Clinical trial NCT02771626
Conditions: Clear Cell Renal Cell Carcinoma (ccRCC) Melanoma Non-small Cell Lung Cancer (NSCLC)
Keywords: RCC Melanoma (MEL) NSCLC Immuno-Oncology Tumor Metabolism Glutaminase Glutaminase Inhibitor
Sponsor: Calithera Biosciences, Inc
Start date: 2016-08-01; Completion date: 2020-04-24
Enrollment: 118 participants; Allocation: NON_RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
This study is an open-label Phase 1/2 evaluation of CB-839 in combination with nivolumab in participants with clear cell renal cell carcinoma, melanoma, and non-small cell lung cancer.

Detailed description:

Arms: arm 1: Telaglenastat 600 mg in combination with standard dose nivolumab in participants with advanced/metastatic clear cell renal cell carcinoma (ccRCC), melanoma, and non-small cell lung cancer (NSCLC). arm 2: Telaglenastat 800 mg/standard dose nivolumab combination in participants with advanced/metastatic ccRCC who have previously received at least one tyrosine kinase inhibitor (TKI) but are treatment naïve to checkpoint modulators programmed death-1/programmed death ligand-1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), or any other agent that specifically targets a T-cell checkpoint or co-stimulation pathway. arm 3: Telaglenastat 800 mg/standard dose nivolumab combination in participants with advanced/metastatic ccRCC who received nivolumab in most recent treatment line that had documented radiological disease progression OR are currently receiving nivolumab with stable disease for at least 24 weeks. arm 4: Telaglenastat 800 mg/standard dose nivolumab combination in participants with advanced/metastatic ccRCC that had documented radiological disease progression while receiving an anti-PD-1/PD-L1 therapy in any prior line of therapy. arm 5: Telaglenastat 800 mg/standard dose nivolumab combination in participants with unresectable or metastatic melanoma that had documented radiological disease progression while receiving an anti-PD-1 therapy in their most recent line of therapy. arm 6: Telaglenastat 800 mg/standard dose nivolumab combination in participants with NSCLC that does not harbor an activating mutation in the epidermal growth factor receptor (EGFR) oncogene and who received nivolumab in most recent treatment line and had documented radiological disease progression OR are currently receiving nivolumab with Stable Disease for at least 24 weeks.
Interventions: intervention 1: CB-839 intervention 2: Nivolumab
Intervention descriptions: intervention 1: Glutaminase inhibitor intervention 2: PD-1 inhibitor

Protocol documents:
Prot_000.pdf: 
CB-839 
Protocol CX-839-004 
14 November 2017 Amendment 2 
 
 
CONFIDENTIAL 
 
1 
Title  
A Phase 1/2 Study of the Safety, Pharmacokinetics, and 
Pharmacodynamics of the Glutaminase Inhibitor CB-839 in Combination 
with Nivolumab in Patients with Advanced/Metastatic Melanoma, Renal 
Cell Carcinoma and Non-Small Cell Lung Cancer 
Protocol Number 
CX-839-004 
IND Number 
118397 
Sponsor 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Sponsor Contact  
 
Director, Clinical Operations 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
Phone:  
 
Date/Version 
14 November 2017/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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Protocol CX-839-004 
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2 
1.0 
TABLE OF CONTENTS 
1.0 
TABLE OF CONTENTS ..................................................................................................2 
2.0 
LIST OF TABLES .............................................................................................................5 
3.0 
LIST OF FIGURES ...........................................................................................................5 
4.0 
CONTACTS .......................................................................................................................6 
5.0 
LIST OF ABBREVIATIONS ...........................................................................................7 
6.0 
CORE PROTOCOL ........................................................................................................11 
6.1 
Objectives ..............................................................................................................11 
6.2 
Sample Size ............................................................................................................12 
6.3 
Study Design ..........................................................................................................12 
6.3.1 
Phase 1 - Dose Escalation .....................................................................13 
6.3.1.1 
Dose Escalation Rules....................................................................14 
6.3.1.2 
Dose-Limiting Toxicity .................................................................15 
6.3.1.3 
Definition of Maximum Tolerated Dose (MTD): ..........................17 
6.3.1.4 
Definition of Recommended Phase 2 Dose (RP2D): .....................17 
6.3.2 
Phase 2 - Cohort Expansion ..................................................................17 
6.3.2.1 
Cohort 1: ccRCC patients naïve to prior checkpoint inhibitor 
therapy ...........................................................................................18 
6.3.2.2 
Cohort 2: ccRCC patients with disease progression or 
prolonged SD (≥ 24 weeks) while receiving nivolumab in their 
most recent line of therapy ............................................................18 
6.3.2.3 
Cohort 3: ccRCC patients with disease progression while 
receiving an anti-PD-1/PD-L1 therapy in any prior line of 
therapy ...........................................................................................19 
6.3.2.4 
Cohort 4: Melanoma patients with disease progression while 
receiving an anti-PD-1 therapy in their most recent line of 
therapy ...........................................................................................20 
6.3.2.5 
Cohort 5: NSCLC patients with disease progression or 
prolonged SD while receiving an anti-PD-1 therapy in their 
most recent line of therapy ............................................................21 
6.3.2.6 
Cohort 6: CB-839 monotherapy in advanced/metastatic 
melanoma patients .........................................................................22 
6.4 
Inclusion Criteria ...................................................................................................23 
6.5 
Exclusion Criteria ..................................................................................................26 
6.6 
Radiological Tumor Assessments ..........................................................................28 
7.0 
PROTOCOL DETAILS ..................................................................................................29 
7.1 
Introduction ............................................................................................................29 
7.1.1 
Background ...........................................................................................29 
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7.1.2 
Preclinical Activity of CB-839 in the Non-Immuno-Oncology 
Setting ...................................................................................................30 
7.2 
Preclinical Activity of CB-839 in the Immuno-Oncology Setting ........................32 
7.2.1 
Previous Human Experience .................................................................34 
8.0 
PRIOR TREATMENT ....................................................................................................34 
8.1 
Prior anti-PD-1/PD-L1 ...........................................................................................35 
9.0 
CONCOMITANT TREATMENT .................................................................................35 
10.0 
PROCEDURES ................................................................................................................36 
10.1 
Screening Evaluation .............................................................................................36 
10.2 
Cycle 1 ...................................................................................................................38 
10.3 
Cycle 2 and all subsequent cycles ..........................................................................38 
10.4 
Other Schedules and Procedures ............................................................................39 
10.5 
End of Treatment (EOT) ........................................................................................40 
10.6 
Follow Up ..............................................................................................................40 
10.7 
Screen Failures .......................................................................................................40 
10.8 
Dose Modification and Management of Toxicities ...............................................41 
10.8.1 
Potential Toxicities................................................................................41 
10.8.1.1 
CB-839 ...........................................................................................41 
10.8.1.2 
Nivolumab......................................................................................42 
10.8.1.3 
CB-839 and Nivolumab Combination ...........................................43 
10.8.2 
Dose Modifications and Toxicity Management ....................................43 
10.8.2.1 
Dose Modification Guidelines .......................................................44 
10.8.2.2 
Resumption of Study Treatment ....................................................45 
10.8.2.3 
Supportive Care Guidelines ...........................................................48 
10.9 
Dose Adjustments, Infusion Delays, and Missed Doses ........................................50 
10.10 Discontinuation of Treatment and Withdrawal of Patients....................................50 
11.0 
TEST ARTICLE/STUDY DRUG ...................................................................................51 
11.1 
Test Article Administration ...................................................................................51 
11.2 
Packaging and Labeling .........................................................................................52 
11.3 
Storage and Stability ..............................................................................................52 
11.4 
CB-839 Accountability, Reconciliation, and Return .............................................52 
11.5 
Test Article Compliance ........................................................................................53 
12.0 
MEASURES TO MINIMIZE/AVOID BIAS ................................................................53 
13.0 
SAFETY EVALUATIONS .............................................................................................53 
13.1 
Physical Examination.............................................................................................54 
13.2 
Vital Signs ..............................................................................................................54 
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13.3 
Electrocardiograms ................................................................................................54 
13.4 
Safety Laboratory Determinations .........................................................................54 
14.0 
BIOMARKER AND PHARMACODYNAMIC SAMPLES ........................................55 
14.1 
Archival Tumor Biopsy Samples ...........................................................................55 
14.2 
Predose and Postdose Tumor Biopsies ..................................................................55 
14.3 
Plasma and Whole Blood Collection for Biomarker Analysis .........................56 
14.4 
Biomarker Assessment...........................................................................................57 
15.0 
PHARMACOKINETIC EVALUATION ......................................................................57 
15.1 
Blood Collection ....................................................................................................57 
15.2 
Bioanalytical Methodology ....................................................................................58 
16.0 
STATISTICAL ANALYSIS ...........................................................................................58 
16.1 
General Statistical Considerations .........................................................................58 
16.2 
Independent Radiology Committee (IRC) .............................................................59 
16.3 
Sample Size and Power ..........................................................................................59 
16.4 
Analysis Populations ..............................................................................................60 
16.4.1 
Safety Population ..................................................................................60 
16.4.2 
DLT-evaluable Populations in Dose Escalation ...................................61 
16.4.3 
Response Evaluable Population ............................................................61 
16.4.3.1 
Melanoma Confirmed PD Population ............................................61 
16.5 
Efficacy Analysis ...................................................................................................62 
16.6 
Safety Analysis ......................................................................................................62 
16.7 
Pharmacokinetic Analysis ......................................................................................63 
16.7.1 
Biomarker Analysis ...............................................................................63 
16.8 
Precautions .............................................................................................................63 
17.0 
ADVERSE EVENTS .......................................................................................................64 
17.1 
Definitions..............................................................................................................64 
17.2 
Recording and Reporting .......................................................................................68 
17.3 
Serious Adverse Event Reporting ..........................................................................69 
18.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION .............................70 
19.0 
INFORMED CONSENT .................................................................................................70 
20.0 
PROTOCOL AMENDMENTS ......................................................................................71 
21.0 
QUALITY CONTROL AND ASSURANCE.................................................................71 
22.0 
DIRECT ACCESS, DATA HANDLING, AND RECORD KEEPING ......................71 
22.1 
Investigator ............................................................................................................71 
22.2 
Sponsor ..................................................................................................................72 
23.0 
PRE-STUDY DOCUMENTATION ...............................................................................72 
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24.0 
RECORDS RETENTION ...............................................................................................73 
25.0 
AUTHORSHIP AND ACCOUNTABILITY .................................................................73 
26.0 
REFERENCES .................................................................................................................74 
ATTACHMENT 1:  SCHEDULE OF STUDY ASSESSMENTS ...........................................77 
ATTACHMENT 2: PHARMACOKINETIC AND BIOMARKER SAMPLING 
SCHEDULE......................................................................................................................79 
ATTACHMENT 3: CLINICAL LABORATORY TESTS ......................................................81 
ATTACHMENT 4:  RECIST CRITERIA VERSION 1.1 .......................................................82 
ATTACHMENT 5: IRECIST: MODIFIED RECIST 1.1 FOR IMMUNE-BASED 
THERAPEUTICS ............................................................................................................94 
ATTACHMENT 6:  CYP2C9 ...................................................................................................105 
ATTACHMENT 7: AMENDMENT 2 SUMMARY OF CHANGES ...................................106 
ATTACHMENT 8: ELECTRONIC PROTOCOL SIGNATURE PAGE ...........................151 
 
2.0 
LIST OF TABLES 
Table 6.3-1: Dose Escalation .........................................................................................................14 
Table 10.7-1: Drug-related AEs reported in ≥2 subjects on study CX-839-001 ...........................41 
Table 10.7-2: Drug-related ≥ Grade 3 AEs reported on study CX-839-001 .................................42 
Table 10.8-1:  Dose Modification Guidelines for irAEs ................................................................46 
Table 14.2-1: Summary of Tumor Biopsy* Collections for Patients ............................................56 
Table 22.2-1: Summary of Sample Size and Power for Expansion Cohorts .................................59 
Table A: Time Point Response:  Patients with Targets (+/- Non-Target) Disease ........................91 
Table B: Time Point Response:  Patients with Non-Target Disease Only ....................................91 
Table C: Best Overall Response when Confirmation of CR and PR Required .............................92 
 
3.0 
LIST OF FIGURES 
Figure 8.2-1.  Antiproliferative and pro-apoptotic activity of CB-839 in lung and kidney 
tumor cell lines in vitro ....................................................................................31 
Figure 8.2-2.  Pharmacodynamic effects of CB-839 in mouse tumor  xenografts and rat 
plasma ..............................................................................................................32 
Figure 8.3-1.  T-cells require glutamine for growth but are largely unaffected by CB-839. .........32 
Figure 8.3-2.  CB-839 combination with anti-PD-1 in vivo. .........................................................33 
 
 
 
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Protocol CX-839-004 
14 November 2017 Amendment 2 
 
 
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6 
4.0 
CONTACTS 
Safety Physician and Medical Monitor 
Name:  
 
Address:  343 Oyster Point Blvd. Suite 200 
South San Francisco, CA  
Phone (Office)
 
Phone (Mobile): 
 
Email: 
  
 
Calithera Head of Clinical Operations  
Name:  
  
Address:  343 Oyster Point Blvd. Suite 200 
South San Francisco, CA  
Phone (Office): 
  
 
Email: 
   
 
 
SAE Reporting Contact 
CRO Safety Lead 
Name: 
 
 
 
 
Phone (Office): 
 
Central Safety Office: 
 
 
SAE Reporting Details (to be used for submitting the SAE forms): 
Central Safety Fax: +1 800 727 8347                  
Email: calithera@primevigilance.com   
 
 
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5.0 
LIST OF ABBREVIATIONS 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALK 
Anaplastic lymphoma kinase 
APTT 
Activated partial thromboplastin time 
α-KG 
α-ketoglutarate 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BIDf 
Twice daily – fed cohort 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
ccRCC 
Clear Cell Renal Cell Carcinoma 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
CR 
Complete remission 
CTA 
Clinical Trial Agreement 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP450 
Cytochrome P450 
D/C 
Discontinue 
DFS 
Disease-Free Survival 
DLBCL 
Diffuse Large B-Cell Lymphoma 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment 
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Abbreviation or Term1 
Definition/Explanation 
FDA 
Food and Drug Administration 
EF 
Ejection fraction 
FFPE 
Fresh Frozen Parafin Embeded 
FH 
Fumarate hydratase 
FISH 
Fluorescence in situ hybridization 
FLC 
Free light chain 
GAC 
Glutaminase C, alternative splice variant of glutaminase 
GCP 
Good Clinical Practice 
g/dL 
Grams per decilitre 
GFR 
Glomerular filtration rate 
GIST 
Gastrointestinal stromal tumor 
GGT 
Gamma glutamyl transpeptidase 
GLP 
Good Laboratory Practice  
GLS 
Glutaminase gene signature 
GLS2 
Glutaminase 2 (liver form of glutaminase) 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HCO3- 
Bicarbonate 
hERG 
Human Ether-à-Go-Go Related Gene 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
HPLC 
High-performance liquid chromatography 
HP-β-CD 
Hydroxypropyl-β-cyclodextrin 
HR 
Heart rate 
Hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
IRC 
Independent Radiology Committee 
iRECIST  
modified RECIST 1.1 for immune-based therapeutics  
irSD 
Immune-related Stable Disease 
IU 
International Unit 
IV 
Intravenous, intravenously 
KGA 
Kidney glutaminase (alternative splice variant of glutaminase) 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
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Abbreviation or Term1 
Definition/Explanation 
LC-MS/MS 
Liquid chromatography-mass spectrometry/mass spectrometry 
mAb 
Monoclonal Antibody 
mcL/ µL 
Microliter  
MedRA 
Medical Dictionary for Drug Regulatory Activities 
MEL 
Melanoma 
mL 
Milliliter 
MTD 
Maximum tolerated dose  
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall Survival 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death ligand 1 
PDn 
Pharmacodynamic(s) 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PSA  
Prostate specific antigen 
PT 
Prothrombin time 
aPTT 
Activated Partial thromboplastin time 
QTcF 
Corrected QT interval, Fridericia’s formula 
RP2D 
Recommended Phase 2 Dose 
RBC 
Red Blood Cell 
RCC 
Renal cell carcinoma 
Rx 
Treatment 
SAE 
Serious adverse event 
SD 
Stable disease 
SDH 
Succinate dehydrogenase 
SFLC 
Serum free light chain 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
STD10 
Severely toxic dose in 10% of animals 
Tmax 
Time of maximum observed concentration 
TEAE 
Treatment-emergent adverse event 
TCA 
Tricarboxylic acid 
TID 
Three times daily 
TIDf 
Three times daily – fed cohort 
TNBC 
Triple negative breast cancer 
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Abbreviation or Term1 
Definition/Explanation 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
WBC 
White blood cell 
1 
All of these abbreviations may or may not be used in protocol. 
 
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CB-839 
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To evaluate biomarkers that may predict the anti-
tumor effect of CB-839 alone and in combination 
with nivolumab in patients with 
advanced/metastatic ccRCC, MEL, and NSCLC 
Analysis of any potential relationship 
between predose biomarkers of tumor or 
immune state and anti-tumor effect, 
including PD-L1 expression in tumor 
To evaluate anti-tumor effect of CB-839 as 
monotherapy in patients with advanced/metastatic 
MEL by modified RECIST 1.1 for immune-based 
therapeutics (iRECIST) 
Assessed by ORR, DOR and PFS per 
iRECIST 
To evaluate anti-tumor effect of CB-839 in 
combination with nivolumab for patients with 
advanced/metastatic ccRCC, MEL, and NSCLC by 
iRECIST 
Assessed by ORR, DOR and PFS per  
iRECIST  
To evaluate anti-tumor effect of CB-839 and 
nivolumab in combination after progression on 
CB-839 monotherapy in patients with 
advanced/metastatic MEL 
Assessed by ORR, DOR and PFS per 
RECIST v1.1 and by iRECIST 
 
6.2 Sample Size 
Dose Escalation: A minimum of 9-12 patients with ccRCC, melanoma, or NSCLC will be 
enrolled in Dose Escalation.  Patients that are considered not evaluable for DLT assessment 
(Section 16.4.2) will be replaced.  Up to 6 additional patients may be enrolled at each dose level 
to further investigate safety and pharmacodynamic biomarkers. 
Dose Expansion:  Approximately 92 patients will be enrolled in Stage 1 across six cohorts.  If a 
patient does not meet criteria for inclusion into the Efficacy Evaluable Population (Section 16.5), 
the patient will be considered not evaluable for efficacy and will be replaced.  If any cohorts 
achieve the pre-defined Stage 1 thresholds for clinical activity, additional patients will be 
enrolled in Stage 2 for that Cohort.  Approximately 195 patients will be enrolled in Stage 2 
across six cohorts if all complete enrollment.  The number of patients may be increased in 
Stage 2 in each expansion cohort based upon observed anti-tumor activity. 
6.3 Study Design 
Protocol CX-839-004 is a Phase 1/2 open-label study of the combination of CB-839 with 
nivolumab in patients with advanced/metastatic ccRCC, MEL, and NSCLC, as well as CB-839 
monotherapy in patients with advanced/metastatic MEL.  Sequential dose escalation of CB-839 
with full dose nivolumab (CB-Nivo) will take place in patients with advanced ccRCC, 
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CB-839 
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CONFIDENTIAL 
 
14 
Dose escalation will continue until identification of a MTD or up to a maximum dose of 800 mg 
orally BID.  Up to 6 additional patients may be enrolled to a dose escalation cohort in order to 
generate additional safety, pharmacokinetic, and biomarker data. 
The starting dose of CB-839 will be 600 mg BID and the maximum dose will be 800 mg BID.  
The first dose of CB-839 will be administered in the morning with breakfast.  The second dose 
will be administered in the evening with a meal approximately 12 hr (± 2 hr) after the morning 
dose.  The dose range and schedule were selected based on the results of three Phase 1 studies of 
CB-839: CX-839-001 (solid tumors), CX-839-002 (multiple myeloma and non-Hodgkin’s 
lymphoma), and CX-839-003 (acute leukemia) in which doses up to 1000 mg BID were 
administered without identification of an MTD.  The dose of 600 mg BID with food has been 
well tolerated and has resulted in good exposure that achieves robust inhibition of glutaminase 
activity in platelets and tumors.  A monotherapy expansion cohort in CX-839-001 is currently 
being enrolled at the 800 mg BID dose and has been tolerated to date. 
Cohorts of three to six patients with ccRCC, MEL, or NSCLC will receive CB-839 capsules 
(200 mg strength) or tablets (200 mg strength) in a dose-escalating fashion together with full 
dose nivolumab according to the rules presented below (Table 6.3-1).  To be enrolled in dose 
escalation, each patient must fulfill the eligibility criteria for one of the Expansion Cohorts 
described in the Cohort Expansion section below. 
Table 6.3-1: Dose Escalation 
CB-839 Capsules or Tablets 
Nivolumab 
Cohort 
Dose (mg) 
BID 
% Increase 
N 
Dose (mg) 
Q2W 
-1 
400 
-50% 
3 – 6 
240 
1* 
600 
 
3 – 6 
240 
2 
800 
33% 
6 
240 
*starting dose level 
 
6.3.1.1 Dose Escalation Rules 
Dose limiting toxicities (DLTs) observed in Cycle 1 (first 28 days of dosing) will be used to 
determine escalation to the next dose level.  The study is using a traditional 3+3 design and the 
dose escalation rules are as follows: 
 An initial cohort of 3 patients is enrolled. 
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 If 0/3 patients develops a DLT, escalation to the next dose will occur. 
 If 1/3 patients develops a DLT: 
o Another 3 patients will be enrolled at this dose level. 
 If 0 of the 3 new patients develops a DLT (for a total of 1/6 patients with a 
DLT at this dose level), escalation to the next dose level will occur. 
 If ≥1 of the 3 new patients develops a DLT (for a total of ≥2/6 patients 
with a DLT at this dose level), the dose escalation stage of the trial will be 
terminated and the dose directly below the current dose will be considered 
the MTD. 
 If ≥2/3 patients develop a DLT, the dose escalation stage of the trial will be terminated 
and the dose directly below the current dose will be considered the MTD. 
 
The highest planned dose of CB-839 to be tested during dose escalation is 800 mg BID.  If 0/3 
patients or ≤1/6 patients develop a DLT at that dose, then 800 mg BID of CB-839 in combination 
with nivolumab (240 mg IV every 2 weeks) will be considered the Recommended Phase 2 Dose 
(RP2D) of the combination.  If ≥ 2/6 patients develop a DLT at the 800 mg BID dose level, then 
600 mg BID will be considered the RP2D, as long as a total of <2/6 patients develops a DLT at 
that dose.  If a dose level below 800 mg BID is selected as the MTD due to only 2 DLTs and 
subsequent clinical data demonstrate the DLT rate at the MTD to be <10% in >10 patients, re-
escalation of the previous dose associated with DLT may be considered.  If re-escalation occurs, 
up to 6 additional patients may be enrolled and the dose level will be considered tolerable if the 
DLT rate is <33%. 
6.3.1.2 Dose-Limiting Toxicity 
During dose escalation, patients must receive at least 75% of the planned CB-839 
administrations and both doses of nivolumab in the first 28-day treatment cycle to be considered 
evaluable for DLT, unless the patient has a DLT or has the study drug held for an adverse event 
(AE) that may herald a DLT.  Patients who discontinue the study during the first cycle prior to 
receiving the requisite study treatment administrations for reasons that include, but are not 
limited to, clinical/radiographic progression, voluntary withdrawal, or complications that the 
Principal Investigator considers secondary to the patient’s malignancy will not be considered 
evaluable for DLT and will be replaced. 
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It is likely that expected Grade 3 AEs associated with nivolumab administration will occur in this 
study and given the small sample size of cohorts this may occur by chance in 2 of 6 patients, the 
usual threshold for unacceptable toxicity.  It will be important to differentiate between immune-
related adverse events (irAEs) expected from nivolumab toxicity as opposed to an increase in 
frequency or a worsening of severity of irAEs as an indicator of unacceptable toxicity related to 
the combination. 
The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
judged by the Investigator to be related (possibly or probably) to study drug administration: 
Non-Hematologic DLT: 
 Any ≥ Grade 4 non-hematological toxicity 
 Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care with 
the exception of: 
o Grade 3 fatigue 
o Grade 3 rash or itching that resolves to ≤ Grade 1 within 3 weeks 
o Grade 3 tumor flare (defined as local pain, irritation or rash localized at sites of 
known or suspected tumor) 
o Grade 3 irAE that resolves to Grade 1 with corticosteroid therapy in ≤ 3 weeks 
o A transient (resolves within 6 hours of onset) Grade 3 infusion-related AE 
o Grade 3/4 elevation in serum amylase and/or lipase that are not associated with 
clinical or radiological evidence of pancreatitis  
 Any clinically meaningful Grade 3 non-hematologic laboratory value if: 
o Medical intervention (other than electrolyte repletion) is required to treat the 
patient, OR 
o The abnormality leads to hospitalization, OR 
o The abnormality persists for >1 week. 
 
Hematologic DLT: 
 Grade ≥ 3 febrile neutropenia (ANC < 1.0 x 109/L with either a single temperature 
≥ 38.3ºC or a sustained temperature of ≥ 38 for more than 1 hr) 
 Grade 4 thrombocytopenia (< 25.0 x 109/L) if associated with: 
o A bleeding event that requires an elective platelet transfusion, OR 
o A life-threatening bleeding event which results in urgent intervention and 
admission to an Intensive Care Unit 
 Any Grade 5 hematologic or non- hematologic toxicity 
 
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Failing to receive 75% of CB-839 doses or 2 doses of nivolumab within Cycle 1 due to a drug-
related AE that is an AE or may herald an AE will be considered a DLT.  In addition, any other 
AE that is felt to be treatment-limiting in the medical opinions of the Principal Investigator and 
the Medical Monitor may be considered a DLT.  AEs should be considered treatment-related, 
unless they fulfill the following criteria: 
 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). 
 
