. everolimus (Choueiri 2015), all in 
predominantly the second line setting, have shown a PFS for everolimus of approximately 3.8 – 
4.9 mo (see Figure 9.6-1, Panel A).  
A 
 
           
 
 
 
      B 
D o s e  ( m g )
B e s t  R e s p o n s e
( %  c h a n g e  i n  t a r g e t  l e s i o n s )
8 0 0
8 0 0
6 0 0
6 0 0
4 0 0
6 0 0
8 0 0
4 0 0
6 0 0
6 0 0
4 0 0
- 8 0
- 6 0
- 4 0
- 2 0
0
2 0
4 0
6 0
8 0
( 0 )
( 0 )
T i m e  ( m o n t h s )
%  C h a n g e  i n  T a r g e t  L e s i o n s
0
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
- 8 0
- 6 0
- 4 0
- 2 0
0
2 0
4 0
6 0
8 0
 
Figure 9.6-1.  Best tumor response, and duration of tumor response for ccRCC patients 
receiving CB-839 + everolimus in Phase 1.  A) Waterfall plot of best change in tumor 
burden, and B) Spider plot of tumor burden over time.   
9.7 
Rationale for CB-839 Dose Selection 
CB-839 will be administered at the Recommended Phase 2 Dose (RP2D) of 800 mg BID 
determined from the Phase 1 dose escalation study of CB-839 + everolimus.  Notably, no dose 
limiting toxicity was reported at this dose level, and the combination regimen was well tolerated 
with no maximum tolerated dose (MTD) determined for CB-839 with everolimus. In total the 
800 mg dose of CB-839 has been administered with good tolerability as monotherapy to 22 
patients with a variety of solid tumors and to an additional 25 patients in combination therapy 
with SOC agents (everolimus, paclitaxel, nivolumab and azacitidine).  As noted above, in 
pharmacokinetic studies, exposures at the 800 mg RP2D and the minus-one dose (600 mg) were 
similar with wide interpatient variability.  In pharmacodynamic studies of glutaminase target 
inhibition in platelets, robust inhibition of glutaminase was demonstrated at CB-839 inter-dose 
trough levels maintained in most patients at doses of 600 mg and 800 mg.  However, all patients 
treated at the 800 mg dose demonstrated ≥ 90% target inhibition in platelets whereas 
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approximately 20% of patients treated at the 600 mg dose level showed target inhibition less than 
90%.  In aggregate these data support the risk: benefit ratio of the 800 mg CB-839 dose level. 
 
10.0 
PROCEDURES 
This section describes evaluations to be performed during the different treatment periods of this 
study. All patients must sign an IRB approved informed consent prior to starting any protocol 
specific procedures, including screening procedures; 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/ EC policies.  During the consent process, the person obtaining consent must inform 
the patient of all elements of informed consent.   
10.1 
Screening 
To determine a patient’s eligibility patients will undergo required screening evaluations as 
outlined in Attachment 1. All previous cancer treatments, including systemic therapies, radiation 
and/or surgical procedures, should be recorded on the patients’ electronic case report forms 
(eCRF). Patients must also meet the inclusion and exclusion criteria to be enrolled in the study. 
10.1.1 Concomitant Treatment 
Concomitant treatment is permitted if the medication is not expected to interfere with the 
evaluation of safety or efficacy of the study drugs and it is not an anti-cancer therapy.  During 
the study, if the use of any concomitant treatment becomes necessary (e.g., for treatment of an 
adverse event), the treatment must be recorded on the appropriate eCRF, including the reason for 
treatment, name of the drug, dosage, route, and start and stop dates of administration. 
Non-protocol systemic anti-cancer treatment, surgical resection of lesions, use of investigational 
therapeutic agents other than the study drugs, and palliative radiation to non-bone tumors are 
NOT permitted while the patient is on study.  In general, palliative (limited field) radiation for 
bone metastasis pain should not be performed while on study.  If palliative radiation to a bone 
lesion is deemed clinically unavoidable for symptoms that in the opinion of the investigator are 
not due to progressive disease, the investigator must seek Sponsor approval prior to the 
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procedure.  Note that these patients may be considered unevaluable and assigned a censoring 
date or progression date.   
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. 
Everolimus is a substrate of CYP3A4 and a substrate and moderate inhibitor of the multidrug 
efflux pump P-Glycoprotein (PgP).  Per everolimus prescribing information, strong inducers and 
inhibitors CYP3A4 should be avoided (Attachment 6).  Refer to the most current everolimus 
prescribing information appropriate to the respective site location about potential drug 
interactions and dosage adjustments suggested for co-administration with moderate inhibitors of 
CYP3A4 and/or PgP.    
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, CB-839 
should be taken 2 hours before antacid therapy.   
10.1.2 Screening Evaluation 
An IRB/IEC-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 C1D1. 
The following screening assessments must be performed within 21 days before study drug 
administration on C1D1 according to the Schedule of Study Assessments in Attachment 1[with 
the exception of imaging (CT/MRI); scans performed within 28 days of study drug 
administration on C1D1 are acceptable].  Procedures listed below that are performed as part of 
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the normal standard of care and within 21 days prior to C1D1 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 with corrected QT interval by Fridericia’s Formula (QTcF) 
 Urinalysis, coagulation, HbA1c, and triglyceride and total cholesterol levels: these 
assessments should be repeated periodically during the course of the study as clinically 
indicated  
 Clinical laboratory evaluation (serum chemistry, and hematology); see Attachment 1 and 
Attachment 2. 
 Serum or urine pregnancy test.  This is only required for females of child-bearing 
potential and must be negative within 3 days prior to C1D1. 
 Radiographic evaluation of tumor burden comprising diagnostic quality CT with 
intravenous contrast or MRI with contrast that is appropriate for RECIST 1.1 assessment 
(Attachment 5).  For patients who cannot receive intravenous CT contrast, non-contrast 
CT of the chest with contrast enhanced MRI of the abdomen and pelvis is acceptable.  
Scans performed within 28 days prior to C1D1 will be accepted and do not need to be 
repeated (Attachment 1).  
 Optional tumor biopsies may be collected from patients who sign a separate tumor biopsy 
informed consent form.  
 Archival tumors, if available, will be collected all patients. 
A patient who meets all of the inclusion criteria will be randomized and enter the study.  Screen 
failures will be marked in the electronic data capture (EDC) system. 
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10.2 
Randomization 
Patients eligible after completing all screening evaluations will be randomly assigned in a 2:1 
ratio to receive CBE or PboE. 
Randomization will be stratified by the following factors: 
 Number of prior VEGFR-targeting TKI therapies: 1 vs. >1 
 Number of risk factors per Memorial Sloan-Kettering Cancer Center prognostic criteria 
for previously treated patients with RCC (Motzer 2004): favorable vs. intermediate/poor 
risk 
Randomization should occur as close as possible to the planned start of treatment (ie, within 24 
hours prior if practicable but no more than 3 days). Patients are defined as enrolled in the study if 
randomized. Patients who signed consent and are screened but never randomized are screen 
failures. 
Crossover between treatment arms will not be allowed.  
10.3 
Study Treatment Procedures 
For the complete list of schedules and 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.  
Clinic visits for safety evaluations will occur on Cycle 1 Day 1 and Cycle 1 Day 15,  then on day 
1 of Cycles 2-12.  Starting with cycle 13, safety evaluations will occur every 3 cycles, or more 
frequently as clinically indicated. The final 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.  
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Radiographic evaluation of tumor burden (e.g., diagnostic CT with intravenous contrast or MRI) 
will occur at Screening and approximately every 8 weeks after study initiation for the first 12 
cycles, or more frequently as clinically indicated.  After 12 cycles, tumor burden will be 
evaluated every 3 cycles or more frequently as clinically indicated. 
10.4 Long Term Follow Up 
Because the primary endpoint in this study is PFS, patients who discontinue study treatment for 
reasons other than progressive disease or death should continue to be followed by imaging per 
protocol schedule until documentation of progressive disease, death, withdrawal of consent, or 
initiation of a new anti-cancer treatment.  Patients who are post-progression and in long term 
survival follow-up should be contacted every 3 mo for the first 12 mo following study 
discontinuation and then once every 6 mo thereafter.  All reasonable efforts must be made to 
contact patient and report their ongoing status.  This includes follow up with persons authorized 
by the patient.  
10.5 Screen Failures 
Patients who sign an informed consent form, are not assigned to a treatment, and do not receive 
either CB-839, placebo, or everolimus are defined as screen failures.  For all screen failures, the 
following information will be captured in the electronic data capture (EDC) system: screening 
number, patient demographics, and reason(s) for screen failure into the EDC system.  Serious 
Adverse Event information will also be captured in the EDC.  
10.6 Procedure Details 
This section describes assessments to be performed and recorded in the EDC.  
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, 12-lead ECGs (including 
QTcF intervals), and clinical laboratory test results. 
After randomization, safety assessments will be performed on day 1 of every cycle for the first 
12 cycles. Starting with cycle 13, safety assessments will be performed on day 1 of every 3 
cycles. More frequent safety evaluations may be performed if clinically indicated or at the 
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discretion of the Investigator.  Unscheduled visits may be performed at any time and all should 
be recorded in the EDC. All AEs will be recorded from the time the patient receives the first 
dose of study drug up to 28 days after the last dose. 
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 anti-
cancer 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 End of Treatment.  Symptom-directed physical 
exam are required as clinically indicated.  
The Karnofsky performance status (Attachment 4) will be assessed during screening to 
determine the eligibility and the prognostic risk score according the MSKCC prognostic criteria 
(Motzer 2004).  The Karnofsky performance status will be used to evaluate the patients’ 
performance at the beginning of every cycle and at the end of treatment.  
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 3-5 min prior to obtaining vital signs.  
10.6.4 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. 
ECGs may be performed periodically as clinically necessary.   
When performed, the ECG must be reviewed, by a qualified physician (or qualified physician’s 
assistant or nurse practitioner) and any clinically important finding recorded on the appropriate 
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eCRF.    ECG results will include heart rate (HR), R-R interval (RR), PR interval, QRS interval, 
QT interval, and QTcF interval.  The corrected QT interval will be corrected for respiratory rate 
according to the following formula: 
Fridericia’s formula:  QTcF = QT/RR0.33 
10.6.5 Laboratory Assessments 
Laboratory evaluations will be performed as noted in the Schedule of Study Assessment 
(Attachment 1). The laboratory analytes are listed in Attachment 2. All laboratory assessments 
will be completed by the sites local laboratory and results entered in the EDC.  
To confirm eligibility, urinalysis, coagulation, HbA1c, and triglycerides, and total cholesterol 
will be performed at screening. These assessments should be repeated periodically during the 
course of the study as clinically indicated. Any clinically significant results should be entered in 
the EDC.  
10.6.6 Patient-Reported Quality of Life Assessment 
Patients will be asked to complete two health related quality of life 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). These 
questionnaires will be completed on day 1 of every cycle for the first 12 cycles then every 3 
cycles starting with cycle 13 and at the End of Treatment.  
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 and return it to the site either during the next 
visit or should send it to the site by fax or mail. Upon completion, the site should carefully 
review for completeness.  
These assessments should be completed regardless of whether study treatment is given, reduces, 
held or discontinued.  
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10.6.7 Tumor Assessments 
Radiographic response and disease progression will be determined using RECIST version 1.1 
and should employ diagnostic quality CT with intravenous contrast or MRI scans (see 
Attachment 5 for methods of assessment discussion of CT and MRI).   
Radiographic tumor assessments will include Chest/ Abdomen/ Pelvis (CAP).  Diagnostic 
quality CT (or MRI) of chest/abdomen/pelvis with intravenous contrast will be performed for all 
patients at screening, every 8 weeks (±5 days) from C1D1 for the first 12 cycles, and every 12 
weeks (± 7 days) beyond 12 cycles on study.  For patients deemed intolerant of intravenous CT 
contrast, a non-contrast CT of the chest may be obtained along with a contrast enhanced MRI of 
the abdomen and pelvis.  
To ensure image consistency, the same imaging modality and acquisition protocols used at 
screening should be used for subsequent tumor assessments.  
For the purpose of patient management and treatment decisions, radiographic response and 
disease progression will be assessed by investigators using RECIST v1.1 (Attachment 5). 
Investigators are encouraged, if any doubt or ambiguities exist about radiographic progression, to 
continue study therapy if the patient is tolerating treatment, and repeat radiographic studies at the 
next scheduled time, and delay determination of progression until the findings indicating 
radiographic progression are unequivocal.  
10.6.8 Tumor Biopsies  
10.6.8.1 
Optional Fresh Tumor Biopsies 
Optional tumor biopsies for exploratory biomarker assessment may be collected at any point on 
this study with patient consent.  Biopsies should not be obtained from target lesions being 
followed for disease assessment.  
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. 
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10.6.8.2 
Archival Tumor Biopsies  
Archival surgical 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 tissues 
collected from recent time points before enrollment is optimal because it more accurately reflects 
the current state of the tumor/microenvironment at the time of study entry.   
 
