Clinical trial NCT02861300
Conditions: Colorectal Cancer Colon Cancer Rectal Cancer Solid Tumor
Keywords: CB-839 PIK3CA capecitabine
Sponsor: David Bajor, MD
Start date: 2016-09-12; Completion date: 2023-01-10
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study has two portions. The main goal of the Phase I portion of this research study is to see what doses of CB-839 and capecitabine can safely be given to patients without having too many side effects. Other purposes of this research study will be to determine what side effects are seen with this combination of medicines. The Phase II portion of the study will test how many patients show shrinkage in their tumor with this combination of medicines and what changes occur inside the cancer cells and blood cells after treatment.

Detailed description:
Phase I Primary Objective:

To determine the safety, tolerability and recommended phase II dose (RP2D) of combination CB-839 and capecitabine chemotherapy in patients with advanced solid tumors for whom there are no remaining treatment options or for whom single agent capecitabine is an acceptable therapy.

Phase II Primary Objective:

To determine the disease control rate of combination CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA mutant colorectal cancers who are refractory to fluoropyrimidine based therapy.

Phase I Secondary Objectives:

To determine the dose-limiting toxicities and maximum tolerated dose of combination therapy with CB-839 and capecitabine in patients with advanced solid tumors for whom there are no remaining treatment options or for whom single agent capecitabine is an acceptable therapy.

To determine the disease control rate as assessed by RECIST criteria of combination therapy with CB-839 and capecitabine in patients with advanced solid tumors for whom there are no remaining treatment options or for whom single agent capecitabine is an acceptable therapy.

Phase II Secondary Objectives:

To determine the progression free survival following treatment with CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer and are refractory to fluoropyrimidine therapy.

To determine the overall survival following treatment with CB-839 and capecitabine chemotherapy in patients who have metastatic PIK3CA mutant colorectal cancer and are refractory to fluoropyrimidine therapy.

Arms: arm 1: Patients will receive CB-839 orally twice daily for 21 days (continuous administration) and capecitabine orally twice daily for 14/21 days. In the phase I portion of the study, patients will receive escalating doses of CB-839 and capecitabine and will have day 15 blood samples drawn and archived for as needed assessment of CB-839 pharmacokinetics. In the phase II portion of the study, patients will receiving 800mg CB-839 and 1000mg/m\^2 capecitabine as were determined to be safe doses during the phase I portion of the study. They will also undergo pre-treatment and post-treatment blood samples and tissue biopsies for evaluation of pharmacodynamic biomarkers.
Interventions: intervention 1: CB-839 intervention 2: Capecitabine
Intervention descriptions: intervention 1: Patients will receive CB-839 orally twice daily during each cycle. Each cycle will be 21 days long. Disease assessment will occur after cycle 3. intervention 2: capecitabine will be given orally twice daily for 14-21 days of cycles. Each cycle will be 21 days long. Disease assessment will occur after cycle 3.

Protocol documents:
Prot_SAP_000.pdf: 


CASE 1216 
 
 
 
Page 2  
 
 
Version date: 12/16/2020 
 
 
STUDY COORDINATOR: 
 
 
 
 
 
  
 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
 
 
SUPPORT/FUNDING: 
 
GI SPORE 1P50 CA150964 
 
SUPPLIED AGENT: 
 
CB-839 
 
IND #:  
 
 
 
130616 
 
 
 
 
OTHER AGENT:  
 
Capecitabine 
 


CASE 1216 
 
 
 
Page 3  
 
 
Version date: 12/16/2020 
 
 
SUMMARY OF CHANGES 
 
Protocol 
Date 
12/16/2020
Section  
Change  
 
Title Page 2 
Erin Anderson, RN is replacing Janette Gortz 
 
Protocol 
Summary, 
Sample Size 
Phase I: 9-24 patients 
Phase II: 10-29 patients 
Males and females permitted 
 
Phase I: 9-24 patients 
Phase II: 18-40 patients 
Males and females permitted 
 
 
STUDY SCHEMA—PHASE II 
 
 
(schema updated to reflect new “N” number) 
 
Phase II: Patients will be treated with CB-839 800 mg by 
mouth twice daily for 21 days (continuous dosing) as well 
as capecitabine 1000 mg/m2 by mouth twice daily for 
14/21 days as were determined to be safe doses during the 
phase I portion of the study. Doses to be administered will 
be determined in the Phase 1 portion of the study. Pre- and 
post-treatment (post-treatment being day 10-15) blood 
samples will be obtained for assessment of glutaminase 
activity. Baseline tissue biopsies and a day 10-15 tissue 
biopsy will be obtained to assess tissue glutaminase 
activity and UPP1 gene expression, glutathione levels, 
nucleotide levels as well as for whole exome sequencing, 
RNA seq and for the production of organoids and 5FU 
incorporation into RNA and DNA. Blood and tissue 
specimens will be collected the same day. Post-15 day 
treatment pharmacokinetics will be obtained and 
correlated with other laboratory assessments. Patients will 


CASE 1216 
 
 
 
Page 4  
 
 
Version date: 12/16/2020 
 
 
undergo a disease assessment with CT imaging of the chest, 
abdomen and pelvis following 3 cycles (9 weeks) of 
treatment. 
 
3.2 
3.2 
Study design for phase II component 
 
The phase II portion of the study is a single arm 
design, assessing the disease control rate of 
combination therapy with CB-839 and capecitabine 
chemotherapy in patients with metastatic PIK3CA 
mutant colorectal cancer who have developed 
fluoropyrimidine resistance. Patients will receive 
combination therapy with CB-839 and capecitabine 
for 21 day cycles and will remain on treatment until 
either disease progression, development of 
unacceptable toxicity or discontinuation per 
patient/physician preference. Patients will receive 
CB-839 800 mg orally twice daily for 21 days 
(continuous administration) and capecitabine 1000 
mg/m2 orally twice daily for 14/21 days as was 
determined during the phase I portion of the study. 
Patients will undergo blood and tissue sampling at 
baseline and 10-15 days post-treatment for 
assessment of glutaminase activity. Tissue specimens 
will also be assessed for changes in nucleotide levels 
as well as for a whole exome analysis, an RNA seq 
analysis and for the generation of organoids. Patients 
will undergo a CT of the chest, abdomen and pelvis 
following 3 cycles of therapy (every 9 weeks). 
 
 
3.2 
3.2 
Number of Patients 
 
A total of 9-24 patients will be enrolled in the phase I 
portion of this trial and a total of 18-40 patients will be 
enrolled in the phase II portion of this trial. 
4.2.1 
Patients must have histologically or cytologically 
confirmed, metastatic colorectal cancer. PIK3CA 
mutant status must be confirmed by tumor 
sequencing conducted in a CLIA certified lab.  Genetic 
sequencing performed on tissue specimens or 
circulating DNA from peripheral blood samples are 
allowed.  Abnormalities in PIK3CA considered to be 
variants of unknown significance (VUS) will not be 
eligible 


CASE 1216 
 
 
 
Page 5  
 
 
Version date: 12/16/2020 
 
 
4.2.3 
Patients must have received and progressed on 
fluoropyrimidine or fluoropyrimidine based therapy.  
Patients must have a history of disease progression 
during treatment with fluoropyrimidine, or within 3 
months of a dose of a fluoropyrimidine-containing 
regimen. Patients who have only progressed during 
treatment holiday of 3 months or greater will not be 
eligible.  Receipt of either oxaliplatin or irinotecan in 
combination with a fluoropyrimidine is required in 
the front line setting unless either of these agents are 
otherwise contraindicated in the opinion of the 
treating physician, in which case a fluoropyrimidine 
only may be used. Prior regorafenib or TAS-102 
therapy is not required. 
4.2.6 
▪  Serum creatinine within the normal institutional 
limits below the institutional upper limit of normal.  
 
10.1.3 
The pre-treatment biopsy must be done after the 4-
week washout from previous systemic therapy. 
 
Four core biopsies will be obtained for each patient 
during each biopsy. 
 
Two cryovials should contain approximately 1.5 ml 
sterile PBS for placement of a fresh specimen and 
then will be placed on wet ice (see section 10.4 for 
further details). 
 
11.4 
c Tumor biopsy may be done up to 14 days prior to 
initiation of treatment. Please allow 28 days washout 
from prior systemic therapy prior to pre-treatment 
biopsy. 
14.1.1 
Phase II: Progression free survival (FPS) on 
combination CB-839 and capecitabine determined by 
clinical assessment and Disease control rate (inclusive 
of CR, PR or SD) as assessed by RECIST criteria of 
combination CB-839 and capecitabine chemotherapy 
in patients with metastatic PIK3CA mutant colorectal 
cancer who are refractory to fluoropyrimidine based 
therapy. Progression free survival is defined as the time 
from randomization to documented progression or 
death without progression. 
14.1.2 
Phase II: Response rate as assessed by RECIST criteria 
of combination CB-839 and capecitabine 
chemotherapy in Progression free survival of patients 


CASE 1216 
 
 
 
Page 6  
 
 
Version date: 12/16/2020 
 
 
with metastatic PIK3CA mutant colorectal cancer who 
are refractory to fluoropyrimidine based therapy. 
Progression free survival is defined as the time from 
randomization to documented progression or death 
without progression.  
14.2 
In the phase II component of this study, the primary 
endpoint is progression free survival at 6 months 
disease control rate (which is to include patients with 
a complete response, partial response or stable 
disease), with a null hypothesis of 185% vs. a target 
of 3620%. Employing a 2-stage design, and assuming 
80% power and a 0.05 significance level, 4029 total 
patients will be required with 1810 in the first stage 
and the probability of early stopping if the null 
hypothesis is correct (<3/18 patients with stable 
disease at 6 months 0/10 responses) will be 
0.5890.5987. If 3 or more patients in 18 has stable 
disease or better at 6 monthsat least 1 patient in 10 
has disease control, an additional 2219 patients will 
be treated (total of 4029 patients). If antitumor 
activity is identified in the PIK3CA mutant population, 
we will consider amending the phase 2 trial to assess 
an additional cohort of patients with wild-type 
PIK3CA. The statistical considerations will follow the 
same rules as in the original mutant cohort. Response 
rate will be determined using RECIST criteria.  
 
14.4 
All correlative studies will be performed in biospecimens 
from the intent to treat population of 10-29 patients from 
the phase II portion of the study. Pre- and post-treatment 
tumor samples from the same patients will be used for 
assessments, except glutaminase activity, which will be 
performed on post-treatment samples only (tumor samples 
and 
platelet 
samples). 
All 
correlative 
continuous 
measurements will be summarized using mean +/- SEM, 
range and median; all categorical measurements will be 
summarized using frequencies and proportions. Change in 
these measurements in tumors before and after therapy will 
be assessed using paired Wilcoxon tests. Unpaired Wilcoxon 
tests will be used for assessment of glutaminase actively in 
post-treatment samples only. Assuming a maximum of 29 
patients (0.05 significance level and 80% power), for the 
paired Wilcoxon tests we can detect normalized differences 
of 5.4 to 21.6% for standard deviations of the difference 
between pairs ranging from 0.10 to 0.40. Correlations of 
plasma trough levels and platelet glutaminase activity will 
be calculated using Spearmans correlation coefficients. 
Assuming a maximum of 29 patients, 0.05 significance level, 


CASE 1216 
 
 
 
Page 7  
 
 
Version date: 12/16/2020 
 
 
we have >95% power to detect a Spearmans correlation 
coefficient of 0.60 or higher. 
 