In general, patients who experience a DLT will not receive further treatment with the study 
drugs.  Patients with toxicities that meet the DLT definition but are rapidly reversible (≤ Grade 1 
within 2 weeks) may be continued on study with Investigator and Medical Monitor agreement.  
6.3.1.3 Definition of Maximum Tolerated Dose (MTD): 
The Maximum Tolerated Dose (MTD) is defined as the highest dose level with no more than 1 
DLT reported in 6 DLT-evaluable patients. 
6.3.1.4 Definition of Recommended Phase 2 Dose (RP2D): 
The Recommended Phase 2 Dose (RP2D) of CB-Nivo will be selected based on the clinical data 
and will not exceed the MTD.  If <2/6 patients experience a DLT at 800 mg BID during dose 
escalation, then 800 mg BID will be considered to be the RP2D.  If ≥ 2/6 patients experience 
DLTs at 800 mg BID, and ≤ 1/6 patients experience a DLT at 600 mg BID, then 600 mg BID 
will be considered the RP2D.  The Sponsor, in consultation with the Study Investigators, will 
continue to evaluate the safety data accumulated during the evaluation of dose expansion cohorts 
and may amend the RP2D with further experience. 
6.3.2 Phase 2 - Cohort Expansion 
To further characterize safety, tolerability, and efficacy, additional patients will be enrolled at the 
RP2D in specific cohorts outlined below. 
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The Sponsor, in consultation with Study Investigators, will evaluate the overall safety profile of 
the CB-Nivo combination during cohort expansions and as a monotherapy in 
advanced/metastatic melanoma.  Safety data (drug-related AEs including Grade ≥ 3 irAEs and all 
SAEs) will be analyzed and reviewed by the Sponsor and Study Investigators.  With ongoing 
safety analysis and review by the Sponsor and Study Investigators, decisions may be made to 
amend the RP2D with further experience in specific diseases.  Cohorts are designed based on 
Simon’s two-stage statistical approach, as described in the Statistical Analysis Section 16.0. 
6.3.2.1 Cohort 1: ccRCC patients naïve to prior checkpoint inhibitor therapy 
This cohort will enroll ccRCC patients that have received a prior anti-VEGF/R therapy but have 
never received therapy with anti-PD-1/PD-L1, CTLA-4, or any other agent that specifically 
targets a T-cell checkpoint or co-stimulation pathway.  This patient population was recently 
studied in a randomized Phase 3 study in which nivolumab was compared to everolimus. 
Nivolumab had an ORR of 25%, PFS of 4.6 mo, and OS of 25.0 mo (Motzer 2015).  The primary 
endpoints of Cohort 1 will be safety/tolerability, ORR, and DOR per Investigator.  Predose 
biopsies will also be collected in order to correlate efficacy with potential predictive biomarkers 
(Section 14.2). 
A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.25 versus the 
alternative that ORR ≥ 0.40; the sample size of 52 patients will maintain an alpha level of 0.10 
and a power of 0.80.  At least 25 evaluable patients will be enrolled in Stage 1.  If at least 8 
patients respond (PR or better) out of 25 response-evaluable patients in Stage 1, then an 
additional 27 evaluable patients will be enrolled in Stage 2 (total of 52 response-evaluable 
patients).  If Stages 1 and 2 are completed, a minimum of 17 patients must demonstrate a 
response (PR or better) to reject the null hypothesis. 
6.3.2.2 Cohort 2: ccRCC patients with disease progression or prolonged SD (≥ 24 weeks) 
while receiving nivolumab in their most recent line of therapy 
This cohort will enroll ccRCC patients that received nivolumab in their most recent line of 
therapy with minimal washout (≤ 8 weeks), with the intent of adding CB-839 to the ongoing 
nivolumab regimen.  Since this patient population has either documented radiological disease 
progression OR long-term SD (≥ 24 weeks), the likelihood of a response on nivolumab 
monotherapy is extremely low and any activity can be confidently attributed to the addition of 
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CB-839.  The primary endpoints of Cohort 2 will be safety/tolerability, ORR, and DOR per 
Investigator.  Predose and postdose biopsies will be collected during Stage 1 in order to 
demonstrate a pharmacodynamic effect of CB-839 in the context of PD-1 inhibition by 
nivolumab and correlate efficacy with potential predictive biomarkers (Section 14.2). 
Since the mechanisms of resistance to nivolumab may be different in the settings of primary 
refractory disease, relapsed, and long-term stable disease, patients in Cohort 2 will fall into one 
of the following subgroups: 
a) Patients with progressive disease after achieving no better than SD 
b) Patients with progressive disease after achieving an objective response  
c) Patients with SD as their best response for > 24 weeks 
A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.05 versus the 
alternative that ORR ≥ 0.15; the sample size of 56 patients will maintain an alpha level of 0.10 
and a power of 0.80.  If at least 2 patients respond (PR or better) out of 20 response-evaluable 
patients in Stage 1, then an additional 36 evaluable patients will be enrolled in Stage 2 (total of 
56 response-evaluable patients).  If Stages 1 and 2 are completed, a minimum of 5 patients must 
demonstrate a response (PR or better) to reject the null hypothesis.  The lower target ORR (15%) 
is based on the heterogeneity of histological subtypes (with potentially differential sensitivity to 
CB-839) in this cohort. 
Of note, up to 5 additional patients may be enrolled in Stage 1 in order to ensure sufficient 
enrollment of each of the subgroups.  Based on emerging data, the Sponsor may choose to 
restrict further enrollment in this cohort to one or two of the three subgroups identified above. 
6.3.2.3 Cohort 3: ccRCC patients with disease progression while receiving an anti-PD-
1/PD-L1 therapy in any prior line of therapy 
This cohort will enroll ccRCC patients that had documented radiological disease progression 
while receiving an anti-PD-1/ PD-L1 therapy in any prior line of therapy.  An active anti-PD-1/ 
PD-L1 agent is defined as an agent that has demonstrated evidence of activity, e.g., nivolumab 
and pembrolizumab, atezolizumab, durvalumab, or avelumab.  Since this patient population had 
documented disease progression on the prior anti-PD-1/ PD-L1 therapy, the likelihood of a 
response on nivolumab monotherapy is very low and evidence of activity can be confidently 
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attributed to the addition of CB-839.  The primary endpoint of Cohort 3 will be 
safety/tolerability, investigator assessed ORR, and DOR per Investigator.  Predose biopsies will 
be collected in order to correlate efficacy with potential predictive biomarkers (Section 14.2). 
A Simon’s two-stage design will test the null hypothesis that ORR ≤ 0.05 versus the alternative 
that ORR ≥ 0.2; the sample size of 24 patients will maintain an alpha level of 0.10 and a power 
of 0.80.  At least 9 evaluable patients will be enrolled in Stage 1.  If at least 1 patient responds 
(PR or better) out of 9 response-evaluable patients in Stage 1, then an additional 15 evaluable 
patients will be enrolled in Stage 2 (total of 24 response-evaluable patients).  If Stages 1 and 2 
are completed, a minimum of 3 patients must demonstrate a response (PR or better) to reject the 
null hypothesis. 
6.3.2.4 Cohort 4: Melanoma patients with disease progression while receiving an anti-PD-1 
therapy in their most recent line of therapy 
This cohort will enroll melanoma patients with radiological disease progression (per Investigator 
assessment) while receiving an anti-PD-1/PD-L1 agent as monotherapy or in a combination 
regimen to treat advanced/metastatic melanoma in the most recent line of therapy. There must be 
≤ 8 weeks elapsed between last dose of anti-PD-1/PD-L1 and C1D1 of the CX-839-004 trial.  
The intent of this cohort is to convert progressing disease to responding disease by the addition 
of CB-839 to ongoing anti-PD-1/PD-L1 therapy.  Because this patient population has 
documented disease progression on anti-PD-1/PD-L1 therapy at study start, the likelihood of a 
response to nivolumab monotherapy is extremely low and any activity can be confidently 
attributed to the addition of CB-839.  Patients on anti-PD-1/PD-L1 agent other than nivolumab 
will switch to nivolumab for treatment on this study.  The primary endpoints of Cohort 4 will be 
ORR and DOR as determined by an Independent Radiology Committee (IRC).  Pre- and post-
dose biopsies will be collected from all patients enrolled into the Expansion phase of Cohort 4 
(so long as deemed safe and technically feasible to biopsy) in order to demonstrate a 
pharmacodynamic effect of CB-839 in the context of PD-1 inhibition and to correlate efficacy 
with potential predictive biomarkers (Section 14.2).   
The original study design with 24 patients tested the null hypothesis that ORR of CB-839 + 
nivolumab was ≤ 5% versus the alternative of ≥ 20% with an alpha level of 0.1 and power of 
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80%.  Per study design, 9 patients would be enrolled in Stage 1 and 1 responder would trigger 
enrollment of an additional 15 patients in Stage 2; while 3 responders out of 24 total patients 
would lead to formal rejection of the null hypothesis.  To date there have been 3 responding 
patients (including one complete response and 2 deep partial responses of -73% and -47%), all 
confirmed responses on repeat scan ≥ 4 weeks after initial response, in 16 evaluable patients.  
Notably, per protocol eligibility, all of these patients were experiencing disease progression on 
PD-1/PD-L1 inhibitor therapy in the immediate prior line of therapy strongly suggesting that the 
response was the result of the addition of CB-839.   
 
As a result of encouraging preliminary clinical activity, Cohort 4 enrollment will be expanded to 
approximately 75 response-evaluable melanoma patients (including patients already enrolled).  
For the purpose of statistical design we assume a background/historical ORR of < 10% in this 
patient population. The total sample size is determined based on the ability to produce a 
confidence interval that would exclude the historic response rate and to provide sufficient 
information for a reliable understanding of the safety profile.  Specifically, the lower limit of the 
95% CI associated with observation of an objective response rate of 18.7% in 75 treated subjects 
(14/75 responders) excludes 10%.  Interim clinical monitoring will be performed in this 
expansion to ensure adequate safety and tolerability as well as favorable risk/benefit by assessing 
preliminary efficacy measures such as objective response rate and duration of response. 
  
6.3.2.5 Cohort 5: NSCLC patients with disease progression or prolonged SD while 
receiving an anti-PD-1 therapy in their most recent line of therapy 
This cohort will enroll patients with NSCLC that does not harbor an activating mutation in the 
epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) oncogene and 
have received anti-PD-1/PD-L1 therapy as the most recent line of therapy with < 8 weeks 
elapsed between last dose of anti-PD-1/PD-L1 and C1D1 of the CX-839-004 trial.  Eligible 
patients will have experienced radiological disease progression or SD without response lasting ≥ 
24 weeks with the intent of adding CB-839 to an ongoing anti-PD-1 regimen.  Driver- mutation 
(EGFR or ALK) positive patients have been excluded because they tend to have lower 
mutational load and are less responsive to immunotherapies (Borghaei 2015).  Patients receiving 
an anti-PD-1 therapy other than nivolumab would switch over to nivolumab.  Because this 
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patient population has documented radiological disease progression or long-term SD (≥ 24 
weeks), the likelihood of a response on nivolumab monotherapy is extremely low and any 
activity can be confidently attributed to the addition of CB-839.  The primary endpoint of Cohort 
5 will be safety/tolerability, ORR, and DOR per Investigator.  Pre-dose and post-dose biopsies 
will also be collected in order to demonstrate a pharmacodynamic effect of CB-839 in the 
context of PD-1 inhibition by nivolumab and correlate efficacy with potential predictive 
biomarkers (Section 14.2). 
A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.05 versus the 
alternative that ORR ≥ 0.15; the sample size of 56 patients will maintain an alpha level of 0.10 
and a power of 0.80.  If at least 2 patients respond (PR or better) out of 20 response-evaluable 
patients in Stage 1, then an additional 36 evaluable patients will be enrolled in Stage 2 (total of 
56 response-evaluable patients).  If Stages 1 and 2 are completed, a minimum of 5 patients must 
demonstrate a response (PR or better) to reject the null hypothesis.  The lower target ORR (15%) 
is based on the heterogeneity of histological subtypes (with potentially differential sensitivity to 
CB-839) in this cohort. 
Enrollment will be monitored in order to ensure at least 8 patients are enrolled from each of the 
two major histological subtypes of NSCLC, squamous and non-squamous.  Based on emerging 
data, the Sponsor may choose to restrict further enrollment in this cohort to a specific 
histological subtype. 
6.3.2.6 Cohort 6: CB-839 monotherapy in advanced/metastatic melanoma patients 
This cohort will enroll patients with advanced/metastatic melanoma with no curative options and 
will assess the anti-tumor activity of single agent CB-839.  Because the combination of CB-839 
and nivolumab has demonstrated activity in nivolumab-refractory disease, unbiased assessment 
of CB-839 as monotherapy is presumed to require full washout of previous PD-1/PD-L1 therapy.  
For the purpose of this study, full washout is defined as a minimum of 4 mo (approximately 5 
half-lives) from the most recent dose of anti-PD-1/PD-L1 therapy to C1D1 of CB-839 
monotherapy.  This washout period will allow any clinical activity to be attributed to CB-839 
alone.  The primary endpoint of Cohort 6 is ORR per RECIST v1.1 as assessed by the 
Investigator.  Pre-dose biopsies will be collected on all patients to evaluate for predictive 
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markers of treatment response.  Because the combination of CB-839 with nivolumab has 
demonstrated activity in nivolumab refractory patients, patients will be eligible to receive the 
combination of CB-839 with nivolumab after disease progression on CB-839 monotherapy.  
These patients will be followed for the exploratory objectives of ORR, DOR, PFS per RECIST 
v1.1 subsequent to starting the combination of nivolumab and CB-839.  
For the primary objective, a Simon’s two-stage design will test the null hypothesis that 
ORR ≤ 0.05 versus the alternative that ORR ≥ 0.2; the sample size of 24 patients will maintain 
an alpha level of 0.10 and a power of 0.80.  At least 9 evaluable patients will be enrolled in 
Stage 1.  If at least 1 patient responds (PR or better) out of 9 response-evaluable patients in 
Stage 1, then an additional 15 evaluable patients will be enrolled in Stage 2 (total of 24 response-
evaluable patients).  If Stages 1 and 2 are completed, a minimum of 3 patients must demonstrate 
a response (PR or better) to reject the null hypothesis. 
6.4 Inclusion Criteria 
1. Patients must have a histological or cytological diagnosis of metastatic cancer or locally 
advanced cancer that is not amenable to local therapy.  Additional criteria specific to 
different Cohorts of the study are provided below. 
2. Ability to provide written informed consent in accordance with federal, local, and 
institutional guidelines 
3. Age ≥ 18 years 
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 
5. Life Expectancy of at least 3 mo 
6. Patient must have adequate organ function as indicated by the following laboratory 
values: 
 
Test 
Value 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Total white blood cell (WBC) count  
≥2,000/mm3 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL 
Serum creatinine 
≤1.5 X upper limit of normal (ULN)  
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin (for patients with Gilbert 
Syndrome and total bilirubin levels >1.5 
ULN) 
≤ ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN 
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International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN* 
 
≤1.5 X ULN 
* Does not apply to patients receiving therapeutic warfarin 
 
7. Measurable Disease: At least one tumor lesion/lymph node that meets the RECIST v1.1 
criteria for measurable disease  
8. 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 methods of 
contraception if sexually active 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. 
9. Resolution of all treatment-related toxicities from any previous cancer therapy (including 
radiation and surgery) to ≤ Grade 1 or to values within those required for eligibility on 
this study prior to the first dose of study treatment. 
a. Exceptions include alopecia, anemia, or endocrinopathies managed by hormone 
replacement 
10. Patients must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing and other requirements of the study. 
 
Phase 1-Dose Escalation-Specific Inclusion Criteria 
1. Meeting the Inclusion Criteria for any of the Phase 2 Expansion Cohorts listed below. 
 
Phase 2-Cohort Expansion Specific Inclusion Criteria 
 
Cohort 1: ccRCC - Checkpoint inhibitor naïve  
1. Histological or cytological diagnosis of RCC with a clear cell component. 
2. Must have received at least one but not more than two prior anti-angiogenic therapy 
regimens in the advanced or metastatic setting. 
3. Must have received no more than three total prior systemic treatment regimens in the 
advanced or metastatic setting. 
 
Cohort 2: ccRCC - Nivolumab in most recent line of therapy (“add-on”) 
1. Histological or cytological diagnosis of RCC with a clear cell component. 
2. Received nivolumab in the immediate prior line of therapy with ≤ 8 weeks elapsed 
between last dose of nivolumab and C1D1 of the CX-839-004 study and EITHER: 
a) Had documented radiological disease progression (per Investigator assessment, 
preferably with confirmation of PD after 4 weeks), OR 
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b) Had documented stable disease (per Investigator assessment) for >24 weeks.  
 
Cohort 3: ccRCC - Any prior anti-PD-1/ PD-L1 
1. Histological or cytological diagnosis of RCC with a clear cell component.  
2. Received an active anti-PD-1 or anti-PD-L1 agent and achieved no better than SD 
prior to demonstrating radiological progression (per Investigator assessment) in any 
prior line of therapy.  An active anti-PD-1 or anti-PD-L1 agent is defined as an agent 
that has demonstrated clear evidence of single agent activity, e.g., nivolumab, 
pembrolizumab, atezolizumab, durvalumab, or avelumab. Any other anti-PD-1 or 
anti-PD-L1 agent need approval from the Medical Monitor.   
3. Must have received at least one prior anti-angiogenic therapy regimen in the 
advanced or metastatic setting. 
 
Cohort 4: Melanoma (progressing while on anti-PD-1/PD-L1 therapy) 
1. Histological or cytological diagnosis of advanced/metastatic melanoma. 
2. Received anti-PD-1/PD-L1 as monotherapy or as part of a combination regimen in 
the most recent line of therapy with (i) documented radiographic disease progression 
(per Investigator assessment, preferably with confirmation of progression after 4 
weeks) and (ii) ≤ 8 weeks elapsed between last dose of anti-PD-1/PD-L1 and C1D1 
of the CX-839-004 trial.  
3. Previously progressed on or was intolerant to BRAFi therapy if BRAF V600E 
mutation is present. 
 
Cohort 5: NSCLC (anti-PD-1/PD-L1 in most recent line of therapy (“add-on”) 
1. Histological or cytological diagnosis of NSCLC that does not harbor an activating 
EGFR or ALK mutation. 
2. Received anti-PD-1/PD-L1 agent as the most recent line of therapy with ≤ 8 weeks 
elapsed between last dose of anti-PD-1/PD-L1 therapy and C1D1 of the CX-839-004 
trial and EITHER: 
a) Had documented radiological disease progression (per Investigator assessment, 
preferably with confirmation of PD after 4 weeks), OR 
b) Had documented stable disease (per Investigator assessment) for ≥ 24 weeks. 
 
Cohort 6: Melanoma (to be treated with CB-839 monotherapy) 
1. Histological or cytological diagnosis of advanced/metastatic melanoma without 
curative options. 
2. At least 4 mo (approximately 5 half-lives) elapsed between most recent dose of anti-
PD-1/PD-L1 therapy and C1D1 of CB-839 monotherapy. 
3. Previously progressed on or was intolerant to BRAFi therapy if BRAF V600E 
mutation is present. 
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6.5 Exclusion Criteria 
1. Intolerance to prior anti-PD-1/PD-L1 therapy including 1) discontinuation due to 
immune-related toxicity or, 2) immune-related toxicities that required intensive or 
prolonged immunosuppression (including high-dose IV corticosteroids, > 2 mo of 
immunosuppressive corticosteroids (i.e., equivalent of >10mg oral prednisone daily) 
or the addition of potent immunosuppression to corticosteroids (e.g., mycophenolate 
mofetil/CellCept or infliximab) to manage. 
 Exception:  Cohort 6 patients are eligible to receive CB-839 monotherapy (but 
not combination with nivolumab) even if prior intolerance of anti-PD-1/PD-
L1 therapy. 
2. Prior severe hypersensitivity reaction to another monoclonal antibody (mAb). 
3. 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, d) or 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. 
4. Cytotoxic chemotherapy, tyrosine kinase inhibitor (or other targeted anti-cancer 
agent), radiation therapy, or hormonal therapy within 14 days or 5 half-lives, 
whichever is longer, prior to Cycle 1 Day 1 (42 days for nitrosoureas or mitomycin 
C). 
5. Immunotherapy or biological therapy (e.g., monoclonal antibodies) within 21 days 
prior to Cycle 1 Day 1. 
 EXCEPTION: Washout of anti-PD-1 therapy is NOT required in Expansion 
Cohorts 2, 4, and 5 and must be > 4 mo in Expansion Cohort 6.  
6. Treatment with an unapproved investigational therapeutic agent within 21 days (or 5 
half-lives for small molecule agents) prior to Cycle 1 Day 1. 
7. Any active known or suspected autoimmune disease.  
Permitted on 
Study 
 
Vitiligo 
 
type I diabetes mellitus 
 
residual hypothyroidism due to autoimmune condition 
only requiring hormone replacement 
 
psoriasis not requiring systemic treatment for 2 years 
 
conditions not expected to recur in the absence of an 
external trigger 
Excluded on 
Study 
 
documented history of inflammatory bowel disease 
(including ulcerative colitis and Crohn’s disease) 
 
symptomatic autoimmune conditions (e.g., rheumatoid 
arthritis, systemic progressive sclerosis [scleroderma]) 
 
systemic lupus erythematosus 
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 
autoimmune vasculitis (e.g., Wegener’s Granulomatosis) 
 
patients with motor neuropathy considered of 
autoimmune origin (e.g., Guillain-Barré Syndrome) 
 
8. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other systemic immunosuppressive medications within 14 
days prior to the first dose of study drug.  Inhaled steroids and adrenal replacement 
steroid doses < 10 mg daily prednisone equivalent are permitted in the absence of 
active autoimmune disease. 
9. Evidence of active or acute (i.e., currently or <4 weeks prior to Screening) 
diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis, 
which are known risks factors for bowel perforation. 
10. Patients with symptomatic ascites or pleural effusion.  A patient who is clinically 
stable following treatment for these conditions (including therapeutic thoraco- or 
para-centesis) is eligible. 
11. Unable to receive medications per os (PO). 
12. Unstable/inadequate cardiac function: 
 Myocardial infarction or symptomatic ischemia within the last 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) 
13. Major surgery within 28 days prior to first dose of study drug. 
14. Infection requiring parenteral antibiotics, antivirals, or antifungals within two weeks 
prior to first dose of study drug. 
15. Patient is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis 
B or Hepatitis C. 
16. Refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, significant 
small bowel resection or gastric bypass surgery, use of feeding tubes or other 
situation that may preclude adequate absorption. 
17. Serious psychiatric or medical conditions that could interfere with treatment or 
protocol-related procedures. 
18. Active and/or untreated central nervous system metastasis.  Subjects with treated 
brain metastases must have (1) documented radiographic stability of at least 4 weeks 
duration demonstrated on baseline CNS imaging prior to study treatment and (2) be 
symptomatically stable and off steroids for at least 2 weeks before administration of 
any study drug. 
19. Patients in whom oral and/or IV fluid hydration are contraindicated. 
20. Patients who are pregnant or lactating. 
 
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Disease-specific Exclusion Criteria: 
Cohort 1: ccRCC - Checkpoint inhibitor naïve  
1. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
CTLA-4 antibody, or any other antibody or drug specifically targeting checkpoint or 
T-cell co-stimulation pathways. Prior IL-2 and IFN therapy is allowed. 
Cohort 3: ccRCC - Any prior anti-PD-1 
1. Patients that achieved an objective response (per investigator assessment) while 
receiving prior anti-PD-1/PD-L1 therapy. 
2. Patients who are eligible for Cohort 2.  
Cohort 4: Melanoma 
1. Patients with ocular melanoma. 
2. Active or untreated CNS metastases. 
Cohort 5: NSCLC 
1. Documented activating mutation in either the epidermal growth factor receptor 
(EGFR) or anaplastic lymphoma kinase (ALK). 
 
6.6  Radiological Tumor Assessments 
All patients will be evaluated for tumor response assessed by Investigator according to both 
RECIST version 1.1 and modified RECIST for immune-based therapeutics (termed iRECIST) 
(Seymour 2017).  The primary study endpoints of response rate and duration of response will be 
determined according to RECIST v1.1 by Investigator assessment except for Cohort 4 which will 
employ IRC adjudication for the primary endpoints.  In contrast to the formal study endpoints, 
patient management and clinical decision making during treatment should follow the principles 
and guidelines for iRECIST (Attachment 5).  These criteria take into account the observation that 
some patients with solid tumors can have an apparent radiographic flare of disease on 
immunotherapy that is transient and followed by radiographic disease response.  If imaging 
shows progressive disease per RECIST v1.1 (unconfirmed PD per iRECIST), it is recommended 
to keep the patient on study treatment until imaging is repeated ≥ 4 weeks later in order to 
confirm PD, as described in the iRECIST recommendations (see Attachment 5).  Patients who 
are deemed clinically unstable or are experiencing rapid progression of disease are not required 
to have repeat imaging for confirmation of PD.  At a minimum, patients must meet the following 
criteria for continued treatment on study after disease progression is identified at a tumor 
assessment:  
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 Absence of symptoms and signs (including worsening of laboratory values) indicating 
disease progression 
 No decline in ECOG performance status 
 Absence of rapid progression of disease or of tumor progression at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention.  
 
If repeat imaging confirms PD as described in Attachment 5, patients will be discontinued from 
study therapy.  If repeat imaging does not confirm PD, treatment with study drugs will continue 
and the next imaging studies will be conducted every 8 weeks as previously scheduled.  In 
patients who discontinue study therapy early without documented disease progression, every 
effort should be made to continue monitoring disease status by radiologic imaging until 
progressive disease, death, withdrawal of consent, or initiation of new anticancer therapy. 
 
7.0 
PROTOCOL DETAILS 
7.1 Introduction 
7.1.1 Background 
CB-839 is an inhibitor of glutaminase 1 that is being developed for the treatment of cancer.  
Single agent antitumor activity of CB-839 has been demonstrated in vitro in a wide range of 
tumor types.  CB-839 has been shown to have antitumor activity in animal studies as a single 
agent and in combination with drugs such as paclitaxel, everolimus, and erlotinib where additive 
or synergistic activities in immunocompromised mice were observed.  Recently, CB-839 was 
shown to enhance the activity of anti-PD-1 and anti-PD-L1, immuno-oncology agents, where 
there was a significant improvement in the incidence of syngeneic tumor regression in immune-
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-
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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 the similar 
response to withdrawal of glutamine, indicating that the antiproliferative activity seen upon 
glutamine withdrawal acts via limiting glutamate utilization through the same mechanism. 
Oral administration of CB-839 to tumor-bearing mice results in a substantial increase in local 
glutamine concentration in the tumor compared with a modest increase in other tissues, 
highlighting the extensive uptake and metabolism of glutamine by tumor cells in vivo.  An 
increase in plasma glutamine concentration is seen in these mice as well as in normal animals 
and in cancer patients following administration of CB-839.  The increase in systemic glutamine 
is likely due to inhibition of glutaminase enzyme in many tissues. 
7.1.2 Preclinical Activity of CB-839 in the Non-Immuno-Oncology Setting 
CB-839 has antiproliferative activity across a wide range of tumor cell types including solid 
tumors (ccRCC, NSCLC, TNBC, etc.) and hematological tumors [multiple myeloma, AML, 
diffuse large B-cell lymphoma (DLBCL)] with IC50 values ranging from 1 to 100 nM. 
The antiproliferative and pro-apoptotic activity of CB-839 has been characterized in panels of  
lung and renal cancer cell lines (Figure 8.2-1).  Of note, CB-839 reduces growth and causes 
cytotoxicity most often in NSCLC cell lines that express KRAS mutations or amplifications or 
express EGFR mutations in comparison to lines not expressing those genetic changes.  Clear cell 
ccRCC cell lines also appear to be more sensitive to the effects of CB-839 as compared with 
other renal cancer cell lines. 
 
 
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34 
7.2.1 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 enrolled RCC 
patients for treatment with CB-839 + cabozantinib and CB-839 + everolimus, as well as TNBC 
patients for treatment with CB-839 + paclitaxel.  In addition, the combination of CB-839 with 
nivolumab is being evaluated in this 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 July 2017, a total of 105 patients received 600, 800, or 1000 mg BID 
CB-839 as a single agent; an additional 59 patients received single agent CB-839 dosed on the 
TID schedule ranging from 100 to 1000 mg TID.  More than 150 patients have received CB-839 
at doses ranging from 400 to 800 mg BID in combination with cabozantinib, erlotinib, 
everolimus, paclitaxel, nivolumab, dexamethasone, pomalidomide, or azacitidine. 
In pharmacokinetic studies, the half-life of CB-839 was approximately 4 hours. A dose-related 
increase in exposure was observed over doses ranging from 100 to 600 mg; exposures for 
600 mg and 800 mg doses were similar albeit with significant interpatient variability.  In 
pharmacodynamic studies, robust inhibition of glutaminase was demonstrated in platelets at 
exposures maintained in most BID-dosed patients at 600 mg and 800 mg inter-dose troughs, with 
the 800 mg dose in particular showing ≥ 90% target inhibition.  Patient tumor biopsies also 
demonstrated robust glutaminase inhibition (> 75% for most patients).   
8.0 
PRIOR TREATMENT 
Reasonable efforts will be made during the screening period to determine all prior therapeutic 
treatments received by the patient.  All previous cancer treatments, including systemic therapies, 
radiation and/or surgical procedures, should be recorded on the patients’ electronic case report 
forms (eCRF). 
 
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35 
8.1 
Prior anti-PD-1/PD-L1  
Patients targeted for Cohorts 2, 4, and 5 may continue to receive anti-PD-1/PD-L1 therapy up to 
3 weeks before C1D1.  If anti-PD-1/PD-L1 has been discontinued, patients targeted for Cohorts 
2, 4 and 5 must have no more than 8 weeks elapse between last administration of anti-PD-1/PD-
L1 agent and C1D1 of this protocol.  Patients receiving an anti-PD-1/PD-L1 therapy other than 
nivolumab will switch to nivolumab for study treatment.  In order to assess CB-839 monotherapy 
activity, Cohort 6 patients must have at least 4 mo (approximately 5 half-lives) elapsed between 
most recent dose of anti-PD-1/PD-L1 therapy and C1D1of CB-839 monotherapy on this study.  
 