10.6.9 Pharmacokinetic Samples 
PK samples will be collected from all patients. Plasma PK samples will be used to measure 
concentrations of CB-839.   Blood samples for PK analysis will be collected at the following 
time points: 
 Cycle 1, Day 15: Pre-dose and 2 hours post dose(± 30 minutes) 
 Cycle 2, Day 1: 4 hours and 6 hours post dose (± 1 hour). Patients can take their morning 
dose at home and PK samples can be drawn at the indicated times after dosing in the 
clinic.  
The actual time of collection must be noted in the source documents and eCRFs. In the event that 
there is a delay in dosing on PK days, the PK sample should be collected during the next visit 
that the patient is in the clinic. On Cycle 1 Day 15, patients will have to arrive at the clinic and 
get their pre-dose PK sample drawn prior to taking their dose. On Cycle 2 Day 1, patients must 
record the time they take their morning dose and report to the site. This information will be 
entered in the EDC.  Refer to the laboratory manual for details on collection kits and sample 
processing. 
The plasma samples will be analyzed for CB-839 by using a validated liquid chromatography 
tandem mass spectrometry (LC-MS/MS) method of appropriate specificity and sensitivity 
according to Good Laboratory Practices (GLPs).   
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11.0 
POTENTIAL TOXICITIES, DOSE MODIFICATION AND MANAGEMENT OF 
TOXICITIES 
11.1 
Potential Toxicities 
11.1.1 CB-839 
The most frequent adverse events (AEs) considered possibly or probably related to CB-839 
monotherapy dosed on the BID schedule on the CX-839-001 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 9.5-2).   
11.1.2 Everolimus 
Adverse events most frequently observed with everolimus are rash, stomatitis/oral mucositis, 
fatigue, headache, anorexia, nausea, vomiting, diarrhea, and infections (see everolimus Package 
Insert).  Overall, the most frequently observed laboratory abnormalities include neutropenia, 
thrombocytopenia, hypercholesterolemia, and/or hypertriglyceridemia.  The majority of these 
AEs have been of mild to moderate severity (CTCAE Grade 1-2).   Everolimus has been 
associated with a low incidence of severe and potentially lethal AEs, including non-infectious 
pneumonitis, infections, and renal failure (see Warnings and Precautions in the Package Insert).  
Everolimus dosing and toxicity should be managed according to the Package Insert and local 
institutional practice. 
11.1.3 CB-839 + Everolimus Combination 
In a cohort of 19 patients treated during the Phase 1 evaluation of CB-839 + everolimus, the most 
frequent adverse events (AEs) considered possibly or probably related to one or both drugs were 
decreased appetite, hyperglycemia, and anemia (see Table 9.5-3).  These have been primarily 
Grade 1/2 AEs. 
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The only Grade 3/4 AEs considered possibly or probably related to either CB-839 or everolimus 
or both drugs in more than 1 patient was hyperglycemia, which occurred in 2 patients, both with 
pre-existing diabetes (see Table 9.5-4).   
11.2 
Dose Modifications and Toxicity Management 
The safety and tolerability profile of CB-839 is summarized above (Section 9.5).  In general, 
management of AEs related to CB-839 and everolimus includes withholding the medication for 
moderate to severe toxicities and providing the appropriate supportive care. 
The safety and tolerability profile of everolimus is well defined and outlined in the everolimus 
Package Insert.  Per Package Insert, monitoring of fasting serum glucose and lipid profile is 
recommended prior to the start of everolimus therapy and periodically thereafter, as well as 
management of metabolic AEs with appropriate medical therapy. More frequent monitoring is 
recommended when everolimus is co-administered with other drugs that may induce 
hyperglycemia. When possible, optimal glucose and lipid control should be achieved before 
starting a patient on everolimus. 
11.2.1 Dose Modification Guidelines 
Patients will be monitored continuously for AEs while on study.  Treatment modifications (e.g., 
dose delay) will be based on specific laboratory and AE criteria.  Guidelines for dose 
modifications due to hematological and non-hematological AEs are provided in Tables 11.2-1 
and 11.2-2, respectively.  The dose levels for CB-839 dose reduction are provided in Table 11.2-
3.  For everolimus dose reduction levels, the most up the most up-to-date everolimus Package 
Insert applicable to the site location should be consulted and followed.  
These dose modification guidelines provided in Tables 11.2-1 and 11.2-2 are based on the 
Package Insert for everolimus (dated September 2017) and the clinical experience with CB-839 
and the combination to date.  These guidelines are intended primarily for toxicities that are not 
easily managed with routine supportive care. Because everolimus prescribing information may 
change over time, the most up-to-date everolimus Package Insert applicable to the site location 
should be consulted and followed. 
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Table 11.2-1: Dose Modifications Guidelines for Hematologic Toxicity 
Toxicity Grade 
(CTCAE v4) 
Management of 
toxicity 
CB-839 
or Placebo 
Everolimus 
Hematologic: 
Grade 3/4 (other 
than those 
highlighted 
below) 
Supportive care, as 
necessary 
Hold and resume at the same 
dose level upon resolution to 
≤ Grade 1 or baseline 
Hold everolimus and resume at 
the same dose level upon 
resolution to ≤ Grade 1 or 
baseline. If toxicity recurs at 
Grade 3, hold and restart at the 
next lower dose 
Grade 3/4 
neutropenia or  
thrombocytopenia 
Supportive care, as 
necessary 
Hold and resume at the same 
dose level upon resolution to 
≤ Grade 1 or baseline 
Hold everolimus and resume at 
one dose level lower upon 
resolution to ≤ Grade 1 or 
baseline 
 
Table 11.2-2: Dose Modifications Guidelines for Non-Hematologic Toxicity 
Toxicity Grade 
(CTCAE v4) 
Management of 
toxicity 
CB-839 
or Placebo 
Everolimus 
Non-hematologic 
clinically 
significant:  (other 
than those 
highlighted below) 
Grade 2 
Initiate appropriate 
medical therapy and 
monitor 
If symptom not tolerable, hold 
and resume at the same dose 
level upon recovery to ≤ Grade 
1 or baseline.  If toxicity 
recurs, hold and restart at next 
lower dose. 
If symptom not tolerable hold 
everolimus and resume at same or 
next lower dose level upon recovery 
to ≤ Grade 1. If toxicity recurs at 
Grade 2, hold and restart at next 
lower dose. 
Non-hematologic 
clinically 
significant:  (other 
than those 
highlighted below) 
Grade 3 
Initiate appropriate 
medical therapy and 
monitor 
Hold and resume at the same 
dose level or the next lower 
dose level upon recovery to ≤ 
Grade 1 or baseline.   
Hold everolimus and resume at the 
next lower dose level upon recovery 
to ≤ Grade 1. If toxicity recurs at 
Grade 3, consider discontinuation. 
 
Non-hematologic 
clinically 
significant:  (other 
than those 
highlighted below) 
Grade 4 
Initiate appropriate 
medical therapy and 
monitor 
Permanently discontinue 
Permanently discontinue everolimus 
Non-infectious 
pneumonitis 
Grade 1 
Monitor by CT at 
least every 3 cycles. 
Continue  
Continue everolimus. 
Grade 2 
Rule out infection and 
consider treatment 
with corticosteroid 
until symptoms 
improve to ≤Grade 1. 
Hold and resume at the same 
dose level upon recovery to ≤ 
Grade 1 or baseline. 
Hold everolimus and resume at the 
next lower dose level upon recovery 
to ≤ Grade 1 or baseline.  
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Toxicity Grade 
(CTCAE v4) 
Management of 
toxicity 
CB-839 
or Placebo 
Everolimus 
Grade 3 
Rule out infection and 
consider treatment 
with corticosteroid 
until symptoms 
improve to ≤Grade 1. 
Hold and resume at the same 
dose level upon recovery to ≤ 
Grade 1 or baseline. 
Hold everolimus and resume at the 
next lower dose level upon recovery 
to ≤ Grade 1 or baseline. If toxicity 
recurs at Grade 3, then consider 
discontinuation. 
Grade 4 
Rule out infection and 
consider treatment 
with corticosteroid 
until symptoms 
improve to ≤Grade 1. 
Hold and resume at the same 
dose level upon recovery to ≤ 
Grade 1 or baseline. 
Permanently discontinue everolimus 
Stomatitis 
Grade 2 
Manage with topical 
analgesic mouth 
treatments as per 
everolimus Package 
Insert and local 
practice. 
Consider holding. 
If held resume at the same 
dose upon recovery to ≤ Grade 
1 
Hold everolimus and resume at the 
same dose level upon recovery to ≤ 
Grade 1.  If toxicity recurs at Grade 2 
hold and resume at next lower dose 
level upon recovery to Grade 1 
Stomatitis 
Grade 3 
Manage with topical 
analgesic mouth 
treatments as per 
everolimus Package 
Insert and local 
practice. 
Hold and resume at the same 
dose or the next lower dose 
upon recovery to ≤ Grade 1 
Hold everolimus and resume at the 
next lower dose upon recovery to ≤ 
Grade 1 
Stomatitis 
Grade 4 
Manage with topical 
analgesic mouth 
treatments as per 
everolimus Package 
Insert and local 
practice. 
Hold and resume at the next 
lower dose upon recovery to ≤ 
Grade 1 
Permanently discontinue everolimus 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia)  
Grade 1-2 
Manage with 
appropriate medical 
therapy. 
Continue  
Continue 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia) 
Grade 3 
Manage with 
appropriate medical 
therapy 
Hold and resume at the same 
dose level or one dose level 
lower upon recovery to  
≤ Grade 1 or baseline  
Hold everolimus and resume at next 
lower dose level upon recovery to ≤ 
Grade 1 or baseline. 
 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia) 
Grade 4 
Manage with 
appropriate medical 
therapy 
Hold and resume at one dose 
level lower upon recovery to  
≤ Grade 1 or baseline 
 