All correlative studies will be performed in 
biospecimens from the intent to treat population of 
18-40 patients from the phase II portion of the study. 
Pre- and post-treatment tumor samples from the 
same patients will be used for assessments, except 
glutaminase activity, which will be performed on 
post-treatment samples only (tumor samples and 
platelet samples). All correlative continuous 
measurements will be summarized using mean +/- 
SEM, range and median; all categorical measurements 
will be summarized using frequencies and 
proportions. Change in these measurements in 
tumors before and after therapy will be assessed 
using paired Wilcoxon tests. Unpaired Wilcoxon tests 
will be used for assessment of glutaminase actively in 
post-treatment samples only.  Assuming a maximum 
of 40 patients (2-sided test with 0.05 significance level 
and 80% power), for the paired T-test we can detect 
normalized differences of 4.5 to 18.2% for standard 
deviations of the difference between pairs ranging 
from 0.10 to 0.40. Correlations of plasma trough levels 
and platelet glutaminase activity will be calculated 
using Spearman correlation coefficients. Assuming a 
maximum of 40 patients, 2-sided test with 0.05 
significance level, we have >98% power to detect a 
Spearman correlation coefficient of 0.60 or higher. 
 
Whole exome sequencing and RNA sequencing will be 
performed on pre and post treatment tissue samples 
and compared for differences for all patients (n=2940
patients maximum).  All of these analyses are 
exploratory, hence no power calculations are shown.  
 
14.5 
In the phase II portion of the study, disease control 
rate is the primary endpoint and the study will be 
conducted using a Simon two-stage design. As 
outlined in section 14.2, a minimum of 1810 and a 
maximum of 4029 patients will be required.  


CASE 1216 
 
 
 
Page 8  
 
 
Version date: 12/16/2020 
 
 
14.6 
Accrual for this study will occur at the University 
Hospitals Seidman Cancer Center and the Cleveland 
Clinic Taussig Cancer Institute, both of the Case 
Comprehensive Cancer Center.   For the phase I 
portion of the trial, we anticipate that it will take 
approximately 6-7 months to complete this portion of 
the trial if all doses levels need to be evaluated. For 
the phase II portion of the study, between the two 
institutions, 719 colorectal cancer patients are seen 
annually. We estimate that approximately 30% of our 
patients will have measureable, metastatic disease 
and that 15% of patients will have a PIK3CA 
mutation, resulting in 32 eligible patients per year. 
Based on our proposed sample size of 18-40 10 29 
patients, we anticipate that it will take approximately 
18 months one year to accrue to the phase II portion 
of the trial.  
 
 
 
Protocol 
Date 
Section 
Change 
01/30/18 
Title page 
David Bajor, MD is replacing Jennifer Eads, MD as the PI 
 
Title page 
All sub-investigators have been removed as they are listed on the delegation 
log instead 
 
Title page 
The Study Coordinators for Phase 1 and Phase 2 have been added 
 
Protocol 
Summary 
Phase II Primary Objective: 
 
To determine the response disease control rate of combination CB-839 and 
capecitabine chemotherapy in patients with metastatic PIK3CA mutant 
colorectal cancers who are refractory to fluoropyrimidine based therapy. 


CASE 1216 
 
 
 
Page 9  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
Protocol 
Summary 
Phase II Correlative Objectives: 
 
To determine the change in UPP1 gene expression in tumor specimens 
following treatment with CB 839 and capecitabine chemotherapy in patients 
with metastatic PIK3CA mutant colorectal cancer who are refractory to 
fluoropyrimidine based therapy. 
 
To determine the change in glutathione levels in tumor specimens following 
treatment with CB 839 and capecitabine chemotherapy in patients with 
metastatic PIK3CA mutant colorectal cancer who are refractory to 
fluoropyrimidine based therapy. 
 
To determine genomic changes in both DNA and RNA in tumor specimens 
following treatment with CB-839 and capecitabine chemotherapy in patients 
with metastatic PIK3CA mutant colorectal cancer who are refractory to 
fluoropyrimidine based therapy. 
 
To determine the level of 5 fluorouracil incorporation into RNA and DNA in 
tumor specimens following treatment with CB 839 and capecitabine 
chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer 
who are refractory to fluoropyrimidine based therapy. 
 
To generate organoids from patient tissue biopsies obtained prior to and 
following treatment in patients treated with CB-839 and capecitabine 
chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer 
who are refractory of fluoropyrimidine based therapy. 
 
 
Protocol 
Summary 
Phase II: Patients will be treated with CB-839 800 mg by mouth twice daily 
for 21 days (continuous dosing) as well as capecitabine 1000 mg/m2 by mouth 
twice daily for 14/21 days as were determined to be safe doses during the 
phase I portion of the study. Doses to be administered will be determined in 
the Phase 1 portion of the study. Pre- and post-treatment (post-treatment being 
day 10-15) blood samples will be obtained for assessment of glutaminase 
activity. Baseline tissue biopsies and a day 10-15 tissue biopsy will be 
obtained to assess tissue glutaminase activity and UPP1 gene expression, 
glutathione levels, nucleotide levels as well as for whole exome sequencing, 
RNA seq and for the production of organoids and 5FU incorporation into RNA 
and DNA. Blood and tissue specimens will be collected the same day. Post-
15 day treatment pharmacokinetics will be obtained and correlated with other 
laboratory assessments. Patients will undergo a disease assessment with CT 
imaging of the chest, abdomen and pelvis following 3 cycles (9 weeks) of 
treatment. 
 
Abbreviati
ons 
PBS: phosphate buffered saline 
TRSRPC: Translational Research and Pharmacology Core Shared Resource  
UHCMC: University Hospitals Case Cleveland Medical Center 


CASE 1216 
 
 
 
Page 10  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
Table 
of 
Contents 
Section 10.0 
10.2 Pharmacokinetic analysis of CB839 UPP1 Gene Expression 
10.3 Pharmacokinetic analysis of CB839 Additional pharmacodynamic 
analyses 
10.4 Generation of organoids 
 
1.2 
CB-
839 
CB 839 treatment induces UPP1, an enzyme that plays an important role in 
converting 5 fluorouracil to an active compound 
 
The mechanism of cytotoxicity of 5 fluorouracil has been ascribed to the mis
incorporation of fluoronucleotides into RNA and DNA and to the inhibition 
of the nucleotide synthetic enzyme thymidylate synthase (13). To interrogate 
the molecular mechanisms by which CB 839 enhances the tumor inhibitory 
effect of 5 fluorouracil, we noted that our gene expression analysis shows that 
glutamine deprivation up regulates uridine phosphorylase 1 (UPP1) in 
PIK3CA mutant cells (Fig 3). UPP1 
facilitates conversion of 5 FU to FdUTP and 
FUTP (14), which can be incorporated into 
DNA and RNA. It has been shown that UPP1 
/  embryonic stem cells are much more 
resistant 
to 
5 FU 
(15), 
whereas 
overexpression 
of 
UPP1 
enhances 
cytotoxicity of 5 FU (16). We examined 
UPP1 gene expression in the isogenic 
HCT116 PIK3CA mut/  and WT/  cell lines. 
CB 839 induced more UPP1 in PIK3CA 
mut/  cells than in the WT/  cells. Similar 
results were observed in the DLD1 PIK3CA 
mut/  and WT/  cell lines. We therefore 
hypothesize that in addition to blocking 
glutamine metabolism, CB 839 treatment 
also induces UPP1 gene expression and thus 
enhances 5 FU toxicity. 
 
Fig. 3. CB-839 induces 
more UPP1 in PIK3CA-
mutant 
cells. 
(A) 
HCT116 PIK3CA -/WT 
and mut/- cell lines were 
treated with 3 μM CB 839 
for the indicated times. 
RNAs were extracted for 
RT-PCR analyses. MWM: 
molecular weight marker. 
(B) Knockout of UPP1 in 
HCT116 cells. Genomic 
fragments encompassing 
the CRISP cutting site (68 
bp) 
of 
parent 
and 
knockout clones. 


CASE 1216 
 
 
 
Page 11  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
 
Combination of CB-839 and 5-fluorouracil depletes cellular dTTP levels 
 
Given that glutamine is a precursor for 
nucleotide synthesis and that 5-FU is a 
thymidylate synthase inhibitor, we set to 
determine how the drug combination 
impacts cellular dTTP levels. As shown in 
Fig. 3, either drug alone significantly 
reduced amounts of dTTP, whereas the 
combination of CB-839 and 5-FU nearly 
completely depleted cellular dTTP. These 
data suggest that CB-839 enhances the 
cytotoxicity of 5-FU by further depleting 
cellular dTTP.   
 
Fig. 3. Combination CB-839 
and 5-FU depletes cellular 
dTTP levels. HCT116 cells 
were 
treated 
with 
the 
indicated 
drugs. 
Cellular 
dTTP amounts were measured 
by LC-MS/MS.  


CASE 1216 
 
 
 
Page 12  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
1.4 
Rationale for clinical and correlative studies 
 
It has been demonstrated that CB-839, via targeting glutaminase, inhibits 
xenograft growth in 2 of 2 PIK3CA mutant colon cancer test xenograft models 
but does not inhibit growth in PIK3CA WT models, supporting that there is 
an addiction of PIK3CA mutant colorectal cancers to glutamine metabolism. 
Furthermore, CB-839 plus 5-FU shrinks 2 of 2 PIK3CA mutant xenografts 
that both grow through maximally tolerated doses of 5-FU alone. Based on 
these findings, we propose to test responses of the CB-839 plus 5 FU and 
fluoropyrimidine combination in 5 FU fluoropyrimidine resistant human 
patients. Based on our preclinical mechanistic studies described above, we 
propose a phase I clinical trial to determine the in vivo pharmacodynamic 
effects of CB 839 in patients with metastatic colorectal cancer who harbor a 
PIK3CA mutation, and to determine the maximum tolerated dose (MTD) and 
recommended phase 2 dose (RP2D) and dose limiting toxicities of CB-839 
plus capecitabine in patients with advanced solid tumors. PIK3CA mutant 
metastatic colorectal cancer. We will test the hypothesis that CB 839 results 
in reduced glutaminase activity in tumors and platelets, as well as induction 
of UPP1 expression in tumors, with trough plasma levels associated with these 
pharmacodynamic effects. The data derived from this trial will be used for a 
subsequent phase II clinical trial where we will estimate the antitumor activity 
and pharmacodynamic effects of CB-839 and capecitabine in patients with 
PIK3CA mutant colorectal cancers that are resistant to fluoropyrimidine 
therapy. We hypothesize that CB-839 in combination with capecitabine will 
overcome fluoropyrimidine resistance and that the addition of capecitabine to 
CB-839 will result in the inhibition of glutaminase in tumors and platelets and 
the reduction in of glutathione and nucleotide levels in tumors, the increase in 
5-FU incorporation into RNA and DNA in tumors and the induction of UPP1 
gene expression in tumors. Genomic abnormalities on the DNA and RNA level 
will also be explored via a whole exome sequencing analysis and an RNA seq 
analysis. 
 