9.0 
CONCOMITANT TREATMENT 
Concomitant treatment is permitted if the medication is not expected to interfere with the 
evaluation of safety or efficacy of the study drugs.  During the study, if the use of any 
concomitant treatment becomes necessary (e.g., for treatment of an adverse event), the treatment 
must be recorded on the appropriate eCRF, including the reason for treatment, name of the drug, 
dosage, route, and start and stop dates of administration. 
Except for erythropoietin or darbepoetin alpha (Aranesp®), use of growth factors (i.e., G-CSF, 
GM-CSF, etc.) is not permitted in the first treatment cycle unless the patient experiences a 
hematologic DLT. 
Use of investigational therapeutic agents other than the study drugs, CB-839 and nivolumab, is 
NOT permitted while the patient is on study. 
CB-839 is metabolized by human hepatocytes primarily through amide hydrolysis.  CB-839 does 
not appear to induce CYP drug-metabolizing enzymes and only weakly inhibits CYP2C9 (~40-
50% inhibition at 5µM) in vitro.  Although CB-839 is not expected to inhibit CYP2C9 at the 
exposure levels planned, caution is warranted when administering CB-839 to patients taking 
drugs that are highly dependent on CYP2C9 for metabolism and have a narrow therapeutic 
index.  A list of medications that are CYP2C9 substrates is provided in Attachment 6.  
Preliminary PK data generated in single agent Phase 1 studies suggest that concomitant use of 
proton pump inhibitors (PPIs) may reduce absorption of CB-839, resulting in decreased systemic 
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exposure.  Although patients are not required to discontinue their use of these agents, the strong 
preference is for patients to discontinue PPIs prior to joining the study.  Antagonists of the H2 
histamine receptor (e.g., ranitidine, famotidine, etc.) may be substituted for PPIs.  For patients 
unable to discontinue PPI therapy or that requires restarting PPI therapy while on study, 
administration of CB-839 with an acidic beverage (e.g., orange juice) or supplement (e.g., citric 
acid) may be an option.  If an acidic beverage/supplement is approved by the Medical Monitor to 
be administered along with the CB-839 dose, it should be recorded on the appropriate eCRF, 
including the identity of the beverage/supplement, dosage, route, and start and stop dates of 
administration.  Finally, if PPI is started while a patient is on-study, a PK profile may be required 
in order to confirm CB-839 exposure, see Section 15.1 for specific time points. 
10.0 
PROCEDURES 
All patients must sign an IRB approved informed consent prior to starting any protocol specific 
procedures, including screening procedures.  During the consent process, the person obtaining 
consent must inform the patient of all elements of informed consent.  Patients must also meet the 
inclusion and exclusion criteria to be enrolled in the study. 
10.1 Screening Evaluation 
The following screening assessments must be performed within 28 days before study drug 
administration on C1D1  according to the Schedule of Study Assessments. Procedures listed 
below that are performed as part of the normal standard of care and within 28 days prior to C1D1 
may be used for screening purposes: 
 Sign and date an IRB/IEC-approved Informed Consent Form (ICF) before any study-
specific (i.e., non-standard of care) screening procedures are performed 
 Demographic information including date of birth, sex, and ethnic origin  
 Medical history including review of prior cancer treatments 
 Review of concomitant medications 
 ECOG performance evaluation 
 Complete physical examination including weight (kg) and height (cm) 
 Vital signs and weight  
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 Standard 12-lead ECG with corrected QT interval by Fridericia’s Formula (QTcF) 
 Clinical laboratory evaluation (hematology, coagulation, serum chemistry, and 
urinalysis); see Attachment 3. 
 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 
 During Phase 1- Dose escalation, predose and postdose tumor biopsies will be collected 
from patients enrolled in the back-fill cohorts.  Predose tumor biopsies will be obtained 
from all patients in the Expansion phase (if considered safe and technically feasible to 
biopsy). Refer to Section 14.2. 
 Coagulation tests must be performed and evaluated within 72 to 24 hr prior to all biopsy 
procedures. Patients in all other cohorts may consent to an optional tumor biopsy. 
 Archival tumors, if available, will be collected from all patients 
 Screening radiographic evaluation of tumor burden (e.g., diagnostic CT or MRI).  For 
this study, radiographic evaluation of baseline and subsequent tumor burden must be 
based on a diagnostic, contrast enhanced, CT or MRI (See Attachment 1 for details and 
exceptions). All scans from the immediate prior line of therapy will be requested for 
Cohorts 2, 4, and 5. 
Screening Evaluation Specific to Cohort 4 
 Cohort 4 patients must have a baseline radiographic tumor assessment (methodology as 
per screening imaging described above) within 7 days prior to C1D1 unless the patient 
has had a previous radiographic tumor assessment that  meets the following requirements: 
a. It was performed within 4 weeks of C1D1 AND 
b. It was performed at least 4 weeks after the date of a prior scan demonstrating 
progressive disease on anti-PD-1/PD-L1 containing therapy in the immediate 
prior line of therapy  
 Cohort 4 patients must have screening contrast-enhanced MRI of the brain to assess for 
brain metastases within 28 days before C1D1  
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A patient who meets all of the inclusion criteria will enter the study.  Screen failures must be 
captured in the electronic data capture (EDC) system. 
10.2 Cycle 1  
Screening urinalysis, serum chemistry, coagulation, and hematology that occurred within 3 days 
prior to C1D1 do not need to be repeated unless a clinically significant change in the interim is 
suspected. 
Patients should be instructed not to eat breakfast prior to their clinic visit on C1D1 and C1D15. 
On these days, patients will have all predose procedures performed, take their dose of CB-839 
with food then receive nivolumab.  Note that all predose assessments must be performed prior to 
nivolumab and CB-839 administration.  The 2nd dose of CB-839 will be self-administered by the 
patient per dosing instructions after all study procedures have been completed. 
A detailed breakdown of the visit schedule and sample collection time points can be found in 
Attachments 1 and 2.  During Cycle 1, patients will undergo the following procedures: 
 AE Monitoring 
 Recording of concomitant medications 
 Vital signs and weight 
 Symptom-directed physical exam 
 ECOG Performance status evaluation 
 Clinical laboratory evaluation (hematology, coagulation, serum chemistry, and urinalysis) 
 Plasma sample collection for PK and biomarker analysis 
 Whole blood sample collection for biomarker analysis  
 ECG with QTcF between 2-4 hr post-dose 
 Administration of CB-839 and nivolumab 
10.3 Cycle 2 and all subsequent cycles 
Patients will return to the clinic and undergo the following procedures: 
 AE monitoring 
 Recording of concomitant medications 
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 Vital signs and weight 
 Symptom-directed physical exam 
 Clinical laboratory values (hematology, coagulation, serum chemistry and urinalysis) 
 ECOG performance status evaluation 
 Plasma sample for collection for biomarker analysis taken prior to dosing on Cycles 2 
and 3 Day 1 
 Whole blood sample collection for biomarker analysis taken prior to dosing on Cycles 2 
and 3 Day 1 
 Administration of CB-839 and nivolumab 
o Patients should be instructed not to eat breakfast prior to their clinic visit on Cycle 
2 Day 1 and Cycle 3 Day 1.  Patients will undergo the predose assessments prior 
to receiving the nivolumab infusion or eating breakfast and receiving the CB-839 
dose.  The 2nd dose of CB-839 will be self-administered by the patient per dosing 
instructions after all study procedures have been completed. 
 A postdose tumor biopsy will be obtained from all patients in Phase 1 backfill cohorts, 
Phase 2- Cohorts 2, 4, and 5 on Cycle 2 Day 1 only (± 1 week).  Coagulation tests must 
be performed and evaluated within 72 to 24 hr prior to all biopsy procedures. 
 Radiographic evaluation (e.g., diagnostic CT or MRI) of tumor burden will occur 
approximately every 8 weeks. The same method of evaluation should be used throughout 
the course of the study. The scans and redacted reports will be collected and sent to a 
central reader for exploratory evaluation. 
10.4 Other Schedules and Procedures 
Radiographic evaluation of tumor burden (e.g., diagnostic CT/MRI) will occur at Screening and 
approximately every 8 weeks from Cycle 1 Day 1 and as clinically indicated.   
Optional tumor biopsies may be obtained at variable time points as advised by the Investigator. 
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10.5 End of Treatment (EOT) 
The End of Treatment (EOT) visit must occur within 28 days of treatment discontinuation and 
prior to initiation of any new anti-cancer therapy/regimen.  All patients discontinuing study 
treatment for any reason should undergo the following EOT procedures: 
 AE monitoring 
 Recording of concomitant medications 
 Vital signs and weight 
 Complete physical examination  
 ECOG performance status evaluation 
 Clinical laboratory values (hematology, coagulation, serum chemistry and urinalysis) 
 Urine pregnancy test for women of child-bearing potential 
 12-lead ECG with QTcF 
 Radiographic evaluation (e.g., diagnostic CT or MRI) of tumor burden. Patients who 
discontinue from study due to objective findings of progressive disease during an on-
treatment evaluation do not need to have repeat scans.  CT or MRI is required for all 
patients who have not had at least 1 post-baseline image. 
10.6 Follow Up 
Patients who discontinue study treatment for reason other than PD or death must continue to be 
followed by radiographic imaging per study schedule until PD, death, withdrawal of consent or 
initiation of another cancer therapy.  All patients who discontinue study treatment will be 
contacted every 3 mo for the first 12 mo and then once every 6 mo thereafter for survival follow-
up.  All reasonable efforts must be made to contact patients and report their ongoing status. This 
includes follow up with persons authorized by the patient.  If the patient or authorized persons 
cannot be contacted, public records may be consulted to establish survival status.  
10.7 Screen Failures 
Patients who sign an informed consent form, are not assigned to a treatment, and do not receive 
either CB-839 or nivolumab are defined as screen failures.  For all screen failures, the 
Investigator will enter the screening number, patient initials, and reason(s) for screen failure into 
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the electronic data capture (EDC) system.  These data will also be retained in the Investigator’s 
study files and can be printed by the site in log format at the end of the study.  
 
10.8 Dose Modification and Management of Toxicities 
10.8.1 Potential Toxicities 
10.8.1.1 
CB-839 
As of 8 Oct 2015, CB-839 had been administered as a single agent to 98 patients with 
advanced/metastatic solid tumors on the Phase 1 CX-839-001 protocol.  During this study, 
CB-839 was dosed either three times daily (TID; 100-1000 mg) without food or twice daily 
(BID; 600-1000 mg) with meals.  Due to differences in the pharmacokinetic and safety profiles 
between the two regimens (including reduced Grade 3/4 liver function test (LFT) elevations; data 
are reported by regimen below), patients enrolled on the current study will receive CB-839 in the 
“BID with meals” regimen. 
The most frequent adverse events (AEs) considered possibly or probably related to CB-839 
monotherapy on the CX-839-001 were fatigue, nausea, LFT elevations and photophobia (Table 
10.7-1). These have been primarily Grade 1/2 AEs that have been manageable and reversible 
with minimal dose modifications or delays. 
Table 10.7-1: Drug-related AEs reported in ≥2 subjects on study CX-839-001 
 All AE Grades 
Number (%) of patients 
MedDRA Preferred Term 
All (N=98) 
TID (N=32) 
BID (N=66) 
Patients with any AE 
 67 (68.4) 
 23 (71.9) 
 44 (66.7) 
FATIGUE 
 24 (24.5) 
  8 (25.0) 
 16 (24.2) 
ALANINE AMINOTRANSFERASE INCREASED 
 14 (14.3) 
  6 (18.8) 
  8 (12.1) 
NAUSEA 
 14 (14.3) 
  2 (6.3) 
 12 (18.2) 
ASPARTATE AMINOTRANSFERASE INCREASED 
 13 (13.3) 
  6 (18.8) 
  7 (10.6) 
PHOTOPHOBIA 
  8 (8.2) 
  1 (3.1) 
  7 (10.6) 
GAMMA-GLUTAMYLTRANSFERASE INCREASED 
  7 (7.1) 
  1 (3.1) 
  6 (9.1) 
VOMITING 
  7 (7.1) 
  4 (12.5) 
  3 (4.5) 
BLOOD ALKALINE PHOSPHATASE INCREASED 
  5 (5.1) 
  2 (6.3) 
  3 (4.5) 
DECREASED APPETITE 
  5 (5.1) 
-- 
  5 (7.6) 
BLOOD CREATININE INCREASED 
  4 (4.1) 
  1 (3.1) 
  3 (4.5) 
CONSTIPATION 
  3 (3.1) 
  2 (6.3) 
  1 (1.5) 
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DYSPEPSIA 
  3 (3.1) 
-- 
  3 (4.5) 
PHOTOSENSITIVITY REACTION 
  3 (3.1) 
-- 
  3 (4.5) 
 
The most frequent Grade 3/4 AEs considered possibly or probably related to monotherapy CB-
839 were LFT elevation (Table 10.7-2).  The rate of Grade 3/4 LFT elevations was notably lower 
when CB-839 was dosed BID with meals as compared to the TID dosing regimen.  When LFT 
elevations occurred, they were generally rapidly reversible and manageable with dose reduction. 
Table 10.7-2: Drug-related ≥ Grade 3 AEs reported on study CX-839-001 
≥ Grade 3 AEs 
Number (%) of patients 
MedDRA Preferred Term 
All (N=98) 
TID (N=32) 
BID (N=66) 
Patients with any AE 
 10 (10.2) 
  7 (21.9) 
  3 (4.5) 
ALANINE AMINOTRANSFERASE INCREASED 
  6 (6.1) 
  5 (15.6) 
  1 (1.5) 
ASPARTATE AMINOTRANSFERASE INCREASED 
  5 (5.1) 
  5 (15.6) 
0 
GAMMA-GLUTAMYLTRANSFERASE INCREASED 
  3 (3.1) 
  1 (3.1) 
  2 (3.0) 
BLOOD ALKALINE PHOSPHATASE INCREASED 
  1 (1.0) 
  1 (3.1) 
0 
BLOOD CREATININE INCREASED 
  1 (1.0) 
  1 (3.1) 
0 
HYPOGLYCAEMIA 
  1 (1.0) 
  1 (3.1) 
0 
  
10.8.1.2 
Nivolumab 
Nivolumab (OPDIVO®) is an anti-PD-1 monoclonal antibody that has been FDA approved for 
the treatment of certain patients with unresectable or metastatic melanoma, metastatic NSCLC, 
and advanced RCC.  The safety profile of nivolumab is fully described in the nivolumab package 
insert and primarily consists of immune-related adverse events (ir-AEs) due to activation and 
proliferation of T-cells.  Ir-AEs can affect any organ or tissue but most frequently occur in the 
skin (rash), gastrointestinal system (diarrhea/colitis), liver (hepatitis), lungs (pneumonitis), 
endocrine system (endocrinopathies due to inflammation of the pituitary, thyroid and adrenals), 
and kidneys (nephritis).  The management of these toxicities is described in the package insert 
but generally includes holding drug for moderate (Grade 2) toxicities and using systemic 
immunosuppression for severe (Grade 3/4) or prolonged moderate (> 1 week) toxicities.  
Additional immunosuppression (e.g., anti-TNFα therapy, infliximab) may be used if IV steroids 
are ineffective. 
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10.8.1.3 
CB-839 and Nivolumab Combination 
The tolerability of CB-839 in combination with nivolumab is not known.  A primary objective of 
the current study is to evaluate the safety and tolerability of the combination of nivolumab and 
CB-839.  There are no clinical data evaluating the combination of these two agents.  Preclinical 
studies of the combination of an anti-PD-1 agent and CB-839 have been performed in mice for 
the purpose of evaluating the anti-tumor activity of the combination.  In these experiments, the 
combination of anti-PD-1 and CB-839 appeared to be well tolerated but an extensive safety 
evaluation was not performed. 
10.8.2 Dose Modifications and Toxicity Management 
The safety and tolerability profile of CB-839 is summarized above (Section 10.8.1.1).  In 
general, management of AEs related to CB-839 includes withholding the medication for 
moderate to severe toxicities and providing the appropriate supportive care. 
The safety and tolerability profile of nivolumab is well defined and outlined in the nivolumab 
package insert.  Ir-AEs are defined in the nivolumab label as those that occur while receiving 
nivolumab, require immunosuppression and have no clear alternate etiology.  Guidelines for the 
management of ir-AEs and study drug dosing are provided below for reference but Investigators 
are encouraged to follow the most current product label for nivolumab.  In general, for moderate 
to severe ir-AEs, nivolumab should be withheld or permanently discontinued and, depending on 
the nature of the AE, it should be managed with high-dose corticosteroids and hormone-
replacement therapy, if necessary.  Upon improvement to Grade 1 or less, a corticosteroid taper 
should be initiated and continued over at least 1 mo.  Restarting nivolumab may be considered 
after completion of corticosteroid taper based on the severity of the event.  In some cases, the 
natural history of AEs associated with immunotherapy can differ from and be more severe than 
AEs caused by agents belonging to other therapeutic classes.  Early recognition and management 
may mitigate severe toxicity.  Evaluation and management guidelines for the following types of 
ir-AEs are provided in the nivolumab package insert: pneumonitis, colitis, hepatitis, 
endocrinopathies, nephritis/renal dysfunction, rash, and encephalitis. 
For patients in the Dose Escalation Phase, dose reductions of CB-839 will be permitted during 
Cycle 1 (first 28 days) only if a patient experiences DLT or a toxicity that may herald a DLT.  If 
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a patient experiences a DLT, treatment continuation at a lower dose of CB-839 will be permitted 
as long as the toxicity has returned to ≤ Grade 1 or baseline within 28 days and nivolumab 
therapy can be continued.  Upon recovery, patients may restart at one CB-839 dose level lower.  
Patients who do not recover within 28 days will not be eligible for resumption of study 
treatment.  After Cycle 1, dose reductions or interruptions for adverse events may take place at 
any time at the discretion of the Principal Investigator in consultation with the Medical Monitor. 
10.8.2.1 
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 AEs are based on the nivolumab product label and the clinical experience 
with CB-839 to date and are provided in Table 10.8-1.  Study drugs may be held and restarted 
independently depending upon the adverse event.  Because product labels may change over time, 
when in doubt investigators should always refer to the most current nivolumab product label. 
The study guidelines are intended primarily for toxicities that are not easily managed with 
routine supportive care.  For example, alopecia does not require dose modification nor does 
Grade 2 nausea/vomiting that are easily managed with anti-emetics.  Importantly, these 
guidelines are not meant to replace the clinical judgment of the Investigator caring for the patient 
or the most recent nivolumab product label and should be used as guidelines.  Additional 
information regarding the management of specific toxicities is provided in Table 10.8-1. 
These parameters are only guidelines and are not intended to supersede the clinical judgment of 
the treating physician.  Investigators should err on the side of caution in the setting of potential 
ir-AEs.   Investigators should contact the Medical Monitor if 1) a dose modification is planned, 
2) systemic immunosuppression is required (however, if immediate systemic 
immunosuppression is required, please DO NOT delay the start of immunosuppressive therapy 
in order to speak with the Medical Monitor), or 3) there is a preference to deviate from the 
guidelines for the management of AEs or dose modifications.  Holding of the study drug and 
study discontinuation for both non-hematological and hematological toxicities will be based on 
the Principal Investigator’s judgment following discussion with the Medical Monitor. 
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10.8.2.2 
Resumption of Study Treatment 
For both CB-839 and nivolumab, treatment may be delayed for up to 4 weeks from the last dose 
before restarting.  CB-839 and nivolumab may be held and restarted independent of each other.  
Treatment delays longer than 4 weeks are allowed only in cases where a prolonged steroid taper 
is required to manage drug-related AEs or, in some cases, if 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 drug(s) for adverse events, the study drug(s) may be restarted when the 
AE has returned to ≤ Grade 1.  For patients that require a steroid taper, nivolumab should not be 
restarted until the steroid taper is complete.  In cases in which a particular toxicity is clearly 
related to only one of the two study drugs, the study drug that is not involved in causing the AE 
may be continued or restarted prior to AE resolution to  Grade 1 or baseline.  If CB-839 is 
restarted after permanent discontinuation of nivolumab, CB-839 should also be permanently 
discontinued for a > Grade 3 recurrence of the AE that resulted in nivolumab discontinuation. 
 
 
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Table 10.8-1:  Dose Modification Guidelines for irAEs 
Adverse 
Reaction 
Severity 
Management 
Dose Modification 
 
Colitis 
Grade 2 
If >5 days, 0.5 to 1 mg/kg/day 
prednisone.  If worsening or no 
improvement, increase to 1 to 2 
mg/kg/day prednisone equiv. 
and consider IV. 
Nivo: Withhold dose 
CB: Withhold dose 
 
Grade 3 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Withhold dose 
CB: Withhold dose 
Grade 4 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Permanently discontinue  
CB: Withhold dose. Consider re-
challenge with monotherapy. 
Pneumonitis 
Grade 2 
1 to 2 mg/kg/day prednisone 
equiv.   
Nivo: Withhold dose 
CB: Withhold dose 
Grade 3 or 4 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Permanently discontinue  
CB: Withhold dose. Consider re-
challenge with monotherapy. 
 
 
Hepatitis 
AST or ALT > 3 to 5x ULN or 
total bilirubin > 1.5 to 3x ULN 
Monitor closely. If continues >1 
week, 1 to 2 mg/kg/day 
prednisone equiv.   
Nivo: Withhold dose 
CB: Withhold dose 
AST or ALT > 5x ULN or total 
bilirubin > 3x ULN 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Permanently discontinue 
CB: Withhold dose. Consider re-
challenge with monotherapy. 
Hypophysitis  
Grade 2 or 3 hypophysitis 
1 mg/kg/day prednisone equiv. 
Nivo: Withhold dose 
CB: Withhold dose 
Grade 4 hypophysitis 
1 mg/kg/day prednisone equiv. 
Nivo: Permanently discontinue 
CB: Withhold dose. Consider re-
challenge with monotherapy. 
Adrenal 
Insufficiency  
Grade 2 adrenal insufficiency 
None 
Nivo: Withhold dose 
CB: Withhold dose 
Grade 3 or 4 adrenal 
insufficiency 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Permanently discontinue 
CB: Withhold dose. Consider re-
challenge with monotherapy. 
Type 1 
Diabetes 
Mellitus  
Grade 3 hyperglycemia 
Manage glucose with insulin 
Withhold both drugs.  Restart 
upon glucose control. 
Grade 4 hyperglycemia 
Manage glucose with insulin 
Nivo: Permanently discontinue 
CB: Withhold dose. Consider re-
challenge with monotherapy. 
 
 
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Adverse 
Reaction 
Severity 
Management 
Dose Modification 
Nephritis and 
Renal 
Dysfunction 
Serum creatinine > 1.5x to 6x 
ULN 
0.5 to 1 mg/kg/day prednisone.  
If worsening or no improvement, 
increase to 1 to 2 mg/kg/day 
prednisone equiv. and consider 
IV. 
Nivo: Withhold dose 
CB: Withhold dose 
Serum creatinine > 6x ULN 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Permanently discontinue 
CB: Withhold dose. Consider re-
challenge with monotherapy. 
Skin 
Grade 3 rash or suspected 
Stevens-Johnson syndrome 
(SJS) or toxic epidermal 
necrolysis (TEN) 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Withhold dose 
CB: Withhold dose 
Grade 4 rash or confirmed SJS 
or TEN 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Permanently discontinue 
CB: Withhold dose. Consider re-
challenge with monotherapy. 
Infusion 
Reaction 
Grade 1 
Manage per product label and 
institutional standard for 
infusion reactions.  For 
subsequent nivolumab doses, 
premedicate with 
diphenhydramine and 
acetaminophen. 
Nivo: No change 
Grade 2 
Manage per product label and 
institutional standard for 
infusion reactions.  For 
subsequent nivolumab doses, 
premedicate with 
diphenhydramine and 
acetaminophen. 
Nivo: Hold dose until resolution 
of symptoms.  Restart at 50% of 
the original infusion rate.  If no 
symptoms for 30 minutes, 
consider returning to 100% of 
the original infusion rate. 
Grade 3 or 4 
Manage per product label and 
institutional standard for 
infusion reactions 
Nivo: Permanently discontinue 
Encephalitis 
New-onset moderate or severe 
neurologic signs or symptoms 
Evaluate to rule out other causes 
(infectious, other). Evaluation 
may include, but not be limited 
to, consultation with a 
neurologist, brain MRI, and 
lumbar puncture. 
If other causes are ruled out, 
start 1 to 2 mg/kg/day 
prednisone equiv.  Consider IV.  
Nivo: Withhold dose 
CB: Withhold dose 
Immune-mediated encephalitis 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Permanently discontinue 
CB: Withhold dose. Consider re-
challenge with monotherapy. 
 
 
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Adverse 
Reaction 
Severity 
Management 
Dose Modification 
Other irAE 
Other Grade 3 adverse reaction 
(with the exception of fatigue 
or clinically irrelevant 
laboratory values) 
 
 
 
First occurrence 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Withhold dose 
CB: Withhold dose 
 
Recurrence of same 
Grade 3 adverse 
reaction 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Permanently discontinue 
CB: Withhold dose. Consider re-
challenge with monotherapy. 
Life-threatening or Grade 4 
adverse reaction 
1 to 2 mg/kg/day prednisone 
equiv.  Consider IV. 
Nivo: Permanently discontinue 
CB: Withhold dose. Consider re-
challenge with monotherapy. 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks 
 
Nivo: Permanently discontinue 
CB: Consider re-challenge/ 
continuation with CB-839 
monotherapy. 
Persistent Grade 2 or 3 adverse 
reactions lasting 12 weeks or 
longer 
 
Nivo: Permanently discontinue 
CB: Permanently discontinue  
 
10.8.2.3 
Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator.  Guidelines outlined below should be used in conjunction with information 
provided in the nivolumab product label: 
Diarrhea: Patients should be monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). In symptomatic patients, infectious etiologies 
should be ruled out, and if symptoms are persistent and/or severe, endoscopic evaluation should 
be considered.  In patients with severe enterocolitis, nivolumab will be permanently discontinued 
and treatment with systemic corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day of 
prednisone or equivalent. In patients that do not respond to high dose steroids with 72 hr, 
consider initiation of additional immunosuppressive therapy (e.g., infliximab).  When symptoms 
improve to Grade 1 or less, corticosteroid taper should be started and continued over at least 
1 mo. 
In patients with moderate enterocolitis, nivolumab should be withheld and antidiarrheal 
treatment should be started. If symptoms are persistent for more than one week, systemic 
corticosteroids should be initiated (e.g., 0.5 mg/kg/day of prednisone or equivalent).  When 
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symptoms improve to Grade 1 or less, corticosteroid taper should be started and continued over 
at least 1 mo.  Regarding guidelines for continuing treatment with CB-839 and nivolumab, see 
Table 10.8-1. 
All patients who experience diarrhea should be advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV 
infusion. 
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic therapy 
according to standard institutional practice. Patients should be strongly encouraged to maintain 
liberal oral fluid intake. 
Anemia: Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia, but should be clearly noted as concurrent medications. 
Neutropenia: Prophylactic use of colony-stimulating factors including Granulocyte Colony-
Stimulating Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage Colony-Stimulating 
Factor GM-CSF is not allowed in this study.  Therapeutic use of G-CSF is allowed in patients 
with Grade 3-4 febrile neutropenia. 
Thrombocytopenia: Transfusion of platelets may be used if clinically indicated. ITP should be 
ruled out before initiation of platelet transfusion. 
Anti-infectives: Patients with a documented infectious complication should receive oral or IV 
antibiotics or other anti-infective agents as considered appropriate by the treating Investigator for 
a given infectious condition, according to standard institutional practice. 
Immune-related adverse events: Patients who develop a Grade 2 or higher irAE (e.g., colitis, 
skin rash, hepatitis, uveitis, hypo- or hyperthyroidism, hypophysitis, or any other), should be 
discussed immediately with the Medical Monitor.  Depending on the type and severity of an 
irAE, oral or intravenous treatment with a corticosteroid should be considered, in addition to 
appropriate symptomatic treatment of a given condition.  For severe immune-mediated adverse 
events that do not respond to high dose IV steroids within 72 hr, consider initiation of additional 
immunosuppressive therapy (e.g., infliximab for non-hepatic toxicities or mycophenolate mofetil 
for immune-mediated hepatotoxicity). 
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Infusion reaction: Infusion reactions may consist of fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness 
or hypertension. Severe reactions may include acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, and cardiogenic shock. Patients should be closely monitored 
for an infusion reaction during and immediately following drug infusion. 
In the event of a Grade 2 infusion reaction, interrupt the infusion until the symptoms resolve and 
then restart at a reduced infusion rate (50% of original rate).  If the symptoms do not return after 
30 minutes at the reduced infusion rate, consider returning to the original infusion rate.  Proper 
medical management should be instituted, as indicated per type of the reaction. This includes but 
is not limited to an antihistamine (e.g., diphenhydramine or equivalent), anti-pyretic (e.g., 
paracetamol or equivalent), and if considered indicated oral or IV glucocorticoids, epinephrine, 
brochodilators, and oxygen. 
In the event of a Grade 3 or 4 infusion reaction, immediately stop the infusion.  Proper medical 
management should be instituted immediately, as indicated per type and severity of the reaction. 
This may include but is not limited to oral or IV anti-histamine, anti-pyretic, glucocorticoids, 
epinephrine, brochodilators, and oxygen. 
10.9 Dose Adjustments, Infusion Delays, and Missed Doses 
Missed doses of CB-839 should be skipped.  If a patient forgets to take a dose of study drug and 
he/she is outside of the allotted window period (± 6 hr), he/she should be instructed to skip that 
dose and NOT to take extra study drug at the next administration. 
Subjects may be dosed with nivolumab no less than 12 days from the previous dose.  If a subject 
cannot receive the 2nd nivolumab dose of the cycle within the 28 day period it will be omitted 
and the next dose received will be considered Day 1 of the next cycle. 
10.10    Discontinuation of Treatment and Withdrawal of Patients 
The reasons a patient may discontinue or be withdrawn from the study include, but are not 
limited to, adverse events, disease progression, patient request, Investigator decision, protocol 
violation, patient noncompliance, and study termination by the Sponsor. 
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When a patient discontinues or is withdrawn from study, the Investigator will notify the Sponsor 
(or designee) and should perform all End of Treatment and follow up procedures as indicated in 
the Schedule of Study Assessments after discontinuation of study drug. 
11.0 
TEST ARTICLE/STUDY DRUG 
11.1 Test Article Administration 
CB-839 
Test article (CB-839) will be administered orally using a capsule (200 mg per capsule) or tablet 
(200 mg per tablet) formulation.  CB-839 will be administered only to patients who have signed 
and dated an Informed Consent Form.  CB-839 will be administered on Days 1 through 28 of 
each 28-day cycle and should be taken orally using the number of capsules or tablets directed in 
the Pharmacy Manual. CB-839 dosing will not be adjusted for body weight or surface area. 
The first CB-839 dose of the day will be administered immediately after breakfast.  The 
evening/second dose should be taken with a meal approximately 12 hr (± 2 hr) after the morning 
dose. 
On PK days (Cycle 1 Days 1 and 15, Cycle 2 Day 1 and Cycle 3 Day 1) patients should be 
instructed NOT to take their morning dose of CB-839 at home.  On PK days, patients will have 
all predose procedures performed, take their dose of CB-839 with food then receive nivolumab.  
The time of dosing will be recorded in the clinic.  The evening dose will be self-administered by 
the patient after all postdose activities have been completed.  On non-PK collection days, 
patients will administer CB-839 per their usual administration schedule. 
Patients who vomit their CB-839 dose should be instructed NOT to make up that dose and to 
report the frequency of vomiting occurrences associated with study drug administration to the 
site.  Patients who report ≥ 3 incidences of vomiting associated with study drug administration 
will have a blood sample drawn for an unscheduled PK analysis. 
 
Nivolumab:  Nivolumab will be administered at a flat dose of 240 mg IV infusion over 60 min 
on Days 1 and 15 of each 28-day cycle.  Nivolumab (Opdivo®) is supplied by Calithera as a 
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10 mg/mL solution for infusion following dilution.  Please refer to the nivolumab package insert 
for specific instructions on nivolumab administration. 
 
11.2 Packaging and Labeling 
CB-839 HCl Capsules (200 mg) and CB-839 HCl Tablets (200 mg) are manufactured, packaged, 
and labeled according to current Good Manufacturing Practices (cGMP).  For additional 
information, please refer to the Pharmacy Manual. 
Nivolumab is available in single use vials containing 40 mg/4 mL or 100 mg/10 mL.  Please 
refer to the nivolumab package insert for specific instructions on packaging and labeling. 
 
11.3 Storage and Stability 
CB-839  
CB-839 HCl Capsules and Tablets will be stored at the clinical site, as indicated on the study 
drug label, i.e. room temperature, between 15º-30ºC (59º-86ºF). 
Patients will be requested to store the test article at the recommended storage conditions noted on 
the label, out of the reach of children or other cohabitants. 
Nivolumab 
Nivolumab vials should be stored under refrigeration at 2°C - 8°C (36°F - 46°F).  Protect from 
light by storing in the original package until time of use.  Do not freeze or shake.  For procedures 
for the proper handling, storage, preparation and administration of nivolumab, please refer to the 
nivolumab package insert. 
11.4 CB-839 Accountability, Reconciliation, and Return 
On Day 1 of Cycle 1, patients will be provided with enough CB-839 to last until their next clinic 
visit.  Patients will return on Day 1 of each cycle thereafter and will receive a 28 day supply of 
CB-839; the number of capsules/tablets remaining from the previous visit will be counted and 
recorded. 
 
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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 
shipment with the appropriate for to the contract distribution center. Returned and unused CB-
839 test article may also be destroyed and documented at the investigative site in accordance 
with approved site/institution standard operating procedures. 
11.5 Test Article Compliance 
At each clinic visit, patients will be asked to return any unused CB-839 test article and will be 
questioned about their test article compliance.  The number of remaining capsules/tablets will be 
recorded in the drug accountability log.  Significant non-compliance (missing > 60% of the study 
drug for reasons other than documented AE) must be reported to the monitor. 
Missed doses of CB-839 should be skipped.  If a patient forgets to take a dose of study drug and 
he/she is outside of the allotted window period (± 6 hr), he/she should be instructed NOT to take 
extra study drug at their next administration. 
12.0 
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. 
13.0 
SAFETY EVALUATIONS 
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. 
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More frequent safety evaluations may be performed if clinically indicated or at the discretion of 
the Investigator.  All AEs will be recorded from the time the patient receives the first dose of 
study drug up to 28 days after the last dose. 
13.1 Physical Examination 
Complete physical examinations will be performed by a licensed physician (or physician’s 
assistant or nurse practitioner) at Screening and End of Treatment.  Symptom-directed physical 
exam are required as clinically indicated. Please refer to the Schedule of Study Assessments 
(Attachment 1). 
13.2 Vital Signs 
Vital signs (blood pressure, respiratory rate, pulse rate, and temperature) will be obtained in the 
sitting position.  All patients should be sitting for 3-5 min prior to obtaining vital signs.  On the 
day of nivolumab infusion, vital signs will be obtained pre-infusion and within 30 min of the end 
of infusion. Vital signs should be collected ± 5 min from the scheduled times noted above. 
13.3 Electrocardiograms 
Patients should rest in the supine 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.  
For safety monitoring purposes, the ECG must be reviewed, signed, and dated promptly by a 
qualified physician (or qualified physician’s assistant or nurse practitioner) and any clinically 
important finding recorded on the appropriate eCRF.  The Investigator is responsible for 
providing the interpretation of all ECGs.  The results will include heart rate (HR), R-R interval 
(RR), PR interval, QRS interval, QT interval, and QTcF interval.  The corrected QT interval will 
be corrected for respiratory rate according to the following formula: 
Fridericia’s formula:  QTcF = QT/RR0.33 
13.4 Safety Laboratory Determinations 
Laboratory evaluations will be performed as noted in the Schedule of Study Assessment. 
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14.0 
BIOMARKER AND PHARMACODYNAMIC SAMPLES  
14.1 Archival Tumor Biopsy Samples 
Archival surgical samples and biopsy specimens must be provided from all patients on study 
who have archival tissue available.  Samples should be collected and shipped according to 
instructions provided in the Laboratory Manual.  
 