Permanently discontinue everolimus 
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Table 11.2-3: Dose Reductions for CB-839 (or Placebo) 
Dose Reductions of CB-839 or Placebo 
Dose Level 
CB-839 Dose 
Number of Tablets 
CB-839 or Placebo 
Starting dose 
800 mg BID 
4 
First dose reduction 
600 mg BID 
3 
Second dose reduction 
400 mg BID 
2 
Third dose reduction 
Discontinue CB-839        
or Placebo 
0 
 
11.2.2 Resumption of Study Treatment 
For everolimus and CB-839 (or placebo), treatment may be delayed for up to 6 weeks from the 
last dose.  Delays longer than 6 weeks are allowed only in cases where the delay was due to a 
non-drug related cause.  Prior to re-initiating treatment in a patient with a dosing interruption 
lasting > 4 weeks, the Medical Monitor must be consulted.  Treatment compliance will be 
monitored by drug accountability as well as the patient’s medical record and eCRF. 
Upon withholding study drugs for adverse events, the study drugs may be restarted when the AE 
has returned to ≤ Grade 1 or baseline.  In cases in which a particular toxicity is clearly related to 
only one of CB-839 or everolimus, the study drug that is not involved in causing the AE may be 
restarted prior to a return to ≤ Grade 1 or baseline.  If CB-839 (or placebo) is restarted after 
permanent discontinuation of everolimus, CB-839 or placebo should be permanently 
discontinued for a ≥ Grade 3 recurrence of the AE that resulted in everolimus discontinuation. 
11.3 
Missed Doses 
Missed doses of CB-839 or everolimus should be skipped.  If a patient forgets to take a dose of 
CB-839 or everolimus and he/she is outside of the allotted window period (± 6 hr), he/she should 
be instructed to skip that dose and NOT to take extra study drug at their next administration. 
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11.4 
  Discontinuation of Treatment and Withdrawal of Patients 
The reasons a patient may discontinue or be withdrawn from the study include, but are not 
limited to, disease progression, adverse events, patient request, withdrawal of consent, 
investigator decision, protocol violation, patient noncompliance, and study termination by the 
Sponsor. 
In unusual 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 
PD may be considered in consultation with the medical monitor.  
When a patient discontinues or is withdrawn, the Investigator will notify the Sponsor (or 
designee) and should perform all End of Treatment and follow up procedures as indicated in the 
schedule of study assessments (Attachment 1) after discontinuation of study drug.  Note that 
patients who discontinue study treatment for reasons other than progressive disease or death 
should be followed by imaging per protocol until progressive disease, death, initiation of a new 
anti-cancer therapy, or withdrawal of consent for study follow-up.  
12.0 
TEST ARTICLE/STUDY DRUG 
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 or placebo will be administered only to patients who have signed 
and dated an Informed Consent Form.  Doses will be administered 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 or 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 should be taken 2 hours before 
antacid therapy. See Section 10.1.1 for discussion of acid suppression therapy. 
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Patients who vomit their CB-839 or placebo dose should be instructed NOT to make up that dose 
and to report the frequency of vomiting occurrences associated with study drug administration to 
the site.   
 
Everolimus Tablets 
Everolimus will be administered to patients who have signed and dated an Informed Consent 
Form.  10 mg everolimus will be administered on Days 1 through 28 of each 28-day cycle and 
should be taken orally QD around the same time every day. Administer either consistently with 
food or consistently without food. Everolimus dosing will not be adjusted for body weight or 
surface area. 
12.2 
Packaging and Labeling 
CB-839 HCl Tablets (200 mg) are manufactured, packaged, and labeled according to current 
Good Manufacturing Practices (GMP).  For additional information, please refer to the Pharmacy 
Manual. 
Everolimus Tablets are available as 2.5, 5, or 10 mg strengths.  Please refer to the everolimus 
Package Insert for specific instructions on packaging and labeling. 
Placebo Tablets (200 mg equivalent) are manufactured, packaged, and labeled according to 
current GMP. For additional information, please refer to the Pharmacy Manual. 
12.3 
Storage and Stability 
CB-839 Tablets or Placebo Tablets 
CB-839 HCl Tablets or placebo tablets will be stored at the clinical site, as indicated on the study 
drug label, i.e., room temperature, between 15 - 30ºC (59 - 86ºF). 
Patients will be requested to store CB-839 or placebo at the recommended storage conditions 
noted on the label, out of the reach of children or other cohabitants. 
Everolimus Tablets 
Everolimus should be stored at 15 - 30ºC (59 - 86ºF).  Protect from light by storing in the 
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original package until time of use.  For procedures for the proper handling, storage, preparation 
and administration of everolimus, please refer to the everolimus Package Insert. 
12.4 
CB-839 Accountability, Reconciliation, and Return 
On Day 1 of Cycle 1, patients will be provided with enough study treatment (everolimus, 
CB-839 or placebo) 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 or placebo 
tablets remaining from the previous visit will be counted and recorded. 
 