As of January 2018, the phase I portion of the study has been fully accrued. A 
total of 16 patients were treated on the study and we were able to assess all of 
the four planned dose levels. No dose limiting toxicities were observed and we 
have therefore determined that the recommended phase II dose be CB-839 
800 mg by mouth twice daily continuously and capecitabine 1000 mg/m2 
orally twice daily on days 1-14 of a 21 day treatment cycle 
 


CASE 1216 
 
 
 
Page 13  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
2.0 
OBJECTIVES 
 
The overall objectives for this study are to 1) determine the recommended 
phase II dose (RP2D) of CB-839 and capecitabine in patients with advanced 
solid tumors who have no further treatment options or patients for whom 
single agent capecitabine is an acceptable treatment regimen and 2) to 
determine the antitumor activity of CB-839 and capecitabine chemotherapy in 
patients with metastatic PIK3CA mutant colorectal cancer who are refractory 
to fluoropyrimidine based therapy. The phase I portion of this study will also 
determine the dose-limiting toxicities of this treatment regimen as well as the 
pharmacokinetics. In the phase II portion of this study, the pharmacodynamic 
effects of CB-839 and capecitabine will be evaluated using multiple biomarker 
studies including glutaminase activity level, and UPP1 gene expression, 
glutathione levels, nucleotide levels as well as a whole exome sequencing 
analysis and an RNA seq analysis. and incorporation of 5 FU into RNA and 
DNA. We hypothesize that we will observe a reduction in glutaminase activity 
in both tumors and platelets and , induction of UPP1 gene expression in 
tumors, a reduction in glutathione levels and nucleotide levels following 
treatment. The whole exome and RNA seq analyses will be exploratory.  and 
an increase in the incorporation of 5 FU into RNA and DNA. The generation 
of organoids from tumor biopsy specimens both prior to and following 
treatment will also be exploratory and will be used for further potential studies 
as additional preclinical information becomes available. 
 
 
2.1 
Primary Objective  
 
2.1.2 - Phase II: To determine the response disease control rate of combination 
CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA 
mutant colorectal cancers who are refractory to fluoropyrimidine based 
therapy. 


CASE 1216 
 
 
 
Page 14  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
2.3 
Correlative Objective(s) 
 
 
2.3.1 
Phase II 
 
 
To determine the change in UPP1 gene expression in tumor specimens 
following treatment with CB 839 and capecitabine chemotherapy in 
patients with metastatic PIK3CA mutant colorectal cancer who are 
refractory to fluoropyrimidine based therapy. 
 
 
To determine the change in glutathione levels in tumor specimens 
following treatment with CB 839 and capecitabine chemotherapy in 
patients with metastatic PIK3CA mutant colorectal cancer who are 
refractory to fluoropyrimidine based therapy. 
 
 
To determine genomic changes in both DNA and RNA in tumor 
specimens following treatment with CB-839 and capecitabine 
chemotherapy in patients with metastatic PIK3CA mutant colorectal 
cancer who are refractory to fluoropyrimidine based therapy. 
 
 
To determine the level of 5 fluorouracil incorporation into RNA and 
DNA in tumor specimens following treatment with CB 839 and 
capecitabine chemotherapy in patients with metastatic PIK3CA 
mutant colorectal cancer who are refractory to fluoropyrimidine based 
therapy. 
 
To generate organoids from patient tissue biopsies obtained prior to 
and following treatment in patients treated with CB-839 and 
capecitabine chemotherapy in patients with metastatic PIK3CA 
mutant colorectal cancer who are refractory of fluoropyrimidine 
based therapy. 
 


CASE 1216 
 
 
 
Page 15  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
3.2 
Study design for phase II component 
 
The phase II portion of the study is a single arm design, assessing the 
antitumor activity disease control rate of combination therapy with CB-839 
and capecitabine chemotherapy in patients with metastatic PIK3CA mutant 
colorectal cancer who have developed fluoropyrimidine resistance. Patients 
will receive combination therapy with CB-839 and capecitabine for 21 day 
cycles and will remain on treatment until either disease progression, 
development of unacceptable toxicity or discontinuation per patient/physician 
preference. Patients will receive CB-839 800 mg orally twice daily for 21 days 
(continuous administration) and capecitabine 1000 mg/m2 orally twice daily 
for 14/21 days as was determined during the phase I portion of the study. 
Doses to be administered will be determined during the phase I portion of the 
study. Patients will undergo blood and tissue sampling at baseline and 10-15 
days post-treatment for assessment of glutaminase activity. Tissue specimens 
will also be assessed for changes in UPP1 gene expression, glutathione levels, 
nucleotide levels as well as for a whole exome analysis, an RNA seq analysis 
and for the generation of organoids. and 5 FU incorporation into DNA and 
RNA. Patients will undergo a CT of the chest, abdomen and pelvis following 
3 cycles of therapy (every 9 weeks). 
 
 
5.0 
REGISTRATION 
 
All patients will be registered through University Hospitals Case Cleveland 
Medical Center/Seidman Cancer Center and will be provided a study number 
by contacting the study coordinator. 
 
 
6.1.2 
6.1.2 
Phase II: Patients will receive combination therapy with CB-839 and 
capecitabine for 21 day cycles and will remain on treatment until 
either disease progression, development of unacceptable toxicity or 
discontinuation per patient/physician preference. Patients will receive 
CB-839 800 mg orally twice daily for 21 days (continuous 
administration) and capecitabine 1000 mg/m2 orally twice daily for 
the first 14/21 days as was determined during the phase I portion of 
the study. Doses to be administered will be determined during the 
phase I portion of the study. Additionally, given that there are ongoing 
studies, the safety profile will continue to be monitored in these 
studies and the RP2D could be adjusted based on emerging safety and 
tolerability data. 
 
 
6.2 
General Agent Administration Guidelines 
 
CB-839 will be supplied as 200 mg capsules tablets.  
 


CASE 1216 
 
 
 
Page 16  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
6.2.1 
6.2.1 
CB-839 Administration 
 
CB-839 will be given orally twice daily in combination with capecitabine 
chemotherapy during a 21 day treatment cycle. Administration of CB-839 will 
be continuous throughout the 21 day treatment cycle. During the phase I 
component of the study, the dose of CB-839 administered will be dictated by 
the dose escalation table. During the phase II component of the study, the dose 
of CB-839 administered will be 800 mg by mouth twice daily as was 
determined during the phase I portion of the study determined during the 
phase 1 component of the study. 
 
 
6.2.2 
 
Capecitabine Administration 
 
Patients will receive capecitabine chemotherapy orally by mouth twice daily 
for the first 14 days of each 21 day treatment cycle. During the phase I 
component of the study, the dose of capecitabine administered will be dictated 
by the dose escalation table. During the phase II component of the study, the 
dose of capecitabine administered will be 1000 mg/m2 twice daily on days 1-
14 of a 21 day treatment cycle as was that determined during the phase I 
component of the study. 
 
 
8.5.1 
SAE Reporting Requirements 
 
 
 
All SAEs should be reported to the study principal investigator: 
 
 
 
Jennifer Eads David Bajor, MD 
 
 
Phone: 
 
 
 
 
 


CASE 1216 
 
 
 
Page 17  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
9.1 
CB-839 
 
  
Name of Agent: CB-839 
 
Other Names:   
NA 
 
Product description: CB-839 is provided as 200 mg opaque Swedish orange 
gelatin capsules or as tablets that are manufactured, packaged, and labeled 
according to current Good Manufacturing Practices (cGMP). 
 
Storage requirements: CB-839 capsules should be stored as will be indicated 
on the study drug label - this should be in a clinical site pharmacy at controlled 
room temperature, defined as between 20° and 25°C +/- 5°C (i.e. between 15° 
and 30°C (59° to 86°F). at room temperature between 15˚ 30˚C (59˚ 86˚F). 
Stability studies being carried out on the phase I clinical supplies support 
storage for CB-839 capsules for at least 24 months at room temperature. CB-
839 HCl tablets must be stored in a secure area with controlled access and 
separately from commercially available and other investigational drugs, 
preferably in a separate location. Any breach of investigational product 
storage conditions including temperature excursions outside the range 15° 
and 30°C must be reported to the Sponsor upon detection and the IP in 
question must be quarantined until the Sponsor authorizes usage or otherwise. 
Patients will be instructed to store medication according to storage conditions 
noted on the label, out of reach of children or other cohabitants. 
 
 
 
Packaging and labeling: Tablets and capsules are packaged in white plastic 
bottles with a label on the outside identifying the investigational product, 
capsule strength, storage conditions, investigational drug supplier, lot number 
and date of manufacture. Each bottle is sealed with a tamper-evident seal and 
a child-proof cap. Each bottle contains fifty (50) tablets or capsules. 
 


CASE 1216 
 
 
 
Page 18  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
10.1.3 
Collection of Specimens 
 
During the phase II component of the study, patients will undergo either CT 
or US guided biopsy of a metastatic focus both prior to the initiation of 
treatment and 10-15 days following initiation of treatment. The pre-treatment 
biopsy may be performed up to 14 days prior to the initiation of treatment. 
 
Tumor Biopsies: Patients will undergo biopsy in the University Hospitals 
Case Cleveland Medical Center (UHCMC) Department of Radiology by study 
interventional radiologist, Dr. Dean Nakamoto. If being treated at the Taussig 
Cancer Institute (TCI) of the Cleveland Clinic, patients will undergo biopsy 
in the Cleveland Clinic Department of Radiology. If being treated at the Weill 
Cornell College of Medicine, patients will undergo biopsy in the Weill Cornell 
College of Medicine Department of Radiology. Use of CT or US guidance for 
each biopsy will be per the discretion of the physician performing the biopsy 
and the same metastatic focus of tumor will be biopsied at baseline and 10-15 
days following initiation of treatment. If for whatever reason the same lesion 
cannot be biopsied, a second lesion may be biopsied but this must be noted 
and recorded. Biopsies will be conducted according to standard practice. 
Three core biopsies will be obtained for each patient during each biopsy. Fine 
needle aspiration biopsies are NOT appropriate. Three RNA cryovials will be 
labeled with the date, patient initials, patients study number and vial number. 
All study personnel, particularly those handling RNA cryovials, must wear 
clean gloves. Each of the three core biopsies will be placed in its own cryovial. 
One cryovial should contain approximately 1.5 ml sterile PBS for placement 
of a fresh specimen and then will be placed on wet ice (see section 10.4 for 
further details). The remaining two The three cryovials will immediately be 
placed in dry ice or liquid nitrogen. Biopsies collected at UHCMC will be and 
transported to the Case Comprehensive Cancer Center, Translational Research 
Shared Resources  and Pharmacology Core Facility for the Wang lab to pick 
up processing. Biopsies collected at TCI will be transported to the Cleveland 
Clinic Central Biorepository for the Wang lab to pick up. Biopsies collected 
at Weill Cornell College of Medicine will be transported to the Laboratory of 
Dr. Manish Shah for processing. The frozen specimens will be processed 
individually with the second and third specimens being processed only if 
insufficient nucleic acid is recovered or if histologic review identifies the 
presence of necrotic tumor in the first specimen. The remaining fresh frozen 
specimens will be stored for later use.  
 