14.2 Predose and Postdose Tumor Biopsies 
Tissue for exploratory biomarker assessment will be obtained from fresh tumor biopsies 
performed prior to the initiation of treatment (“predose”) and while on treatment (“postdose”).  
These samples will be used for a) the analysis of gene expression levels and b) for 
immunohistochemical/immunofluorescence analysis.  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. 
Predose biomarkers will be used primarily to identify potential biomarkers that are predictive of 
response to therapy.  In order to assess the impact of CB-839 on the pharmacodynamic effects of 
nivolumab, mandatory pre- and-post treatment biopsies will be obtained from patients who 
progressed on nivolumab or pembrolizumab in the immediate prior line of therapy (Cohort 2, 4, 
and 5).  Table 14.2-1 below indicates which patients are required to have tumor biopsies. 
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Table 14.2-1: Summary of Tumor Biopsy* Collections for Patients 
 
 
Cohorts 
Predose Biopsy 
Postdose Biopsy 
C2D1 (± 1 week)** 
Phase 1: Dose 
Escalation 
600 mg CB-Nivo  
800 mg CB-Nivo 
(400 mg CB-Nivo if 
required) 
Optional 
Optional  
Backfill patients 
Mandatory 4-6 cores 
Mandatory 4-6 cores 
Phase 2: Cohort 
Expansion 
Cohort 1: ccRCC - 
Checkpoint inhibitor naïve  
Mandatory 4-6 cores 
(Archival accepted if 
taken <1 yr) 
Optional 
Cohort 2: ccRCC - Nivo in 
most recent line of therapy 
(“add-on”) 
Mandatory 4-6 cores 
Mandatory 4-6 cores 
Cohort 3: ccRCC - Any prior 
anti-PD-1 
Mandatory 4-6 cores 
Optional 
Cohort 4: Melanoma 
Mandatory *** 
Mandatory*** 
Cohort 5: NSCLC 
Mandatory 4-6 cores 
Mandatory 4-6 cores 
 
Cohort 6: Melanoma 
Mandatory *** 
Optional 
*Biopsies are not required if deemed unsafe or technically unfeasible.  Discuss with Medical Monitor. 
 **The timing of the post dose biopsy will be subject to clinical feasibility and if this window cannot be met, this can 
be discussed with the Medical Monitor. 
*** Excisional or punch biopsies are preferred.  Core biopsies are acceptable.  
 
Biopsies will be processed and shipped according to the instructions provided in the Laboratory 
Manual.  Enrollment of patients for whom tumor biopsy is not safe or feasible to perform may be 
considered based on discussion with the Medical Monitor. 
Optional tumor biopsies for exploratory biomarker assessment may be collected at any point on 
this study with patient consent (e.g., progression biopsies). 
14.3 Plasma and Whole Blood Collection for Biomarker Analysis 
Plasma Collection: Whole blood will be collected via peripheral venipuncture into EDTA tubes 
(lavender top) to monitor cytokine and glutamine levels. Samples with be centrifuged and plasma 
collected and stored at -70oC. 
Whole Blood Collection: Whole Blood samples will be collected via peripheral venipuncture 
into three different blood collection tubes: 
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1. Blood RNA tubes: to monitor immune gene expression 
2. CPT tubes: to monitor immune cell subsets  
3. EDTA tube: to monitor T-Cell Receptor (TCR) clonality 
All Plasma and Whole Blood Samples will be collected at the time points indicated in the PK 
and Biomarker Sampling Schedule (Attachment 2) and will be processed and shipped according 
to instructions provided in the Laboratory Manual. 
The biomarker samples 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. 
14.4 
Biomarker Assessment 
Biomarkers assessed on tumor tissue are designed to measure biological effect of CB-839 in 
combination with nivolumab to identify potential predictors of response. 
Target expression: Tumor glutaminase gene expression profiles will be determined and tumor 
glutaminase protein will assessed via immunohistochemistry (IHC) 
Target engagement will be assessed by measuring levels of plasma glutamine 
The glutaminolytic signature will be measured in the tumor via gene expression and IHC for 
Myc and p-S6 protein 
Immune marker expression and modulation will be assessed in peripheral blood and tumor tissue 
(cytokines and immune cell populations) 
15.0 
PHARMACOKINETIC EVALUATION 
15.1 Blood Collection 
Plasma PK samples will be used to measure concentrations of CB-839 and its major metabolite 
110826.  These samples may also be used for exploratory biomarker analyses including, but not 
limited to, measurements of amino acid levels, enzymes such as glutaminase, glutamine 
synthetase, pyruvate carboxylase, and arginase.  Blood samples for PK analysis should be 
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collected at the requested time but must be obtained within a 15 min window of the requested 
time.  The exact actual time of collection must be noted in the source documents and eCRFs. 
 
During the Phase 1 Dose Escalation, plasma PK samples will be collected on Cycle 1, Days 1 
and 15 at predose and postdose at 0.5, 1, 2, 4, 6, and 8 hr as well as predose on Cycle 2 Day 1 
and Cycle 3 Day 1. Patients enrolled on study who start taking PPIs will have plasma PK 
samples drawn at the same time points indicated above within 2 weeks of starting PPIs. During 
the Phase 2 Cohort Expansion, plasma PK will be collected for population PK analysis prior to 
dosing on Cycle 1, Day 1 and Day 15, Cycle 2 Day 1, and Cycle 3 Day 1. Refer to the PK and 
Biomarker Sampling Schedule (Attachment 2) for time points and blood volumes to be collected. 
 
15.2 Bioanalytical Methodology 
The plasma samples will be analyzed for CB-839 and its major metabolite 110826 by using a 
validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method of appropriate 
specificity and sensitivity according to Good Laboratory Practices (GLPs). 
16.0 
STATISTICAL ANALYSIS 
16.1 General Statistical Considerations 
Protocol CX-839-004 is a Phase 1/2 multicenter, open-label study in patients with advanced and 
metastatic or refractory solid tumors. 
Since this is an open-label clinical trial, descriptive statistics will be employed to analyze the 
data by tumor type.  Summary statistics for continuous variables will include the mean, standard 
deviation, median, and range (minimum/maximum).  Categorical variables will be presented by 
tumor type as frequency counts and percentages, and time-to-event variables will be summarized 
by Kaplan-Meier plots, medians, and ranges. 
The data will be tabulated and analyzed with respect to patient enrollment and disposition, 
demographic and baseline characteristics, prior and concomitant medications, efficacy, and 
safety measures.  The efficacy analysis will be conducted on the Efficacy Evaluable Population 
as well as on all treated patients.  The safety analysis will be performed on the Safety Population. 
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All confidence intervals will be constructed at the 95% confidence level.  Data listings will be 
created to support each table and to present all data collected. 
16.2 
Independent Radiology Committee (IRC) 
An IRC will be established to evaluate tumor scans from patients in Cohort 4 only in a central 
and independent fashion.  The IRC will comprise board-certified radiologists who will determine 
radiographic responses and progression following study start.  Additional imaging results may be 
requested by the Sponsor for IRC review. 
Additional details regarding IRC member qualification, training, methods, procedures, and other 
issues relevant to committee operations will be described in the IRC Charter.  
16.3 Sample Size and Power 
Dose Escalation:  The goal is to determine a dose level of CB-839 for which the rate of DLTs is 
less than 33%.  A minimum of 9-12 patients are planned for Dose Escalation. 
Dose Expansion:  For Cohorts 1-6, Simon's two-stage design (Simon 1989) will be used as 
outlined in Table 22.2-1 below.  The null hypothesis that the response rate is [ p0 ] will be tested 
against a one-sided alternative.  In the first stage, [ n1 ] patients will be accrued.  If there are 
[ r1 ] or fewer responses in these [ n1 ] patients, the study will be stopped.  Otherwise, [ n - n1 ] 
additional patients will be accrued for a total of [ n ].  The null hypothesis will be rejected if 
[ r2 + 1 ] or more responses are observed in [ n ] patients.  This design yields a type I error rate 
of 0.1 and power of 80% when the true response rate is [ p1 ]. 
Table 22.2-1: Summary of Sample Size and Power for Expansion Cohorts 
Cohort 
p0 
(Background 
ORR (%)) 
p1  
(Target ORR 
(%)) 
Α 
Power 
(%) 
n1 for Stage 1 
(r1) 
n2 (n - n1) 
for Stage 
2 
Total n 
(r2) 
1 
25% 
40% 
0.1 
80 
25 (7) 
27 
52 (16) 
2 
5% 
15% 
0.1 
80 
20 (1) 
36 
56 (4) 
3 
5% 
20% 
0.1 
80 
9 (0) 
15 
24 (2) 
4 
5% 
20% 
0.1 
80 
9 (0)** 
66 
75 (13) 
5 
5% 
15% 
0.1 
80 
20 (1) 
36 
56 (4) 
6 
5% 
20% 
0.1 
80 
9 (0) 
15 
24 (2) 
*For all cohorts, false positive rate (α) = 0.1 
**Completed prior to protocol Amendment 2 expansion of cohort 
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Expanded Cohort 4 
A multi-stage design will be used as a guide for the melanoma expansion cohort 4 to decide 
whether the treatment of CB-839 in combination with nivolumab warrants more extensive 
development in this population.  At first, a Simon 2-stage design (Table 22.2-1) with a 
reasonable false positive rate (eg, FPR < 10%) and false negative rate (eg, FNR < 20%) was used 
for the decision making based on assumptions of target (20%) and background (5%) response 
rate. Following a positive result in the initial two stage design and preliminary evidence of a 
treatment effect that may represent substantial improvement over available therapies, 
approximately 75 subjects in total will be treated in Cohort 4. The sample size at this expanded 
stage is determined based on the ability to produce a confidence interval that would exclude the 
historic response rate (assumed to be 10%) and to provide sufficient information for a reliable 
understanding of the safety profile.  Specifically, the lower limit of the 95% CI associated with 
observation of an objective response rate of 18.7% in 75 treated subjects (14/75 responders) 
excludes 10%.  Interim clinical monitoring will be performed in this expansion to ensure 
adequate safety and tolerability as well as favorable risk/benefit by assessing preliminary 
efficacy measures such as objective response rate and duration of response. 
 
16.4 Analysis Populations 
16.4.1 Safety Population 
All patients who receive at least 1 dose of CB-839 or nivolumab will be included in the analysis 
of safety, regardless of the duration of treatment.  
AE and laboratory data from all patients in the safety population will be evaluated for safety.  
Patients from dose escalation will be combined with patients from cohort expansion for safety 
evaluation; all safety evaluation will be evaluated by tumor type.  Data will be tabulated to 
examine the frequency, organ systems affected, and relationship to study drugs.  No formal 
interim analysis is planned; however, safety data will be examined on an ongoing basis to ensure 
safety of the study patients and compliance with the trial dose escalation and expansion rules. 
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16.4.2 DLT-evaluable Populations in Dose Escalation 
DLTs will be evaluated during dose escalation.  Unless doses are missed in Cycle 1 due to 
DLT(s), a patient must receive at least 75% of the planned CB-839 doses (43 of 56 total doses) 
to be considered evaluable for DLT.  If a patient received less than 43 doses of CB-839 in the 
first 28 days of treatment for reasons other than a DLT, the patient will be considered non-
evaluable for DLT and replaced.  Patients must receive both doses of nivolumab in Cycle 1 in 
order to be evaluable for DLT. 
Patients who discontinue the study prior to receiving the requisite study treatment 
administrations for reasons that include, but are not limited to, clinical/radiographic progression, 
voluntary withdrawal, or complications that the Principal Investigator considers secondary to the 
patient’s malignancy will not be considered evaluable for DLT and will be replaced. 
 
16.4.3 Response Evaluable Population 
Patients treated in the protocol expansion phase or at the RP2D in the escalation phase who have 
measurable disease at baseline and complete at least one post-baseline tumor assessment, or 
discontinue study medication early due to study drug-related toxicity, or experience clinical 
disease progression will be considered evaluable for RECIST 1.1 response evaluation.  Patients 
who discontinue study due to early disease-related death will be included in the response 
evaluable population if they received at least 21 days of treatment (approximately 42 doses of 
CB-839 and 2 doses of nivolumab).  Patients who do not meet the aforementioned requirements 
will be considered non-evaluable for response and will be replaced.   
16.4.3.1 Melanoma Confirmed PD Population 
In addition to the above criteria, melanoma patients who have confirmation of PD > 4 weeks 
after the initial date of PD in the immediate prior line of treatment will be included in the 
Confirmed PD population.  
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16.5 Efficacy Analysis 
For the primary efficacy analysis, response to treatment will be evaluated by RECIST v1.1.  For 
all cohorts except for Cohort 4, the primary endpoint will be investigator-assessed, while for 
Cohort 4 the primary endpoint will be IRC assessed. 
The Kaplan-Meier method will be used to estimate the median Duration of Response (DOR), 
Progression-Free Survival (PFS), and overall survival (OS) for each treatment cohort in Dose 
Expansion. 
 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 required a 
minimum of 4 weeks after the date of the initial determination of response.   
 DOR is defined as the number of days from the date of initial response (PR or better) to 
the date of first documented disease progression/relapse or death, whichever occurs first. 
 PFS is defined as the number of days from the date of treatment initiation (i.e., C1D1) to 
the date of documented disease progression (radiographic or clinical) or death from any 
cause, whichever occurs first, and will be calculated for all patients who receive at least 
one dose of study treatment.  In the event that no disease progression or death is 
documented prior to study termination, analysis cutoff, or the start of confounding 
anticancer therapy, these endpoints will be censored at the date of last available tumor 
assessment. 
 OS is defined as the number of days from the date of treatment initiation (i.e., Cycle 1 
Day 1) to the date of death from any cause and will be calculated for all patients who 
receive at least one dose of treatment.  In the event that no death is documented prior to 
study termination or analysis cutoff, OS will be censored at the last date the patient is 
known to be alive. 
16.6 Safety Analysis 
Safety variables to be analyzed by tumor type are AEs, laboratory test results (hematology, 
coagulation, serum chemistry, and urinalysis), ECG, weight, and vital signs. 
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Adverse event terms recorded on the eCRFs will be mapped to preferred terms using the most 
recent version of the Medical Dictionary for Drug Regulatory Activities (MedDRA®). All AEs 
will be summarized according to the system organ class and preferred term within the organ 
class.  Adverse events will be tallied for overall frequency (number and percentage of patients), 
worst reported severity, and relationship to study drug for each preferred term per patient.  
Serious adverse events will be similarly summarized.  Listings of deaths, SAEs, and AEs leading 
to early termination of study treatment or premature withdrawal from study will also be 
provided. 
Laboratory variables will be examined using mean change in value from baseline to scheduled 
time points.  The baseline value of a variable is defined as the last value obtained on or before 
the date and time of the first dose of CB-839 or nivolumab. 
ECG, weight, and vital signs will also be summarized by changes from baseline to scheduled 
time points using descriptive statistics. 
16.7 Pharmacokinetic Analysis 
For Phase 1- Dose Escalation PK samples, a noncompartmental method of analysis will be used 
to analyze the plasma concentrations of CB-839.  Cmax and the time to attain the Cmax (Tmax) will 
be determined directly from the observed data.  A partial AUC (AUC0-8) will be calculated on 
Days 1 and 15 in Cycle 1.  For Phase 2- Cohort Expansion, plasma samples will be collected to 
perform population PK analysis. 
16.7.1 Biomarker Analysis 
Measures of pharmacodynamic activity in blood samples will be explored.  PDn data from each 
assay will be listed, and possible relationships between PK and PDn variables will be explored.  
Any biological activity will be described.  In addition, relationships between antitumor activity, 
PDn markers, exploratory biomarkers, and drug exposure levels will be explored. 
 
16.8 Precautions 
Although major adverse events are not anticipated, the Investigator must proceed with utmost 
caution.  Equipment, supplies, and properly skilled medical personnel must be immediately 
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available for emergency use in the event of an unexpected reaction.  Patients must be selected 
carefully and closely monitored. 
For a complete description of preclinical studies of CB-839, please refer to the CB-839 
Investigator’s Brochure. For a description of precautions with nivolumab, please refer to the 
Product Label. 
17.0 
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 the most recent version of the Investigator’s Brochure.  For 
safety information on nivolumab, refer to the Product Label. 
17.1 Definitions 
An adverse event (AE) is any untoward, undesired, or unplanned event in the form of signs, 
symptoms, disease, or laboratory or physiologic observations occurring in a person given a test 
article or associated with other protocol interventions in a clinical study.  The event does not 
need to be causally related to the test article.  An AE includes, but is not limited to, the 
following: 
 Any AE not previously observed in the patient that emerges during the protocol 
specified AE reporting period 
 Any clinically significant worsening of a preexisting condition 
 Complications occurring as a result of protocol-mandated interventions (e.g., invasive 
procedure such as biopsies), including in the period prior to receiving the first dose of 
the test article that are related to the protocol-mandated intervention (e.g., medication 
wash out, biopsies) 
 An AE occurring from overdose (i.e., a dose higher than that indicated in the 
protocol) of a test article, whether accidental or intentional 
 An AE occurring from abuse (e.g., use for nonclinical reasons) of a test article 
 An AE that has been associated with the discontinuation of the use of a test article 
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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 
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 
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reported as an adverse event, and hospitalizations due to the progression of cancer do not 
necessarily qualify for an SAE.  All deaths including those related to progression of disease and 
sudden and unexplained death should be reported as an SAE. If there is any uncertainty about a 
finding being due solely to progression of neoplasia, the finding should be reported as an AE or 
SAE as appropriate. 
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. 
 The hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (e.g., stent removal after surgery).  This should be recorded in the 
study file. 
 Hospitalization for survey visits or annual physicals falls into the same category. 
In addition, hospitalizations planned before the start of the study, for a preexisting condition that 
has not worsened, do not constitute an SAE.  Visits to the Emergency Room that do not result in 
hospital admission are not considered hospitalizations, but may constitute a medically important 
event. 
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Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt about whether the information constitutes an SAE, the information is treated 
as an SAE. 
Causality Attribution Guidance: 
AEs should be considered (probably or possibly) treatment-related, unless they fulfill the 
following criteria (in which circumstances it should be considered unlikely related or unrelated): 
 Evidence exists that the AE has an etiology other than the investigational product (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication), and/or 
 The AE has no plausible temporal relationship to administration of the investigational 
product (e.g., a new cancer diagnosed 2 days after first dose of study drug). 
Relatedness to study medication will be graded as either, “probably”, “possibly”, “unlikely”, or 
“unrelated” as follows: 
Probably Related – The adverse event 
 Follows a reasonable temporal sequence from drug administration 
 Abates upon discontinuation of the drug 
 Cannot be reasonably explained by the known characteristics of the patient’s clinical 
state 
Possibly Related – The adverse event 
 Follows a reasonable temporal sequence from drug administration 
 Could have been produced by the patient’s clinical state or by other modes of therapy 
administered to the patient 
Unlikely Related - The adverse event 
 Is most likely to be explained by the patient’s clinical state or by other modes of therapy 
administered to the patient 
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Unrelated – The adverse event 
 Does not follow a reasonable sequence from drug administration 
 Is readily explained by and considered by the Principal Investigator to be an expected 
complication of the patient’s primary malignancy, clinical state, concurrent medical 
conditions, or by other modes of therapy administered to the patient 
A protocol-related adverse event is an AE occurring during a clinical study that is not related 
to the test article, but is considered by the Investigator or the  Medical Monitor (or designee) to 
be related to the research conditions, i.e., related to the fact that a patient is participating in the 
study.  For example, a protocol-related AE may be an untoward event occurring during a 
washout period or an event related to a medical procedure required by the protocol. 
Other Reportable Information:  certain information, although not considered an SAE, must be 
recorded, reported, and followed up as indicated for an SAE.  This includes: 
 A case involving a pregnancy exposure to a test article, unless the product is indicated for 
use during pregnancy e.g., prenatal vitamins.  Information about use in pregnancy 
encompasses the entire course of pregnancy and delivery and perinatal and neonatal 
outcomes, even if there were no abnormal findings.  If a pregnancy is confirmed, test 
article must be discontinued immediately.  All reports of pregnancy must be followed for 
information about the course of the pregnancy and delivery, as well as the condition of 
the newborn.  When the newborn is healthy, additional follow-up is not needed. 
Pregnancies occurring up to 6 mo after completion of the study treatment must also be 
reported to the Investigator. 
 Overdose (e.g., a dose higher than that indicated in the protocol) with or without an AE 
 Abuse (e.g., use for nonclinical reasons) with or without an AE 
17.2 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. 
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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. 
17.3 Serious Adverse Event Reporting 
All SAEs regardless of attribution, other reportable information, and follow-up information must 
be reported within 1 business day of learning of the event by completing the SAE form and 
either emailing or faxing the form to the SAE Reporting Contact.  Calithera Biosciences (or 
designee) will process and evaluate all SAEs as soon as the reports are received.  For each SAE 
received, Calithera Biosciences will make a determination as to whether the criteria for expedited 
reporting have been met.  The Medical Monitor should also be contacted for any fatal or life-
threatening SAE that is considered possibly or probably related to study drug. 
Calithera Biosciences, Inc. (or designee) is responsible for reporting relevant SAEs to the 
relevant regulatory authorities and participating Investigators, in accordance with FDA 
regulations 21 CFR 312.32, ICH Guidelines, European Clinical Trials Directive (Directive 
2001/20/EC), and/or local regulatory requirements and monitoring the safety profile of the study 
drug.  To meet this requirement, Calithera Biosciences, Inc. (or designee) may request additional 
information from the sites including, but not limited to, hospitalization records.  Any requests for 
such information should be addressed in a timely manner.  Additionally, any SAE considered by 
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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. 
18.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION  
The Sponsor may suspend or terminate the study or any part of the study at any time for any 
reason.  If the Investigator suspends or terminates the study, the Investigator will promptly 
inform the Sponsor and the IRB/IEC and provide a detailed written explanation.  The 
Investigator will also return all CB-839 test article(s), 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. 
19.0 
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 
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20.0 
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. 
21.0 
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.  
22.0 
DIRECT ACCESS, DATA HANDLING, AND RECORD KEEPING 
22.1 Investigator 
The Investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and documents. 
All study-related information will be recorded on source documents.  All required data will be 
recorded in the eCRFs.  All eCRF data must be submitted to the Sponsor throughout and at the 
end of the study. 
If an Investigator retires, relocates, or otherwise withdraws from conducting the study, the 
Investigator must notify the Sponsor to agree upon an acceptable storage solution.  Regulatory 
agencies will be notified with the appropriate documentation. 
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. 
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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. 
22.2 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. 
23.0 
PRE-STUDY DOCUMENTATION 
The Investigator must provide the Sponsor with the following documents BEFORE enrolling any 
patients: 
 Completed and signed form 1572 
 All applicable country-specific regulatory forms 
 Current, dated curricula vitae for the Investigator, Sub-Investigators, and other 
individuals having significant investigator responsibility who are listed on the Form 1572 
or equivalent, or the clinical study information form. 
 Copy of the IRB/IEC approval letter for the protocol and informed consent.  All 
advertising, recruitment, and other written information provided to the patient must be 
approved by the IRB/IEC.  Written assurance of continuing approval (at least annually) 
as well as a copy of the annual progress report submitted to the IRB/IEC must also be 
provided to the Sponsor.  
 Copy of the IRB/IEC-approved Informed Consent Form to be used 
 Where applicable, a list of the IRB/IEC members or a Federal-Wide Assurance/ 
Department of Health and Human Services (FWA/DHHS) number 
 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) 
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 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. 
 
24.0 
RECORDS RETENTION 
The Investigator shall retain and preserve one copy of all data generated in the course of the 
study, specifically including but not limited to those defined by GCP as essential, for the longer 
of: (i) 2 years after the last marketing authorization for the study drug has been approved or the 
Sponsor has discontinued its research with respect to such drug or (ii) such longer period as 
required by applicable global regulatory requirements.  At the end of such period, the 
Investigator shall notify the Sponsor in writing of its intent to destroy all such material.  The 
Sponsor shall have 30 days to respond to the Investigator’s notice, and the Sponsor shall have a 
further opportunity to retain such materials at the Sponsor’s expense.  
25.0 
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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26.0 
REFERENCES 
 
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in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-1639. 
Calithera Biosciences, Inc. CB-839 Investigator’s Brochure 
Cassago A, Ferreira AP, Ferreira IM, Fornezari C, Gomes ER, Greene KS, et al. Mitochondrial 
localization and structure-based phosphate activation mechanism of glutaminase C with 
implications for cancer metabolism.  Proc Natl Acad Sci USA 2012;109:1092-1097. 
 
Chang MY, Smith C, DuHadaway JB, Pyle JR, Boulden J, Soler AP, et al. Cardiac and 
gastrointestinal liabilities caused by deficiency in the immune modulatory enzyme indoleamine 
2,3-dioxygenase.  Cancer Biol Therap. 2011;12:1050-1058. 
 
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 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 
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Kung HN, Marks JR, Chi JT. Glutamine synthetase is a genetic determinant of cell type-specific 
Glutamine independence in breast epithelia. PLoS Genet 2011;7:1-15. 
 
Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, et al. Glucose-independent glutamine 
metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 2012;15:110-
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Liu B, Song K, Kwong M, Gao M, Hong, Nannini, et al. AACR 2013, Abstract # 4618: 
Elucidating the role of distinct glutaminase isoforms in cancer. 
 
Motzer, R., Escudier, B., McDermott, D., et al. Nivolumab versus Everolimus in Advanced 
Renal-Cell Carcinoma. NEJM 2015; 373: 1803-1813 
 
Nishino et al. Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements, Clinical Cancer Research 2013; 
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Nivolumab package insert 
 
Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, et al. PD-1 alters T-cell metabolic 
reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.. Nature 
Commun 2015; 6:6692.  
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Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, et al. Inhibition of 
glutaminase preferentially slows growth of glioma cells with mutant IDH1.  Cancer Res 
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Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al., iRECIST: 
Guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017; 
18: e143-152. 
 
Shroff, EH, Eberlin LS., Dang, VM., Gouw, AM., Gabay, M., Adam SJ., MYC Oncogene 
overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. 
PNAS 2015 112 (21) 6539-6544 
 
Simon R, Freidlin B, Rubenstein L, Arbuck S, Collins J, Christian MC. Accelerated Titration 
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Explanation of Superscripts 
1. 
Complete physical exam is required at Screening and at End of Treatment. A symptom-directed physical exam can be done on all other visits. System exams are only 
required as clinically indicated.  
2. 
Assessment to be completed on Day 1 of every cycle. 
3. 
Vital sign measurements include temperature, pulse, respiratory rate and resting systolic and diastolic blood pressure. On the day of nivolumab infusion, vital signs will 
be obtained pre-infusion and within 30 minutes of the end of the infusion. Vital signs should be collected ± 5 minutes from the scheduled times noted above.  
4. 
Duplicate ECGs are NOT required.  
5. 
ECG to be performed within approximately 2 to 4 hr postdose of CB-839 administration. 
6. 
Does not need to be repeated if the Screening sample was obtained within 3 days prior to C1D1 unless a clinically significant change is suspected. 
7. 
Serum chemistry, coagulation, hematology and urinalysis laboratory tests should be performed and reviewed before dosing. These labs may be performed up to 48 hours 
prior to the planned dosing. Note that coagulation tests must be performed and reviewed within 72 to 24 hr prior to all biopsy procedures. Any new ≥Grade 3 laboratory 
abnormality, or change consistent with a possible irAE (as opposed to disease progression), such as liver function test elevations, electrolyte fluctuation, or hematologic 
deterioration should be assessed for potential risk to continue dosing. In the event of uncertainty, the medical monitor should be contacted. 
8. 
Required of all females of child-bearing potential. Screen pregnancy test must occur within 3 days prior to C1D1. 
9. 
Samples are collected on C1D1, C1D15, C2D1 and C3D1. See attachment 2 for specific time points and volume of blood collection. 
10. Nivolumab dosing will take place on D1 and D15 of every cycle.  On PK days (C1D1, C1D15, C2D1 and C3D1), patients will bring their morning dose of CB-839 to 
clinic. Pre-dose procedures must be completed, then the patient will eat breakfast and take their CB-839 dose and then the infusion of nivolumab will be administered.  
Cohort 6 patients have the option to add Nivolumab at progression on CB-839 monotherapy.  
11. CB-839 is given BID with food approximately 12 hours apart. On PK days (C1D1, C1D15, C2D1 and C3D1), patients will bring their morning dose of CB-839 to clinic. 
Pre-dose procedures must be completed, then the patient will eat breakfast and take their CB-839 dose and then the infusion of nivolumab will be administered. 
12. Whenever possible, imaging should be done at the same institution/ facility and with the same modality which will be used to measure response during the patient’s 
participation in the study. The redacted copies of the reports will be submitted and the scans must be sent to a reader for exploratory analyses. All scans from the 
immediate prior line of therapy will be requested for Cohorts 2, 4, and 5. 
13. For Cohort 4 only: baseline radiographic imaging of disease will also occur within 7 days prior to C1D1 unless the screening assessment meets the criteria described in 
Section 10.1. 
14. Completed approximately every 8 weeks from Cycle 1 Day 1 per RECIST 1.1. Studies should include chest/abdomen/pelvis and all other known areas of disease. 
Evaluations may occur more frequently as clinically indicated. Patients with an objective response (CR or PR) should have repeat imaging at least 4 weeks later to 
confirm the objective response. In addition, patients with progressive disease should undergo a second scan at least 4 weeks later to confirm progression. 
15. Cohort 4 only 
16. To be included for patients with known CNS disease. 
17. Archival tumor tissue must be provided from all patients on study who have archival tissue available.  
18. A baseline tumor biopsy is required for all patients enrolled in Phase 2. Postdose tumor biopsies are required for all patients in Cohorts 2 and 5 and should be collected 
on Cycle 2 Day 1 (± 1 week).  Predose and postdose biopsies will be collected for the first 30 patients enrolled into stage 2 of Cohort 4. For all subsequently enrolled 
patients, only a pre-dose biopsy will be collected.  Coagulation tests must be performed and evaluated within 72 to 24 hr prior to all biopsy procedures. Instructions on 
biopsy processing can be found in the Laboratory Manual.  
19. Patients who discontinue study treatment for reason other than PD or death must continue to be followed by radiographic imaging per study schedule until PD, death, 
withdrawal of consent, or initiation of another cancer therapy. 
20. Patients will be contacted every 3 mo for the first 12 mo then every 6 mo thereafter to confirm survival or public records may be consulted to establish survival status.  
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ATTACHMENT 2: PHARMACOKINETIC AND BIOMARKER SAMPLING SCHEDULE 
Detailed instructions on sample collection and shipment can be found in the Laboratory Manual. 
 