The Investigator or designee must maintain an accurate record of dispensing the study drug in a 
Drug Accountability Log, a copy of which must be given to the Sponsor at the end of the study. 
The Drug Accountability Log will record the study drugs received, dosages prepared, time 
prepared, doses dispensed, and doses and/ or bottles destroyed.  The Drug Accountability Log 
will be reviewed by the field monitor during site visits and at the completion of the study. 
If evidence of tampering is observed, notify the Sponsor and return the questionable CB-839 or 
placebo shipment with the appropriate form to the contract distribution center.  Returned/ 
partially used, and unused CB-839 test article or placebo control article may also be destroyed 
and documented at the investigative site in accordance with approved site/institution standard 
operating procedures. If the investigative site does not have an approved standard operating 
procedure, investigative product may be returned to the distribution center for destruction.  
12.5 
Test Article Compliance 
At each clinic visit, patients will be asked to return any unused CB-839 test article or placebo 
control article and will be questioned about their compliance.  The number of remaining tablets 
will be recorded in the drug accountability log.  Significant non-compliance (missing > 60% of 
the study drug for reasons other than documented AE) must be reported to the monitor. 
Missed doses of CB-839 or placebo should be skipped.  If a patient forgets to take a dose of 
study drug and he/she is outside of the allotted window period (± 6 hr), he/she should be 
instructed NOT to take extra study drug at their next administration. 
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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 
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 and refractory ccRCC.  Patients will be 
randomized to either the CB-839 with everolimus or to placebo with everolimus in a 2:1 ratio.  
The primary endpoint of this Phase 2 study is progression free survival (PFS) assessed by 
investigator per RECIST 1.1.  The key secondary endpoint is overall survival (OS).  Patients will 
be stratified by: a) prior VEGFR targeting TKI therapy (1 vs. > 1) and b) MSKCC Prognostic 
Criteria for Previously Treated Metastatic RCC (favorable vs. intermediate/poor risk)  
14.2 
Analysis Patient Sets 
14.2.1 
Efficacy Analysis Patient Set 
The modified intention-to-treat (mITT) patient set will be the basis for the primary efficacy 
analysis for this study.  The mITT set comprises all randomized patients who receive at least one 
tablet of any study-specific treatment (CB-839, placebo, or everolimus).  With a double-blind 
design, patients who drop out before receiving any treatment are not influenced by the unknown 
treatment assignment.  Therefore, the exclusion of such patients does not introduce bias to the 
between-arm patient balance. Patients in the mITT set will be analyzed according to the 
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treatment group to which they are randomized regardless of post randomization protocol 
deviations. 
14.2.2 
Safety Analysis Set 
All patients who receive at least 1 tablet of any study-specific treatment (CB-839, placebo or 
everolimus) will be included in the analysis of safety and analyzed according to the actual 
treatment received.  Patients randomized to the placebo arm having taken any dose of CB-839 
will be analyzed in the CB-839 with everolimus combination arm. 
14.3 
Efficacy Analysis 
14.3.1 
Primary Efficacy Endpoint: Investigator-Assessed PFS 
The primary efficacy endpoint is PFS defined as the time from randomization to the earlier of 
disease progression or death due to any cause.  Radiographic disease progression will be 
assessed using the RECIST 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 radiographic disease assessment if any of the following scenarios 
occur: 
 Patient is alive and progression free at the time of analysis data cutoff 
 Disease progression or death occurs after missing data [including a non-evaluable (NE) 
status for overall response assessment] for two consecutive radiographic disease 
assessments 
 Patient receives non-protocol RCC treatment prior to documentation of disease 
progression 
 Patient is missing baseline disease assessment (censored at date of randomization) 
The primary inferential comparison between the two treatment arms will use the log-rank test 
stratified by the randomization stratification factor for risk profile [MSKCC Prognostic Criteria 
for Previously Treated Metastatic RCC (favorable vs. intermediate/poor risk) and number of 
prior therapies with a TKI (1 vs. > 1)].  A 1-sided log-rank p < 0.2 will be regarded as a positive 
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sign in favor of the CB-839 + everolimus experimental treatment.  The experimental over control 
hazard ratio will be estimated using a Cox proportional hazards model stratified by the 
randomization stratification factors.  Kaplan-Meier curves will be presented with median 
estimates to visually display the disease progression distributions.  
14.3.2 
Secondary Efficacy Endpoints 
Overall Survival (OS) 
OS is defined as the time from randomization to death due to any cause.  For patients alive at 
time of analysis, OS will be censored at the time when the patient is last known to be alive.  OS 
analyses will be the similar to the PFS analyses. 
14.3.3 
Additional Endpoints 
Overall Response Rate (ORR) 
ORR is defined as the percentage of patients with complete response (CR) or partial response 
(PR) according to the RECIST 1.1 criteria.  Response confirmation is not required in this double-
blind protocol.  Patients with no 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 14.4.1 conventions regarding PD censoring will apply.  Response 
duration will be descriptively presented by Kaplan Meier curve and median estimate for 
responders in each treatment arm.  
Disease Control Rate (DCR) 
DCR is defined as the summed percentage of patients with CR, PR and SD according to RECIST 
1.1 criteria documented at least 8 weeks following treatment initiation. 
Patient Reported Outcomes 
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Subjects 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). 
Details of the planned analyses for these outcomes will be provided in the SAP. 
14.3.4 
Exploratory Analyses 
To explore the effects of the following baseline factors, a multivariate Cox model regression 
analysis will be conducted for PFS.  The model will include treatment arm as an independent 
variable with the following variables as covariates.  Univariate plots will also be presented for 
descriptive purposes.   
 Race (Caucasian vs. all others)  
 Sex (male vs. female) 
 Age (18–65 vs. > 65 years) 
 Number of previous TKI therapies (1 vs. >1)  
 Favorable vs. intermediate/poor risk prognosis group 
 No prior immunotherapy vs. prior immunotherapy 
14.4 
Safety Analysis 
Safety will be assessed by the incidence and severity of adverse events (AEs); the analysis will 
be performed on the Safety Analysis Patient Set as defined in Section 14.4.2.   
Adverse events will be coded by System Organ Class (SOC) and Preferred Term (PT) using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The number and proportion of 
patients reporting a given AE will be tabulated by treatment group according to the worst 
severity reported.  Separate tables will be constructed for a) all reported AE’s, b) serious AEs 
(SAEs), and c) AE’s leading to permanent discontinuation of study treatment.  The above tables 
will also be presented for treatment-emergent AEs (TEAEs) judged to be related to the study 
treatment. 
14.5 
Sample Size Estimation 
A median PFS of 3.7 mo is estimated for the everolimus control group based on published data 
for 3rd line treatment of advanced ccRCC.  The published data include non-randomized 
everolimus-specific PFS (Heng 2015), PFS across the 3rd line setting for all commonly used 
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agents (ibid.), and results from a Phase 3 randomized 3rd line study of dovitinib vs. sorafenib 
(GOLD study, Motzer 2014).  In total across the IMDC database and the randomized GOLD 
study, these data represent 1490 unique patient outcomes specific to the 3rd line setting. 
The proposed study of CBE vs. PboE will enroll patients with a 2:1 randomization between 
experimental and control arms with an accrual period of 8 mo and additional follow-up of 6 mo. 
If the control arm PFS is 3.7 mo and the true PFS hazard ratio of experimental patients to control 
patients is 0.60, the study will require approximately 42 experimental patients and 21 control 
patients in order to reject the null hypothesis of equal PFS between the two treatment arms with a 
power of 0.80.   This estimation assumes a 1-sided type I error rate of 0.2, uniform accrual, 
exponential PFS distributions and the log-rank test for PFS comparison.  The expected total PFS 
event count is 48 under the above assumptions. 
15.0 
Adverse Events 
Single agent CB-839 has been well tolerated in three different Phase 1 clinical trials.  For safety 
information on CB-839, refer to Section 9.5 above and to the most recent version of the 
Investigator’s Brochure.  For safety information on everolimus, refer to the everolimus Package 
Insert. 
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 
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the test article that are related to the protocol-mandated intervention (e.g., medication 
wash out, biopsies) 
 An AE occurring from overdose (i.e., a dose higher than that indicated in the 
protocol) of a test article, whether accidental or intentional 
 An AE occurring from abuse (e.g., use for nonclinical reasons) of a test article 
 An AE that has been associated with the discontinuation of the use of a test article 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., meeting 
one or more of the following conditions, should be recorded as a single diagnosis on the adverse 
event page in the eCRF: 
 Accompanied by clinical symptoms 
 Leading to a change in study medication (e.g., dose modification, interruption, or 
permanent discontinuation) 
 Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 
A serious adverse event (SAE) is an AE that: 
 Results in death (NOTE:  death is an outcome, not an event) 
 Is life-threatening (NOTE: see definition below) 
 Requires inpatient hospitalization or prolongation of an existing hospitalization 
 Results in a persistent or significant disability or incapacity 
 Results in a congenital anomaly or birth defect 
 Additionally, important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered SAEs when, based on 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such events include allergic bronchospasm requiring 
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intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
Clear progression of neoplasia should not be reported as an AE or SAE (unless the 
investigator considers the progression of underlying neoplasia to be atypical in its nature, 
presentation or severity from the normal course of the disease in a particular patient).  Findings that 
are clearly consistent with the expected progression of the underlying cancer should not be 
reported as an adverse event, and hospitalizations due to the progression of cancer do not 
necessarily qualify for an SAE.  However, 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 
a serious adverse event (SAE).  In the absence of an AE, a hospitalization or prolongation of a 
hospitalization should not be reported as an SAE.  This is the case in the following situations: 
 The hospitalization or prolongation of hospitalization is needed for a procedure required 
by the protocol.  Day or night survey visits for biopsy or surgery required by the protocol 
are not considered serious. 
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 The hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (e.g., stent removal after surgery).  This should be recorded in the 
study file. 
 Hospitalization for survey visits or annual physicals falls into the same category. 
In addition, hospitalizations planned before the start of the study, for a preexisting condition that 
has not worsened, do not constitute an SAE.  Visits to the Emergency Room that do not result in 
hospital admission are not considered hospitalizations, but may constitute a medically important 
event. 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt about whether the information constitutes an SAE, the information is treated 
as an SAE. 
Causality Attribution Guidance: 
AEs should be considered (probably or possibly) treatment-related, unless they fulfill the 
following criteria (in which circumstances it should be considered unlikely related or unrelated): 
 Evidence exists that the AE has an etiology other than the investigational product (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication), and/or 
 The AE has no plausible temporal relationship to administration of the investigational 
product (e.g., a new cancer diagnosed 2 days after first dose of study drug). 
Relatedness to study medication will be graded as either, “probably”, “possibly”, “unlikely”, or 
“unrelated” as follows: 
Probably Related – The adverse event 
 Follows a reasonable temporal sequence from drug administration 
 Abates upon discontinuation of the drug 
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 Cannot be reasonably explained by the known characteristics of the patient’s clinical 
state 
Possibly Related – The adverse event 
 Follows a reasonable temporal sequence from drug administration 
 Could have been produced by the patient’s clinical state or by other modes of therapy 
administered to the patient 
Unlikely Related - The adverse event 
 Is most likely to be explained by the patient’s clinical state or by other modes of therapy 
administered to the patient 
Unrelated – The adverse event 
 Does not follow a reasonable sequence from drug administration 
 Is readily explained by and considered by the Principal Investigator to be an expected 
complication of the patient’s primary malignancy, clinical state, concurrent medical 
conditions, or by other modes of therapy administered to the patient 
A protocol-related adverse event is an AE occurring during a clinical study that is not related 
to the test article, but is considered by the Investigator or the  Medical Monitor (or designee) to 
be related to the research conditions, i.e., related to the fact that a patient is participating in the 
study.  For example, a protocol-related AE may be an untoward event occurring during a 
washout period or an event related to a medical procedure required by the protocol. 
Other Reportable Information:  certain information, although not considered an SAE, must be 
recorded, reported, and followed up as indicated for an SAE.  This includes: 
 A case involving a pregnancy exposure to a test article, unless the product is indicated for 
use during pregnancy e.g., prenatal vitamins.  Information about use in pregnancy 
encompasses the entire course of pregnancy and delivery and perinatal and neonatal 
outcomes, even if there were no abnormal findings.  If a pregnancy is confirmed, test 
article must be discontinued immediately.  All reports of pregnancy must be followed for 
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information about the course of the pregnancy and delivery, as well as the condition of 
the newborn.  When the newborn is healthy, additional follow-up is not needed. 
Pregnancies occurring up to 6 mo after completion of the study treatment must also be 
reported to the Investigator. 
 Overdose (e.g., a dose higher than that indicated in the protocol) with or without an AE 
 Abuse (e.g., use for nonclinical reasons) with or without an AE 
15.2 Recording and Reporting 
After informed consent, but prior to initiation of study drug, only SAEs caused by protocol- 
mandated interventions (i.e., a protocol-related SAE such as a biopsy) will be collected. 
Patients will be followed for AEs or SAEs from the time the patient initiates treatment with the 
study regimen up to 28 days after the last dose or until the start of a new treatment, whichever 
occurs first. The Investigator must follow up on all drug-related AEs, SAEs, and other reportable 
information until the events have subsided, returned to baseline, the patient has initiated any 
other anticancer treatment, or in case of permanent impairment, until the condition stabilizes. 
All AEs and SAEs must be recorded on source documents and collected in EDC. 
Although AEs should be based on the signs or symptoms detected during the physical 
examination and on clinical evaluation of the patient, a specific diagnosis should be reported as 
the AE whenever feasible. In addition to the information obtained from those sources, the patient 
should be asked the following nonspecific question:  “How have you been feeling since your last 
visit?” Signs and symptoms should be recorded using standard medical terminology. 
Any unanticipated risks to the patients must be reported by the investigator promptly to the 
Sponsor and IRB/IEC. 
15.3 Serious Adverse Event Reporting 
All SAEs regardless of attribution, other reportable information, and follow-up information must 
be reported within 1 business day of learning of the event by completing the SAE form and 
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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 Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC) will be done in accordance with the standard operation procedures and 
policies of the IRB/IEC.  Adequate documentation must be maintained showing that the IRB/IEC 
was properly notified. 
16.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION 
The Sponsor may suspend or terminate the study or any part of the study at any time for any 
reason.  If the Investigator suspends or terminates the study, the Investigator will promptly 
inform the Sponsor and the IRB/IEC and provide a detailed written explanation.  The 
Investigator will also return all CB-839 test 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. 
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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. 
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 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. 
20.2 Sponsor 
The data will be checked for completeness and correctness in real-time online. 
Data are checked as they are entered into the EDC system.  Off-line checks will also be run to 
assess the need for additional data review. 
20.3 Pre-Study Documentation 
The Investigator must provide the Sponsor with the following documents BEFORE enrolling any 
patients: 
 Completed and signed form 1572 
 All applicable country-specific regulatory forms 
 Current, dated curricula vitae for the Investigator, Sub-Investigators, and other 
individuals having significant investigator responsibility who are listed on the Form 1572 
or equivalent, or the clinical study information form. 
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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 
 Fully executed Clinical Trial Agreement (CTA) 
 Financial disclosure form for the Principal Investigator and any other persons listed in the 
1572 
 A written document containing the name, location, certification number, and date of 
certification of the laboratory to be used for laboratory assays and those of other facilities 
conducting tests.  This document should be returned along with the 1572. The Sponsor 
must be notified if the laboratory is changed or if any additional laboratory is to be used. 
 
20.4 Records Retention 
The Investigator shall retain and preserve one copy of all data generated in the course of the 
study, specifically including but not limited to those defined by GCP as essential, for the longer 
of:  (i) 2 years after the last marketing authorization for the study drug has been approved or the 
Sponsor has discontinued its research with respect to such drug or (ii) such longer period as 
required by applicable global regulatory requirements.  At the end of such period, the 
Investigator shall notify the Sponsor in writing of its intent to destroy all such material.  The 
Sponsor shall have 30 days to respond to the Investigator’s notice, and the Sponsor shall have a 
further opportunity to retain such materials at the Sponsor’s expense.  
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21.0 
AUTHORSHIP AND ACCOUNTABILITY 
Per the International Committee of Medical Journal Editors (ICMJE) recommendations, an 
author is generally considered to be anyone who provides substantive intellectual contributions 
to a published study.  Specifically, authorship credit should be based on 1) substantial 
contributions to study conception and design, or acquisition, analysis and interpretation of data, 
and 2) drafting the article or revising it critically for important intellectual content, 3) final 
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 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
CBE 
CB-839 plus everolimus combination treatment 
Ccr 
Creatinine Clearance 
ccRCC 
Clear Cell Renal Cell Carcinoma 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
cm 
Centimeters 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
CR 
Complete remission 
CTA 
Clinical Trial Agreement 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP, CYP450 
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 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
g/dL 
Grams per deciliter 
GLP 
Good Laboratory Practice  
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HbA1C 
Glycated Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
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Abbreviation or Term1 
Definition/Explanation 
hr 
Hour or hours 
ibid 
The same reference as above 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IMDC 
International Metastatic Renal Cell Carcinoma Database 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous, intravenously 
kg 
Kilogram 
KPS 
Karnofsky Performance Score 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
LC-MS/MS 
Liquid chromatography-mass spectrometry/mass spectrometry 
mcL/ µL 
Microliter  
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mg 
Miligram 
mL 
Milliliter 
mo 
Months 
MOA 
Mechanism of Action 
mRCC 
Metastatic Renal Cell Carcinoma 
MRI 
Magnetic Resonance Imaging 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTD 
Maximum tolerated dose  
mTOR 
Mechanistic Target of Rapamycin 
NHL 
Non-Hodgkin’s Lymphoma 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Overall response rate 
OS 
Overall Survival 
PboE 
Placebo tablets plus everolimus treatment 
PD-1 
Programmed Cell Death protein 1 
PD-L1 
Programmed Death Ligand 1 
PgP 
P-Glycoprotein 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PPI 
Proton Pump Inhibitors 
PR 
Partial response 
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Abbreviation or Term1 
Definition/Explanation 
PSA 
Prostate Specific Antigen 
PT 
Prothrombin time 
QD 
Once-daily dosing 
QTcF 
Corrected QT interval, Fridericia’s formula 
RP2D 
Recommended Phase 2 Dose 
RBC 
Red Blood Cell 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
Scr 
Serum Creatinine 
SD 
Stable disease 
TKI 
Tyrosine Kinase Inhibitor 
Tmax 
Time of maximum observed concentration 
TEAE 
Treatment-emergent adverse event 
TID 
Three times daily 
TNBC 
Triple negative breast cancer 
ULN 
Upper limit of normal 
VEGF 
Vascular Endothelial Growth Factor 
1 
This may not be a comprehensive list of all abbreviations in this document. All of these abbreviations may or 
may not be used in this document.  
 