Platelets: Approximately 24ml of whole blood will be collected via peripheral 
venipuncture into 3, 10 ml yellow top ACD-A (Acid Citric Dextrose (ACD) 
Solution A) tubes dextrose/citrate for analysis of glutaminase activity in 
platelets. Whole blood samples will be collected on wet ice and transported to 
the Translational Research Share Resource and Pharmacology Core Facility 
for processing and storage. Specimens will be collected at the time of the pre-
treatment tissue biopsy as well as 10-15 days following initiation of treatment 
(obtained on the same day as the tissue biopsy). 
 


CASE 1216 
 
 
 
Page 19  
 
 
Version date: 12/16/2020 
 
 
 
10.1.4 
Handling of Specimens at UHCMC 
 
The vial containing PBS will be placed on wet ice (>5 lb), and the other two 
cryovials will immediately be placed in dry ice (>5 lb). Personnel from the 
Case Comprehensive Cancer Center, Translational Research Shared 
Resource will then be contacted (see below) for transportation, tracking and 
storage. Upon acquisition, TRSR personnel will contact the Wang Lab to pick 
up the PBS containing vial for organoid culture and analyses as described in 
the Laboratory Manual and the frozen specimens for storing at -80°C. 
 
Specimens will be transported on either dry ice or liquid nitrogen (tumor 
biopsies) from the Interventional Radiology suite of either UHCMC or the 
TCI to the Translational Research and Pharmacology Core Facility (TRPC) 
for further processing. Whole blood will be transported on wet ice (platelets) 
from the Coleman Research Unit (UHCMC) or from either the outpatient 
clinic area or Clinical Research Unit (CRU) of the TCI, also to the TRPC. All 
specimens collected at TCI will be collected as outlined and will be delivered 
by courier to the TRPC. TRPC personnel will log collected specimens for each 
patient into the OnCore database using the assigned patient and specimen 
numbers assigned at the time of study enrollment and tissue acquisition 
respectively.  
 
Translational Research Shared Resource Contact Information (UH Seidman) 
and Pharmacology Core 
ATTN: Erin Hohler 
University Hospitals Cleveland Case Medical Center 
 
Wang Lab Contact Information: 
Yiqing Zhao 
 
 
 
 
John Wang 
 
 
 
 
Wolstein Research Building 
 
2013 Cornell Road 
Cleveland, OH 44106 
 
10.1.4.2 Handling of Specimens at TCI 
The fresh biopsy vial (containing PBS) will be placed on wet ice (>5 lb), and 
the other two cryovials will immediately be placed in dry ice (>5 lb). 
Personnel from the Cleveland Clinic Central Biorepository will then be 
contacted (see below) for transportation, tracking and storage. Upon 
acquisition, the Cleveland Clinic Central Biorepository personnel will contact 
the Wang Lab to pick up the PBS containing vial for organoid culture and 
analysis as described in the Laboratory Manual and the frozen specimens for 
storing at -80°C. 




CASE 1216 
 
 
 
Page 21  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
10.1.5 
Analytical Laboratory 
 
Personnel in the Tissue Resources Core Facility Wang lab will process fresh 
frozen specimens. One core biopsy per patient will be divided on a metal plate 
that is kept cold with dry ice. Additional biopsies will be archived and used 
on an as needed basis (see section 10.1.3). Each biopsy will be sectioned into 
5 sections. Light microscopy to confirm the histologic presence of viable 
cancer tissue will be conducted on peripheral sections (H&E staining). Tissue 
sections immediately adjacent to and internal to the microscopy confirmed 
sections will be used for subsequent pharmacodynamic analysis (glutaminase 
activity, DNA extraction, RNA extraction) (22). 
 
Wang Lab Contact Information: 
Yiqing Zhao  
 
 
 
  
John Wang 
 
  
 
 
Wolstein Research Building 
 
2013 Cornell Road 
Cleveland, OH 44106 
 
 
 
 
 
 
 
 
 
 
 
 
Histologically confirmed fresh frozen specimens will be used by the 
Translational Research Shared Resource or the Wang Lab and Pharmacology 
Core for conduct of the glutaminase assay. 
 
Translational Research Shared Resource and Pharmacology Core 
ATTN: Erin Hohler 
University Hospitals Cleveland Case Medical Center 
 


CASE 1216 
 
 
 
Page 22  
 
 
Version date: 12/16/2020 
 
 
 
10.2 
10.2 
UPP1 Gene Expression 
 
The purpose of assessing the change in UPP1 gene expression is to determine 
if administration of CB 839 results in an upregulation of UPP1 gene 
expression in post treatment biopsy specimens as compared to prior to CB
839 treatment. UPP1 gene expression will be assessed using RT PCR. 
 
10.2.1  Background  
 
The mechanism of cytotoxicity of 5 fluorouracil has been ascribed to the mis
incorporation of fluoronucleotides into RNA and DNA and to the inhibition 
of the nucleotide synthetic enzyme thymidylate synthase (13). To interrogate 
the molecular mechanisms by which CB 839 enhances the tumor inhibitory 
effect of 5 fluorouracil, we noted that our gene expression analysis shows that 
glutamine deprivation up regulates uridine phosphorylase 1 (UPP1) in 
PIK3CA mutant cells. UPP1 facilitates conversion of 5 FU to FdUTP and 
FUTP (14), which can be incorporated into DNA and RNA. It has been shown 
that UPP1 /  embryonic stem cells are much more resistant to 5 FU (15), 
whereas overexpression of UPP1 enhances cytotoxicity of 5 FU (16). We 
examined UPP1 gene expression in the isogenic HCT116 PIK3CA mut/  and 
WT/  cell lines. CB 839 induced more UPP1 in PIK3CA mut/  cells than in 
the WT/  cells. Similar results were observed in the DLD1 PIK3CA mut/  and 
WT/  cell lines. We therefore hypothesize that in addition to blocking 
glutamine metabolism, CB 839 treatment also induces UPP1 gene expression 
and thus enhances 5 FU toxicity. 
 
10.2.2  Rationale for Analysis 
 
Demonstration of upregulation of UPP1 gene expression in tumor specimens 
following treatment with single agent CB 839 as compared to prior to 
initiation of treatment will provide a pharmacodynamic marker indicating that 
CB 839 up regulates UPP1 via the inhibitory effect of CB 839 on glutamine 
metabolism in PIK3CA mutant colorectal cancers. See section 14.0 for 
statistical plan. 
 
10.2.3  Collection of Specimens 
 
During the phase II component of the study, the first 10 patients will undergo 
either CT or US guided biopsy of a metastatic focus both prior to the initiation 
of treatment and 10-15 days following initiation of treatment. The pre-
treatment biopsy may be performed up to 14 days prior to the initiation of 
treatment. 
 
Tumor Biopsies: Patients will undergo biopsy in the University Hospitals 
Case Medical Center (UHCMC) Department of Radiology by study 
interventional radiologist, Dr. Dean Nakamoto. If being treated at the Taussig 
Cancer Institute (TCI) of the Cleveland Clinic, patients will undergo biopsy 
in the Cleveland Clinic Department of Radiology. Use of CT or US guidance 
for each biopsy will be per the discretion of the physician performing the 
biopsy and the same metastatic focus of tumor will be biopsied at baseline and 
10 15 days following initiation of treatment. Biopsies will be conducted 


CASE 1216 
 
 
 
Page 23  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
according to standard practice. Three core biopsies will be obtained for each 
patient during each biopsy. Fine needle aspiration biopsies are NOT 
appropriate. Three RNA cryovials will be labeled with the date, patient 
initials, patients study number and vial number. All study personnel, 
particularly those handling RNA cryovials, must wear clean gloves. Each of 
the three core biopsies will be placed in its own cryovial. The three cryovials 
will immediately be placed in dry ice or liquid nitrogen and transported to the 
Case 
Comprehensive 
Cancer 
Center, 
Translational 
Research 
and 
Pharmacology Core Facility for processing Specimens will be processed 
individually with the second and third specimens being processed only if 
insufficient nucleic acid is recovered or if histologic review identifies the 
presence of necrotic tumor in the first specimen. The remaining fresh frozen 
specimens will be stored for later use.  
 
10.2.4  Handling of Specimens 
 
See section 10.1.4 for handling of specimens. 
 
10.2.5  Analytical Laboratory 
 
UPP1 gene expression will be conducted in the laboratory of Dr. Zhenghe 
Wang. 
Dr. Zhenghe Wang 
Wolstein Research Building 
Case Western Reserve University 
2103 Cornell Road, WRB 
 
Cleveland, OH 44106 
 
 
 
  
 
 
 
10.2.6  Methods 
Fresh frozen tumor tissue will be obtained, de identified, from the TRPC 
facility. Total RNAs will be isolated using the Qiagen RNeasy Kit and 
reverse transcription will be performed using the first strand synthesis kit from 
Invitrogen. 
UPP1 
will 
be 
amplified 
using 
primer 
pairs 
AACAGAGCAGGCAGTGGATA and ATACGCCTGCTTGTCCTTCT.   
 
 
10.2.2 
10.2.3.2  
Rationale for Analysis 
 
Pharmacokinetic analysis of patients receiving CB-839 at each dose level will 
allow for correlations to be made between trough levels of CB-839 and both 
glutaminase activity level and UPP1 gene expression. 
 
 


CASE 1216 
 
 
 
Page 24  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
10.3 
10.34 Additional Pharmacodynamic Analyses
An evaluation of glutathione levels, nucleotide levels as well as a whole exome 
analysis and an RNA seq analysis and the incorporation of 5 fluorouracil into 
RNA and DNA will be conducted on baseline and post-treatment tissue 
biopsies to determine the pharmacodynamic effect of CB-839 and 
capecitabine on PIK3CA mutant colorectal cancer. This will be conducted 
during the phase II portion of the trial.  
10.3.4.1 Background and Rationale 
We have hypothesized that CB 839 treatment will induce UPP1 gene 
expression (section 10.2.1) in PIK3CA mutant colorectal cancers. UPP1 
facilitates the conversion of 5 FU to FdUTP and FUTP (14), which can be 
incorporated into both RNA and DNA. We therefore hypothesize that in 
addition to blocking glutamine metabolism, CB 839 treatment will also 
induce UPP1 gene expression, subsequently leading to enhanced 5 FU 
toxicity and greater incorporation of 5 FU into RNA and DNA.  
 