Study Day 
Time 
point 
(Relative 
to CB-839 
Dosing) 1 
Phase 1 
only  
PK/ 
Biomarker2 
Phase 2 
only 
PK/ 
Biomarker3  
Phase 1 and 
Phase 2 
Biomarker: 
RNA4 
 
Phase 1 and 
Phase 2 
Biomarker: 
CPT5 
 
Phase 1 and 
Phase 2 
Biomarker: 
TCR6 
 
Phase 1 and 
Phase 2 
Tumor 
Biopsy7 
Screening 
 
 
 
 
 
 
4-6 Cores 
Cycle 1 Day 1 
Predose 
3 mL 
3 mL 
5 mL 
32 mL 
3 mL 
 
Cycle 1 Day 1 
0.5 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 1 
1 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 1 
2 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 1 
4 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 1 
6 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 1 
8 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 15 
Predose 
3 mL 
3 mL 
5 mL 
 
3 mL 
 
Cycle 1 Day 15 
0.5 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 15 
1 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 15 
2 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 15 
4 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 15 
6 hr 
3 mL 
 
 
 
 
 
Cycle 1 Day 15 
8 hr 
3 mL 
 
 
 
 
 
Cycle 2 Day 1 
Predose 
3 mL 
3 mL 
5 mL 
32 mL 
 
4-6 Cores 
Cycle 3 Day 1 
Predose 
3 mL 
3 mL 
5 mL 
32 mL 
3 mL 
 
Total sample 
collected 
 
48 mL 
blood 
12 mL 
blood 
20 mL 
blood 
96 mL  
blood 
9 mL 
blood 
 
 
1. Where applicable, the collection window is ±15 minutes. The actual sample collection time will be entered in the EDC. 
2. Blood samples will be collected for all patients enrolled in the Phase 1 Dose Escalation. 
3. Blood samples will be collected from all patients enrolled in the Phase 2 Dose Expansion 
4. 2.5 mL of whole blood will be collected in to two Paxgene Blood RNA tubes. 
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5. 8 mL of whole blood will be collected in to four Vacutainer CPT cell preparation tubes with sodium heparin. The CPT tubes will be 
centrifuged at room temperature for 30 min at 1800 RCF (relative centrifugal force). 
6. 3mL of whole blood will be collected in to 1 EDTA tubes. The EDTA tubes should be placed in -80ºC storage. 
7. At least 4-6 tissue cores will be collected from patients. 14-18 gauge needle core biopsies are preferred however, 20 gauge needles can be 
used at the discretion of the radiologist and treating physician.  For melanoma patients, excisional or punch biopsies are preferred.  
 
 
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ATTACHMENT 3: CLINICAL LABORATORY TESTS 
Hematology (Peripheral Blood Sample) 
 Hemoglobin and hematocrit 
 RBC count 
 White blood cell count with differential 
 Platelet count 
Coagulation Tests 
 PT, aPTT and INR 
Serum Chemistry-Full Metabolic Panel (Peripheral Blood Sample) with additional analytes 
 Sodium 
 Potassium 
 Chloride 
 CO2  
 Calcium 
 Glucose1 
 Blood urea nitrogen 
 Total protein 
 Albumin 
 Total bilirubin2 
 Aspartate aminotransferase (AST) 
 Alanine aminotransferase (ALT) 
 Alkaline phosphatase (AP) 
 Lactate dehydrogenase (LDH) 
Creatinine 
 Thyroid Stimulating Hormone (TSH)2 
1 
Fasting glucose (8-10 hour fast) is required on PK days only (C1D1, C1D15, C2D1 and C3D1). 
2 
Thyroid functioning will be monitored by measuring thyroid stimulating hormone (TSH) only, with a full 
panel run of TFTs if there is an abnormal TSH result or thyroid dysfunction is suspected.   
 
Pregnancy test (urine -HCG):  Women of child-bearing potential 
Urinalysis 
 Only institutional standard urinalysis is required 
 
 
 
 
 
 
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ATTACHMENT 4:  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 
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The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
and  10 mm diameter as assessed using calipers (e.g., skin nodules).  For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
suggested.  As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. Still, non-contrast CT is preferred over chest X-ray. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g., for body scans). 
If prior to enrolment it is known that a patient is not able to undergo CT scans with IV contrast 
due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (with 
or without IV contrast) will be used to evaluate the 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. 
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Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess objective tumor response.  If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response.  Because tumor markers are disease specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis.  Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and 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 
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organ will be recorded as non-measurable lesions (even if size is greater than 10 mm by CT 
scan). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor.  Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital or coronal).  The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis  10 mm 
but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
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 
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 Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
 Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progression). 
 Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 
Special notes on the assessment of target lesions 
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. Case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis < 10 mm.  For PR, SD, and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
Target lesions that become ‘too small to measure’:  While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
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). 
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This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness).  The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm and in that case BML should not be ticked.  (BML is 
equivalent to a less than sign <) 
Lesions that split or coalesce on treatment:  When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note:  the 
appearance of one or more new lesions is also considered progression). 
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. 
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When the patient has only non-measurable disease:  This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease.  The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition:  if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease:  i.e., an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’.  If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point.  While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal:  i.e., not attributable to differences in scanning technique, change in imaging 
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 
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dedicated anatomic imaging (CT or MRI). The following modifications to RECIST v1.1. will be 
applied to this study: 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.  *Confirmation of the new lesion by CT or MRI scan is 
required per protocol. 
 No FDG-PET at baseline and a positive FDG-PET at follow-up: 
o If the positive FDG-PET at follow-up corresponds to a new sign of disease 
confirmed by CT, this is PD 
o If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal *CT scan). 
o If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
*reflects study-specific modification to RECIST v.1.1 
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 
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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. 
If one or more target lesions were not assessed either because the scan was not done, or could not 
be assessed because of poor image quality or obstructed view, the Response for Target Lesions 
should be “Unable to Assess” since the patient is not evaluable.  Similarly, if one or more non-
target lesions are indicated as ‘not assessed’, the response for non-target lesions should be 
“Unable to Assess” (except where there is clear progression).  Overall response would be 
“Unable to Assess” if either the target response or the non-target response is “Unable to Assess” 
(except where this is clear evidence of progression) as this equates with the case being not 
evaluable at that time point. 
Best overall response:  All time points 
The best overall response (Table C) will be determined by statistical programming once all the 
data for the patient are known. 
Table A: Time Point Response:  Patients with Targets (+/- Non-Target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. Note:  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
 
Table B: Time Point Response:  Patients with Non-Target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
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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 
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 
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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 
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 5: iRECIST: MODIFIED RECIST 1.1 FOR IMMUNE-BASED 
THERAPEUTICS  
(Source: Seymour 2017) 
 
A consensus guideline—iRECIST—was developed by the RECIST working group for the use of 
modified Response Evaluation Criteria in Solid Tumors (RECIST version1.1) in cancer 
immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing 
collection of trial data, and ultimate validation of the guideline.  This guideline describes a 
standard approach to solid tumor measurements and definitions for objective change in tumor 
size for use in trials in which an immunotherapy is used.  A comparison of RECIST and 
iRECIST is shown in Table S1 below, 
 
 
Table S1 Comparison of RECIST v 1.1 and iRECIST 
 
Protocol criteria for measurement of study endpoint  
 
1. Definitions  
 
1.1 
Evaluable for adverse events. All patients will be evaluable for adverse event evaluation from the 
time of their first treatment.  
 
1.2 
Evaluable for response.  All patients who have received at least one cycle of therapy and have 
their disease re-evaluated will be considered evaluable for response (exceptions will be those who 
exhibit objective disease progression prior to the end of Cycle 1 who will also be considered 
evaluable).  Patients on therapy for at least this period and who meet the other listed criteria will 
have their response classified according to the definitions set out below. 
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Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumors) committee as well 
as the modified iRECIST guidelines.  Investigators should note the different requirements for 
confirmatory scans as well as follow up for the two criteria.  See Section 3.11 for criteria for 
continuing treatment past RECIST 1.1 disease progression.  
 
2     RECIST 1.1 Response and Evaluation Endpoints  
 
2.1  
Measurable Disease. Measurable tumor lesions (nodal, subcutaneous, lung parenchyma, solid 
organ metastases) are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 20 mm with chest x-ray and as ≥ 10 mm with CT scan or 
clinical examination.  Bone lesions are considered measurable only if assessed by CT scan and 
have an identifiable soft tissue component that meets these requirements (soft tissue component 
≥10 mm by CT scan). Malignant lymph nodes must be ≥ 15 mm in the short axis to be considered 
measurable; only the short axis will be measured and followed.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimetres).  Previously irradiated lesions are 
not considered measurable unless progression has been documented in the lesion.  
 
2.2 
Non-measurable Disease.  All other lesions (or sites of disease), including small lesions are 
considered non-measurable disease. Bone lesions without a measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, lymphangitic involvement of lung or skin and abdominal masses 
followed by clinical examination are all non-measurable.  Lesions in previously irradiated areas 
are non-measurable, unless progression has been demonstrated.  
 
2.3  
Target Lesions.  When more than one measurable tumor lesion is present at baseline all lesions up 
to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
baseline.  Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  Note that pathological nodes must meet the 
criterion of a short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will 
contribute to the baseline sum. 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. At baseline, the sum of the 
target lesions (longest diameter of tumor lesions plus short axis of lymph nodes: overall 
maximum of 5) is to be recorded.  
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately 
measured but are deemed to be present, a default value of 5 mm may be used. If lesions are too 
small to measure and indeed are believed to be absent, a default value of 0 mm may be used.  
 
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2.4 
Non-target Lesions.  All non-measurable lesions (or sites of disease) plus any measurable lesions 
over and above those listed as target lesions are considered non-target lesions. Measurements are 
not required but these lesions should be noted at baseline and should be followed as “present” or 
“absent”.  
 
2.5 
Response.  All patients will have their BEST RESPONSE from the start of study treatment until 
the end of treatment classified as outlined below and shown in Table S2:  
 
Complete Response (CR): disappearance of target and non-target lesions and normalization of 
tumor markers. Pathological lymph nodes must have short axis measures < 10 mm (Note: 
continue to record the measurement even if < 10 mm and considered CR).  Residual lesions 
(other than nodes <10 mm) thought to be non-malignant should be further investigated (by 
cytology specialized imaging or other techniques as appropriate for individual cases4 before CR 
can be accepted. Confirmation of response is only required in non-randomised studies.  
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for 
tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline 
sum of diameters. Non target lesions must be non-PD. Confirmation of response is only required 
in non-randomised studies.  
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters on study.  
 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of measured lesions 
taking as references the smallest sum of diameters recorded on study (including baseline) AND 
an absolute increase of ≥ 5 mm.  Appearance of new lesions will also constitute progressive 
disease (including lesions in previously unassessed areas).  In exceptional circumstances, 
unequivocal progression of non-target disease may be accepted as evidence of disease 
progression, where the overall tumor burden has increased sufficiently to merit discontinuation of 
treatment or where the tumor burden appears to have increased by at least 73% in volume. 
Modest increases in the size of one or more non-target lesions are NOT considered unequivocal 
progression.  If the evidence of PD is equivocal (target or non-target), treatment may continue 
until the next assessment, but if confirmed, the earlier date must be used. 
 
 
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3  iRECIST Response Assessment  
Overall response will also be assessed using iRECIST.  Immunotherapeutics may result in infiltration 
of immune cells leading to transient increase in the size in malignant lesions, or undetectable lesions 
becoming detectable.  The criteria are identical to those of RECIST 1.1 in many respects but have 
been adapted to account for instances where an increase in tumor burden, or the appearance of new 
lesions, does not reflect true tumor progression.  
Key differences are described below.  All responses defined using iRECIST criteria are designated 
with a prefix.  iRECIST time-point and best overall responses will be recorded separately.  
 
3.1  
Confirming Progression  
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms iUPD 
(unconfirmed progression) and iCPD (confirmed progression) as described below and shown in 
Table S3.  Confirmatory scans should be performed at least 4 weeks, but no longer than 8 weeks 
after iUPD.   
Progression is confirmed (iCPD) if further increase in tumor burden, compared to the last 
assessment, is evidenced by one or more of the following:  
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• Continued increase in tumor burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target disease, non-target disease or new lesions  
o Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum  
o Continued unequivocal progression in non-target disease with an increase in 
tumor burden  
o Increase in size of previously identified new lesion(s) (an increase of at least 
5 mm in the absolute value of the sum of those considered to be target new 
lesions) or additional new lesions.  
• RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions.  
 
If progression is not confirmed at the next assessment, then the appropriate response will be 
assigned (iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria 
are met compared to baseline).  As can be seen in Table S2, the prior documentation of iUPD 
does not preclude assigning iCR, iPR, or iSD in subsequent time-point assessments or as best 
overall response (BOR) providing that iCPD is not documented at the next assessment after 
iUPD.  
 
3.2 
New lesions 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short 
axis for nodal lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target 
(NLNT) to allow clear differentiation from baseline target and non-target lesions.  
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD).  However, 
the measurements of target lesions should NOT be included in the sum of measures of original 
target lesions identified at baseline.  Rather, these measurements will be collected on a separate 
table in the case record form.  
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 
weeks (but not more than 8 weeks) after iUPD confirms further progression from iUPD with 
either an increase of at least 5 mm in the absolute value of the sum of NLT OR an increase (but 
not necessarily unequivocal increase) in the size of NLNT lesions OR the appearance of 
additional new lesions. 
 
 
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All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined in Table S4. 
 
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5. Response and Stable Disease Duration (RECIST 1.1 and iRECIST)  
Response duration will be measured from the time measurement criteria for CR/PR or iCR/iPR 
(whichever is first recorded) are first met until the first date that recurrent or progressive disease is 
objectively documented, taking as reference the smallest measurements recorded on study (including 
baseline).  
Stable disease duration will be measured from the time of start of treatment until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline).  
 
6  Methods of Measurement  
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.  Assessments should be identified on 
a calendar schedule and should not be affected by delays in therapy.  While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g., 2 mm).  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.  For lesions 
which fragment/split, add together the longest diameters of the fragmented portions; for lesions which 
coalesce, measure the maximal longest diameter for the “merged lesion”.  
 
6.1 
Clinical Lesions.  Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm 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 
recommended.  If feasible, imaging is preferred. 
 
6.2 
 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 ≥ 20 mm on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
 
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6.3  
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).  Other specialized imaging or 
other techniques may also be appropriate for individual cases.4  For example, while PET scans are 
not considered adequate to measure lesions, PET-CT scans may be used providing that the 
measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast).  
 
6.4  
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT is advised.  
 
6.5  
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.  
 
6.6  
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.  
 
6.7 
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 when the measurable tumor has met criteria for response or stable 
disease is advised to differentiate between response or stable disease and progressive disease. 
 
8. Examples of scenarios 
The tables below exhibit various response scenarios using iRECIST. 
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ATTACHMENT 6:  CYP2C9 
CYP2C9 Substrates with a narrow therapeutic index* 
 
S-Warfarin (anticoagulant) 
 
Phenytoin (antiepileptic) 
*Narrow therapeutic index is defined as “CYP substrates with narrow therapeutic range refers 
to drugs whose exposure-response relationship indicates that small increases in their exposure 
levels by the concomitant use of CYP inhibitors may lead to serious safety concerns (e.g., 
Torsades de Pointes).” 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm 
Other CYP2C9 Substrates 
 
NSAIDs (analgesic, antipyretic, anti-inflammatory)  
o celecoxib 
o lornoxicam 
o diclofenac 
o ibuprofen  
o naproxen 
o ketoprofen 
o piroxicam 
o meloxicam 
o suprofen 
 
fluvastatin (statin) 
 
sulfonylureas (antidiabetic)  
o glipizide 
o glibenclamide 
o glimepiride 
o tolbutamide 
o glyburide 
 
irbesartanlosartan 
 
sildenafil (in erectile dysfunction) 
 
terbinafine (antifungal) 
 
amitriptyline (tricyclic antidepressant) 
 
fluoxetine (SSRI antidepressant) 
 
nateglinide (antidiabetic) 
 
rosiglitazone (antidiabetic) 
 
tamoxifen (SERM) 
 
torasemide (loop diuretic)  
 
ketamine
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ATTACHMENT 7: AMENDMENT 2 SUMMARY OF CHANGES 
Major Modifications 
Section(s) 
Amendment 1 
Amendment 2 
Rationale 
Cover page, Title 
A Phase 1/2 Study of the Safety, 
Pharmacokinetics, and 
Pharmacodynamics of the Glutaminase 
Inhibitor CB-839 in Combination with 
Nivolumab in Patients with Clear Cell 
Renal Cell Carcinoma and Other Solid 
Tumors 
A Phase 1/2 Study of the Safety, 
Pharmacokinetics, and 
Pharmacodynamics of the 
Glutaminase Inhibitor CB-839 in 
Combination with Nivolumab in 
Patients with Advanced/Metastatic 
Melanoma, Renal Cell Carcinoma 
and Non-Small Cell Lung Cancer 
Updated study title to 
clarify other solid tumors 
included in the trial 
6.1, Primary Endpoints 
Assessed by overall response rate 
(ORR) per Response Evaluation 
Criteria in Solid Tumors (RECIST) 
v1.1 
Overall response rate (ORR) and 
duration of response (DOR) per 
Investigator assessed Response 
Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 
Addition of Duration of 
Response per 
Investigator assessed 
RECIST to Primary 
Endpoint 
6.1, Primary Objectives 
Not included in Amendment 1 
To evaluate anti-tumor effect of 
CB-839 in combination with 
nivolumab for patients with 
advanced/metastatic MEL by 
Independent Radiology 
Committee (IRC) 
Cohort 4 enrollment has 
been expanded to 
approximately 75 
patients. With this larger 
sample size, an 
additional primary 
objective was added 
specifically for the 
melanoma cohort. 
Clarification was also 
added that the primary 
objective will be 
determined by IRC  
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Section(s) 
Amendment 1 
Amendment 2 
Rationale 
6.1, Primary Endpoints 
Not included in Amendment 1 
Overall response rate (ORR) and 
duration of response (DOR) by 
Independent Radiology 
Committee (IRC)-assessed 
Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 
Addition of primary 
endpoints for the 
expanded melanoma 
cohort 
6.1, Secondary 
Objectives 
To evaluate the anti-tumor effect of 
CB-839 in combination with 
nivolumab for patients with 
advanced/metastatic ccRCC, MEL, and 
NSCLC by standard RECIST criteria  
To evaluate the progression-free 
survival (PFS) and overall 
survival (OS) of CB-839 in 
combination with nivolumab for 
patients with advanced/metastatic 
ccRCC, MEL, and NSCLC by 
standard RECIST criteria  
Clarification of anti-
tumor assessments for 
secondary objective 
6.1, Secondary 
Endpoints 
Assessed by duration of response 
(DOR), progression-free survival (PFS) 
per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 and 
overall survival (OS) 
Assessed by progression-free 
survival (PFS) per RECIST v1.1 
and overall survival (OS) 
DOR was removed as a 
secondary endpoint and 
added as an exploratory 
endpoint 
6.1, Secondary 
Objectives 
Not included in Amendment 1 
To evaluate anti-tumor effect of 
CB-839 as monotherapy in 
patients with advanced/metastatic 
MEL 
This cohort was added to 
test the anti-tumor 
activity of single-agent 
CB-839 in melanoma 
patients following a 4 
month washout period 
from last dose of 
previous PD-1/PD-L1 
therapy. 
6.1, Secondary 
Endpoints 
Not included in Amendment 1 
Assessed by ORR, DOR and PFS 
per RECIST v1.1  
Anti-tumor assessments 
for cohort 6 were added 
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Amendment 2 
Rationale 
6.1, Exploratory 
Objectives 
To evaluate the pharmacodynamic 
effects of CB-839 in combination with 
nivolumab in patients with 
advanced/metastatic ccRCC, MEL, and 
NSCLC 
To evaluate the pharmacodynamic 
effects of CB 839 alone and in 
combination with nivolumab in 
patients with advanced/metastatic 
ccRCC, MEL, and NSCLC 
PD effects will be tested 
in cohort 6 with single 
agent CB-839  
6.1, Exploratory 
Objectives 
  
To evaluate anti-tumor effect of 
CB-839 and nivolumab 
combination after progression on 
CB-839 monotherapy in patients 
with advanced/metastatic MEL 
Moved from secondary 
to exploratory objective 
6.1, Exploratory 
Endpoints 
  
Assessed by ORR, DOR and PFS 
per RECIST v1.1 and by 
iRECIST 
Moved from secondary 
to exploratory endpoint 
6.1, Exploratory 
Objectives 
  
To evaluate anti-tumor effect of 
CB-839 as monotherapy in 
patients with advanced/metastatic 
MEL by immune-related 
response criteria 
Exploratory objectives 
added for cohort 6  
6.1, Exploratory 
Endpoints 
  
Assessed by ORR, DOR and PFS 
per modified RECIST 1.1 for 
immune-based therapeutics 
(iRECIST) 
Exploratory endpoints 
added for cohort 6 
6.1, Exploratory 
Objectives 
  
To evaluate anti-tumor effect of 
CB-839 in combination with 
nivolumab for patients with 
advanced/metastatic ccRCC, 
MEL, and NSCLC by iRECIST 
Clarification of 
exploratory objectives 
6.1, Exploratory 
Endpoints 
  
Assessed by ORR, DOR and PFS 
per iRECIST 
Clarification of 
exploratory endpoints  
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Amendment 2 
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6.2, Sample Size 
Approximately 92 patients are planned 
for recruitment to this study.  The 
number of patients may be increased in 
Stage 2 in each expansion cohort based 
upon observed anti-tumor activity. 
Assuming full enrollment of the dose 
escalation cohort and positive results in 
all Expansion Cohorts, up to 242 
evaluable patients would be enrolled. 
Not included in Amendment 2 
Revised sample 
size language in 
amended Section 6.2 
6.2, Sample Size 
Dose Expansion:  Approximately 83 
patients are expected in total to be 
enrolled and treated in Stage 1 across 
five cohorts.  If a patient does not meet 
criteria for inclusion into the Efficacy 
Evaluable Population (Section 16.4), 
the patient will be considered to be not 
evaluable for efficacy and will be 
replaced.  If any cohorts achieve the 
pre-defined Stage 1 thresholds for 
clinical activity, additional patients will 
be enrolled in Stage 2 for that Cohort. 
Dose Expansion:  Approximately 
96 patients will be enrolled in Stage 
1 across six cohorts.  If a patient 
does not meet criteria for inclusion 
into the Efficacy Evaluable 
Population (Section 16.4), the 
patient will be considered to be not 
evaluable for efficacy and will be 
replaced.  If any cohorts achieve the 
pre-defined Stage 1 thresholds for 
clinical activity, additional patients 
will be enrolled in Stage 2 for that 
Cohort.  Approximately 144 
patients will be enrolled in Stage 
2 across six cohorts if all complete 
enrollment.  The number of 
patients may be increased in 
Stage 2 in each expansion cohort 
based upon observed anti-tumor 
activity. 
Enrollment numbers 
updated to reflect the 
expansion of cohort 4 
and the addition of 
cohort 6.  
6.3, Study Design 
Protocol CX-839-004 is a Phase 1/2 
open-label study of the combination of 
CB-839 with nivolumab.  Sequential 
Protocol CX-839-004 is a Phase 1/2 
open-label study of the combination 
of CB-839 with nivolumab in 
Addition of dosing 
language for CB-839 
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Amendment 2 
Rationale 
dose escalation of CB-839 with full 
dose nivolumab (CB-Nivo) will take 
place in patients with advanced 
ccRCC, unresectable or metastatic 
MEL, or metastatic NSCLC.  
Subsequently, multiple disease-specific 
single-arm cohorts will be enrolled in 
which CB-839 will be administered in 
combination with the full approved 
dose of nivolumab.  CB-839 will be 
administered at the RP2D established 
in dose escalation.  Patients in dose 
escalation must be eligible for one of 
the dose expansion cohorts. 
patients with advanced/metastatic 
MEL, RCC and NSCLC, as well 
as CB-839 monotherapy in 
patients with advanced/metastatic 
MEL.  Sequential dose escalation 
of CB-839 with full dose nivolumab 
(CB-Nivo) will take place in 
patients with advanced ccRCC, 
advanced/metastatic MEL, or 
metastatic NSCLC.  Subsequently, 
multiple disease-specific single-arm 
cohorts will be enrolled in which 
CB-839 will be administered in 
combination with the full approved 
dose of nivolumab.  CB-839 will be 
administered at the RP2D 
established in dose escalation.  
Patients in dose escalation must be 
eligible for one of the dose 
expansion cohorts.  CB-839 
monotherapy will be 
administered at the previously 
established monotherapy RP2D 
of 800 mg PO BID. 
6.3 Study Design 
Study design schema 
Study design schema 
Updated schema, 
increased cohort 4 
sample size, and added 
cohort 6. 
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6.3.2 Phase 2 - Cohort 
Expansion 
The Sponsor, in consultation with 
Study Investigators, will evaluate the 
overall safety profile of the CB-Nivo 
combination during cohort expansion.  
The Sponsor, in consultation with 
Study Investigators, will evaluate 
the overall safety profile of the CB-
Nivo combination during cohort 
expansions and as a monotherapy 
in advanced/metastatic 
melanoma. 
Updated to reflect 
addition of monotherapy 
melanoma cohort. 
6.3.2.1 Cohort 1: 
ccRCC patients naïve to 
prior checkpoint 
inhibitor therapy 
The primary endpoint will be ORR.   
The primary endpoint of cohort 1 
will be safety/tolerability, ORR 
and DOR. 
Addition of 
safety/tolerability and 
duration of response 
(DOR) to the primary 
endpoint for cohort 1  
6.3.2.2 Cohort 2: 
ccRCC patients with 
disease progression or 
prolonged SD (≥24 
weeks) while receiving 
nivolumab in their most 
recent line of therapy 
The primary endpoint will be ORR.   
The primary endpoint of cohort 2 
will be safety/tolerability, ORR 
and DOR per Investigator. 
Addition of 
safety/tolerability and 
duration of response 
(DOR) to the primary 
endpoint for cohort 2. 
Clarification added that 
the endpoints are per 
investigator assessment  
6.3.2.3 Cohort 3: 
ccRCC patients with 
disease progression 
while receiving an anti-
PD-1/PD-L1 therapy in 
any prior line of therapy 
The primary endpoint will be ORR. 
The primary endpoint of cohort 3 
will be safety/tolerability, 
investigator assessed ORR and 
DOR.  
Addition of 
safety/tolerability and 
duration of response 
(DOR) to the primary 
endpoint for cohort 1. 
Clarification added that 
the endpoints are per 
investigator assessment. 
6.3.2.4 Cohort 4: 
Melanoma patients with 
disease progression 
while receiving an anti-
This cohort will enroll melanoma 
patients that had documented 
radiological disease progression while 
receiving an anti-PD-1 therapy in their 
This cohort will enroll melanoma 
patients with radiological disease 
progression (per Investigator 
assessment) while receiving an 
Rationale language 
added to section 6.3.2.4 
(Cohort 4) to explain the 
increase in enrollment 
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Amendment 2 
Rationale 
PD-1 therapy in their 
most recent line of 
therapy 
most recent line of therapy with 
minimal washout (< 8 weeks), with the 
intent of adding CB-839 to an ongoing 
anti-PD-1 regimen. An anti-PD-1 agent 
is defined as an agent that has 
demonstrated clear evidence of single 
agent activity, e.g., nivolumab and 
pembrolizumab. Patients receiving an 
anti-PD-1 therapy other than 
nivolumab would switch over to 
nivolumab.  Since this patient 
population has documented disease 
progression, the likelihood of a 
response on nivolumab monotherapy is 
extremely low and any activity can be 
confidently attributed to the addition of 
CB-839.  The primary endpoint will be 
ORR.  Paired predose and postdose 
biopsies will be collected in order to 
demonstrate a pharmacodynamic effect 
of CB-839 in the context of PD-1 
inhibition by nivolumab and correlate 
efficacy with potential predictive 
biomarkers (Section 14.2).  
 