 
 
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23.0 
REFERENCES 
 
Calithera Biosciences, Inc. CB-839 Investigator’s Brochure 
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. 
 
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. 
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 D  Stukalin I, Wells C, Donskov F, Rini BI, Lee JL, et al, Third-line therapy in metastatic 
renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium 
(IMDC). J Clin Oncol 2015;30:suppl;abstr e15578. 
 
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  
 
Motzer RJ, Bacik J, Scwartz LH, et al.  Prognostic factors for survival in previously treated 
patients with Metastatic Renal Cell Carcinoma. J Clin Oncol 2004; 22:454-63. 
 
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of 
everolimus for metastatic renal cell carcinoma: Final results and analysis of prognostic factors. 
Cancer 2010;116:4256–4265. 
 
Motzer RJ, Porta C, Vogelzang NJ, et al Dovitinib versus sorafenib for third-line targeted 
treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 
trial. Lancet Oncol 2014; 15: 286–96 
 
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 2015a;373:1803-1813. 
 
Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, 
everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, 
Phase 2, open-label, multicentre trial. Lancet Oncol 2015b;16:1473–1482. 
 
 
 
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ATTACHMENT 1: SCHEDULE OF STUDY ASSESSMENTS 
  (1 cycle = 28 days) 
Pre-randomization 
Post-randomization 
Visit 
Screening1 
Cycle 1 
Cycle 2+ 
Cycle 13+ 
(Every 3 cycles) 13 
End of Treatment/ 
Follow up 
Assessments 
≤ 21 days prior to 
C1D1 
Day 12 
(≤3 days post 
randomization) 
Day 15 
(± 2 days) 
Day 1 
(± 5 days) 
Day 1 
(± 7 days) 
EOT: Within 28 days 
post treatment 
discontinuation 
Written Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
Physical Examination3 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
Vital Signs4 
X 
X 
X 
X 
X 
X 
Karnofsky Performance Status 
X 
X 
 
X 
X 
X 
12-lead ECG with QTcF 
X 
 
 
 
 
 
Urinalysis5 
X 
 
 
 
 
 
HgA1c levels5, 6 
X 
 
 
 
 
 
Triglyceride and total cholesterol 
levels5, 7 
X 
 
 
X 
 
 
Coagulation tests5 
X 
 
 
 
 
 
Serum Chemistry levels 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy Test8 
X 
 
 
 
 
X 
Pharmacokinetic (PK) Assay9 
 
 
X 
X 
 
 
CB-839 or  Placebo Dosing 
 
CB-839 or Placebo will be administered twice daily (BID) with food 
 
Everolimus Dosing 
 
Everolimus will be administered once daily (QD) at the same time every day. 
 
Optional Tumor Biopsy 
Can be collected any time on study. Patients must sign the optional tumor biopsy consent 
Archival Tumor Collection 
X 
 
 
 
 
 
 
 
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(1 cycle = 28 days) 
Pre-randomization 
Post-randomization 
Visit 
Screening1 
Cycle 1 
Cycle 2+ 
Cycle 13+ 
(Every 3 cycles) 13 
End of Treatment/ 
Follow up 
Assessments 
≤ 21 days prior to 
C1D1 
Day 12 
(≤3 days post 
randomization) 
Day 15 
(± 2 days) 
Day 1 
(± 5 days) 
Day 1 
(± 7 days) 
EOT: Within 28 days 
post treatment 
discontinuation 
Radiographic Evaluation of Tumor 
Burden (diagnostic CT with 
intravenous contrast or MRI)10 
X11 
 
 
Every 8 weeks 
Every 12 weeks 
X 
Quality of Life Questionnaires 
 
X 
 
X 
X 
X 
Adverse Events 
 
Document new or worsening AEs from time of first dose through 28 days after study treatment 
discontinuation. AE information will be collected at study visits and may also be collected via 
any other forms of communication or by subject report. Certain AEs and SAEs that are ongoing 
28 days after study discontinuation are to be followed until resolution or determination by the 
investigator that the event is stable or irreversible.  
Concomitant Medications 
Document concomitant medication taken from time of informed consent through 28 days after study treatment 
discontinuation.  
Follow up 
 
 
 
 
 
X12 
 
Explanation of Superscripts 
1. 
Results of screening assessments must be reviewed before randomization to confirm that the patient meets all eligibility criteria. An IRB/IEC-approved Informed 
Consent Form (ICF) must be signed and dated ≤42 days prior to C1D1. 
2. 
Assessments on C1D1 should be completed prior to first dose of study treatment unless otherwise indicated.  
3. 
Complete physical exam is required at Screening and at End of Treatment. A symptom-directed physical exam can be done on all other visits. System exams are only 
required as clinically indicated  
4. 
Vital sign measurements include temperature, pulse, respiratory rate and resting systolic and diastolic blood pressure.  
5. 
Assessment completed at screening. Investigators should monitor during the study if it is deemed necessary per everolimus Package Insert 
6. 
Investigators should periodically monitor fasting glucose as per everolimus Package Insert.  
7. 
Triglycerides should be repeated at Cycle 2 (+/-5days). Total cholesterol levels are required at baseline only. 
8. 
Required for all females of child-bearing potential. Screening pregnancy test must occur within 3 days prior to C1D1. 
9. 
Samples are collected on C1D15: pre-dose and 2 hrs post dose and on C2D1: 4 hrs and 6 hrs post dose. Refer to the laboratory manual for detailed instructions on 
samples kits, collection, and shipment to a central laboratory.  
10. Imaging should be done at the same institution/facility and with the same modality which will be used to measure response during the patient’s participation in the study.   
11. Tumor assessments within 28 days prior to C1D1 will be accepted.  
12. Patients will be contacted every 3 mo for the first 12 mo then every 6 mo thereafter to confirm survival. 
13. Starting with Cycle 13, assessments will be completed every 3 cycles (12 weeks). More frequent visits should be completed if clinically indicated. 
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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 
 
 Sodium 
 Potassium 
 Chloride 
 CO2  
 Calcium 
 Glucose 
 Blood urea nitrogen 
 Total protein 
 Albumin 
 Total and direct bilirubin1 
 Aspartate aminotransferase (AST) 
 Alanine aminotransferase (ALT) 
 Alkaline phosphatase (AP) 
 Lactate dehydrogenase (LDH) 
Creatinine 
1 
Direct bilirubin is only required if Total Bilirubin is above the upper limit of normal.  
 
Pregnancy test (urine or serum -HCG):  Women of child-bearing potential 
Urinalysis 
 Protein 
 Glucose 
 Ketones 
 Hemoglobin 
 Nitrite 
 
 Leukocyte esterase 
 pH 
 Specific gravity 
 Urobilinogen 
 Microscopic evaluation(performed at the 
discretion of the Investigator based on 
results of routine urinalysis or as clinically 
indicated) 
 
 
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ATTACHMENT 3: MSKCC PROGNOSTIC SCORE 
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 MSKCC 
prognostic score.  
 
Parameter 
Risk Factor 
Criteria Value 
Patient Value 
If Patient Value meets 
criteria, enter 1 
KPS 
Low PS 
˂ 80% 
 
 
Corrected 
Calcium* 
High Corrected 
Calcium 
≥ 10 mg/ dL 
 
 
Hemoglobin 
Low Hemoglobin 
Males: ≤ 13 g/dL 
Females: ≤ 11.5 g/dL 
 
 
Sum total= MSKCC Prognostic Score: 
 
*Corrected Calcium = ([ 4 – serum albumin in g/ dL] x 0.8 + serum calcium) 
 
Risk Group Based on MSKCC Prognostic Score 
 
Risk Group 
MSKCC Prognostic Score 
Favorable- Risk 
0 
Intermediate- Risk 
1 
Poor- Risk 
2 or 3 
 
 
 
 
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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 
Source: Eisenhauer 2009 
Sponsor’s Note: CB-839, may affect glucose metabolism in both normal and tumor tissues. 
Preclinical data suggest that glucose uptake may increase with glutaminase inhibition in sensitive 
tissues, reflecting the pharmacodynamics effects of CB-839. False positive interpretations of 
progressive disease with FDG-PET scans may occur. Therefore, all FDG-PET findings 
suggestive of progressive disease should be confirmed by dedicated anatomic imaging (CT or 
MRI) for this study. 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions will be categorized measurable or non-measurable as follows. 
Measurable tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:   
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm by caliper measurement (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be  15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed.  See also section below on ‘Baseline documentation of target and 
non-target lesions’ for information on lymph node measurement. 
Non-measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter <10 mm or 
pathological lymph nodes with  10 to < 15 mm short axis) as well as truly non-measurable 
lesions.  Lesions considered truly non-measurable include:  leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, peritoneal spread, abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
 
 
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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 subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  For this protocol, these tumor lesions will be 
considered non-measurable lesions. 
Specifications by methods of measurements 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
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always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
and  10 mm diameter as assessed using calipers (e.g., skin nodules).  For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
suggested.  As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. Still, non-contrast CT is preferred over chest X-ray. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g., for body scans). 
If prior to enrollment it is known that a patient is not able to undergo CT scans with IV contrast 
due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (with 
or without IV contrast) will be used to evaluate the patient at baseline and follow-up, should be 
guided by the tumor type under investigation and the anatomic location of the disease.  For 
patients who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed, 
should also be based on the tumor type, anatomic location of the disease and should be optimized 
to allow for comparison to the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, the 
patient should be considered not evaluable from that point forward. 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
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Tumor markers:  Tumor markers alone cannot be used to assess objective tumor response.  If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response.  Because tumor markers are disease specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis.  Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published.  In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 
Cytology, histology:  These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain).  When effusions are known to be a 
potential adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for response 
or stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
Tumor response evaluation 
Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements.  Only patients 
with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint.  Measurable disease is defined by the presence of at least one 
measurable lesion.  In studies where the primary endpoint is tumor progression (either time to 
progression or proportion with progression at a fixed date), the protocol must specify if entry is 
restricted to those with measurable disease or whether patients having non-measurable disease 
only are also eligible.  
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
This means in instances where patients have only one or two organ sites involved a maximum of 
two (one site) and four lesions (two sites), respectively, will be recorded.  Other lesions in that 
organ will be recorded as non-measurable lesions (even if size is greater than 10 mm by CT 
scan). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
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not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor.  Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital or coronal).  The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis  10 mm 
but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression.’  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
Evaluation of target lesions 
 Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
 Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
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also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progression). 
 Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 
Special notes on the assessment of target lesions 
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. Case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis < 10 mm.  For PR, SD, and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
Target lesions that become ‘too small to measure’:  While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small to 
measure’.  When this occurs it is important that a value be recorded on the case report form: 
 If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  If the lesion is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned 
and BML (below measurable limit) should be ticked (Note:  It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when 
normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned in this circumstance as well and BML 
should also be ticked). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness).  The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm and in that case BML should not be ticked.  (BML is 
equivalent to a less than sign <) 
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Lesions that split or coalesce on treatment:  When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note:  the 
appearance of one or more new lesions is also considered progression). 
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease:  In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease in a magnitude that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status.  The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 
When the patient has only non-measurable disease:  This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease.  The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition:  if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease:  i.e., an increase in tumor burden representing an 
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additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’.  If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point.  While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal:  i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the patient’s baseline lesions show partial or complete response.  For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is 
the patient who has visceral disease at baseline and while on study has a brain CT or MRI 
ordered which reveals metastases.  The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)For the purposes of 
this study, progressive disease should not be made solely on FDG-PET findings because the 
mechanism of the study drug, CB-839, may affect glucose metabolism in both normal and tumor 
tissues. All FDG-PET findings suggestive of progressive disease should be confirmed by 
dedicated anatomic imaging (CT or MRI). The following modifications to RECIST v1.1. will be 
applied to this study: 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.  *Confirmation of the new lesion by CT or MRI scan is 
required per protocol. 
 No FDG-PET at baseline and a positive FDG-PET at follow-up: 
o If the positive FDG-PET at follow-up corresponds to a new sign of disease 
confirmed by CT, this is PD 
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o If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal *CT scan). 
o If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
*reflects study-specific modification to RECIST v.1.1 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation.  On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation.  The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions.  Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement.  Specifically, in nonrandomized trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall 
response’.  This is described further below. 
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs.  Table A 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table B is to be used.  
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point.  If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered not evaluable at that time point, unless a convincing argument 
can be made that the contribution of the individual missing lesion(s) would not change the 
assigned time point response.  This would be most likely to happen in the case of PD. 
For example, if a patient had a baseline sum of 50 mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved PD status, regardless of the contribution of the missing lesion. 
Best overall response:  All time points 
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The best overall response (Table C) will be determined by statistical programming once all the 
data for the patient are known. 
Table A: Time Point Response:  Patients with Targets (+/- Non-Target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. Note:  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
 