Genome wide changes are anticipated to occur with the administration of CB-
839 and capecitabine on both the DNA and RNA level. We will therefore use 
tumor tissue to determine changes occurring in DNA with pre- and post-
treatment assessments of the genome via whole genome sequencing and also 
changes in tumor tissue at the expression level by performing pre- and post-
treatment RNA seq analyses. 
 
Glutamine is converted to glutamate by glutaminase where glutamate can then 
act as a substrate for glutathione synthesis. Following administration of CB
839, we anticipate that glutaminase inhibition will deplete the glutamate pool, 
thereby decreasing the production of glutathione and therefore decreasing 
glutathione levels. 




CASE 1216 
 
 
 
Page 26  
 
 
Version date: 12/16/2020 
 
 
Protocol 
Date 
Section 
Change 
 
10.4.4 
Methods 
 
Please see the Laboratory Manual for methods on measurement of glutathione 
levels, measurement of nucleotide levels whole exome sequencing and RNA 
seq and measurement of the incorporation of 5 FU into RNA and DNA. 
 
 
 
 


CASE 1216 
 
 
 
Page 27  
 
 
Version date: 12/16/2020 
 
 
STUDY SCHEMA—PHASE I 
 
Phase I dose-escalation study of CB-839 and capecitabine in patients with advanced solid tumors 
and patients for whom single agent capecitabine is an acceptable treatment option 
 
 
 
PHASE I DOSE ESCALATION STRATEGY 
 
DOSE ESCALATION SCHEDULE 
Dose Level 
CB-839 (mg) orally twice 
daily x 21 days 
Capecitabine (mg/m2) orally 
twice daily for 14/21 days 
-1 
400 
500 
1 
400 
750 
2 
600 
750 
3 
600 
1000 
4 
800 
1000 
 
3A 
400 
1000 
 
 
 
*3A to be conducted only if dose level 3 is too toxic* 
 
Phase I: Patients will be treated with CB-839 by mouth twice daily for 21 days (continuous dosing) 
as well as capecitabine by mouth twice daily for 14/21 days. Doses will be determined per the 
phase I dose escalation schedule. Day 15 trough CB-839 pharmacokinetics will be obtained. 
Patients will undergo a disease assessment with CT imaging of the chest, abdomen and pelvis 
following 3 cycles (9 weeks) of treatment. 
 
 
 
 
 
 
 
 
 
 
 


CASE 1216 
 
 
 
Page 28  
 
 
Version date: 12/16/2020 
 
 
STUDY SCHEMA—PHASE II 
 
Phase II study of CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA 
mutant colorectal cancer that is refractory to front-line fluoropyrimidine based therapy 
 
 
 
Phase II: Patients will be treated with CB-839 800 mg by mouth twice daily for 21 days 
(continuous dosing) as well as capecitabine 1000 mg/m2 by mouth twice daily for 14/21 days as 
were determined to be safe doses during the phase I portion of the study. Pre- and post-treatment 
(post-treatment being day 10-15) blood samples will be obtained for assessment of glutaminase 
activity.  Baseline tissue biopsies and a day 10-15 tissue biopsy will be obtained to assess tissue 
glutaminase activity and nucleotide levels as well as for whole exome sequencing, RNA seq and 
for the production of organoids. Blood and tissue specimens will be collected the same day. Post-
15 day treatment pharmacokinetics will be obtained and correlated with other laboratory 
assessments. Patients will undergo a disease assessment with CT imaging of the chest, abdomen 
and pelvis following 3 cycles (9 weeks) of treatment. 
 
 
 
 
 
 
 
 
 
 
 
 


CASE 1216 
 
 
 
Page 29  
 
 
Version date: 12/16/2020 
 
 
PROTOCOL SUMMARY 
 
Protocol 
Number/Title 
CASE 1216: Phase I/II study of CB-839 and capecitabine in patients with 
advanced solid tumors and fluoropyrimidine resistant PIK3CA mutant 
colorectal cancer 
 
Study Phase 
Phase I/II 
 
Brief 
Background/
Rationale 
 
 
 
Colorectal cancer is the third most common cause of cancer and second 
highest cause of cancer related death in the United States. Limited treatment 
options are available and the median overall survival is just over two years. 
Approximately 15-30% of colorectal cancers harbor a mutation in PIK3CA. 
Recent preclinical data suggest that PIK3CA mutant colorectal cancers may 
be more dependent on glutamine for growth and inhibition of glutamine 
metabolism with CB-839 inhibits growth. Additionally, treatment with CB-
839 induces UPP1 gene expression and may potentiate the activity of 
fluoropyrimidines. In the phase I portion of this study, we will evaluate the 
safety, toxicity and pharmacokinetics of CB-839 and capecitabine 
chemotherapy in patients with advanced solid tumors for whom there are 
no further treatment options or for whom capecitabine is an acceptable 
treatment option. In the phase II portion of the study, we will evaluate the 
antitumor activity and survival benefit of combination CB-839 and 
capecitabine chemotherapy in patients with metastatic PIK3CA mutant 
colorectal cancer who are refractory to fluoropyrimidine based therapy, and 
will also explore the pharmacodynamics of this combination therapy in pre- 
and post-treatment blood and tissue specimens.  
 
Primary 
Objective  
Phase I Primary Objective: 
 
To determine the safety, tolerability and recommended phase II dose 
(RP2D) of combination CB-839 and capecitabine chemotherapy in patients 
with advanced solid tumors for whom there are no remaining treatment 
options or for whom single agent capecitabine is an acceptable therapy. 
 
Phase II Primary Objective: 
 
To determine the disease control rate of combination CB-839 and 
capecitabine chemotherapy in patients with metastatic PIK3CA mutant 
colorectal cancers who are refractory to fluoropyrimidine based therapy. 
 
Secondary 
Objectives 
Phase I Secondary Objectives: 
 
To determine the dose-limiting toxicities and maximum tolerated dose of 
combination therapy with CB-839 and capecitabine in patients with 
advanced solid tumors for whom there are no remaining treatment options 
or for whom single agent capecitabine is an acceptable therapy. 


CASE 1216 
 
 
 
Page 30  
 
 
Version date: 12/16/2020 
 
 
 
To determine the antitumor response as assessed by RECIST criteria of 
combination therapy with CB-839 and capecitabine in patients with 
advanced solid tumors for whom there are no remaining treatment options 
or for whom single agent capecitabine is an acceptable therapy. 
 
Phase II Secondary Objectives: 
 
To determine the progression free survival following treatment with CB-
839 and capecitabine chemotherapy in patients with metastatic PIK3CA 
mutant colorectal cancer and are refractory to fluoropyrimidine based 
therapy. 
 
To determine the overall survival following treatment with CB-839 and 
capecitabine chemotherapy in patients who have metastatic PIK3CA 
mutant colorectal cancer and are refractory to fluoropyrimidine based 
therapy. 
 
Correlative 
Objectives 
 
Phase II Correlative Objectives: 
 
To determine the change in glutaminase activity level in tumor specimens 
and platelets following treatment with CB-839 and capecitabine 
chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer 
who are refractory to fluoropyrimidine based therapy. 
 
To determine the reduction in nucleotide levels in tumor specimens 
following treatment with CB-839 and capecitabine chemotherapy in 
patients with metastatic PIK3CA mutant colorectal cancer who are 
refractory to fluoropyrimidine based therapy. 
 
To determine genomic changes in both DNA and RNA in tumor specimens 
following treatment with CB-839 and capecitabine chemotherapy in 
patients with metastatic PIK3CA mutant colorectal cancer who are 
refractory to fluoropyrimidine based therapy. 
 
To determine the correlation between plasma trough levels of CB-839 and 
biomarkers of interest in patients with metastatic PIK3CA mutant 
colorectal cancer who are refractory to fluoropyrimidine based therapy and 
who have received treatment with CB-839 and capecitabine chemotherapy.
 
To determine the correlation between clinical response to treatment and 
biomarkers of interest in patients with metastatic PIK3CA mutant 
colorectal cancer who are refractor to fluoropyrimidine based therapy and 
who have received treatment with CB-839 and capecitabine chemotherapy.
 
To generate organoids from patient tissue biopsies obtained prior to and 


CASE 1216 
 
 
 
Page 31  
 
 
Version date: 12/16/2020 
 
 
following treatment in patients treated with CB-839 and capecitabine 
chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer 
who are refractory of fluoropyrimidine based therapy. 
Sample Size 
Phase I: 9-24 patients 
Phase II: 18-40 patients 
Males and females permitted 
 
Disease sites/ 
Conditions 
Phase I: all solid tumors 
Phase II: metastatic colorectal cancer, PIK3CA mutant 
 
Interventions 
Phase I: Patients will receive CB-839 orally twice daily for 21 days 
(continuous administration) and capecitabine orally twice daily for 14/21 
days. Dosing of CB-839 and capecitabine will occur according to the 
aforementioned dosing table. Day 15 trough CB-839 pharmacokinetics will 
be assessed. Patients will undergo a disease assessment with CT imaging 
of the chest, abdomen and pelvis following 3 cycles (9 weeks) of treatment.
 
 
Phase II: Patients will be treated with CB-839 800 mg by mouth twice daily 
for 21 days (continuous dosing) as well as capecitabine 1000 mg/m2 by 
mouth twice daily for 14/21 days as was determined during the phase I 
portion of the study. Pre-treatment and post-10-15 day treatment blood 
samples will be obtained for assessment of glutaminase activity (to be 
obtained the same day as the post-treatment biopsy). Day 15 blood samples 
will also be archived for as needed assessment of CB-839 
pharmacokinetics. Baseline tissue biopsies and a day 10-15 tissue biopsy 
will be obtained to assess tissue glutaminase activity and nucleotide levels 
as well as for whole exome sequencing, RNA seq and for the production of 
organoids. Patients will be assessed with CT scans of the chest, abdomen 
and pelvis every 3 cycles (9 weeks).  Treatment will continue until disease 
progression, until unacceptable toxicity develops or per patient/physician 
preference. 
 