A Simon’s two-stage design will test 
the null hypothesis that ORR ≤0.05 
versus the alternative that ORR ≥0.2; 
the sample size of 24 patients will 
maintain an alpha level of 0.10 and a 
power of 0.80.  At least 9 evaluable 
patients will be enrolled in stage 1.  If 
anti-PD-1/PD-L1 agent as 
monotherapy, or in a 
combination regimen, to treat 
advanced/metastatic melanoma in 
the most recent line of therapy. 
There must be ≤ 8 weeks between 
last dose of anti-PD-1/PD-L1 and 
completion of the study screening 
assessments.  The intent of this 
cohort is to convert progressing 
disease to responding disease by 
the addition of CB-839 to ongoing 
anti-PD-1/PD-L1 therapy.   
Because this patient population has 
documented disease progression on 
anti-PD-1/PD-L1 therapy at study 
start, the likelihood of a response 
to nivolumab monotherapy is 
extremely low and any activity can 
be confidently attributed to the 
addition of CB-839.  Patients on 
anti-PD-1/PD-L1 agent other 
than nivolumab will switch to 
nivolumab for treatment on this 
study.  The primary endpoints of 
Cohort 4 will be ORR and DOR as 
determined by an Independent 
Radiology Committee (IRC).  
Pre- and post-dose biopsies will be 
collected from all patients 
enrolled into the Expansion phase 
of Cohort 4 (so long as deemed 
and the intent of the 
cohort. Language has 
been added to update the 
primary endpoints and 
statistical assumptions.  
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Amendment 2 
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at least 1 patient responds (PR or 
better) out of 9 response-evaluable 
patients in stage 1, then an additional 
15 evaluable patients will be enrolled 
in stage 2 (total of 24 response-
evaluable patients).  If stages 1 and 2 
are completed, a minimum of 3 
patients must demonstrate a response 
(PR or better) to reject the null 
hypothesis. 
safe and technically feasible to 
biopsy) in order to demonstrate a 
pharmacodynamic effect of CB-839 
in the context of PD-1 inhibition 
and to correlate efficacy with 
potential predictive biomarkers 
(Section 14.2).   
The original study design with 24 
patients tested the null hypothesis 
that ORR of CB-839 + nivolumab 
was ≤ 5% versus the alternative of 
≥20% with an alpha level of 0.1 
and power of 80%.  Per study 
design, 9 patients would be 
enrolled in Stage 1 and 1 
responder would trigger 
enrollment of an additional 15 
patients in Stage 2; while 3 
responders out of 24 total patients 
would lead to formal rejection of 
the null hypothesis.  To date there 
have been 3 responding patients 
(including one complete response 
and 2 deep partial responses of -
73% and -47%), all confirmed 
responses on repeat scan ≥4 
weeks after initial response, in 16 
evaluable patients.  Notably, per 
protocol eligibility, all of these 
patients were experiencing 
disease progression on PD-1/PD-
L1 inhibitor therapy in the 
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Amendment 2 
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immediate prior line of therapy 
strongly suggesting that the 
response was the result of the 
addition of CB-839.   
As a result of encouraging 
preliminary clinical activity, 
Cohort 4 enrollment will be 
expanded to approximately 75 
response-evaluable melanoma 
patients (including patients 
already enrolled).  For the 
purpose of statistical design we 
assume a background/historical 
ORR of < 10% in this patient 
population. The total sample size 
is determined based on the ability 
to produce a confidence interval 
that would exclude the historic 
response rate and to provide 
sufficient information for a 
reliable understanding of the 
safety profile.  Specifically, the 
lower limit of the 95% CI 
associated with observation of an 
objective response rate of 18.7% 
in 75 treated subjects (14/75 
responders) excludes 10%.  
Interim clinical monitoring will 
be performed in this expansion to 
ensure adequate safety and 
tolerability as well as favorable 
risk/benefit by assessing 
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Amendment 2 
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preliminary efficacy measures 
such as objective response rate 
and duration of response. 
6.3.2.5, Cohort 5: 
NSCLC patients with 
disease progression or 
prolonged SD while 
receiving an anti-PD-1 
therapy in their most 
recent line of therapy 
This cohort will enroll patients with 
NSCLC that does not harbor an 
activating mutation in the epidermal 
growth factor receptor (EGFR) or 
anaplastic lymphoma kinase (ALK) 
oncogene and have received an anti-
PD-1 monotherapy in their most recent 
line of therapy with minimal washout 
(< 8 weeks), with the intent of adding 
CB-839 to an ongoing anti-PD-1 
regimen.  EGFR-mutant patients have 
been excluded because they tend to 
have lower mutational load and are less 
responsive to immunotherapies 
(Borghaei et al.).Patients receiving an 
anti-PD-1 therapy other than 
nivolumab would switch over to 
nivolumab.  Since this patient 
population either has documented 
radiological disease progression or 
long-term SD (>24 weeks), the 
likelihood of a response on nivolumab 
monotherapy is extremely low and any 
activity can be confidently attributed to 
the addition of CB-839.  The primary 
endpoint will be ORR.  Paired predose 
and postdose biopsies will also be 
collected in order to demonstrate a 
pharmacodynamic effect of CB-839 in 
This cohort will enroll patients with 
NSCLC that does not harbor an 
activating mutation in the epidermal 
growth factor receptor (EGFR) or 
anaplastic lymphoma kinase (ALK) 
oncogene and have received anti-
PD-1/PD-L1 therapy as the most 
recent line of therapy with < 8 
weeks between last dose of anti-
PD-1/PD-L1 and completion of 
screening for the CX-839-004 
study.  Eligible patients will have 
experienced radiological disease 
progression or SD without 
response lasting ≥ 24 weeks with 
the intent of adding CB-839 to an 
ongoing anti-PD-1 regimen.  
Driver- mutation (EGFR or ALK) 
positive patients have been 
excluded because they tend to have 
lower mutational load and are less 
responsive to immunotherapies 
(Borghaei 2015).  Patients receiving 
an anti-PD-1 therapy other than 
nivolumab would switch over to 
nivolumab.  Because this patient 
population has documented 
radiological disease progression or 
long-term SD (≥ 24 weeks), the 
Additional language 
added to specify the time 
period from last dose of 
prior PD-1/PD-L1 
therapy and completion 
of screening 
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Amendment 2 
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the context of PD-1 inhibition by 
nivolumab and correlate efficacy with 
potential predictive biomarkers 
(Section 14.2). 
A Simon’s two-stage design will test 
the null hypothesis that the ORR ≤ 0.05 
versus the alternative that ORR ≥ 0.15; 
the sample size of 56 patients will 
maintain an alpha level of 0.10 and a 
power of 0.80.  If at least 2 patients 
respond (PR or better) out of 20 
response-evaluable patients in stage 1, 
then an additional 36 evaluable patients 
will be enrolled in stage 2 (total of 56 
response-evaluable patients).  If stages 
1 and 2 are completed, a minimum of 5 
patients must demonstrate a response 
(PR or better) to reject the null 
hypothesis.  The lower target ORR 
(15%) is based on the heterogeneity of 
histological subtypes (with potentially 
differential sensitivity to CB-839) in 
this cohort. 
Enrollment will be monitored in order 
to ensure at least 8 patients are enrolled 
from each of the two major histological 
subtypes of NSCLC, squamous and 
non-squamous.  Based on emerging 
data, the Sponsor may choose to 
restrict further enrollment in this cohort 
to a specific histological subtype. 
likelihood of a response on 
nivolumab monotherapy is 
extremely low and any activity can 
be confidently attributed to the 
addition of CB-839.  The primary 
endpoint of Cohort 5 will be 
safety/tolerability, ORR and DOR 
per Investigator.  Predose and 
postdose biopsies will also be 
collected in order to demonstrate a 
pharmacodynamic effect of CB-839 
in the context of PD-1 inhibition by 
nivolumab and correlate efficacy 
with potential predictive biomarkers 
(Section 14.2). 
A Simon’s two-stage design will 
test the null hypothesis that the 
ORR ≤ 0.05 versus the alternative 
that ORR ≥ 0.15; the sample size of 
56 patients will maintain an alpha 
level of 0.10 and a power of 0.80.  
If at least 2 patients respond (PR or 
better) out of 20 response-evaluable 
patients in Stage 1, then an 
additional 36 evaluable patients will 
be enrolled in Stage 2 (total of 56 
response-evaluable patients).  If 
Stages 1 and 2 are completed, a 
minimum of 5 patients must 
demonstrate a response (PR or 
better) to reject the null hypothesis.  
The lower target ORR (15%) is 
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Amendment 2 
Rationale 
All enrolled patients will remain on 
study until disease progression, 
intolerable toxicity, withdrawal of 
consent or the patient is discontinued 
by Investigator or Sponsor due to 
failure to follow study requirements or 
administrative or other safety reasons.  
For patients who discontinue study 
therapy early without documented 
disease progression, every effort 
should be made to continue monitoring 
their disease status by radiologic 
imaging following the guidelines 
described in Attachments 4 and 5. 
based on the heterogeneity of 
histological subtypes (with 
potentially differential sensitivity to 
CB-839) in this cohort. 
Enrollment will be monitored in 
order to ensure at least 8 patients 
are enrolled from each of the two 
major histological subtypes of 
NSCLC, squamous and non-
squamous.  Based on emerging 
data, the Sponsor may choose to 
restrict further enrollment in this 
cohort to a specific histological 
subtype. 
 
6.3.2.6, Cohort 6: CB-
839 monotherapy in 
advanced/metastatic 
melanoma patients 
Not included in Amendment 1 
This cohort will enroll patients 
with advanced/metastatic 
melanoma with no curative 
options and will assess the anti-
tumor activity of single agent CB-
839.  Because the combination of 
CB-839 and nivolumab has 
demonstrated activity in 
nivolumab refractory disease, 
unbiased assessment of CB-839 as 
monotherapy is presumed to 
require full washout of previous 
PD-1/PD-L1 therapy.  For the 
purpose of this study, full 
washout is defined as a minimum 
of 4 mo (approximately 5 half-
lives), from the most recent dose 
Section added to explain 
the rationale for adding 
cohort 6. This includes 
the patient population to 
be enrolled, the primary 
endpoint and addition of 
nivolumab at treatment 
progression with single 
agent CB-839. 
Statistical assumptions 
have also been added. 
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Amendment 2 
Rationale 
of anti-PD-1/PD-L1 therapy to 
C1D1 of CB-839 monotherapy.  
This washout period will allow 
any clinical activity to be 
attributed to CB-839 alone.  The 
primary endpoint of cohort 6 is 
ORR per RECIST v1.1 as 
assessed by the Investigator.  Pre-
dose biopsies will be collected on 
all patients to evaluate for 
predictive markers of treatment 
response. Because the 
combination of CB-839 with 
nivolumab has demonstrated 
activity in nivolumab refractory 
patients, patients will be eligible 
to receive the combination of CB-
839 with nivolumab after disease 
progression on CB-839 
monotherapy.  These patients will 
be followed for the exploratory 
objectives of ORR, DOR, PFS per 
RECIST v1.1 subsequent to 
starting the combination of 
nivolumab and CB-839.  
For the primary objective, a 
Simon’s two-stage design will test 
the null hypothesis that ORR 
≤0.05 versus the alternative that 
ORR ≥0.2; the sample size of 24 
patients will maintain an alpha 
level of 0.10 and a power of 0.80.  
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Amendment 2 
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At least 9 evaluable patients will 
be enrolled in stage 1.  If at least 1 
patient responds (PR or better) 
out of 9 response-evaluable 
patients in stage 1, then an 
additional 15 evaluable patients 
will be enrolled in stage 2 (total of 
24 response-evaluable patients).  
If stages 1 and 2 are completed, a 
minimum of 3 patients must 
demonstrate a response (PR or 
better) to reject the null 
hypothesis. 
6.4, Inclusion Criteria; 
Phase 2-Cohort 
Expansion Specific 
Inclusion Criteria, 
Cohort 4 
Cohort 4: Melanoma 
1. Histological or cytological diagnosis 
of advanced/metastatic melanoma 
2. Received an active anti-PD-1 agent 
as the most recent line of therapy with 
≤ 8 weeks elapsed prior to completion 
of screening for the current trial. An 
anti-PD-1 agent is defined as an agent 
that has demonstrated clear evidence of 
single agent activity, e.g., nivolumab 
and pembrolizumab.  Any other anti-
PD-1 agents need approval from the 
Medical Monitor.   
3. Have documented disease 
radiological progression (per 
Investigator assessment, preferably 
with confirmation of PD after 4 weeks) 
while receiving anti-PD-1 in the most 
recent line of therapy. 
Cohort 4: Melanoma (progressing 
while on anti-PD-1/PD-L1 
therapy) 
1. Histological or cytological 
diagnosis of advanced/metastatic 
melanoma 
2. Received anti-PD-1/PD-L1 as 
monotherapy or as part of a 
combination regimen in the most 
recent line of therapy with (i) 
documented radiographic disease 
progression (per Investigator 
assessment, preferably with 
confirmation of progression after 4 
weeks) and (ii) ≤ 8 weeks elapsed 
between last dose of anti-PD-
1/PD-L1 and C1D1 of the CX-839-
004 trial  
3. Previously progressed on or 
Amended language to 
clarify patients that are 
eligible to be enrolled 
into cohort 4. This 
includes prior treatment 
and washout period 
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Amendment 2 
Rationale 
was intolerant to BRAFi therapy 
if BRAF V600E mutation is 
present. 
6.4, Inclusion Criteria; 
Phase 2-Cohort 
Expansion Specific 
Inclusion Criteria, 
Cohort 5 
Cohort 5: NSCLC 
3. Histological or cytological 
diagnosis of NSCLC that does not 
harbor an activating EGFR or 
ALK mutations 
4. Received anti-PD-1 agent as the 
most recent line of therapy with ≤ 
8 weeks elapsed prior to 
completion of screening for the 
current trial and EITHER: 
a. Had documented radiological 
disease progression (per 
Investigator assessment, preferably 
with confirmation of PD after 4 
weeks) while receiving anti-PD-1 
therapy, OR 
b. Had documented stable disease 
(per Investigator assessment) for 
>24 weeks while receiving anti-
PD-1 
Cohort 5: NSCLC (anti-PD-1/PD-
L1 in most recent line of 
therapy (“add-on”) 
1. Histological or cytological 
diagnosis of NSCLC that does 
not harbor an activating EGFR 
or ALK mutation. 
2. Received anti-PD-1/PD-L1 
agent as the most recent line of 
therapy with ≤ 8 weeks elapsed 
between last dose of anti-PD-
1/PD-L1 therapy and C1D1of 
the CX-839-004 trial and 
EITHER: 
c) Had documented 
radiological disease 
progression (per 
Investigator assessment, 
preferably with 
confirmation of PD after 4 
weeks), OR 
d) Had documented stable 
disease (per Investigator 
assessment) for ≥ 24 weeks 
 
Language added to allow 
prior PD-L1 treatment 
for cohort 5 and clarified 
washout period 
6.4, Inclusion Criteria; 
Phase 2-Cohort 
Expansion Specific 
Not included in Amendment 1 
Cohort 6: Melanoma (to be 
treated with CB-839 
monotherapy) 
1. Histological or cytological 
Addition of inclusion 
criteria for cohort 6 
eligibility 
 
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Amendment 2 
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Inclusion Criteria, 
Cohort 6 
diagnosis of advanced/metastatic 
melanoma without curative 
options 
2. At least 4 mo (approximately 5 
half-lives) elapsed between most 
recent dose of anti-PD-1/PD-L1 
therapy and C1D1 of CB-839 
monotherapy 
3. Previously progressed on or 
was intolerant to BRAFi therapy 
if BRAF V600E mutation is 
present 
6.5, Exclusion Criteria 
1 
1.     Intolerance to prior anti-PD-1/PD-
L1 therapy including 1) discontinuation 
due to immune-related toxicity or, 2) 
immune-related toxicities that that 
required intensive or prolonged 
immunosuppression (including, high-
dose IV corticosteroids, > 2 months of 
immunosuppressive corticosteroids 
(i.e., equivalent of >10mg oral 
prednisone daily) or the addition of 
potent immunosuppression to 
corticosteroids (e.g., mycophenolate 
mofentil/CellCept or infliximab) to 
manage. 
1. Intolerance to prior anti-PD-
1/PD-L1 therapy including 1) 
discontinuation due to immune-
related toxicity or, 2) immune-
related toxicities that required 
intensive or prolonged 
immunosuppression (including, 
high-dose IV corticosteroids, > 2 
mo of immunosuppressive 
corticosteroids (i.e., equivalent of 
>10mg oral prednisone daily) or the 
addition of potent 
immunosuppression to 
corticosteroids (e.g., mycophenolate 
mofentil/CellCept or infliximab) to 
manage. 
• Exception:  Cohort 6 patients 
are eligible to receive CB-839 
monotherapy (but not 
combination with nivolumab) 
Clarification added for 
cohort 6 patient 
exclusion regarding prior 
PD-1/PD-L1 intolerance  
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even if prior intolerance of anti-
PD-1/PD-L1 therapy 
6.5, Exclusion Criteria 
5 
5. Immunotherapy or biological 
therapy (e.g., monoclonal antibodies) 
within 21 days prior to Cycle 1 Day 1 
• EXCEPTION: Washout of anti-PD-1 
therapy is NOT required in Expansion 
Cohorts 2, 4, and 5.  
5. Immunotherapy or biological 
therapy (e.g., monoclonal 
antibodies) within 21 days prior to 
Cycle 1 Day 1  
• EXCEPTION: Washout of anti-
PD-1 therapy is NOT required in 
Expansion Cohorts 2, 4, and 5 and 
must be > 4 mo in Expansion 
Cohort 6. 
Language added to 
clarify that the washout 
period for prior PD-1 
therapy in cohort 6  
6.5, Exclusion Criteria 
18 
18. Patients with prior brain metastases 
or CNS disease are permitted, but must 
have completed treatment and either 
(1) have no evidence of active CNS 
disease for at least 4 weeks prior to the 
first dose OR (2) have stable CNS 
lesions, defined as not requiring 
intrathecal chemotherapy for at least 6 
weeks or systemic steroid treatment to 
prevent CNS complications for at least 
3 weeks prior to first dose.  Patients 
with CNS disease must also have a 
Screening head CT or MRI 
demonstrating stable disease compared 
to their most recent CNS evaluation. 
18. Active and/or untreated 
central nervous system 
metastasis. Subjects with treated 
brain metastases must have (1) 
documented radiographic 
stability of at least 4 weeks 
duration demonstrated on 
baseline CNS imaging prior to 
study treatment and (2) be 
symptomatically stable and off 
steroids for at least 2 weeks 
before administration of any 
study drug 
Updated language 
regarding enrollment 
requirements of patients 
with treated brain 
metastasis  
6.5, Exclusion Criteria, 
Disease-specific 
Exclusion Criteria, 
Cohort 4: Melanoma 
1. Patients with ocular melanoma; 
mucosal melanoma is allowed. 
1. Patients with ocular melanoma 
2. Active or untreated CNS 
metastases 
Updated exclusion for 
cohort 4 
6.6, Radiological 
Tumor Assessments  
All patients will be evaluated for tumor 
response according to RECIST version 
All patients will be evaluated for 
tumor response assessed by 
Clarification language 
added regarding use of 
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1.1 and immune-related response 
criteria using unidimensional 
measurements (irRECIST; Perrone ) 
which is based on RECIST 1.1, irRC 
and the findings in Nishino et al and as 
described below. Although the primary 
endpoint for analysis of clinical 
activity is RECIST 1.1, patient 
management will follow the principles 
and guidelines for immunotherapies of 
solid tumors, specifically as outlined in 
the irRECIST criteria.  On-study 
assessments by irRECIST take into 
account the observation that some 
patients with solid tumors can have a 
transient tumor flare in the first few 
months after start of immunotherapy 
with subsequent disease response. 
Clinical decisions will be based on the 
interpretation of the investigator at the 
site treating the patient in real time 
using the irRECIST criteria. RECIST 
1.1 imaging analyses will be performed 
by the local radiologists and then 
images will be collected and held by an 
independent imaging vendor in order to 
enable future independent image 
analysis. 
investigator according to both 
RECIST version 1.1 and modified 
RECIST for immune-based 
therapeutics (termed iRECIST) 
(Seymour 2017).   The primary 
study endpoints of response rate 
and duration of response will be 
determined according to RECIST 
v1.1 by investigator assessment 
except for cohort 4 which will 
employ IRC-adjudication for the 
primary endpoints.  In contrast to 
the formal study endpoints, patient 
management and clinical decision 
making during treatment should 
follow the principles and guidelines 
for iRECIST (appendix 5).  These 
criteria take into account the 
observation that some patients with 
solid tumors can have an apparent 
radiographic flare of disease on 
immunotherapy that is transient 
and followed by radiographic 
disease response.  If imaging 
shows progressive disease per 
RECIST v1.1 (unconfirmed PD per 
iRECIST), it is recommended to 
keep the patient on study treatment 
until imaging is repeated ≥ 4 weeks 
later in order to confirm PD, as 
described in the iRECIST 
recommendations (see Attachment 
iRECIST to be used for 
patient management.  
The updated iRECIST 
guidelines (Seymour 
2017) replaces previous 
immune-related 
modified RECIST. 
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5).  Patients who are deemed 
clinically unstable or are 
experiencing rapid progression of 
disease are not required to have 
repeat imaging for confirmation of 
PD.   At a minimum, patients must 
meet the following criteria for 
continued treatment on study after 
disease progression is identified at a 
tumor assessment:  
• Absence of symptoms and signs 
(including worsening of laboratory 
values) indicating disease 
progression  
• No decline in ECOG performance 
status  
• Absence of rapid progression of 
disease or of tumor progression at 
critical anatomical sites (e.g., cord 
compression) requiring urgent 
alternative medical intervention.  
 
If repeat imaging confirms PD as 
described in Attachment 5, patients 
will be discontinued from study 
therapy.  If repeat imaging does not 
confirm PD, treatment with study 
drugs will continue and the next 
imaging studies will be conducted 
every 8 weeks as previously 
scheduled.  In patients who 
discontinue study therapy early 
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without documented disease 
progression, every effort should be 
made to continue monitoring 
disease status by radiologic imaging 
until progressive disease, death, 
withdrawal of consent, or 
initiation of new anticancer 
therapy. 
7.2.1, 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 and -003 
are ongoing.  During dose escalation in 
all three 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 8 Oct 2015 for CX-839-001 and 20 
Nov 2015 for CX-839-002 and CX-
839-003, a total of 63, 11 and 5 
patients, respectively, have received 
600, 800, and 1000 mg BID CB-839 as 
a single agent across all three studies 
and an additional 59 patients received 
CB-839 dosed on the TID schedule 
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 enrolled 
RCC patients for treatment with 
CB-839 + cabozantinib and CB-
839 + everolimus, as well as 
TNBC patients for treatment with 
CB-839 + paclitaxel.  In addition, 
the combination of CB-839 with 
nivolumab is being evaluated in 
the Phase 1/2 study, CX-839-004.  
During dose escalation in all three 
Phase 1 studies, single agent CB-
839 was administered initially three 
times daily (TID) without meals 
Updated section to 
reflect new clinical data 
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ranging from 100 to 1000 mg TID. 
A dose-related increase in exposure 
was observed on all studies and the 
half-life of CB-839 was approximately 
4 hr.  Robust inhibition of glutaminase 
(>90%) was demonstrated in platelets 
at exposures that are maintained in 
most patients at interdose trough 
timepoints.  Tumor biopsies also 
demonstrated robust glutaminase 
inhibition (>75% for most patients).    
CB-839 was well tolerated, with no 
maximum tolerated dose (MTD) 
identified.  On the recommended 
dosing regimen (administered BID 
with food) on the solid tumor CX-839-
001 study (where the bulk of the BID 
patients have been treated), 1 of 66 
safety-evaluable patients (1.5%) 
experienced a Grade 3 increase in 
alanine aminotransferase (ALT) 
whereas, on the TID schedule (dosed 
without food), 5 of 32 (17%) safety-
evaluable patients who received 400-
1000 mg TID had Grade 3 increases in 
ALTA Recommended Phase 2 Dose 
(RP2D) was established at 600 – 800 
mg BID, based on the 
pharmacokinetics, pharmacodynamics 
and safety profile of CB-839 at these 
doses when administered with food. 
Please refer to the most recent CB-839 
and was later changed to twice daily 
(BID) with breakfast and dinner.   
As of data cuts on 23 July 2017, a 
total of 105 patients received 600, 
800, or 1000 mg BID CB 839 as a 
single agent; an additional 59 
patients received single agent CB-
839 dosed on the TID schedule 
ranging from 100 to 1000 mg 
TID.  More than 150 patients 
have received CB-839 at doses 
ranging from 400 to 800 mg BID 
in combination with cabozantinib, 
erlotinib, everolimus, paclitaxel, 
nivolumab, dexamethasone, 
pomalidomide, or azacitidine. 
In pharmacokinetic studies, the 
half-life of CB-839 was 
approximately 4 hours. A dose-
related increase in exposure was 
observed over doses ranging from 
100 to 600 mg; exposures for 600 
mg and 800 mg doses were similar 
albeit with significant interpatient 
variability.  In pharmacodynamic 
studies, robust inhibition of 
glutaminase was demonstrated in 
platelets at exposures that are 
maintained in most BID-dosed 
patients at 600 mg and 800 mg 
inter-dose troughs, with the 800 
mg dose in particular showing ≥ 
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Investigator’s Brochure for information 
from the Phase 1 studies. 
90% target inhibition.  Patient 
tumor biopsies also demonstrated 
robust glutaminase inhibition 
(>75% for most patients).  
8.1, Prior anti-PD1/PD-
L1 
Not in Amendment 1 
Patients targeted for Cohorts 2, 4, 
and 5 may continue to receive 
anti-PD-1/PD-L1 therapy up to 3 
weeks before C1D1.  If anti-PD-
1/PD-L1 has been discontinued, 
patients targeted for Cohorts 2, 4 
and 5 must have no more than 8 
weeks elapse between last 
administration of anti-PD-1/PD-
L1 agent and C1D1 of this 
protocol.  Patients receiving an 
anti-PD-1/PD-L1 therapy other 
than nivolumab will switch to 
nivolumab for study treatment.  
In order to assess CB-839 
monotherapy activity, Cohort 6 
patients must have at least 4 mo 
(approximately 5 half-lives) 
elapsed between most recent dose 
of anti-PD-1/PD-L1 therapy and 
C1D1of CB-839 monotherapy on 
this study.  
Clarified anti-PD-1/PD-
L1 therapy for cohorts 
2,4,5, and 6 period prior 
to C1D1 
10.1, Screening 
Evaluation 
Patients that are currently on therapy 
with nivolumab (Cohorts 2, 4, and 5), 
nivolumab should be administered 
continuously, if possible.  If nivolumab 
has been discontinued, patients must 
have no more than 8 weeks between 
The following screening 
assessments must be performed 
within 28 days before study drug 
administration on C1D1 according 
to the Schedule of Study 
Assessments. Procedures listed 
Removed duplicate 
requirement for ECG; 
Added MRI of the brain 
for cohort 4. Updated to 
include a baseline 
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discontinuation of nivolumab and 
completion of screening for the current 
trial. Patients receiving an anti-PD-1 or 
PD-L1 therapy other than nivolumab 
would switch over to nivolumab. The 
following screening assessments must 
be performed within 28 days before 
study drug administration on C1D1 
according to the Schedule of Study 
Assessments [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 the 
normal standard of care and within 28 
days prior to C1D1 may be used for 
screening purposes: 
 Sign and date an IRB/IEC-
approved Informed Consent 
Form (ICF) before any study-
specific (i.e., non-standard of 
care) screening procedures are 
performed 
 Demographic information 
including date of birth, sex, and 
ethnic origin  
 Medical history including 
review of prior cancer 
treatments 
 Review of concomitant 
medications 
below that are performed as part of 
the normal standard of care and 
within 28 days prior to C1D1 may 
be used for screening purposes: 
 Sign and date an IRB/IEC-
approved Informed Consent 
Form (ICF) before any 
study-specific (i.e., non-
standard of care) screening 
procedures are performed 
 Demographic information 
including date of birth, sex, 
and ethnic origin  
 Medical history including 
review of prior cancer 
treatments 
 Review of concomitant 
medications 
 ECOG performance 
evaluation 
 Complete physical 
examination including 
weight (kg) and height (cm) 
 Vital signs and weight  
 Standard 12-lead ECG with 
corrected QT interval by 
Fridericia’s Formula (QTcF) 
 Clinical laboratory 
evaluation (hematology, 
coagulation, serum 
chemistry, and urinalysis); 
see Attachment 3. 
radiographic tumor 
assessment for Cohort 4. 
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 ECOG performance evaluation 
 Complete physical examination 
including weight (kg) and 
height (cm) 
 Vital signs and weight  
 Standard duplicate 12-lead 
ECG with corrected QT interval 
by Fridericia’s Formula (QTcF) 
 Clinical laboratory evaluation 
(hematology, coagulation, 
serum chemistry, and 
urinalysis); see Attachment 3. 
 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 (e.g., diagnostic 
CT or MRI).  Scans performed 
within 28 days prior to C1D1 
will be accepted and do not 
need to be repeated.  See 
Attachment 1. Note: For this 
study, evaluation of tumor 
burden must be based on a 
diagnostic CT or MRI. 1-3 
scans prior to the start of study 
and redacted scan reports will 
also be collected and sent to a 
central reader for exploratory 
evaluation. 
 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. 
 During Phase 1- Dose 
escalation, predose and 
postdose tumor biopsies will 
be collected from patients 
enrolled in the back-fill 
cohorts. Predose tumor 
biopsies will be obtained 
from all patients in the 
Expansion phase (if 
considered safe and 
technically feasible to 
biopsy). Refer to Section 
14.2.  
 Coagulation tests must be 
performed and evaluated 
within 24 hr prior to all 
biopsy procedures. Patients 
in all other cohorts may 
consent to an optional tumor 
biopsy. 
 Archival tumors, if 
available, will be collected 
from all patients 
 Screening radiographic 
evaluation of tumor burden 
(e.g., diagnostic CT or 
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 During Phase 1- Dose 
escalation, predose and 
postdose tumor biopsies will be 
collected from patients enrolled 
in the back-fill cohorts. During 
Phase 2- Cohort Expansion, 
predose tumor biopsies will be 
obtained from all patients and 
postdose tumor biopsies will be 
obtained from patients in 
Cohorts 2, 4, and 5.  
Coagulation tests must be 
performed and evaluated within 
24 hr prior to all biopsy 
procedures. Patients in all other 
cohorts can consent to an 
optional tumor biopsy. 
 Archival tumors, if available, 
will be collected from all 
patients 
A patient who meets all of the 
inclusion criteria will enter the study.  
Screen failures will be marked in the 
electronic data capture (EDC) system. 
MRI).  For this study, 
radiographic evaluation of 
baseline and subsequent 
tumor burden must be 
based on a diagnostic, 
contrast enhanced, CT or 
MRI (See Attachment 1 for 
details and exceptions). All 
scans from the immediate 
prior line of therapy will 
be requested for Cohorts 
2, 4, and 5. 
Screening Evaluation Specific to 
Cohort 4  
 Cohort 4 patients must have a 
baseline radiographic tumor 
assessment (methodology as 
per screening imaging 
described above) within 7 
days prior to C1D1 unless the 
patient has had a previous 
radiographic tumor 
assessment that  meets the 
following requirements: 
a. It was performed within 4 
weeks of C1D1 AND 
b. It was performed at least 4 
weeks after the date of a prior 
scan demonstrating 
progressive disease on anti-
PD-1/PD-L1 containing 
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therapy in the immediate 
prior line of therapy  
 Cohort 4 patients must have 
screening contrast-enhanced 
MRI of the brain to assess for 
brain metastases within 28 
days before C1D1  
A patient who meets all of the 
inclusion criteria will enter the 
study.  Screen failures must be 
captured in the electronic data 
capture (EDC) system. 
10.2, Cycle 1  
 
Patients should be instructed not to eat 
breakfast prior to their clinic visit on 
C1D1 and C1D15. On these days, 
patients will undergo the predose 
assessments, receive their nivolumab 
infusion, eat breakfast and then receive 
the CB-839 dose.   Note that all 
predose assessments must be 
performed prior to nivolumab and CB-
839 administration.  The 2nd dose of 
CB-839 will be self-administered by 
the patient per dosing instructions after 
all study procedures have been 
completed. 
Patients should be instructed not to 
eat breakfast prior to their clinic 
visit on C1D1 and C1D15. On these 
days, patients will have all predose 
procedures performed, take their 
dose of CB-839 with food then 
receive nivolumab.  Note that all 
predose assessments must be 
performed prior to nivolumab and 
CB-839 administration.  The 2nd 
dose of CB-839 will be self-
administered by the patient per 
dosing instructions after all study 
procedures have been completed. 
Updated to clarify the 
dosing order on PK 
days. 
10.4, Other Schedules 
and Procedures 
Radiographic evaluation of tumor 
burden (e.g., diagnostic CT/MRI) will 
occur at Screening and approximately 
every 8 weeks after study initiation, or 
more frequently as clinically indicated.  
Radiographic evaluation of tumor 
burden (e.g., diagnostic CT/MRI) 
will occur at Screening and 
approximately every 8 weeks from 
Cycle 1 Day 1, and as clinically 
indicated.  For Cohort 4 only, 
Updated to clarify the 
timing of the 
radiographic evaluations.  
Removed the medical 
monitor requirement 
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Optional tumor biopsies may be 
obtained at variable time points as 
advised by the Investigator and 
Medical Monitor. 
baseline radiographic imaging of 
disease will also occur between 
day -7 and day -1 unless the 
screening assessment meets the 
criteria described in Section 10.1.    
Optional tumor biopsies may be 
obtained at variable time points as 
advised by the Investigator. 
regarding optional tumor 
biopsies. 
10.6, Follow Up 
Patients who discontinue from study 
treatment must continue to be followed 
for collection of survival follow-up 
data. Patients will be contacted every 3 
months for the first 12 months and then 
once every 6 months thereafter. All 
reasonable efforts must be made to 
contact patients and report their 
ongoing status. This includes follow up 
with persons authorized by the patient.  
If the patient or authorized persons 
cannot be contacted, public records 
may be consulted to establish survival 
status.  
 