Table B: Time Point Response:  Patients with Non-Target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
2. Note:  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
a = ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised. 
 
Table C: Best Overall Response when Confirmation of CR and PR Required 
Overall Response  
First Time Point 
Overall Response  
Subsequent Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for 
SD duration met, otherwise, NE 
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PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for 
SD duration met, otherwise, NE 
NE 
NE 
NE 
3. Note:  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
a = If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of ‘zero’ on the case report form (CRF). 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination.  The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression.  For 
example, in most trials it is reasonable to consider a patient with time point responses of PR-NE-
PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’.  Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response:  it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target disease. 
Conditions that define ‘early progression, early death, and non-evaluability are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
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complete response.  FDG-PET may be used to upgrade a response to a CR in a manner similar to 
a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication.  However, it 
must be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected
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ATTACHMENT 6: DRUG INTERACTIONS 
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 Everolimus 
Per the everolimus Package Insert, everolimus is a substrate of CYP3A4, and also a substrate and 
moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive 
inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.  
Agents That May Increase Everolimus Blood Concentrations  
CYP3A4 Inhibitors and PgP Inhibitors  
In healthy subjects, compared to everolimus treatment alone there were significant increases in 
everolimus exposure when everolimus was co-administered with:  
 
 ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 
3.9- and 15.0-fold, respectively.  
 erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased 
by 2.0- and 4.4-fold, respectively.  
 verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 
2.3- and 3.5-fold, respectively.  
 
Concomitant strong inhibitors of CYP3A4/PgP should not be used. 
 
Use caution when everolimus is used in combination with moderate CYP3A4/PgP inhibitors. If 
alternative treatment cannot be administered reduce the everolimus dose. 
Agents That May Decrease Everolimus Blood Concentrations  
CYP3A4/PgP Inducers  
In healthy subjects, co-administration of everolimus with rifampin, a strong inducer of CYP3A4 
and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, 
compared to everolimus treatment alone. Consider a dose increase of everolimus when co-
administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered.  
 
 
 
 
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ATTACHMENT 7: NCCN-FACIT MEASUREMENT SYSTEM (FKSI-19) 
QUESTIONNAIRE/SCALE 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to  
the past 7 days. 
 
 
 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of 
energy
 ............................................................................ 
0 
1 
2 
3 
4 
GP4 
I have 
pain
 ............................................................................ 
0 
1 
2 
3 
4 
C2 
I am losing 
weight
 ............................................................................ 
0 
1 
2 
3 
4 
HI7 
I feel 
fatigued
 ............................................................................ 
0 
1 
2 
3 
4 
B1 
I have been short of 
breath
 ............................................................................ 
0 
1 
2 
3 
4 
BRM3 
I am bothered by fevers (episodes of high body 
temperature)
 ............................................................................ 
 
0 
 
1 
 
2 
 
3 
 
4 
BP1 
I have bone 
pain
 ............................................................................ 
0 
1 
2 
3 
4 
L2 
I have been 
coughing
 ............................................................................ 
0 
1 
2 
3 
4 
HI12 
I feel weak all 
over
 ............................................................................ 
0 
1 
2 
3 
4 
RCC2 
I have had blood in my 
urine
 ............................................................................ 
0 
1 
2 
3 
4 
D
R
S-
P 
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C6 
I have a good 
appetite
 ............................................................................ 
0 
1 
2 
3 
4 
GF5 
I am sleeping 
well
 ............................................................................ 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get 
worse
 ............................................................................ 
0 
1 
2 
3 
4 
GP2 
I have 
nausea
 ............................................................................ 
0 
1 
2 
3 
4 
C5 
I have diarrhea 
(diarrhoea)
 ............................................................................ 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of 
treatment
 ............................................................................ 
0 
1 
2 
3 
4 
GF1 
I am able to work (include work at 
home)
 ............................................................................ 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy 
life
 ............................................................................ 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
now
 ............................................................................ 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
 
T
S
E 
F 
W 
B 
D
R
S-
E 
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ATTACHMENT 8: EUROQOL QUESTIONNAIRE ED-5D-5L (US ENGLISH SAMPLE 
VERSION)
 
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ATTACHMENT 9: AMENDMENT 2 SUMMARY OF CHANGES 
The major changes and rationale for Amendment 2 are listed below: 
 
1. Section 8.1.2f and 9.1: Inclusion criteria for prior treatment has been revised to remove the 
specific requirement for PD on the most recent VEGF TKI and to remove the requirement for 
prior cabozantinib or nivolumab.  Patients are required to have received at least 2 prior lines 
of therapy and have received at least one VEGF TKI and have progressive disease on or after 
the most recent therapy and within 6 mo of C1D1 on the ENTRATA study.    
a. Rationale: the original protocol inadvertently excluded late-line and treatment-
refractory patients who our investigators feel should be eligible for this study.  This 
change opens the study to patients who have treatment refractory disease even if the 
most recent TKI was discontinued for toxicity or intolerance, so long as the patient 
has progressive cancer on the most recent therapy and within 6 mo of C1D1 on 
ENTRATA.  Also the requirement for prior treatment with cabozantinib or nivolumab 
was for the ENTRATA study when it specifically had registrational intent.  The 
current study which is focused on detection of activity beyond everolimus alone does 
not require that language. 
 
2. Section 8.2.1b: Exclusion criteria for washout period from completion of any anticancer 
therapy was changed for TKI and investigational therapy to be within 2 weeks or 5 half-lives, 
whichever is longer. 
a. Rationale: to allow a minimum time of 2 weeks for a TKI therapy or investigational 
therapy to be washed out. 
 
3. Section 10.1.2 and Attachment 1: Screening evaluations amended to allow patients to sign 
the informed consent form ≤42 days prior to C1D1. 
a. Rationale: to not restrict the time from signing the informed consent form to C1D1. 
 
4. Section 10.3: Clinic visits for safety evaluations will occur on Cycle 1 Day 1 and Cycle 1 
Day 15 then during day 1 at Cycles 2 – 12. Starting with Cycle 13, safety evaluations will 
occur every 3 cycles, or more frequently as clinically indicated. The final assessment will 
occur at the End of treatment visit. 
a. Rationale: the requirement for weekly visits during Cycle 1 was condensed to be 
consistent with standard of care visits.  
 
5. Section 11.3: If CB-839 and everolimus doses were skipped outside of ± 6 hr then it should 
not be made up.  
a. Rationale: clarified to include everolimus as well as CB-839. 
 
6. Section 12.1: CB-839 should be taken 2 hours before antacid therapy. 
a. Rationale: to clarify the appropriate time interval between CB-839 drug 
administration if a patient is receiving antacid therapy. 
 
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Signature Page for VV-TMF-23519 v1.0
Signature Page for VV-TMF-23519 v1.0
Reason for signing: Approved
Name: Sam Whiting
Role: Clinical Development
Date of signature: 07-Aug-2018 22:10:25 GMT+0000
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SAP_001.pdf: 
Calithera Biosciences, Inc. 
Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN 
Calithera Biosciences, Inc. 
CX-839-005 
 
 
 
 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Phase 2 
Study Comparing CB-839 in Combination with Everolimus 
(CBE) vs. Placebo with Everolimus (PboE) in Patients with 
Advanced or Metastatic Renal Cell Carcinoma (RCC) 
Protocol Version 
and Date: 
Amendment 2 / 07 August 2018 
 
Sponsor: 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Prepared By: 
 
Precision for Medicine, Oncology and Rare Disease 
6005 Hidden Valley Road, Suite 170 
Carlsbad, CA 92011 
Document Version 
and Date: 
Version 1.0; 12 March 2019 
 


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1 
STATISTICAL ANALYSIS PLAN APPROVAL 
Sponsor: 
Calithera Biosciences, Inc. 
Clinical Protocol Number: CX-839-005 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled 
Phase 2 Study Comparing CB-839 in Combination with 
Everolimus (CBE) vs. Placebo with Everolimus (PboE) 
in Patients with Advanced or Metastatic Renal Cell 
Carcinoma (RCC) 
Document File Name: 
Calithera_CX-839-005_SAP_v1.0_12MAR2019 
Document Version and 
Effective Date: 
Version 1.0; 12 March 2019 
Approved By: 
 
 
 
 
  
 
Director of Biometrics 
Calithera Biosciences, Inc. 
 Date 
 
  
 
 
 
  
 
Biostatistician I 
Precision for Medicine, Oncology and Rare Disease 
 Date 
 
 
 
 
  
 
  
 
Manager, Biostatistics 
Precision for Medicine, Oncology and Rare Disease 
 Date 


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2 
TABLE OF CONTENTS 
 
1 
Statistical Analysis Plan Approval ............................................................................2 
2 
Table of Contents ........................................................................................................3 
3 
List of Abbreviations ..................................................................................................5 
4 
Introduction .................................................................................................................7 
5 
Study Design ................................................................................................................7 
5.1 
Protocol Synopsis ...................................................................................................8 
5.2 
Study Endpoints .....................................................................................................9 
5.2.1 
Efficacy Endpoints ...........................................................................................9 
5.2.2 
Pharmacokinetic Endpoint .............................................................................9 
5.2.3 
Safety Endpoints ............................................................................................10 
5.3 
Determination of Sample Size .............................................................................10 
5.4 
Analysis Timing ....................................................................................................10 
6 
Study Conduct ...........................................................................................................10 
6.1 
Data Monitoring ...................................................................................................10 
7 
Statistical Methods ....................................................................................................11 
7.1 
Analysis Populations ............................................................................................11 
7.2 
Analysis of Study Conduct ..................................................................................11 
7.3 
Analysis of Treatment Group Comparability ...................................................11 
7.4 
Efficacy Analysis ..................................................................................................11 
7.4.1 
Primary Analysis of Progression-Free Survival ..........................................11 
7.4.2 
Secondary Analysis ........................................................................................14 
7.4.3 
Additional Analyses .......................................................................................15 
7.5 
Pharmacokinetic Analyses ..................................................................................16 
7.6 
Safety Analyses .....................................................................................................17 
7.6.1 
Exposure of Study Medication ......................................................................17 
7.6.2 
Adverse Events ...............................................................................................17 
7.6.3 
Laboratory Data.............................................................................................17 
7.6.4 
Vital Signs .......................................................................................................17 
7.7 
Missing Data .........................................................................................................18 
7.8 
Unblinding ............................................................................................................18 
8 
References ..................................................................................................................19 
9 
Appendix A: Protocol Synopsis ...............................................................................20 
10  Appendix B: Schedule of Study Assessments .........................................................22 
 