 
 
 
 
 
 


CASE 1216 
 
 
 
Page 32  
 
 
Version date: 12/16/2020 
 
 
ABBREVIATIONS  
 
5-FU 
5-fluorouracil 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the curve 
BID 
twice a day 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CCCC 
Case Comprehensive Cancer Center 
Cmax 
maximum concentration 
Cmin 
minimum concentration 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CRU 
Clinical Research Unit 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DSMP 
Data Safety Monitoring Plan 
DSTC 
Data Safety Toxicity Committee 
DVT 
deep vein thrombosis 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDTA 
ethylenediaminetetraacetic acid 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FdUTP 
5-fluoro-2’-deoxyuridine-5’-triphosphate 
FH 
fumarate-hydratase 
FUTP 
5-formyluridine-5’-triphosphate 
GDH 
glutamate dehydrogenase 
GI50 
dose of 50% growth inhibition 
GIST 
gastrointestinal stromal tumor 
GLP 
good laboratory practice 
GLS 
glutaminase 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IDH 
isocitrate dehydrogenase 


CASE 1216 
 
 
 
Page 33  
 
 
Version date: 12/16/2020 
 
 
 
 
 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
LC-MS 
liquid chromatography-mass spectrometry 
LFTs 
liver function tests 
MDS 
myelodysplastic syndrome 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NCI 
National Cancer Institute 
PARP 
poly ADP ribose polymerase 
PBS 
Phosphate buffered saline 
PD 
progressive disease 
PE 
pulmonary embolism 
PET 
positron emission tomography 
PFS 
progression free survival 
PIK3CA 
phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
recommended phase II dose 
RT-PCR 
reverse transcriptase polymerase chain reaction 
SAE 
serious adverse event 
SD 
stable disease 
SDH 
succinate dehydrogenase 
TCA 
tricarboxylic acid 
TCI 
Taussig Cancer Institute 
TID 
three times a day 
TRSR 
Translational Research Shared Resource 
UHCMC
University Hospitals Cleveland Medical Center 
ULN 
upper limit of normal 
UPP1 
uridine phosphorylase 1 
US 
ultrasound 
VEGF 
vascular endothelial growth factor 
WT 
wild-type 


CASE 1216 
 
 
 
Page 34  
 
 
Version date: 12/16/2020 
 
 
TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Background of Colorectal Cancer  
1.2  
CB-839 
1.3  
Capecitabine 
1.4 
Rationale for clinical trial and correlative studies 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objectives 
2.3 
Correlative Objectives 
 
3.0 
STUDY DESIGN 
3.1 
Study design including dose escalation/cohorts 
3.2 
Number of Patients 
3.3 
Replacement of Patients 
3.4 
Expected Duration of Treatment and Patient Participation 
 
 
4.0  
PATIENT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Treatment Regimen Overview  
6.2 
Phase I Dose Escalation  
6.3  
Definition of Dose Limiting Toxicity 
6.4 
General Concomitant Medications and Supportive Care Guidelines 
6.5 
Criteria for Removal from Study 
6.6 
Duration of Follow-Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
7.1 
CB-839 Dose Modifications 
7.2 
Capecitabine Dose Modifications 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
8.1  
CB-839 
8.2 
Capecitabine 
8.3 
Definitions 
8.4 
Serious Adverse Event Report Form 
8.5 
Reporting Procedures for Serious Adverse Event  
8.6 
Serious Adverse Events and OnCoreTM    
8.7 
Data Safety Toxicity Committee 


CASE 1216 
 
 
 
Page 35  
 
 
Version date: 12/16/2020 
 
 
8.8 
Data and Safety Monitoring Plan 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
CB-839 
 
9.2 
Capecitabine 
 
10.0 
CORRELATIVE STUDIES 
10.1  Glutaminase Activity Level 
10.2 
Pharmacokinetic analysis of CB-839 
10.3  Additional pharmacodynamic analyses 
10.4 
Generation of organoids 
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.1 
Study Parameters 
11.2 
Calendar 
 
12.0 
MEASUREMENT OF EFFECT  
12.1 
Definitions 
12.2 
Disease Parameters 
12.3 
Methods for Evaluation of Measureable Disease 
12.4 
Response Criteria 
12.5 
Progression Free Survival 
 
13.0 
DATA RECORDING/REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
14.1 
Study Design/Endpoints 
14.2 
Analytic Plan for Primary Objective 
14.3 
Analytic Plan for Secondary Objectives 
14.4 
Analytic Plan for Correlative Objectives 
14.5 
Sample Size Justification 
14.6 
Accrual Rate Estimate 
 
REFERENCES 
 
  
APPENDICES  
 
APPENDIX I—ECOG/Karnofsky Performance Status Criteria 
 
 
APPENDIX II—Patient Pill Diary (CB-839) 
 
 
APPENDIX III—Patient Pill Diary (Capecitabine) 
 


CASE 1216 
 
 
 
Page 36  
 
 
Version date: 12/16/2020 
 
 
1.0 
INTRODUCTION 
 
1.1 
Background of Colorectal Cancer 
 
Colorectal cancer is the second most commonly diagnosed cancer within the United States with 
an estimated 132,700 new cases in 2015. It is also the third most common cause of cancer related 
death in both males and females with approximately 49,700 colorectal cancer related deaths 
occurring in 2015 (1). For patients with metastatic disease, combination therapy with cytotoxic 
chemotherapeutic agents and biologic agents are typically used. Cytotoxic therapies include 
fluoropyrimidines (5-fluorouracil (5-FU) or capecitabine, the oral prodrug of 5-FU), oxaliplatin 
and irinotecan while biologic agents include bevacizumab (a vascular endothelial growth factor 
inhibitor), cetuximab or panitumumab (epidermal growth factor receptor inhibitors) in patients 
harboring a ras mutation and regorafenib (a multi-target tyrosine kinase inhibitor also with 
inhibitory vascular endothelial growth factor pathway effects) (2). However, despite optimal 
utilization of all of these agents, median overall survival is still poor at approximately 2 years. 
Improved treatment strategies for these patients are therefore very much in need. 
 
Multiple mutations have been identified in colorectal cancers including mutations in several ras 
genes, BRAF and PIK3CA. To date, targeted agents acting upon these mutations are only available 
to patients harboring a ras mutation (approximately 40% of patients) but no targeted therapy exists 
for patients with PIK3CA mutations, which are thought to be present in approximately 15-30% of 
colorectal cancers (3). 
 
Role of glutamine in cancer 
 
It has been well described that tumor cancer cells are dependent on glutamine for survival. Both 
the “Warburg effect” and “glutamine dependency” are well-known metabolic reprogramming 
events that occur in cancer cells (4). In normal cells, glucose is converted to acetyl-CoA, which 
enters the tricarboxylic acid (TCA) cycle and undergoes oxidative phosphorylation in the 
mitochondria (5). In cancer cells however, glucose is converted to lactate even in the presence of 
oxygen (the “Warburg effect”) (5). It was previously thought that the Warburg effect is caused by 
impaired mitochondrial function in cancer cells however recent studies clearly demonstrate that 
most cancer cells retain functional mitochondria (6). Instead of using glucose, cancer cells utilize 
glutamine to replenish the TCA cycle (7). To enter the TCA cycle, glutamine is first deaminated 
by glutaminase (GLS) to generate glutamate. Glutamate is then converted to alpha-ketoglutarate 
(alpha-KG), a TCA cycle intermediate, by either an aminotransferase (e.g. GPTs and GOTs) or a 
glutamate dehydrogenase.  
 
 
 
 
Glutamine metabolites are utilized to produce ATP, lipids and other macromolecules, thereby 
promoting tumor growth (4). 
 
 
 


CASE 1216 
 
 
 
Page 37  
 
 
Version date: 12/16/2020 
 
 
PIK3CA mutations render cancer cells dependent on glutamine 
 
Most PIK3CA mutations are clustered in two hot spots: H1047R in the kinase domain and E545K 
in the helical domain (3). Preclinical work conducted by our group sought to demonstrate that 
PIK3CA mutations reprogram cell metabolism in colorectal cancers (CRCs). The CRC cell line 
HCT116 harbors a heterozygous H1047R mutation, whereas DLD1 CRC cells express a 
heterozygous E545K mutation. To interrogate how PIK3CA mutations impact cancer metabolism, 
we exploited isogenic cell lines with either the WT or mutant alleles of PIK3CA knocked out (gift 
from Dr. Bert Vogelstein) to test their sensitivity to glucose or glutamine deprivation. We termed 
the parental cells as Mut/WT, the WT PIK3CA allele knockout as Mut/-, and the mutant allele 
knockout as -/WT. As had been previously reported (8), the parent cells and knockout cells grew 
at a similar rate under normal conditions in the presence of glucose and glutamine. However, 
glutamine deprivation (-Gln) induced more apoptosis in PIK3CA Mut/- cells than PIK3CA -/WT 
cells as assayed by percentages of sub-GI cells, amounts of cleaved PARP and counting of viable 
cells. Similar results were observed with both HCT116 and DLD1 cell lines. In contrast, none of 
these cell lines showed differential sensitivity to glucose deprivation. Glutamine sensitivity tested 
in two additional cell lines with PIK3CA mutations—RKO with a PIK3CA H1047R mutation and 
HT29 with a PIK3CA P449T mutation—and two CRC cell lines with WT PIK3CA (SW480 and 
LOVO) generated similar results; glutamine deprivation induced significantly more apoptotic cells 
in the two PIK3CA mutant cell lines than in the two WT PIK3CA cell lines, suggesting that these 
results are generalizable. Prior studies have demonstrated that KRAS increases glutamine 
metabolism in pancreatic cancers (9). Both the HCT116 and DLD1 CRC cell lines harbor a 
heterozygous oncogenic KRAS mutation. Using isogenic HCT116 and DLD1 clones with either 
WT or mutant KRAS knockout (10), we showed that KRAS mutant and WT clones did not show 
differential sensitivity to glutamine deprivation. Overall, this suggests that mutant PIK3CA/p110α, 
but not mutant KRAS, renders CRC cells dependent on glutamine to grow and provides the first 
evidence that oncogenic PIK3CA mutations cause glutamine dependency in cancer cells. 
  
1.2  
CB-839 
 
1.2.1  Preclinical Data  
 
PIK3CA mutant CRC cells are more sensitive to a 
glutaminase inhibitor—CB-839 
 
Glutaminases have been shown to be overexpressed in 
CRCs (11). CB-839 is a highly selective, reversible, 
allosteric inhibitor of glutaminase (12). We have shown 
that isogenic PIK3CA Mut/- cells are more sensitive to 
CB-839 than their WT counterparts (Fig 1). The GI50 
(dose of 50% growth inhibition) of CB-839 of the PIK3CA 
Mut/- cell lines are 3-4 fold lower than the isogenic 
PIK3CA -/WT cell lines derived from either HCT116 or 
DLD1 CRC cell lines. In CRC xenografts treated with CB-
839, CB-839 inhibited xenograft tumors with PIK3CA 
mutations. In contrast, xenografts with WT PIK3CA did 
Fig. 1. CB-839 inhibits xenograft tumor growth of 
PIK3CA mutant, but not WT, CRCs. (A) PIK3CA mut/- 
(Mut) cells are more sensitive to CB-839 than isogenic 
PIK3CA -/WT cells. (B) to (D) Xenograft tumors were 
treated with vehicle, CB-839 (200 mg/kg) once or twice 
(bid) per day orally. (B) HCT116; (C) SW480; (D) A 
colon cancer patient-derived xenograft (PDX).