Patients who discontinue study 
treatment for reason other than 
PD or death must continue to be 
followed by radiographic imaging 
per study schedule until PD, 
death, withdrawal of consent or 
initiation of another cancer 
therapy. All patients who 
discontinue study treatment will 
be contacted every 3 mo for the 
first 12 mo and then once every 6 
mo thereafter for survival follow-
up. All reasonable efforts must be 
made to contact patients and report 
their ongoing status. This includes 
follow up with persons authorized 
by the patient.  If the patient or 
authorized persons cannot be 
contacted, public records may be 
consulted to establish survival 
status.  
Updated procedures for 
follow up for patients 
who discontinue 
treatment for reason 
other than PD or death 
10.8.2.1, Dose 
Modification 
Guidelines 
Patients will be monitored 
continuously for AEs while on study.  
Treatment modifications (e.g., dose 
Patients will be monitored 
continuously for AEs while on 
study.  Treatment modifications 
Dose modification 
guidelines updated to 
include language 
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delay) will be based on specific 
laboratory and AE criteria.  Guidelines 
for dose modifications due to AEs are 
provided in Table 10.8.2-1.  These 
guidelines are based on the Product 
Label for nivolumab and the clinical 
experience with CB-839 to date.  These 
guidelines are intended primarily for 
toxicities that are not easily managed 
with routine supportive care.  For 
example, alopecia does not require 
dose modification, nor does Grade 2 
nausea/vomiting that are easily 
managed with anti-emetics.  
Importantly, these guidelines are not 
meant to replace the clinical judgment 
of the Investigator caring for the 
patient and should be used as 
guidelines. Additional information 
regarding the management of specific 
toxicities is provided in Table 10.8.2-1. 
 
(e.g., dose delay) will be based on 
specific laboratory and AE criteria.  
Guidelines for dose modifications 
due to AEs are based on the 
nivolumab product label and the 
clinical experience with CB-839 to 
date and are provided in Table 
10.8-1.  Study drugs may be held 
and restarted independently 
depending upon the adverse 
event.  Because product labels 
may change over time, when in 
doubt investigators should always 
refer to the most current 
nivolumab product label. The 
study guidelines are intended 
primarily for toxicities that are not 
easily managed with routine 
supportive care.  For example, 
alopecia does not require dose 
modification, nor does Grade 2 
nausea/vomiting that are easily 
managed with anti-emetics.  
Importantly, these guidelines are 
not meant to replace the clinical 
judgment of the Investigator caring 
for the patient, or the most recent 
nivolumab product label, and 
should be used as guidelines.  
Additional information regarding 
the management of specific 
regarding drug hold and 
for investigators to refer 
to the most current 
nivolumab package 
insert for dose 
modifications 
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toxicities is provided in Table 10.8-
1. 
Table 10.8-1.  Dose 
Modification 
Guidelines for irAEs 
 
Other.  
 Severity: Life-threatening or Grade 
4 adverse reaction.  
 Dose Modification: Nivo: 
Permanently discontinue; CB: 
Withhold dose. Consider re-
challenge with monotherapy. 
Other irAE.  
 Severity: Life-threatening or 
Grade 4 adverse reaction.  
 Management: 1 to 2 mg/kg/day 
prednisone equiv.  Consider 
IV. 
 Dose Modification:  
o Nivo: Permanently 
discontinue 
o CB: Withhold dose. 
Consider re-challenge 
with monotherapy. 
Clarification language 
added to include steroid 
dose and schedule for 
grade 4 irAE. 
10.8.2.2, Resumption of 
Study Treatment 
 
For both CB-839 and nivolumab, 
treatment may be delayed for up to 4 
weeks from the last dose.  Delays 
longer than 4 weeks are allowed only 
in cases where a prolonged steroid 
taper is required to manage drug-
related AEs or, in some cases, if 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 
For both CB-839 and nivolumab, 
treatment may be delayed for up to 
4 weeks from the last dose before 
restarting.  CB-839 and 
nivolumab may be held and 
restarted independent of each 
other.  Treatment delays longer 
than 4 weeks are allowed only in 
cases where a prolonged steroid 
taper is required to manage drug-
related AEs or, in some cases, if 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 
Clarification added that 
CB-839 and nivolumab 
may be held and 
restarted independently 
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≤ Grade 1.  For patients that require a 
steroid taper, nivolumab should not be 
restarted until the steroid taper is 
complete.  In cases in which a 
particular toxicity is clearly related to 
only one of the two study drugs, the 
study drug that is not involved in 
causing the AE may be restarted prior 
to a return to  Grade 1.  If CB-839 is 
restarted after permanent 
discontinuation of nivolumab, CB-839 
should be permanently discontinued for 
a > Grade 3 recurrence of the AE that 
resulted in nivolumab discontinuation. 
 
well as the patient’s medical record 
and eCRF. 
Upon withholding study drug(s) for 
adverse events, the study drug(s) 
may be restarted when the AE has 
returned to ≤ Grade 1.  For patients 
that require a steroid taper, 
nivolumab should not be restarted 
until the steroid taper is complete.  
In cases in which a particular 
toxicity is clearly related to only 
one of the two study drugs, the 
study drug that is not involved in 
causing the AE may be continued 
or restarted prior to AE resolution 
to  Grade 1 or baseline.  If CB-
839 is restarted after permanent 
discontinuation of nivolumab, CB-
839 should also be permanently 
discontinued for a > Grade 3 
recurrence of the AE that resulted in 
nivolumab discontinuation. 
10.9, Dose 
Adjustments, Infusion 
Delays, and Missed 
Doses 
In the case that the nivolumab infusion 
cannot be administered at a scheduled 
visit, it has to be administered as soon 
as possible. If the delay is between 1 
and 7 days, the procedures at the 
original scheduled visit should be 
performed, and subsequent visits will 
follow every 2 weeks (the infusion at 
the original schedule visit will be 
considered a missed dose). Patients 
Subjects may be dosed with 
nivolumab no less than 12 days 
from the previous dose. If a 
subject cannot receive the 2nd 
nivolumab dose of the cycle 
within the 28 day period it will be 
omitted and the next dose 
received will be considered Day 1 
of the next cycle. 
 
Clarification language 
added to explain 
nivolumab dose delays 
and impact on cycles 
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with infusion delays >35 days should 
discontinue from the study unless 
approved by the Medical Monitor in 
settings where benefit/ risk may justify 
continued study therapy. 
11.1 Test Article 
Administration 
CB-839: 
On PK days (Cycle 1 Days 1 and 15, 
Cycle 2 Day 1 and Cycle 3 Day 1) 
patients should be instructed NOT to 
take their morning dose of CB-839 at 
home.  During Cycle 1 Days 1 and 15, 
patients will have all predose 
procedures performed then receive 
nivolumab. Once the nivolumab 
infusion is complete, patients should be 
instructed to eat breakfast and then take 
their morning dose of CB-839. Note 
that on Cycle 2 Day 1 and Cycle 3 Day 
1, patients may eat breakfast and take 
their morning dose of CB-839 prior to 
the nivolumab infusion after all 
predose procedures are performed. The 
time of dosing will be recorded in the 
clinic.  The evening dose will be self-
administered by the patient after all 
postdose activities have been 
completed.  On non-PK collection 
days, patients will administer CB-839 
per their usual administration schedule. 
CB-839: 
On PK days (Cycle 1 Days 1 and 
15, Cycle 2 Day 1 and Cycle 3 Day 
1) patients should be instructed 
NOT to take their morning dose of 
CB-839 at home.  On PK days 
patients will have all predose 
procedures performed, take their 
dose of CB-839 with food, then 
receive nivolumab. The time of 
dosing will be recorded in the 
clinic.  The evening dose will be 
self-administered by the patient 
after all postdose activities have 
been completed.  On non-PK 
collection days, patients will 
administer CB-839 per their usual 
administration schedule. 
 
Clarification added on 
timing of CB-839 and 
nivolumab 
administration on PK 
days 
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11.1 Test Article 
Administration 
Nivolumab:  240 mg/kg of nivolumab 
will be administered as an IV infusion 
over 60 min on Days 1 and 15 of each 
28-day cycle.  Nivolumab (Opdivo®) is 
supplied as a 4 mg/mL or 10 mg/mL 
solution for infusion following 
dilution.  Please refer to the nivolumab 
package insert for specific instructions 
on nivolumab administration. 
Nivolumab:  nivolumab will be 
administered at a flat dose of 240 
mg IV infusion over 60 min on 
Days 1 and 15 of each 28-day cycle.  
Nivolumab (Opdivo®) is supplied 
by Calithera as a 10 mg/mL 
solution for infusion following 
dilution.  Please refer to the 
nivolumab package insert for 
specific instructions on nivolumab 
administration. 
Updated to reflect the 
revised nivolumab 
prescribing information 
released in Sep2017 
13.2, Vital Signs 
Vital signs (blood pressure, respiratory 
rate, pulse rate, and temperature) will 
be obtained in the sitting position.  All 
patients should be sitting for 3-5 min 
prior to obtaining vital signs. On the 
day of nivolumab infusion, vital signs 
will be obtained pre-infusion, every 15 
minutes during the infusion, at the end 
of infusion, and 15, 30, 60 minutes 
after completion of the infusion. Vital 
signs should be collected ± 5 minutes 
from the scheduled times note above. 
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. On the day of 
nivolumab infusion, vital signs will 
be obtained pre-infusion and 
within 30 minutes of the end of 
infusion. Vital signs should be 
collected ± 5 minutes from the 
scheduled times note above. 
 
Clarifying the timing of 
collecting vital signs  
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13.3, 
Electrocardiograms 
Patients should rest in the supine 
position for at least 5 min before each 
12-lead ECG recording is started.  
Duplicate ECG recordings must be 
performed approximately 5 min after 
the initial ECG recording using a 
standard, high-quality, high-fidelity 
electrocardiograph machine equipped 
with computer-based interval 
measurements. The average of values 
will used for Inclusion/Exclusion and 
AE reporting purposes. 
Patients should rest in the supine 
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.  
 
Removed the 
requirement for 
duplicate ECGs. 
Table 14.2-1, Summary 
of Tumor Biopsy* 
Collections for Patients 
Cohort 6 not included in Amendment 1 
Cohort 6: Melanoma 
Predose Biopsy: Mandatory 
Postdose Biopsy C2D1 (±1 week): 
Optional 
Footnote: *Biopsies are not required if 
deemed unsafe or technically unfeasible.  
Discuss with Medical Monitor. 
Updated table to include 
biopsy collection for  
Cohort 6 
14.3, Plasma and Whole 
Blood Collection for 
Biomarker Analysis 
 
Whole Blood Collection: Whole Blood 
samples will be collected via peripheral 
venipuncture into two different blood 
collection tubes: 
4. Blood RNA Tubes: to monitor 
immune gene expression 
5. CPT tubes: to monitor immune cell 
subsets  
Whole Blood Collection: Whole 
Blood samples will be collected via 
peripheral venipuncture into three 
different blood collection tubes: 
1. Blood RNA Tubes: to monitor 
immune gene expression 
2. CPT tubes: to monitor immune 
cell subsets  
3. EDTA tube: to monitor T-Cell 
Receptor (TCR) clonality 
Addition of an EDTA 
tube for TCR analysis 
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14.4, Biomarker 
Assessment 
Not included in Amendment 1 
Biomarkers assessed on tumor 
tissue are designed to measure 
biological effect of CB-839 in 
combination with nivolumab to 
identify potential predictors of 
response. 
Target expression: Tumor 
glutaminase gene expression 
profiles will be determined and 
tumor glutaminase protein will 
assessed via 
immunohistochemistry (IHC) 
Target engagement will be 
assessed by measuring levels of 
plasma glutamine 
The glutaminolytic signature will 
be measured in the tumor via 
gene expression and IHC for Myc 
and p-S6 protein 
Immune marker expression and 
modulation will be assessed in 
peripheral blood and tumor tissue 
(cytokines and immune cell 
populations) 
 
Addition of biomarker 
assessments section to 
outline types of analyses 
to be performed 
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16.2, Independent 
Radiology Committee 
(IRC) 
Not included in Amendment 1 
An IRC will be established to 
evaluate tumor scans in a central 
and independent fashion.  The 
IRC will comprise board-certified 
radiologists who will determine 
radiographic responses and 
progression following study start.  
Additional imaging results may 
be requested by the Sponsor for 
IRC review. 
Additional details regarding IRC 
member qualification, training, 
methods, procedures, and other 
issues relevant to committee 
operations will be described in 
the IRC Charter.  
 
Addition of language to 
explain the role of the 
IRC in the study 
Table 22.2-1, Summary 
of Sample Size and 
Power for Expansion 
Cohorts 
Cohort 4 
 
p0 (Background ORR (%)): 5% 
 
p1 (Target ORR (%)): 20% 
 
α: 0.1 
 
Power (%): 80 
 
n1 for Stage 1 (r1): 9 (0) 
 
n2 (n - n1) for Stage 2: 15 
 
Total n (r2): 24 (2) 
Cohort 4 
 
p0 (Background ORR (%)): 5% 
 
p1 (Target ORR (%)): 20% 
 
α: 0.1 
 
Power (%): 80 
 
n1 for Stage 1 (r1): 9 (0)** 
 
n2 (n - n1) for Stage 2: 66 
 
Total n (r2): 75 (13) 
 
**Completed prior to protocol 
Amendment 2 expansion of cohort 
Table 22.2-1 was 
updated to reflect the 
increased patient 
numbers for cohort 4  
Table 22.2-1, Summary 
of Sample Size and 
Power for Expansion 
Cohorts 
Cohort 6 not included in Amendment 1 
Cohort 6 
 
p0 (Background ORR (%)): 5% 
 
p1 (Target ORR (%)): 20% 
 
α: 0.1 
 
Power (%): 80 
 
n1 for Stage 1 (r1): 9 (0) 
Updated table to include 
Cohort 6 
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 
n2 (n - n1) for Stage 2: 15 
 
Total n (r2): 24 (2) 
16.3, Sample Size and 
Power 
 
Expanded Cohort 4 not in Amendment 
1 
Expanded Cohort 4 
A multi-stage design will be used 
as a guide for the melanoma 
expansion cohort 4 to decide 
whether the treatment of CB-839 
in combination with nivolumab 
warrants more extensive 
development in this population.  
At first, a Simon 2-stage design 
(Table 22.2-1) with a reasonable 
false positive rate (eg, FPR < 
10%) and false negative rate (eg, 
FNR < 20%) was used for the 
decision making based on 
assumptions of target (20%) and 
background (5%) response rate. 
Following a positive result in the 
initial two stage design and 
preliminary evidence of a 
treatment effect that may 
represent substantial 
improvement over available 
therapies, approximately 75 
subjects in total will be treated in 
Cohort 4. The sample size at this 
expanded stage is determined 
based on the ability to produce a 
confidence interval that would 
exclude the historic response rate 
(assumed to be 10%) and to 
Due to expanded patient 
number for cohort 4, 
updated language was 
added regarding the 
statistical design. 
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provide sufficient information for 
a reliable understanding of the 
safety profile.  Specifically, the 
lower limit of the 95% CI 
associated with observation of an 
objective response rate of 18.7% 
in 75 treated subjects (14/75 
responders) excludes 10%.  
Interim clinical monitoring will 
be performed in this expansion to 
ensure adequate safety and 
tolerability as well as favorable 
risk/benefit by assessing 
preliminary efficacy measures 
such as objective response rate 
and duration of response. 
16.4.3, Response 
Evaluable Population 
All patients who complete at least one 
post-baseline tumor assessment or who 
discontinue study medication early due 
to study drug-related toxicity will be 
considered evaluable for efficacy.  
Patients who discontinue study due to 
disease-related death must have 
received at least 42 doses of CB-839 
and 2 doses of nivolumab (i.e., 21 days 
of treatment) to be considered 
evaluable for efficacy.  Patients who do 
not meet the aforementioned 
requirements will be considered non-
evaluable for response and will be 
replaced. 
Patients treated in the protocol 
expansion phase or at the RP2D 
in the escalation phase who have 
measurable disease at baseline 
and complete at least one post-
baseline tumor assessment, or 
discontinue study medication early 
due to study drug-related toxicity, 
or experience clinical disease 
progression will be considered 
evaluable for RECIST 1.1 
response evaluation.  Patients who 
discontinue study due to early 
disease-related death will be 
Clarification has been 
added regarding the 
requirements for patients 
to be considered as 
response evaluable 
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The efficacy evaluable population for 
each tumor type will include all 
efficacy-evaluable patients in dose 
escalation and cohort expansion who 
initiate dosing with the RP2D for CB-
839 and who meet the criteria for 
inclusion in a specific expansion 
cohort. 
 
included in the response 
evaluable population if they 
received at least 21 days of 
treatment (approximately 42 
doses of CB-839 and 2 doses of 
nivolumab).  Patients who do not 
meet the aforementioned 
requirements will be considered 
non-evaluable for response and will 
be replaced.   
 
16.4.3.1, Melanoma 
Confirmed PD 
Population 
Not included in Amendment 1 
In addition to the above criteria, 
melanoma patients who have 
confirmation of PD > 4 weeks 
after the initial date of PD in the 
immediate prior line of treatment 
will be included in the Confirmed 
PD population.  
 
Language added for 
confirmation of 
progression requirement 
16.5, Efficacy Analysis 
Response to treatment will be 
evaluated using RECIST v1.1. 
The Kaplan-Meier method will be used 
to estimate the median Duration of 
Response (DOR), Progression-Free 
Survival (PFS), and overall survival 
(OS) for each treatment cohort in Dose 
Expansion. 
For each patient with objectively 
measurable disease, as defined by 
RECIST v1.1, response to therapy, 
For the primary efficacy analysis, 
response to treatment will be 
evaluated by RECIST v1.1.  For all 
cohorts except for cohort 4, the 
primary endpoint will be 
investigator-assessed, while for 
cohort 4 the primary endpoint 
will be IRC assessed. 
The Kaplan-Meier method will be 
used to estimate the median 
Duration of Response (DOR), 
Language added to 
clarify efficacy 
endpoints 
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DOR, PFS, ORR and OS will be 
calculated. 
 DOR is defined as the number 
of days from the date of initial 
response (PR or better) to the 
date of first documented disease 
progression/relapse or death, 
whichever occurs first. 
 PFS is defined as the number of 
days from the date of treatment 
initiation (i.e., C1D1) to the 
date of documented disease 
progression or death from any 
cause, whichever occurs first, 
and will be calculated for all 
patients.  In the event that no 
disease progression or death is 
documented prior to study 
termination, analysis cutoff, or 
the start of confounding 
anticancer therapy, these 
endpoints will be censored at 
the date of last available tumor 
assessment. 
 ORR is defined as the response 
of the proportion of efficacy 
evaluable patients with tumor 
size reduction from the time the 
start of treatment until 
documented tumor progression. 
ORR includes complete 
Progression-Free Survival (PFS), 
and overall survival (OS) for each 
treatment cohort in Dose 
Expansion. 
 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 required a 
minimum of 4 weeks after 
the date of the initial 
determination of response.   
 DOR is defined as the 
number of days from the 
date of initial response (PR 
or better) to the date of first 
documented disease 
progression/relapse or death, 
whichever occurs first. 
 PFS is defined as the 
number of days from the 
date of treatment initiation 
(i.e., C1D1) to the date of 
documented disease 
progression (radiographic 
or clinical) or death from 
any cause, whichever occurs 
first, and will be calculated 
for all patients who receive 
at least one dose of study 
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response (CR) and partial 
response (PR). 
 OS is defined as the number of 
days from the date of treatment 
initiation (i.e., Cycle 1 Day 1) 
to the date of death from any 
cause.  In the event that no 
death is documented prior to 
study termination or analysis 
cutoff, OS will be censored at 
the last date the patient is 
known to be alive. 
In addition, relationships between 
antitumor activity, PDn markers, 
exploratory biomarkers, and drug 
exposure levels will be explored. 
treatment.  In the event that 
no disease progression or 
death is documented prior to 
study termination, analysis 
cutoff, or the start of 
confounding anticancer 
therapy, these endpoints will 
be censored at the date of 
last available tumor 
assessment. 
 OS is defined as the number 
of days from the date of 
treatment initiation (i.e., 
Cycle 1 Day 1) to the date 
of death from any cause and 
will be calculated for all 
patients who receive at 
least one dose of 
treatment.  In the event that 
no death is documented 
prior to study termination or 
analysis cutoff, OS will be 
censored at the last date the 
patient is known to be alive. 
Attachment 1:  
Schedule of Study 
Assessments 
 
Not included in Amendment 1 
MRI brain with contrast 
Language added to 
include MRI of the brain 
for all cohort 4 patients 
to determine baseline 
status 
Attachment 1:  
Schedule of Study 
Assessments 
Explanation of Superscripts 
3. Vital sign measurements include 
temperature, pulse, respiratory rate 
Explanation of Superscripts 
3. Vital sign measurements include 
temperature, pulse, respiratory rate 
Updated the vital sign 
measurement schedule 
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Section(s) 
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Amendment 2 
Rationale 
 
and resting systolic and diastolic 
blood pressure. On the day of 
nivolumab infusion, vital signs will 
be obtained pre-infusion, every 15 
minutes during the infusion, at the 
end of infusion, and 15, 30, 60 
minutes after completion of the 
infusion. Vital signs should be 
collected ± 5 minutes from the 
scheduled times note above.  
 
and resting systolic and diastolic 
blood pressure. On the day of 
nivolumab infusion, vital signs will 
be obtained pre-infusion and 
within 30 minutes of the end of the 
infusion. Vital signs should be 
collected ± 5 minutes from the 
scheduled times noted above 
Attachment 1:  
Schedule of Study 
Assessments 
 
Explanation of Superscripts 
4. To be performed in duplicate and 
should be performed approximately 
5 min apart 
Explanation of Superscripts 
4. Duplicate ECGs are NOT 
required. 
Removed requirement 
for duplicated ECGs 
Attachment 1:  
Schedule of Study 
Assessments 
 
Explanation of Superscripts 
10. Nivolumab dosing will take place 
on D1 and D15 of every cycle.  
Infusion of nivolumab will precede 
CB-839 dosing and PK analysis on 
C1D1 and C1D15. 
Explanation of Superscripts 
10. Nivolumab dosing will take 
place on D1 and D15 of every 
cycle.  On PK days (C1D1, 
C1D15, C2D1 and C3D1), 
patients will bring their morning 
dose of CB-839 to clinic. Pre-dose 
procedures must be completed, 
then the patient will eat breakfast 
and take their CB-839 dose and 
then the infusion of nivolumab 
will be administered.  Cohort 6 
patients have the option to add 
Nivolumab at progression on CB-
839 monotherapy.  
Clarified dosing 
procedures during PK 
days 
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Amendment 2 
Rationale 
Attachment 1:  
Schedule of Study 
Assessments 
 
Explanation of Superscripts 
11. CB-839 is given BID on C1D1, 
C1D15, C2D1 and C3D1, patients 
should be instructed not to eat 
breakfast prior to their clinic visit. The 
morning dose of CB-839 will be 
administered during the clinic visit 
after all pre-dosing procedures and 
predose PK blood sampling, has 
occurred. On C2D1 and C3D1 and CB-
839 may be administered prior to the 
nivolumab infusion, but pre-dose 
procedures must be completed prior to 
CB-839. 
Explanation of Superscripts 
11. CB-839 is given BID with food 
approximately 12 hours apart. 
On PK days (C1D1, C1D15, C2D1 
and C3D1), patients will bring their 
morning dose of CB-839 to clinic. 
Pre-dose procedures must be 
completed, then the patient will 
eat breakfast and take their CB-
839 dose and then the infusion of 
nivolumab will be administered. 
 
Clarified dosing 
procedures during PK 
days 
Attachment 1:  
Schedule of Study 
Assessments 
 
Explanation of Superscripts 
12. Whenever possible, imaging should 
be done at the same institution/ facility 
and with the same modality which will 
be used to measure response during the 
patient’s participation in the study. The 
redacted copies of the reports will be 
submitted and the scans must be sent to 
a reader for exploratory analyses. If 
available, 1-3 redacted scan reports for 
scans that occurred prior to screening 
will be requested. 
Explanation of Superscripts 
12. Whenever possible, imaging 
should be done at the same 
institution/ facility and with the 
same modality which will be used 
to measure response during the 
patient’s participation in the study. 
The redacted copies of the reports 
will be submitted and the scans 
must be sent to a reader for 
exploratory analyses. All scans 
from the immediate prior line of 
therapy will be requested for 
Cohorts 2, 4, and 5. 
Addition of archival scan 
collection for Cohorts 2, 
4, and 5. 
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Section(s) 
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Amendment 2 
Rationale 
Attachment 1:  
Schedule of Study 
Assessments 
 
Explanation of Superscripts 
 
Not in Amendment 1 
Explanation of Superscripts 
13. For Cohort 4 only: baseline 
radiographic imaging of disease 
will also occur within 7 days prior 
to C1D1 unless the screening 
assessment meets the criteria 
described in Section 10.1. 
Updated the baseline 
radiographic imaging 
requirement for Cohort 4 
Attachment 1:  
Schedule of Study 
Assessments 
 
Explanation of Superscripts 
14. Completed approximately every 8 
weeks per RECIST 1.1. Evaluations 
may occur more frequently as 
clinically indicated. 
 
Explanation of Superscripts 
14. Completed approximately every 
8 weeks from Cycle 1 Day 1 per 
RECIST 1.1. Studies should 
include chest/abdomen/pelvis and 
all other known areas of disease. 
Evaluations may occur more 
frequently as clinically indicated. 
Patients with an objective 
response (CR or PR) should have 
repeat imaging at least 4 weeks 
later to confirm the objective 
response. In addition, patients 
with progressive disease should 
undergo a second scan at least 4 
weeks later to confirm 
progression. 
Clarified the timing and 
procedures of follow up 
scans 
Attachment 1:  
Schedule of Study 
Assessments 
 
Explanation of Superscripts 
 
Not in Amendment 1 
Explanation of Superscripts 
16. To be included for patients 
with known CNS disease. 
Additional MRI 
requirement for patients 
with known CNS disease 
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149 
Section(s) 
Amendment 1 
Amendment 2 
Rationale 
Attachment 1:  
Schedule of Study 
Assessments 
 
Explanation of Superscripts 
16. A baseline tumor biopsy is required 
for all patients enrolled in Phase 2. 
Postdose tumor biopsies are required 
for all patients in Cohorts 2, 4, and 5 
and should be collected on Cycle 2 
Day 1 (± 1 week).  Coagulation tests 
must be performed and evaluated 
within 24 hr prior to all biopsy 
procedures. Instructions on biopsy 
processing can be found in the 
Laboratory Manual.  
 