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TABLE OF TABLES 
Table 1 
List of Abbreviations .................................................................................5 
Table 2 
PrimaryAnalysis: The Censor/Event Rules for Progression Free 
Survival and Duration of Responsea ......................................................13 
Table 3 
Sensitivity Analysis: The Censor/Event Rules for Progression Free 
Survival and Duration of Responsea ......................................................14 
 
 
 


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3 
LIST OF ABBREVIATIONS  
Table 1 
List of Abbreviations  
Abbreviation 
Definition  
AE 
adverse event 
ALT 
alanine aminotransferase 
AP 
alkaline phosphate 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
twice daily 
BMI 
body mass index 
BOR 
best overall response 
CBE 
CB-839 in combination with everolimus 
ccRCC 
clear cell renal cell carcinoma 
CO2 
carbon dioxide 
CR 
complete response 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DOR 
duration of response 
DRS-E 
disease-related symptoms - emotional 
DRS-P 
disease-related symptoms - physical 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EQ 5D-5L 
EuroQol 5D 
ET 
Early Termination 
FACT 
Functional Assessment of Cancer Therapy 
FDA 
Food and Drug Administration 
FKSI-19 
Functional Assessment of Cancer Therapy Kidney Cancer 
Symptom Index 
FWB 
function and well-being 
HR 
heart rate 
ICH 
International Conference on Harmonization 
IxRS 
Interactive voice/web response system 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRCC 
metastatic renal cell carcinoma 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 


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Abbreviation 
Definition  
ORR 
overall response rate 
OS 
overall survival 
PboE 
placebo in combination with everolimus 
PD 
pharmacodynamics 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
once every two weeks 
QTcF 
corrected QT interval by Fridericia’s Formula 
RCC 
renal cell carcinoma 
RECIST 
response evaluation criteria in solid tumors 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SI 
Système International 
TEAE 
treatment-emergent adverse event 
TFT 
thyroid function test 
TKI 
tyrosine kinase inhibitor 
VEGFR 
vascular endothelial growth factor receptor 
WHO 
World Health Organization 
 
 


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4 
INTRODUCTION  
The statistical analysis plan (SAP) provides details of the planned analyses and statistical 
methods for the study CX-839-005 (A Randomized, Double-Blind, Placebo-Controlled 
Phase 2 Study Comparing CB-839 in Combination with Everolimus [CBE] vs. Placebo 
with Everolimus [PboE] in Patients with Advanced or Metastatic Renal Cell Carcinoma 
[mRCC]).  The background and rationale for the study can be found in the study protocol.  
5 
STUDY DESIGN 
Protocol CX-839-005 is a randomized, Phase 2, multicenter, double-blind, placebo-
controlled study designed to evaluate the safety and efficacy of CBE compared with 
PboE in patients with advanced or mRCC. Figure 1: Study Design SchemaFigure 1 
illustrates the study design.   
Patients eligible after completing all screening evaluations will be randomly assigned in a 
2:1 ratio to receive one of the following treatments:  
 CBE - The glutaminase inhibitor CB-839 [4 x 200 mg tablets (800 mg) twice 
daily (BID)] and the mTOR inhibitor everolimus [10 mg once daily (QD)] 
 
 PboE - Placebo tablets [4 tablets BID] and everolimus [10 mg QD] 
Randomization will be stratified by the following factors: 
 Number of prior VEGFR-targeting TKI therapies: 1 vs. >1 
 Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria for 
previously treated patients with mRCC: favorable vs. intermediate/poor risk 
Treatment administrations are per the instructions and schedule of events outlined in the 
protocol.  Crossover between treatment arms will not be allowed. 
CB-839 or placebo will be administered BID with food.  Everolimus will be administered 
QD at the same time every day.  Patients will receive the treatment determined by 
randomization in 28-day cycles until disease progression or unacceptable toxicity 
(whichever occurs first).  Patients will be followed for 28 additional days from last dose 
date or early discontinuation of treatment for safety follow-up.  Patients who discontinue 
study treatment for reasons other than disease progression or death will remain in follow-
up including protocol-defined imaging.  Long-term follow up for survival will continue 
until death or withdrawal of consent to follow-up.  
 
 
 


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Figure 1: Study Design Schema 
 
*Long-term follow-up every 3 mo for 1 year from discontinuation of treatment, every 6 mo 
thereafter 
5.1 
Protocol Synopsis 
6 
THE PROTOCOL SYNOPSIS IS IN APPENDIX A: PROTOCOL 
SYNOPSIS.  FOR ADDITIONAL DETAILS, SEE THE SCHEDULE OF 
ASSESSMENTS IN 


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Appendix B: Schedule of Study Assessments.  
6.1 
Study Endpoints  
6.1.1 
Efficacy Endpoints 
6.1.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is investigator-assessed PFS defined as the time from 
randomization to the earlier of documented disease progression or death due to any cause, 
whichever occurs first. Radiographic disease progression will be assessed using the 
RECIST 1.1 criteria per investigator.  
6.1.1.2 
Secondary Efficacy Endpoints 
The secondary endpoint OS is defined as the time from randomization to death due to any 
cause.  
6.1.1.3 
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 
investigator.  
 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 investigator.  
 Disease control rate (DCR), defined as the summed percentage of patients with 
best overall response (BOR) of CR, PR and stable disease (SD) according to 
RECIST 1.1 criteria per investigator documented at least 8 weeks following 
treatment initiation.  
 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). 
6.1.2 
Pharmacokinetic Endpoint 
 Maximum observed serum CB-839 concentration (Cmax) after dosing (CBE arm)  
 Minimum observed serum CB-839 concentration (Cmin) prior to dosing at selected 
cycles, at treatment discontinuation (CBE arm) 


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Additional pharmacokinetics may be summarized in a separate report and may be outside 
the scope of the CSR. 
6.1.3 
Safety Endpoints 
The safety endpoints are: 
 Type, incidence, seriousness, nature, severity, and drug-relatedness of adverse 
events graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0) 
 Changes in vital signs, physical findings, and clinical laboratory test results and 
following study treatment administration 
6.2 
Determination of Sample Size 
A median PFS of 3.7 months is estimated for the everolimus control group based on 
published data for 3rd line treatment of advanced ccRCC (7).  The proposed study of CBE 
vs. PboE will enroll approximately 63 patients with a 2:1 randomization between 
experimental and control arms with an accrual period of 8 months and additional follow-
up of 6 months.  If the control arm’s median PFS is 3.7 months and the true PFS hazard 
ratio of experimental patients to control patients is 0.60, the study will require 
approximately 48 PFS events in order to reject the null hypothesis of equal PFS between 
the two treatment arms with a power of 0.80 and 1-sided type I error rate of 0.2 
(exponential PFS distribution and log-rank test for PFS comparison).     
6.3 
Analysis Timing 
There is no interim analyses planned for the primary endpoint of PFS in this study. The 
PFS primary analysis will be conducted when approximately 48 events (PD or death) 
have occurred in the intention-to-treat (ITT) population, which is approximately 20 
months from the first patient randomized.  The number of events correspond to a 
minimum detectable difference in HR of approximately 0.77 for one-sided alpha-level of 
0.2. 
7 
STUDY CONDUCT 
7.1 
Data Monitoring 
Since there is no efficacy interim analysis planned prior to the study unblinding, no data 
monitoring was set up for efficacy.   
Safety data from the study is monitored on an ongoing basis via routine PrimeVigilance 
activities.  In addition to real time medical review of emergent SAEs, a cross functional 
sponsor safety review team performs regular periodic aggregate data reviews across all 
CB-839 studies.  


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8 
STATISTICAL METHODS 
8.1 
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 voice/Web response 
system (IxRS). Patients in the ITT set will be analyzed according to the treatment 
group to which they are randomized regardless of post randomization protocol 
deviations. 
 Safety Analysis Population: Includes all patients who receive at least 1 tablet of 
any study-specific treatment (CB-839, placebo or everolimus) and will be 
analyzed according to the actual treatment received.  Patients randomized to the 
placebo arm having taken any CB-839 will be analyzed in the CB-839 with 
everolimus combination arm.  Similarly, patients randomized to the CB-839 with 
everolimus combination arm without receiving any CB-839 will be analyzed in 
the placebo plus everolimus arm. 
8.2 
Analysis of Study Conduct 
Subject disposition, including enrollment, analysis populations, major protocol deviations 
(including major deviations of inclusion and/or exclusion criteria), reason for 
discontinuation from the study, and on-study status will be summarized by treatment arm 
and overall for all subjects combined for the ITT.  
8.3 
Analysis of Treatment Group Comparability  
Demographic and baseline characteristics, including age, sex, race, ethnicity, baseline 
medical history, prior medications, disease characteristics, histology subtype, current 
disease status, and stratification factors will be summarized by treatment arm and overall 
subjects combined for the ITT and safety populations.  
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.  
8.4 
Efficacy Analysis 
8.4.1 
Primary Analysis of Progression-Free Survival 
Progression free survival is defined as the time from randomization to the first occurrence 
of disease progression as determined by the investigator using RECIST v1.1 or death 
from any cause, whichever occurs first. Patients who have not experienced disease 
progression or death at the time of analysis will be censored at the time of the last tumor 
assessment. Additional censoring applies for missing scans.  The duration of primary 
analysis of PFS will be censored as outlined in Table 2.  A sensitivity analysis will be 


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performed by handling patients having a PFS event at any time by data cutoff as an event 
regardless of missing scans.  See Table 3 for details for censor/event rules for PFS 
sensitivity analysis.  
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 IxRS (MSKCC and number of prior therapies with TKI).  A 1-sided log-rank p < 0.2 
in favor of the CBE experimental treatment will be regarded as a positive result. The null 
and alternative hypotheses can be phrased in terms of the survival functions SPFS_CBE (t) 
and SPFS_PboE (t) in arm CBE and arm PboE, respectively:  
H0: SPFS_CBE (t)=SPFS_PboE (t) versus H1: SPFS_CBE (t)>SPFS_PboE (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_CBE/λPFS_PboE, where λPFS_CBE and λPFS_PboE represent the 
hazard of PFS in arm CBE and arm PboE, respectively, will be estimated with a stratified 
Cox regression model and the same stratification variables used for the stratified log-rank 
test.  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. 
Results from an unstratified analysis will also be provided. 
 