CASE 1216 
 
 
 
Page 38  
 
 
Version date: 12/16/2020 
 
 
not respond to CB-839. 
 
Combination CB-839 and 5-fluorouracil shrinks PIK3CA mutant xenograft tumors 
 
Based on tissue culture data demonstrating that 5-fluorouracil enhanced cytotoxicity of CB-839, 
our group sought to determine if CB-839 alone or in combination with 5-fluorouracil inhibits 
xenograft tumor growth of a PIK3CA mutant colorectal cancer. A dose of 30mg/kg of 5-
fluorouracil was tested after it was determined that 40mg/kg was the maximum tolerated dose in 
mice. Mice were treated with 200mg/kg CB-839 and 30mg/kg 5-fluorouracil combination therapy 
which induced tumor regression (Fig 2). In contrast, although CB-839 and 5-fluorouracil alone 
each inhibited tumor growth to various extents, neither induced tumor regression. Furthermore, 
combination of CB-839 and 5-
fluorouracil also induced tumor 
regression of a patient derived 
xenograft. Overall, these results 
provide a strong rationale for 
conduct 
of 
a 
clinical 
trial 
assessing the combination of 
CB-839 and 5-fluorouracil in 
colorectal cancer with PIK3CA 
mutations. 
 
 
 
Combination of CB-839 and 5-fluorouracil depletes cellular dTTP levels 
 
Given that glutamine is a precursor for nucleotide synthesis and 
that 5-FU is a thymidylate synthase inhibitor, we set to determine 
how the drug combination impacts cellular dTTP levels. As 
shown in Fig. 3, either drug alone significantly reduced amounts 
of dTTP, whereas the combination of CB-839 and 5-FU nearly 
completely depleted cellular dTTP. These data suggest that CB-
839 enhances the cytotoxicity of 5-FU by further depleting 
cellular dTTP.   
 
 
 
 
 
 
 
1.2.2 Clinical Data 
 
A phase I study assessed CB-839 administered as a single agent in patients with metastatic solid 
tumors (17, 18), cumulative exposure to date is 125 patients (data cut 26 January 2016). Patients 
received CB-839 according to either a three times daily (TID) dosing schedule or a twice daily 
Fig. 2. Combination of CB-839 with 5-FU shrinks PIK3CA mutant CRCs. (A) & (B) When 
HCT116 PIK3CA mutant xenograft tumors reached ~200 mm3 size, mice were treated daily 
with vehicle, CB-839 (200 mg/Kg, oral gavage), 5-FU (30 mg/kg, IP) or combination of CB-839 
with 5-FU (5 mice/group). Representative images of a tumor regressing over time in the 
combination treatment group (A). Growth curves of tumors (B). (C) Combination of CB-839 with 
5-FU shrinks a PIK3CA-mutant colon cancer patient-derived xenograft (PDX). 
Fig. 3. Combination CB-839 and 5-FU 
depletes cellular dTTP levels. HCT116 
cells were treated with the indicated drugs. 
Cellular dTTP amounts were measured by 
LC-MS/MS.  


CASE 1216 
 
 
 
Page 39  
 
 
Version date: 12/16/2020 
 
 
dosing schedule (BID with food) during a 21-day treatment cycle. A standard 3+3 dose escalation 
strategy was employed assessing dose levels ranging from 100-800 mg TID (n=32), and 600-800 
mg BID with food (n=27). Treatment was well tolerated with 16% of patients across all trials 
experiencing a grade 3/4 treatment related adverse event. One dose limiting toxicity occurred 
(grade 3 creatinine in a patient with known diabetes). The majority of adverse events were related 
to asymptomatic, reversible elevations in liver function tests (LFTs). Twice daily dosing with food 
resulted in a lower frequency (1.5%) of grade 3 treatment-related LFT abnormalities than TID 
dosing and hence has been selected as the dosing schedule to pursue in subsequent studies (18). 
Pharmacodynamic analyses (see section 1.2.3) have demonstrated that 600 mg BID results in 
continuous strong glutaminase inhibition in most patients and is a sufficient dose for further study. 
Expansion cohorts assessing single agent activity of CB-839 600 mg BID have been enrolled in 
triple negative breast cancer, KRAS-mutant non-small cell lung cancer, renal cell carcinoma, 
mesothelioma, fumarate-hydratase (FH)-deficient solid tumors, succinate dehydrogenase (SDH)-
deficient GIST, succinate dehydrogenase (SDH)-deficient non-GIST and isocitrate dehydrogenase 
(IDH)-mutant solid tumors and have confirmed the adverse event profile and recommended phase 
2 dose (18). Monotherapy dosing at 800 mg BID has also been shown to be safe and well tolerated 
and is being further explored in the clinic—this dose could eventually become the preferred 
recommended phase 2 dose. Two-drug combination studies with CB-839 and either paclitaxel, 
erlotinib, everolimus or docetaxel are planned.  
 
Two phase I studies of CB-839 administered as a single agent were also conducted in patients with 
hematologic malignancies: relapsed and/or treatment refractory multiple myeloma or non-
Hodgkins lymphoma (CX-839-02) and relapsed and/or treatment refractory leukemia and IDH-
mutated myelodysplastic syndrome (CX-839-003) were also conducted (19). Totals of 14 and 18 
patients received CB-839 in CX-839-002 and CX-839-003, respectively according to the same 
treatment strategy employed in the aforementioned solid tumor study. Treatment was similarly 
tolerated with 21% and 14% of patients respectively experiencing a grade 3/4 adverse event 
thought to be related to CB-839. The majority of the adverse events were due to asymptomatic, 
reversible LFT abnormalities or hematological adverse events. Given the larger experience in the 
solid tumor phase I study, BID dosing was selected for subsequent studies hematologic malignancy 
studies. Expansion cohorts assessing single agent activity of CB-639 600 mg BID are ongoing in 
acute myeloid leukemia (IDH wild-type), acute lymphoid leukemia, acute myeloid leukemia 
(IDH1 or IDH2 mutant) and myelodysplastic syndrome (IDH1 or IDH2 mutant). 
 
1.2.3 Clinical Pharmacokinetics and Pharmacodynamics 
 
Pharmacokinetic sampling was performed on Cycle 1, Day 1 (C1D1), C1D15 and D1 of each 
subsequent treatment cycle in each of the conducted phase I studies (17-19). A dose dependent 
relationship was observed with CB-839 exposure increasing with dose. The half-life of CB-839 
was determined to be 4 hours. Additionally, Cmin fell below a target concentration of 200 ng/mL 
in 46% of patients receiving 400 mg or higher TID regimens while a large majority of patients 
receiving BID dosing with 600 mg maintained a Cmin greater than the 200 ng/mL target 
concentration. Additionally, an assessment of the effect of food on the PK profile of CB-839 
demonstrated a modest positive food effect and delayed absorption, which resulted in similar 
Cmax and Cmin for the 600 mg TID and 600 mg BID fed regimens. Given the favorable adverse 
event profile observed with the 600 mg BID fed regimen, this is the favored dosing regimen. 


CASE 1216 
 
 
 
Page 40  
 
 
Version date: 12/16/2020 
 
 
Pharmacodynamics of CB-839 was also assessed in both studies. Glutaminase activity was 
measured in circulating platelets as well as tumor biopsy specimens. Blood samples collected at 
baseline and four hours following CB-839 treatment were assessed for glutaminase inhibition and 
demonstrated a dose dependent relationship. At a CB-839 treatment dose of 600 mg BID, greater 
than 90% glutaminase inhibition should be observed even at Cmin for most patients. An evaluation 
of glutaminase activity assessed approximately 4 hours after the C1D15 CB-839 dose within five 
(5) tumor specimens also demonstrated clear inhibition of glutaminase activity and suggested a 
dose-response relationship (18). 
 
Based on both pharmacokinetics and pharmacodynamics, CB-839 600 mg BID or 800 mg BID for 
a 21-day treatment cycle, to be repeated every 21 days has been determined as the single agent 
dose for pursuit in further clinical trials.   
 
1.3  
Capecitabine 
 
1.3.1 Clinical Data 
 
Capecitabine is an oral fluoropyrimidine and is a prodrug of 5-fluorouracil. Per the National 
Comprehensive Cancer Network guidelines (2), capecitabine and 5-FU are considered equivalent 
and either may be used as frontline treatment for colorectal cancer, typically in combination with 
another chemotherapeutic agent (oxaliplatin or irinotecan) and a biologic agent (either an EGFR 
inhibitor or a VEGF inhibitor). It may also be used as a single agent as a maintenance therapy. 
Ultimately patients develop resistance to fluoropyrimidine therapy and hence disease progression. 
However, based on our preclinical data outlined in section 1.2.1, we hypothesize that co-
administration of CB-839 with capecitabine will overcome fluoropyrimidine resistance, 
particularly in PIK3CA mutant colorectal cancers, and therefore capecitabine will be used as the 
cytotoxic backbone for this study. 
 
1.4 
Rationale for clinical and correlative studies 
 
It has been demonstrated that CB-839, via targeting glutaminase, inhibits xenograft growth in 2 of 
2 PIK3CA mutant colon cancer test xenograft models but does not inhibit growth in PIK3CA WT 
models, supporting that there is an addiction of PIK3CA mutant colorectal cancers to glutamine 
metabolism. Furthermore, CB-839 plus 5-FU shrinks 2 of 2 PIK3CA mutant xenografts that both 
grow through maximally tolerated doses of 5-FU alone. Based on these findings, we propose to 
test responses of the CB-839 and fluoropyrimidine combination in fluoropyrimidine resistant 
human patients. Based on our preclinical mechanistic studies described above, we propose a phase 
I clinical trial to determine the maximum tolerated dose (MTD), recommended phase 2 dose 
(RP2D) and dose limiting toxicities of CB-839 plus capecitabine in patients with advanced solid 
tumors. The data derived from this trial will be used for a subsequent phase II clinical trial where 
we will estimate the antitumor activity and pharmacodynamic effects of CB-839 and capecitabine 
in patients with PIK3CA mutant colorectal cancers that are resistant to fluoropyrimidine therapy. 
We hypothesize that CB-839 in combination with capecitabine will overcome fluoropyrimidine 
resistance and that the addition of capecitabine to CB-839 will result in the inhibition of 
glutaminase in tumors and platelets and the reduction in nucleotide levels in tumors. Genomic 
abnormalities on the DNA and RNA level will also be explored via a whole exome sequencing 


CASE 1216 
 
 
 
Page 41  
 
 
Version date: 12/16/2020 
 
 
analysis and an RNA seq analysis. 
 