Explanation of Superscripts 
18. A baseline tumor biopsy is 
required for all patients enrolled in 
Phase 2. Postdose tumor biopsies 
are required for all patients in 
Cohorts 2 and 5 and should be 
collected on Cycle 2 Day 1 (± 1 
week).  Predose and postdose 
biopsies will be collected for the 
first 30 patients enrolled into 
stage 2 of Cohort 4. For all 
subsequently enrolled patients, 
only a pre-dose biopsy will be 
collected.  Coagulation tests must 
be performed and evaluated within 
72 to 24 hr prior to all biopsy 
procedures. Instructions on biopsy 
processing can be found in the 
Laboratory Manual. 
Updated biopsy 
assessment for Cohort 4 
and increased the 
window for coagulation 
testing prior to biopsy 
procedure 
Attachment 1:  
Pharmacokinetic and 
Biomarkers Sampling 
Schedule 
 
Not in Amendment 1 
Phase 1 and Phase 2 Biomarker: 
TCR6 
 Cycle 1 Day 1: 3 mL 
 Cycle 1 Day 15: 3 mL 
 Cycle 3 Day 1: 3 mL 
 Total sample: 9 mL 
Addition of collection 
time points for TCR 
analysis 
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Amendment 2 
Rationale 
Attachment 3: Clinical 
Laboratory Tests 
Serum Chemistry-Full Metabolic Panel 
(Peripheral Blood Sample) with 
additional analytes 
 
Serum Chemistry-Full Metabolic 
Panel (Peripheral Blood Sample) 
with additional analytes 
 
Thyroid Stimulating Hormone 
(TSH) 
 
Updated serum 
chemistry to remove 
magnesium, phosphorus, 
uric acid, direct 
bilirubin, and thyroid 
function tests and add 
thyroid stimulating 
hormone test. 
Attachment 3: Clinical 
Laboratory Tests 
Urinalysis 
Urinalysis 
 Only institutional standard 
urinalysis is required 
Updated urinalysis to 
require only institutional 
standards 
Attachment 5: 
iRECIST: modified 
RECIST 1.1 for 
immune-based 
therapeutics 
Attachment 5: Immune Related 
RECIST Criteria (based on RECIST 
1.1) 
 
Attachment 5: iRECIST: modified 
RECIST 1.1 for immune-based 
therapeutics  
 
For consistency across 
all sites, the updated 
iRECIST guidelines will 
be implemented 
 
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SAP_001.pdf: 
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Statistical Analysis Plan 
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Page 1  of 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Calithera Biosciences, Inc. 
 
CX-839-004 
 
 
 
 
 
 
 
Protocol Title: 
A Phase 1/2 Study of the Safety, Pharmacokinetics, and 
Pharmacodynamics of the Glutaminase Inhibitor CB-839 in 
Combination 
with 
Nivolumab 
in 
Patients 
with 
Advanced/Metastatic Melanoma, Renal Cell Carcinoma and 
Non-Small Cell Lung Cancer 
 
Protocol Version 
and Date: 
Amendment 2 / 14 November 2017 
 
Sponsor: 
Calithera Biosciences, Inc. 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
 
Prepared By: 
Yongmei Zhou 
Biostatistician Contracted to Calithera 
343 Oyster Point Blvd, Suite 200 
South San Francisco, CA 94080 
 
 
Document Version 
and Date: 
Version 2.0; 08 July 2020 


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1 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
Sponsor: 
Calithera Biosciences, Inc. 
 
Clinical Protocol Number: 
CX-839-004 
 
Protocol Title: 
A Phase 1/2 Study of the Safety, Pharmacokinetics, and 
Pharmacodynamics of the Glutaminase Inhibitor CB-839 in 
Combination 
with 
Nivolumab 
in 
Patients 
with 
Advanced/Metastatic Melanoma, Renal Cell Carcinoma and 
Non-Small Cell Lung Cancer 
 
Document File Name: 
Calithera_CX-839-004_SAP_v2.0_08JUL2020 
 
Document Version and 
Effective Date: 
 
Approved By: 
Version 2.0; 08 Jul 2020 
 
 
 
 
 
 
 
Yijing Shen, Ph.D 
Director of Biometrics 
Calithera Biosciences, Inc. 
Date 
 
 
Laura Holland, MS 
Biostatistician II 
Precision for Medicine, Oncology and Rare Disease 
Date 
 
 
 
 
 
 
 
Whitney Stemple, MS 
Senior Manager, Biostatistics 
Precision for Medicine, Oncology and Rare Disease 
Date 


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2 
TABLE OF CONTENTS 
 
Contents 
1 
STATISTICAL ANALYSIS PLAN APPROVAL ......................................... 2 
2 
TABLE OF CONTENTS ................................................................................. 3 
3 
LIST OF ABBREVIATIONS .......................................................................... 5 
4 
INTRODUCTION ............................................................................................ 6 
5 
STUDY DESIGN .............................................................................................. 6 
5.1 
Protocol Synopsis .............................................................................................. 7 
5.2 
Study Endpoints ................................................................................................ 7 
5.2.1 
Efficacy Endpoints ........................................................................................................ 7 
5.2.2 
Safety Endpoints ........................................................................................................... 8 
5.3 
Sample Size and Power .................................................................................... 8 
6 
STUDY CONDUCT ......................................................................................... 9 
6.1 
Safety Data Monitoring .................................................................................... 9 
7 
STATISTICAL METHODS ............................................................................ 9 
7.1 
Analysis Sets ...................................................................................................... 9 
7.1.1 
Efficacy Evaluable Population for ORR– Response Evaluable Analysis Set ............. 9 
7.1.2 
Efficacy Evaluable Population for PFS – PFS Evaluable Analysis Set ................... 10 
7.1.3 
Safety Analysis Set ...................................................................................................... 10 
7.2 
Analysis of Study Conduct ............................................................................. 10 
7.3 
Analysis of Treatment Group Comparability .............................................. 10 
7.4 
Efficacy Analysis ............................................................................................. 10 
7.4.1 
Primary Analysis of Overall Response Rate .............................................................. 10 
7.4.2 
Secondary Analyses..................................................................................................... 11 
7.5 
Safety................................................................................................................ 12 
7.5.1 
Treatment Exposure .................................................................................................... 12 
7.5.2 
Adverse Events ............................................................................................................ 13 
7.5.3 
Laboratory Data .......................................................................................................... 13 
7.5.4 
ECG and Vital Signs ................................................................................................... 13 
7.6 
Missing Data .................................................................................................... 13 
7.7 
Changes in the Conduct of the Study or Planned Analyses ........................ 14 
7 
REFERENCES ............................................................................................... 15 
APPENDIX A:  SCHEDULE OF STUDY ASSESSMENTS .................................. 16 


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TABLE OF TABLES 
 
Table 1 
Summary of Sample Size and Power for Expansion Cohorts ...................................................... 9 
Table 2 
The Censor/Event Rules for Progression Free Survival and Duration of Responsea ...................... 12 


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3 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
BID 
Twice daily 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
hr 
Hour or hours 
IRC 
Independent radiology committee 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Preferred term 
QTcF 
Corrected QT interval, Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 


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4 INTRODUCTION 
 
The statistical analysis plan (SAP) provides details of the planned analyses and statistical 
methods for the study CX-839-004 (A Phase 1/2 Study of the Safety, Pharmacokinetics, 
and Pharmacodynamics of the Glutaminase Inhibitor CB-839 in Combination with 
Nivolumab in Patients with Advanced/Metastatic Melanoma, Renal Cell Carcinoma and 
Non-Small Cell Lung Cancer). The background and rationale for the study can be found 
in the study protocol. 
 
5 
STUDY DESIGN 
 
Protocol CX-839-004 is a Phase 1/2 open-label study of the combination of CB-839 with 
nivolumab in patients with advanced/metastatic ccRCC, MEL, and NSCLC, as well as 
CB-839 monotherapy in patients with advanced/metastatic MEL. Sequential dose 
escalation of CB-839 with full dose nivolumab (CB-Nivo) will take place in patients with 
advanced ccRCC, advanced/metastatic MEL, or metastatic NSCLC. Subsequently, 
multiple disease-specific single-arm cohorts will be enrolled in which CB-839 will be 
administered in combination with the full approved dose of nivolumab. CB-839 will be 
administered at the RP2D established in dose escalation. Patients in dose escalation must 
be eligible for one of the dose expansion cohorts. CB-839 monotherapy will be 
administered at the previously established monotherapy RP2D of 800 mg PO BID (twice 
daily). 
 
 


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Dose escalation will use a 3+3 design and will enroll cohorts of 3-5 patients with advanced 
ccRCC, advanced/ metastatic MEL, or metastatic NSCLC at escalating doses as outlined in 
Table 6.3-1 in the protocol amendment 2. Patients will receive escalating doses of CB-839 in 
combination with the FDA-approved anti-PD-1 agent nivolumab. Nivolumab will be 
administered at the FDA-approved dose of 240 mg every 2 weeks without adjustment for 
body weight. 
 
Dose limiting toxicities (DLTs) observed in Cycle 1 (first 28 days of dosing) will be 
used to determine escalation to the next dose level. In general, patients who 
experience a DLT will not receive further treatment with the study drugs. 
 
The Maximum Tolerated Dose (MTD) is defined as the highest dose level with no 
more than 1 DLT reported in 6 DLT-evaluable patients. 
 
During dose escalation, patients must receive at least 75% of the planned CB-839 
administrations and both doses of nivolumab in the first 28-day treatment cycle to be 
considered evaluable for DLT, unless the patient has a DLT or has the study drug 
held for an adverse event (AE) that may herald a DLT. 
 
The starting dose of CB-839 will be 600 mg BID. The first dose of CB-839 will be 
administered in the morning with breakfast. The second dose will be administered in 
the evening with a meal approximately 12 hr (± 2 hr) after the morning dose. 
 
Dose escalation will continue until identification of a MTD or up to a maximum 
dose of 800 mg orally BID, thus the maximum dose will be 800 mg BID. Up to 6 
additional patients may be enrolled to a dose escalation cohort in order to generate 
additional safety, pharmacokinetic (PK), and biomarker data. 
 
The Recommended Phase 2 Dose (RP2D) of CB-Nivo will be selected based on the 
clinical data and will not exceed the MTD. To further characterize safety, 
tolerability, and efficacy, additional patients will be enrolled at the RP2D in specific 
cohorts in Phase 2 – Cohort Expansion. Please refer to Section 6.3.2 in the protocol 
for details. 
 
5.1 
Protocol Synopsis 
Please refer to protocol amendment 2 dated 14 Nov 2017 (1). The Schedule of 
Assessments is in Appendix A: Schedule of Study Assessments. 
 
5.2 
Study Endpoints 
 
5.2.1 
Efficacy Endpoints 
5.2.1.1 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the confirmed overall response rate (ORR) and 
duration of response (DOR) of patients treated with CB-839 in combination with 
nivolumab. Overall Response Rate is defined as the percentage of patients with 
complete response (CR) or partial response (PR) per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1. DOR is defined as the time between the first 


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documentation of a PR or a CR per RECIST v1.1 to the first documentation of 
progressive disease (PD) or death. For all cohorts, the primary end point is 
investigator assessed. 
 
5.2.1.2 
Secondary Efficacy Endpoints 
 
The secondary efficacy endpoints are: 
 
• 
Progression free survival (PFS) of patients treated with CB-839 plus 
nivolumab. PFS is defined as time from first dose date to the earlier of either 
progression of disease per RECIST v1.1 or death from any cause. 
• 
Overall survival (OS) of patients treated with CB-839 plus nivolumab. 
Overall Survival is assessed by time from first dose date to death due to any 
cause. 
 
5.2.2 
Safety Endpoints 
The safety endpoints are: 
 
• Type, incidence, seriousness, nature, severity, and drug-relatedness of 
adverse events graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0) 
 
• Changes in vital signs, physical findings, and clinical laboratory test results 
following study treatment administration 
 
5.3 
Sample Size and Power 
Dose Escalation: The goal is to determine a dose level of CB-839 for which the rate of 
DLTs is less than 33%. A minimum of 9-12 patients are planned for Dose Escalation. 
 
Dose Expansion: For Cohorts 1-5, Simon's two-stage design (Simon 1989) (3) will be used 
as outlined in Table 1 below. The null hypothesis that the response rate is [ p0 ] will be 
tested against a one-sided alternative. In the first stage, [ n1 ] patients will be accrued. If 
there are [ r1 ] or fewer responses in these [ n1 ] patients, the study will be stopped. 
Otherwise, [ n - n1 ] additional patients will be accrued for a total of [ n ]. The null 
hypothesis will be rejected if [ r2 + 1 ] or more responses are observed in [ n ] patients. This 
design yields a type I error rate of 0.1 and power of 80% when the true response rate is [ p1 
]. 


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Table 1 Summary of Sample Size and Power for Expansion Cohorts 
 
Cohort 
p0 
(Background 
ORR (%)) 
p1 
(Target ORR 
(%)) 
Α 
Power 
(%) 
n1 for 
Stage 1 
(r1) 
n2 
(n - n1) 
for Stage 2 
Total n 
(r2) 
1 
25% 
40% 
0.1 
80 
25 (7) 
27 
52 (16) 
2 
5% 
15% 
0.1 
80 
20 (1) 
36 
56 (4) 
3 
5% 
20% 
0.1 
80 
9 (0) 
15 
24 (2) 
4 
5% 
20% 
0.1 
80 
9 (0)** 
66 
75 (13) 
5 
5% 
15% 
0.1 
80 
20 (1) 
36 
56 (4) 
6 
5% 
20% 
0.1 
80 
9 (0) 
15 
24 (2) 
*For all cohorts, false positive rate (α) = 0.1 
**Completed prior to protocol Amendment 2 expansion of cohort 
 
Expanded Cohort 4 
 
A multi-stage design will be used as a guide for the melanoma expansion cohort 4 to decide 
whether the treatment of CB-839 in combination with nivolumab warrants more extensive 
development in this population. At first, a Simon 2-stage design (Table 1) with a reasonable 
false positive rate (eg, FPR < 10%) and false negative rate (eg, FNR < 20%) was used for 
the decision making based on assumptions of target (20%) and background (5%) response 
rate. Following a positive result in the initial two stage design and preliminary evidence of a 
treatment effect that may represent substantial improvement over available therapies, 
approximately 75 subjects in total will be treated in Cohort 4. The sample size at this 
expanded stage is determined based on the ability to produce a confidence interval (CI) that 
would exclude the historic response rate (assumed to be 10%) and to provide sufficient 
information for a reliable understanding of the safety profile. Specifically, the lower limit of 
the 95% CI associated with observation of an objective response rate of 18.7% in 75 treated 
subjects (14/75 responders) excludes 10%. Interim clinical monitoring will be performed in 
this expansion to ensure adequate safety and tolerability as well as favorable risk/benefit by 
assessing preliminary efficacy measures such as objective response rate and duration of 
response. 
 
6 
STUDY CONDUCT 
 
6.1 
Safety Data Monitoring 
Safety data from the study is monitored on an ongoing basis via routine PrimeVigilance 
activities. In addition to real time medical review of emergent SAEs, a cross functional 
sponsor safety review team performs regular periodic aggregate data reviews across all CB- 
839 studies. 
 
7 
STATISTICAL METHODS 
 
7.1 
Analysis Sets 
7.1.1 
Efficacy Evaluable Population for ORR– Response Evaluable Analysis Set 
All patients who have measurable disease at baseline, receive at least one dose of study drug 
(CB-839 or nivolumab), and complete at least one post-baseline tumor assessment, will be 
considered evaluable for efficacy. In addition, patients who discontinue treatment for study- 


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drug related toxicity or for disease-related death also are included in the efficacy evaluable 
population for ORR. 
All response efficacy analyses will be performed by cohort. 
 
7.1.2 
Efficacy Evaluable Population for PFS – PFS Evaluable Analysis Set 
All patients who receive at least one dose of any study-specific treatment (CB-839 or 
nivolumab) will be included in the analysis of safety. The PFS analysis will be performed by 
cohort. 
 
7.1.3 
Safety Analysis Set 
All patients who receive at least 1 dose of any study-specific treatment (CB-839 or 
nivolumab) will be included in the analysis of safety. All safety analyses will be performed 
by cohort. 
 
7.2 
Analysis of Study Conduct 
 
Subject disposition, including enrollment, analysis populations, reason for discontinuation 
from the study, and on-study status will be summarized by cohort and overall for the safety 
analysis set. Protocol deviations are not collected in the case report form but entered 
manually and provided by electronic data transfer. If protocol deviations are sufficiently 
standardized to allow summarization, major protocol deviations (including major deviations 
of inclusion and/or exclusion criteria) will be summarized. Protocol deviations will be listed 
regardless of the level of standardization. 
 
7.3 
Analysis of Treatment Group Comparability 
 
Demographic and baseline characteristics, including age, sex, race, ethnicity, and disease 
characteristics will be summarized by cohort and overall for the safety analysis set. 
 
Baseline values are defined as the last available data obtained prior to the patient receiving 
the first dose of any study treatments on Cycle 1 Day 1 visits unless otherwise noted. 
 
7.4 
Efficacy Analysis 
 
Efficacy analyses will be performed by cohort. Response to treatment will be evaluated per 
Investigator assessed using RECIST v1.1. 
 
The cohorts are based on patient’s tumor type instead of randomization, therefore formal 
hypothesis testing among cohorts will not be performed. 
 
7.4.1 
Primary Analysis of Overall Response Rate 
Overall Response Rate (ORR) will be assessed by cohort where ORR is defined as the 
percentage of patients with complete response (CR) or partial response (PR) per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1. To be assigned a status of CR or PR, 
changes in tumor measurements must be confirmed by repeat assessment performed no less 
than 4 weeks after the criteria for response were first met. Patients without assessed 
response will be treated as non-responders. 


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The analysis set for ORR will be the response evaluable analysis set. An estimate of ORR 
and its 95% CI will be calculated with the Clopper-Pearson method. Best Overall Response 
(BOR) Rate is defined as the percentage of patients with their best of response being will be 
estimated in the same approach as for ORR. 
 
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. Patients who 
are alive and have not experienced disease progression at the time of the analysis will follow 
the censoring rules in Table 2 where only assessments after first response will be included. 
The determination of DOR is based on responders only. 
 
Kaplan-Meier methodology will be used to estimate median DOR for each cohort and 
construct survival curves for visual description. The Brookmeyer-Crowley methodology 
will be used to construct the 95% CI for the median DOR for each cohort (2). DOR will be 
analyzed using response evaluable analysis set. 
 
DOR will be reported for patients with confirmed OR. 
 
7.4.2 
Secondary Analyses 
Progression Free Survival: PFS is defined as time from the first dose date to the earlier of 
either progression of disease per RECIST 1.1 or death from any cause. If the disease 
progression assessment involves more than one date, the earliest date will be used as the 
event date. 
 
The duration of PFS will be censored at the date of the last radiographic disease assessment 
if: 
 
• Patient is alive and progression free at the time of analysis data cutoff. 
• Disease progression or death occurs after missing data (including an inevaluable 
status for overall response assessment) for two consecutive radiographic disease 
assessments. 
• Patient receives non-protocol treatment prior to documentation of disease 
progression. 
Patients missing baseline disease assessment will be censored at the first dose date (C1D1). 
Patients who come off of study for reason other than PD or death should continue to be 
followed with radiographic assessment until PD by RECIST 1.1, death, withdrawal of 
consent, or initiation of another systemic anti-cancer treatment. Censoring rules are 
summarized in Table 2 
 
The analysis set for PFS will be the PFS evaluable analysis set. Kaplan-Meier methodology 
will be used to estimate median PFS for each cohort and construct survival curves for visual 
description. The Brookmeyer-Crowley methodology will be used to construct the 95% CI 
for the median PFS for each cohort (2). 
 
Overall Survival (OS): OS is defined as the time from the first dose date to death due to any 
cause. For patients alive at time of analysis, OS will be censored at the time when the 


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patient is last known to be alive. Patients who discontinue study for reason other than death 
should continue to be followed for survival status until death or withdrawal of consent. 
Because OS may require longer follow up than the primary PFS analysis, additional OS 
analyses may be performed after the time of PFS primary analysis. OS will be analyzed with 
the same methodologies and analysis set as PFS. 
 
Table 2 The Censor/Event Rules for Progression Free Survival and Duration 
of Responsea 
 
 
Situation 
Date of Event or 
Censoring 
Outcome 
No baseline disease assessment 
Date of first dose 
Censored 
No post-baseline assessments and no death 
Date of first dose 
Censored 
No progression and no death 
Date of last evaluable 
tumor assessment 
Censored 
Additional cancer therapy prior to documentation 
disease progression or death 
Date of last evaluable 
tumor assessment 
prior to first new 
cancer therapy 
Censored 
Documented RECIST progression per 
investigator or death within 2 scheduled scan 
intervals following previous evaluable 
radiological tumor assessment 
First date of evaluation 
of overall response of PD 
or death is determined 
Event 
RECIST progression or death documented to 
occur after missing 2 scheduled disease 
assessments (including an overall response of 
non-evaluable) following previous evaluable 
radiological tumor assessment 
Date of last evaluable 
tumor assessment 
with no progression 
prior to the first of 
these missed visits 
Censored 
PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors 
aRECIST progression or death can occur either on study or during the survival follow up 
period after treatment discontinuation for symptomatic deterioration, adverse event, or 
other reason not related to disease and prior to the initiation of new cancer therapy. 
 
 
7.5 
Safety 
 
Unless specified otherwise, safety analyses described in this section will be conducted for 
the Safety analysis set. 
 
7.5.1 
Treatment Exposure 
Extent of exposure to both study treatments (CB-839 and nivolumab), including treatment 
duration, total dose received (mg for CB-839 and mg/m2 for nivolumab), number of cycles, 
will be evaluated by summary statistics (N, mean, standard deviation, median, minimum and 


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maximum). Percent of patients and cycles with dose delays and reductions will be 
calculated. 
 
Exposures will be summarized by cohort for CB-839 and nivolumab separately. 
 
7.5.2 
Adverse Events 
Verbatim description of adverse events will be coded to System Organ Class (SOC) and 
Preferred Term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) and 
graded by the investigator according to NCI CTCAE v4.03. Treatment-emergent AEs 
(TEAEs) are defined as AEs started or worsened on or after first dose and will be tabulated. 
The number and proportion of patients reporting a given TEAE will be tabulated according 
to the worst severity grade reported. Separate tables will be constructed for a) all reported 
TEAE’s, b) serious TEAEs (treatment-emergent SAEs), c) severe TEAEs (Grade ≥ 3), and 
d) TEAE’s leading to permanent discontinuation or interruption of study treatments. The 
above tables will also be presented for TEAEs judged to be related to either study treatment. 
 
Multiple occurrences of the same event will be counted once at the maximum grade. In 
order to accurately summarize the true TEAE rate, all TEAE summaries will not count 
grade 5 events for patients who died due to progressive disease. 
 
All listings of adverse events will include both TEAEs and non-TEAEs. 
 
Deaths reported during the study treatment period and the follow-up period after treatment 
completion/discontinuation will be listed and summarized by cause. 
 
7.5.3 
Laboratory Data 
Laboratory variables will be examined using mean change in value from baseline to 
scheduled time points. The baseline value of a variable is defined as the last value obtained 
on or before the date and time of the first dose of CB-839 or nivolumab. Proportion of 
patients with laboratory measurement outside the normal range and by NCI CTCAE v4.03 
grade will be summarized. 
 
7.5.4 
ECG and Vital Signs 
Electrocardiogram (ECG), weight, and vital signs will be summarized by changes from 
baseline to scheduled time points using descriptive statistics. Baseline is defined the same 
way as for laboratory measurements. 
 
7.6 
Missing Data 
 
Patients with missing response assessment will be treated as non-responders in analyzing 
ORR. Table 3 will be followed to censor these patients in analyzing PFS and DOR. 
Missing laboratory, ECG and vital sign measurements will not be imputed and included in 
the analysis. AEs with missing or partial start date that cannot be definitively determined to 
be earlier than first dose will be treated as TEAE. AEs with missing relationship to study 
treatments will be treated as related. 


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7.7 
Changes in the Conduct of the Study or Planned Analyses 
 
The SAP version 2.0 is amended from version 1.0 to remove restriction on the 
primary end point for Cohort 4 so that Cohort 4 is investigator assessed, rather than 
IRC assessed. That is, the primary end point for Cohort 4 is the same as the other 
cohorts. This decision was made by the sponsor Calithera. 
SAP version 2.0 also removes references to Cohort 6 because this cohort was never 
enrolled. 
SAP version 2.0 does not require the summarization of protocol deviations because 
protocol deviations may not be sufficiently standardized to allow for summarization. 
Though referenced in the study protocol, no iRECIST analyses are to be conducted 
per the SAP. 


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7 REFERENCES 
1. 
Protocol CX-839-004 Amendment 2, dated 14 Nov 2017 
 
2. 
Brookmeyer, R. and Crowley, J. (1982) A confidence interval for the median 
survival time. Biometrics, 38, 29-41. doi:10.2307/2530286 
 
3. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled 
Clinical Trials 1989; 10: 1 - 10 
 
4. 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. Statistical principles for clinical trials 
(E9). International Conference on Harmonization; 1998. 
 
5. 
Data Standards: Position on Use of SI Units for Lab Tests. U.S Food and Drug 
Administration; 25 October 2013. Available 
from: http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/ucm37 
2553.htm 
 
6. 
U.S. Department of Health and Human Services. Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.03. 14 June 2010. Available 
from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 
14_QuickReference_8.5x11.pdf. 


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APPENDIX A: SCHEDULE OF STUDY ASSESSMENTS 
Visit 
Screening 
Cycle 1 
Cycle 2+ 
End of Treatment/ Follow 
up 
Day 
-28 to -1 
Day 1 
(-1 day) 
Days 8 and 22 
(± 2 days) 
Day 15 
(± 2 days) 
Days 1 and 15 
(± 5 days) 
EOT: Within 28 days post 
treatment discontinuation 
Written Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Demographics and Medical History 
X 
Physical Examination1 
X 
X 
X 
X 
X2 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X2 
X 
Vital Signs3 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X2 
X 
12-lead ECG with QTcF4 
X 
X5 
X5 
X 
Urinalysis7 
X 
X6 
X 
X 
X 
X 
Serum Chemistry levels7 
X 
X6 
X 
X 
X 
X 
Coagulation tests7 
X 
X6 
X 
X 
X 
X 
Hematology7 
X 
X6 
X 
X 
X 
X 
Serum or Urine Pregnancy Test8 
X 
X 
Pharmacokinetic (PK) Assay9 
X 
X 
X9 
Biomarker Assay9 
X 
X 
X9 
Nivolumab Dosing10 
X 
X 
X 
CB-839 Dosing11 
X 
X 
X 
X 
Baseline Radiographic Evaluation of Tumor 
Burden (diagnostic CT or MRI) 
X12, 13 
X14 
X19 
MRI brain with contrast 
X15 
X16 
Archival Tumor Collection17 
X 
Tumor Biopsy for Tumor Biomarkers18 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Follow up 
X20 


Calithera Biosciences, Inc. 
CX-839-004 
Statistical Analysis Plan 
Version 2.0; 08Jul2020 
Page 17  of 
 
 
 
Explanation of Superscripts: 
1. 
Complete physical exam is required at Screening and at End of Treatment. A symptom-directed physical exam can be done on all other visits. System exams are only required 
as clinically indicated. 
2. 
Assessment to be completed on Day 1 of every cycle. 
3. 
Vital sign measurements include temperature, pulse, respiratory rate and resting systolic and diastolic blood pressure. On the day of nivolumab infusion, vital signs will be 
obtained pre-infusion and within 30 minutes of the end of the infusion. Vital signs should be collected ± 5 minutes from the scheduled times noted above. 
4. 
Duplicate ECGs are NOT required. 
5. 
ECG to be performed within approximately 2 to 4 hr postdose of CB-839 administration. 
6. 
Does not need to be repeated if the Screening sample was obtained within 3 days prior to C1D1 unless a clinically significant change is suspected. 
7. 
Serum chemistry, coagulation, hematology and urinalysis laboratory tests should be performed and reviewed before dosing. These labs may be performed up to 48 hours prior 
to the planned dosing. Note that coagulation tests must be performed and reviewed within 72 to 24 hr prior to all biopsy procedures. Any new ≥Grade 3 laboratory 
abnormality, or change consistent with a possible irAE (as opposed to disease progression), such as liver function test elevations, electrolyte fluctuation, or hematologic 
deterioration should be assessed for potential risk to continue dosing. In the event of uncertainty, the medical monitor should be contacted. 
8. 
Required of all females of child-bearing potential. Screen pregnancy test must occur within 3 days prior to C1D1. 
9. 
Samples are collected on C1D1, C1D15, C2D1 and C3D1. See Protocol Amendment 2 attachment 2 for specific time points and volume of blood collection. 
10. Nivolumab dosing will take place on D1 and D15 of every cycle. On PK days (C1D1, C1D15, C2D1 and C3D1), patients will bring their morning dose of CB-839 to clinic. 
Pre-dose procedures must be completed, then the patient will eat breakfast and take their CB-839 dose and then the infusion of nivolumab will be administered. 
11. CB-839 is given BID with food approximately 12 hours apart. On PK days (C1D1, C1D15, C2D1 and C3D1), patients will bring their morning dose of CB-839 to clinic. Pre- 
dose procedures must be completed, then the patient will eat breakfast and take their CB-839 dose and then the infusion of nivolumab will be administered. 
12. Whenever possible, imaging should be done at the same institution/ facility and with the same modality which will be used to measure response during the patient’s 
participation in the study. The redacted copies of the reports will be submitted and the scans must be sent to a reader for exploratory analyses. All scans from the immediate 
prior line of therapy will be requested for Cohorts 2, 4, and 5. 
13. For Cohort 4 only: baseline radiographic imaging of disease will also occur within 7 days prior to C1D1 unless the screening assessment meets the criteria described in 
Protocol Amendment 2 Section 10.1. 
14. Completed approximately every 8 weeks from Cycle 1 Day 1 per RECIST 1.1. Studies should include chest/abdomen/pelvis and all other known areas of disease. Evaluations 
may occur more frequently as clinically indicated. Patients with an objective response (CR or PR) should have repeat imaging at least 4 weeks later to confirm the objective 
response. In addition, patients with progressive disease should undergo a second scan at least 4 weeks later to confirm progression. 
15. Cohort 4 only 
16. To be included for patients with known CNS disease. 
17. Archival tumor tissue must be provided from all patients on study who have archival tissue available. 
18. A baseline tumor biopsy is required for all patients enrolled in Phase 2. Postdose tumor biopsies are required for all patients in Cohorts 2 and 5 and should be collected on 
Cycle 2 Day 1 (± 1 week). Predose and postdose biopsies will be collected for the first 30 patients enrolled into stage 2 of Cohort 4. For all subsequently enrolled patients, 
only a pre-dose biopsy will be collected. Coagulation tests must be performed and evaluated within 72 to 24 hr prior to all biopsy procedures. Instructions on biopsy 
processing can be found in the Laboratory Manual. 
19. Patients who discontinue study treatment for reason other than PD or death must continue to be followed by radiographic imaging per study schedule until PD, death, 
withdrawal of consent, or initiation of another cancer therapy. 
20. Patients will be contacted every 3 mo for the first 12 mo then every 6 mo thereafter to confirm survival or public records may be consulted to establish survival status. 


 
 
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