 


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Table 2 
Primary Analysis: The Censor/Event Rules for Progression Free 
Survival and Duration of Responsea 
Situation 
Date of Event or Censoring 
Outcome 
No baseline disease assessment 
Date of 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 
Censored 
Documented RECIST progression per 
investigator or death within 2 scheduled 
scan intervals following previous evaluable 
radiological tumor assessment  
First date of evaluation of 
overall response of PD or 
death is determined 
Event 
RECIST progression or death documented 
to occur after missing 2 scheduled disease 
assessments (including an overall response 
of non-evaluable) following previous 
evaluable radiological tumor assessment 
Date of last evaluable tumor 
assessment with no 
progression prior to the first 
of these missed visits 
Censored 
PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors 
aRECIST progression or death can occur either on study or during the survival follow up 
period after treatment discontinuation for symptomatic deterioration, adverse event, or other 
reason not related to disease and prior to the initiation of new cancer therapy. 


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PFS (month) = (date of event / censor – date of randomization + 1) / 30.4375 
8.4.2 
Secondary Analysis 
8.4.2.1 
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.  Because OS may require 
longer follow up than the primary PFS analysis, additional OS analyses may be 
performed after the time of PFS primary analysis. 
OS will be analyzed with the same methodologies as PFS.   
Table 3 
Sensitivity Analysis: The Censor/Event Rules for Progression Free 
Survival and Duration of Responsea 
Situation 
Date of Event or Censoring 
Outcome 
No baseline disease assessment 
Date of 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 
Censored 
Documented RECIST progression per 
investigator or death within 2 scheduled 
scan intervals following previous evaluable 
radiological tumor assessment  
First date of evaluation of 
overall response of PD or 
death is determined 
Event 
RECIST progression or death documented 
to occur after missing 2 scheduled disease 
assessments following previous evaluable 
radiological tumor assessment 
First date of evaluation of 
overall response of PD or 
death is determined 
Event 
PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors 
aRECIST progression or death can occur either on study or during the survival follow up 
period after treatment discontinuation for symptomatic deterioration, adverse event, or other 
reason not related to disease and prior to the initiation of new cancer therapy. 


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8.4.3 
Additional Analyses 
8.4.3.1 
Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of patients who had an 
objective response (unconfirmed). An objective response is defined as either complete 
response (CR) or partial response (PR), as determined by the investigator with use of 
RECIST v1.1. Patients not meeting these criteria, including patients without any post-
baseline tumor assessments, will be considered non-responders.  Confirmation is not 
required in this double-blind protocol, but for exploratory purposes ORR with 
confirmation by investigator will also be summarized. ORR must be sustained 28 days, 
when confirmation is reported.  
The analysis population for ORR will be the ITT population.  An estimate of BOR and 
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 95% CI will 
be computed using the normal approximation to the binomial distribution and wald with 
continuity correction.  The ORR will be also be compared between the two arms using 
stratified logistic regression. The sensitivity analysis will be computed using the stratified 
Cochran-Mantel-Haenszel test, stratified by the same factors used in the primary PFS and 
OS analyses (see Section 7.5.1).  
8.4.3.2 
Duration of Response 
Duration of Response (DOR) is defined as the time from the first documented objective 
response (PR or CR) to documented PD as determined by the investigator with use of 
RECIST v1.1 or death from any cause, whichever occurs first.  Data for 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 objective response (CR or 
PR), DOR will be censored at the date of the first occurrence of the objective response.  
Censoring rules for DOR will follow those in Table 2.  The determination of DOR is 
based on a non-randomized subset of patients (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. 


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8.4.3.3 
Disease Control Rate 
Disease Control Rate (DCR) is defined as the summed percentage of patients with CR, 
PR and stable disease (SD) according to RECIST v1.1 per investigator criteria 
documented at least 8 weeks following treatment initiation.  
8.4.3.4 
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.  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 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 summarized and analyzed as continuous measures.  Patients without post-baseline 
assessments will be excluded from this analysis.  EQ-5D-5L data will not be reported in 
the CSR. 
8.4.3.5 
Subgroup Analyses  
The consistency of PFS results in subgroups will be examined in the populations where 
PFS benefit has been demonstrated.  To assess the consistency of the study results in 
subgroups defined by demographics (e.g., age, sex, and race/ethnicity), baseline 
prognostic characteristics (e.g., KPS performance status, number of previous TKI 
therapies, MSKCC prognostic criteria, prior anti-PD-1/PD-L1 immunotherapy, etc.),  on 
study proton pump inhibitors, nivo/ipi and nivo use, number of prior lines, and the 
duration of PFS in these subgroups will be examined. Summaries of PFS, including 
unstratified HRs estimated from Cox proportional hazards models and Kaplan-Meier 
estimates of median PFS, will be produced separately for each level of the categorical 
variables for the comparisons between treatment arms and displayed in a forest plot 
(Error! Reference source not found.). 
8.5 
Pharmacokinetic Analyses 
PK analyses will be performed for the PK-evaluable population, defined as all CBE 
patients who have received at least one dose of CB-839 and at least one evaluable PK 
sample.  CB-839 serum concentration data (Cmin and Cmax) will be tabulated and 
summarized.  Descriptive statistics will include means, medians, ranges, and SDs, as 
appropriate. 


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8.6 
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 CB-
839 treatment.   
8.6.1 
Exposure of Study Medication 
Study drug exposure statuses, which include treatment duration, total dose received (mg), 
number of cycles, dose intensity (mg/day), and relative dose intensity (%), will be 
summarized for each treatment arm for the Safety population.  
8.6.2 
Adverse Events 
Verbatim description of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA, v19.1) 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 
(Grade ≥ 3), and adverse events leading to study drug discontinuation or interruption will 
be summarized accordingly.  Multiple occurrences of the same event 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.    
For reporting purposes, “treatment emergent” is defined as 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 completion and/or discontinuation will be listed by treatment arm. 
8.6.3 
Laboratory Data 
Laboratory data will be summarized by treatment arm.  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 v4.3 grade. 
8.6.4 
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.  


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8.7 
Missing Data 
See Section 7.5  for methods for handling missing data for primary and secondary 
endpoints.   
8.8 
Unblinding 
As directed by Calithera, Precision and Calithera will be unblinded at the time of the PFS 
primary analysis when approximately 48 events (PD or death) have occurred in the ITT 
population, prior to final database lock.  
 


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9 
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. 
7. Heng D Stukalin I, Wells C, Donskov F, Rini BI, Lee JL, et al, Third-line therapy 
in metastatic renal cell carcinoma (mRCC): Results from the International mRCC 
Database Consortium (IMDC). J Clin Oncol 2015; 30:suppl; abstr e15578. 
 
 
 


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10 APPENDIX A: PROTOCOL SYNOPSIS 
 
Name of Sponsor:  
Calithera Biosciences, Inc. 
 
Name of Investigational Product:  
CB-839/placebo and everolimus 
 
Title of Study:  
A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study Comparing CB-839 in 
Combination with Everolimus (CBE) vs. Placebo with Everolimus (PboE) in Patients with 
Advanced or Metastatic Renal Cell Carcinoma (RCC) 
 
Protocol Number: CX-839-005 
 
Study Centers:  
Multicenter: Unites States and Europe 
 
Study period (years):  
Estimated 35 months including enrollment and follow-up 
 
Phase of development:  
Phase 2 
 
Objectives:  
Primary Objective 
The primary objective is to compare the progression free survival (PFS) per Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 of patients treated with CB-839 + everolimus (CBE) 
versus placebo + everolimus (PboE) for advanced or metastatic clear cell RCC (ccRCC) 
previously treated with: 
 
At least 2 lines of therapy, including at least one vascular endothelial growth factor 
receptor (VEGFR) tyrosine kinase inhibitor (TKI) 
 
Radiographic progression of mRCC must have occurred (per investigator assessment) on 
or after the most recent systemic therapy and within 6 months prior to C1D1. 
 
Secondary Objective  
The secondary objective is to compare the overall survival (OS) of study patients treated with 
CBE vs. PboE. 
 
Additional Objectives 
The additional objectives are to: 
 
To compare the objective response rate (ORR), Duration of Response (DOR), and 
Disease Control Rate (DCR) of CBE vs. PboE 
 
To compare the safety and tolerability of CBE vs. PboE 
 
To investigate the population pharmacokinetics (PK) of CB-839 


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 
To investigate the relationship of genetic variants and response to CBE vs. PboE 
 
Change in kidney-cancer related symptoms 
 
Change in mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, and global health 
 
Study Design:  
Protocol CX-839-005 is a randomized, Phase 2, multicenter, double-blind, placebo-controlled 
study designed to evaluate the safety and efficacy of CBE compared with PboE in patients with 
advanced or mRCC.  Figure 1: Study Design SchemaFigure 1 illustrates the study design.   
Patients eligible after completing all screening evaluations will be randomly assigned in a 2:1 
ratio to receive one of the following treatments:  
 
CBE - The glutaminase inhibitor CB-839 [4 x 200 mg tablets (800 mg) twice daily 
(BID)] and the mTOR inhibitor everolimus [10 mg once daily (QD)] 
 
 
PboE - Placebo tablets [4 tablets BID] and everolimus [10 mg QD] 
Randomization will be stratified by the following factors: 
 
Number of prior VEGFR-targeting TKI therapies: 1 vs. >1 
 
Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria for previously 
treated patients with mRCC: favorable vs. intermediate/poor risk 
Treatment administrations are per the instructions and schedule of events outlined in the protocol.  
Crossover between treatment arms will not be allowed. 
 


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11 APPENDIX B: SCHEDULE OF STUDY ASSESSMENTS 
 
(1 cycle = 28 days) 
Pre-randomization 
Post-randomization 
Visit 
Screening1 
Cycle 1 
Cycle 2+ 
Cycle 13+ 
(Every 3 cycles)13 
End of Treatment/ 
Follow up 
 
≤21 days 
prior to C1D1 
Day 12 
(≤3 days post 
randomization) 
Day 15 
(± 2 days) 
Day 1 
(± 5 days) 
Day 1 
(± 7 days) 
EOT: Within 28 days post 
treatment discontinuation 
Written Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
Physical Examination3 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
Vital Signs4 
X 
X 
X 
X 
X 
X 
Karnofsky Performance Status 
X 
X 
 
X 
X 
X 
12-lead ECG with QTcF 
X 
 
 
 
 
 
Urinalysis5 
X 
 
 
 
 
 
HbA1c levels5, 6 
X 
 
 
 
 
 
Triglyceride and total cholesterol levels5, 7 
X 
 
 
X 
 
 
Coagulation tests5 
X 
 
 
 
 
 
Serum Chemistry levels 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy Test8 
X 
 
 
 
 
X 
Pharmacokinetic (PK) Assay9 
 
 
X 
X 
 
 
CB-839 or Placebo Dosing 
 
CB-839 or Placebo will be administered twice daily (BID) with food 
 
Everolimus Dosing 
 
Everolimus will be administered once daily (QD) at the same time every day 
 
Optional Tumor Biopsy 
Can be collected any time on study. Patients must sign the optional tumor biopsy consent 
Archival Tumor Collection 
X 
 
 
 
 
 
Radiographic Evaluation of Tumor Burden 
(diagnostic CT with intravenous contrast 
or MRI)10 
X11 
 
 
Every 8 weeks 
Every 12 weeks 
X 
Quality of Life Questionnaires 
 
X 
 
X 
X 
X 
Adverse Events 
 
 
Concomitant Medications 
Document new or worsening AEs from time of first dose through 28 days after study treatment discontinuation. AE information will be collected at study visits and 
may also be collected via any other forms of communication or by subject report. Certain AEs and SAEs that are ongoing 28 days after study discontinuation are to be 
followed until resolution or determination by the investigator that the event is stable or irreversible.  
Follow up 
 
 
 
 
 
X12 


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