As of January 2018, the phase I portion of the study has been fully accrued. A total of 16 patients 
were treated on the study and we were able to assess all of the four planned dose levels. No dose 
limiting toxicities were observed and we have therefore determined that the recommended phase 
II dose be CB-839 800 mg by mouth twice daily continuously and capecitabine 1000 mg/m2 orally 
twice daily on days 1-14 of a 21 day treatment cycle.  
 
2.0  
OBJECTIVES 
 
The overall objectives for this study are to 1) determine the recommended phase II dose (RP2D) 
of CB-839 and capecitabine in patients with advanced solid tumors who have no further treatment 
options or patients for whom single agent capecitabine is an acceptable treatment regimen and 2) 
to determine the antitumor activity of CB-839 and capecitabine chemotherapy in patients with 
metastatic PIK3CA mutant colorectal cancer who are refractory to fluoropyrimidine based therapy. 
The phase I portion of this study will also determine the dose-limiting toxicities of this treatment 
regimen as well as the pharmacokinetics. In the phase II portion of this study, the 
pharmacodynamic effects of CB-839 and capecitabine will be evaluated using multiple biomarker 
studies including glutaminase activity level and nucleotide levels as well as a whole exome 
sequencing analysis and an RNA seq analysis. We hypothesize that we will observe a reduction in 
glutaminase activity in both tumors and platelets and a reduction in nucleotide levels following 
treatment. The whole exome and RNA seq analyses will be exploratory. The generation of 
organoids from tumor biopsy specimens both prior to and following treatment will also be 
exploratory and will be used for further potential studies as additional preclinical information 
becomes available 
 
2.1  
Primary Objective  
 
2.1.1 Phase I: To determine the safety, tolerability and recommended phase II dose (RP2D) of 
combination CB-839 and capecitabine chemotherapy in patients with advanced solid 
tumors for whom there are no remaining treatment options or for whom single agent 
capecitabine is an acceptable therapy. 
 
2.1.2 Phase II: To determine the disease control rate of combination CB-839 and capecitabine 
chemotherapy in patients with metastatic PIK3CA mutant colorectal cancers who are 
refractory to fluoropyrimidine based therapy.   
 
2.2 
Secondary Objectives 
 
2.2.1 Phase I 
 
 
To determine the dose-limiting toxicities and maximum tolerated dose of combination 
therapy with CB-839 and capecitabine in patients with advanced solid tumors for whom 
there are no remaining treatment options or for whom single agent capecitabine is an 
acceptable therapy. 
 


CASE 1216 
 
 
 
Page 42  
 
 
Version date: 12/16/2020 
 
 
 
To determine the antitumor response as assessed by RECIST criteria of combination 
therapy with CB-839 and capecitabine in patients with advanced solid tumors for whom 
there are no remaining treatment options or for whom single agent capecitabine is an 
acceptable therapy. 
 
2.2.2 Phase II 
 
 
To determine the progression free survival following treatment with CB-839 and 
capecitabine chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer 
and are refractory to fluoropyrimidine based therapy. 
 
 
To determine the overall survival following treatment with CB-839 and capecitabine 
chemotherapy in patients who have metastatic PIK3CA mutant colorectal cancer and are 
refractory to fluoropyrimidine based therapy. 
 
2.3 
Correlative Objective(s)  
 
2.3.1 Phase II 
 
 
To determine the change in glutaminase activity level in tumor specimens and platelets 
following treatment with CB-839 and capecitabine chemotherapy in patients with 
metastatic PIK3CA mutant colorectal cancer who are refractory to fluoropyrimidine based 
therapy. 
 
 
To determine the reduction in nucleotide levels in tumor specimens following treatment 
with CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA mutant 
colorectal cancer who are refractory to fluoropyrimidine based therapy. 
 
To determine genomic changes in both DNA and RNA in tumor specimens following 
treatment with CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA 
mutant colorectal cancer who are refractory to fluoropyrimidine based therapy. 
 
 
To determine the correlation between plasma trough levels of CB-839 and biomarkers of 
interest in patients with metastatic PIK3CA mutant colorectal cancer who are refractory to 
fluoropyrimidine based therapy and who have received treatment with CB-839 and 
capecitabine chemotherapy. 
 
 
To determine the correlation between clinical response to treatment and biomarkers of 
interest in patients with metastatic PIK3CA mutant colorectal cancer who are refractory to 
fluoropyrimidine based therapy and who have received treatment with CB-839 and 
capecitabine chemotherapy. 
 
To generate organoids from patient tissue biopsies obtained prior to and following 
treatment in patients treated with CB-839 and capecitabine chemotherapy in patients with 
metastatic PIK3CA mutant colorectal cancer who are refractory of fluoropyrimidine based 
therapy. 


CASE 1216 
 
 
 
Page 43  
 
 
Version date: 12/16/2020 
 
 
 
3.0 
STUDY DESIGN 
 
3.1  
Study design including dose escalation / cohorts for phase I component 
 
This is a standard 3+3 phase I dose escalation trial to determine the maximum tolerated dose and 
dose limiting toxicities of combination therapy with CB-839 and capecitabine chemotherapy in 
patients with advanced solid tumors with no remaining treatment options or for whom single agent 
capecitabine is an acceptable therapy. Patients will receive combination therapy with CB-839 and 
capecitabine for 21 day cycles and will remain on treatment until either disease progression, 
development of unacceptable toxicity or discontinuation per patient/physician preference. Patients 
will receive CB-839 orally twice daily for 21 days (continuous administration) and capecitabine 
orally twice daily for 14/21 days. Dosing of CB-839 and capecitabine will occur according to the 
following dosing table. Day 15 trough CB-839 levels will be obtained for pharmacokinetic 
assessment. Patients will undergo a CT of the chest, abdomen and pelvis every 3 cycles (9 weeks). 
A minimum of three patients will be assessed at each dose level until the maximum tolerated dose 
has been determined. Please see section 6.1 for details. 
 
DOSE ESCALATION SCHEDULE 
Dose Level 
CB-839 (mg) orally twice 
daily x 21 days 
Capecitabine (mg/m2) orally 
twice daily for 14/21 days 
-1 
400 
500 
1 
400 
750 
2 
600 
750 
3 
600 
1000 
4 
800 
1000 
 
3A 
400 
1000 
 
 
 
*3A to be conducted only if dose level 3 is too toxic* 
 
3.2 
Study design for phase II component 
 
The phase II portion of the study is a single arm design, assessing the disease control rate of 
combination therapy with CB-839 and capecitabine chemotherapy in patients with metastatic 
PIK3CA mutant colorectal cancer who have developed fluoropyrimidine resistance. Patients will 
receive combination therapy with CB-839 and capecitabine for 21 day cycles and will remain on 
treatment until either disease progression, development of unacceptable toxicity or discontinuation 
per patient/physician preference. Patients will receive CB-839 800 mg orally twice daily for 21 
days (continuous administration) and capecitabine 1000 mg/m2 orally twice daily for 14/21 days 
as was determined during the phase I portion of the study. Patients will undergo blood and tissue 
sampling at baseline and 10-15 days post-treatment for assessment of glutaminase activity. Tissue 
specimens will also be assessed for changes in nucleotide levels as well as for a whole exome 
analysis, an RNA seq analysis and for the generation of organoids. Patients will undergo a CT of 
the chest, abdomen and pelvis following 3 cycles of therapy (every 9 weeks). 
 


CASE 1216 
 
 
 
Page 44  
 
 
Version date: 12/16/2020 
 
 
 
3.2 
Number of Patients 
 
A total of 9-24 patients will be enrolled in the phase I portion of this trial and a total of 18-40 
patients will be enrolled in the phase II portion of this trial. 
  
3.3 
Replacement of Patients  
 
3.3.1 Phase I: If a patient is withdrawn from the study for any reason other than a dose limiting 
toxicity prior to completing the first 21 days of combination therapy with CB-839 and 
capecitabine, a replacement patient will be enrolled and will be assigned to the same dose 
level. 
 
Unless the patient has had their study drug held for an adverse event that may herald a 
DLT, if a patient does not take at least 75% of the planned doses of each of the two agents 
(CB-839 and capecitabine), the patient will be replaced because he/she has not taken 
enough drug to confirm safety at that dose level. 
 
3.3.2 Phase II: If a patient does not take at least 75% of the planned doses of each of the two 
agents (CB-839 and capecitabine) prior to the first disease assessment (9 weeks), the 
patient will be replaced because he/she has not taken enough drug to assess efficacy. 
 
3.4  
Expected Duration of Treatment and Patient Participation 
 
Patients will receive treatment with combination CB-839 and capecitabine in 21 day treatment 
cycles. Patients will continue to receive treatment until they develop disease progression, 
unacceptable toxicity or per the preference of the patient or treating physician. Patients will be 
followed for toxicity for a minimum of 30 days upon discontinuation of treatment. If treatment 
related toxicities have not resolved to at least a grade 1 by 30 days following discontinuation of 
treatment, patients will be followed for treatment related toxicities until grade 1 toxicity or better.  
 
 
 


CASE 1216 
 
 
 
Page 45  
 
 
Version date: 12/16/2020 
 
 
4.0 
PATIENT SELECTION 
 
Each of the criteria in the sections that follow must be met in order for a patient to be considered 
eligible for this study. Use the eligibility criteria to confirm a patient’s eligibility.  
 
Patient’s Name _____________________________________________________________ 
 
Medical Record # ___________________________________________________________ 
 
Research Nurse / Study Coordinator Signature: 
_________________________________________________ 
 
 
Date __________ 
 
Treating Physician [Print] ____________________________________________________ 
 
Treating Physician Signature: _________________________________________________ 
 
 
Date __________ 
 
4.1 
Phase I Inclusion Criteria  
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
 
 
4.1.1  Patients must have an advanced solid tumor malignancy with no remaining standard 
treatment options or for whom single agent capecitabine is an acceptable therapy. Patients 
with colorectal cancer must have progressed on at least one line of fluoropyrimidine 
containing therapy. Receipt of either oxaliplatin or irinotecan in combination with a 
fluoropyrimidine is required in the front line setting for all colorectal cancer patients unless 
either of these agents are otherwise contraindicated in the opinion of the treating physician. 
Prior regorafenib or TAS-102 therapy is not required. 
 
 
 
4.1.2  Patients must be >18 years of age. Because no dosing or adverse event data are 
currently available on the use of CB-839 either as a single agent or in combination with 
capecitabine in patient’s ≤18 years of age, children are excluded from this study. 
  
 
 
4.1.3  Patients must have an ECOG performance status of 0-1 (See Appendix 1).  
 
 
 
4.1.4 Patients must have normal organ and marrow function as defined below:   
▪   Hemoglobin ≥ 9.0 g/dl 
▪   Leukocytes ≥ 3,000/mcL 
▪   Absolute neutrophil count ≥ 1,500/mcL 
▪   Platelet count ≥ 100,000/mcL 
▪   Serum creatinine ≤ 1.5 X institutional upper limit of normal 
▪   Total bilirubin ≤ 1.5 mg/dL 
▪   AST (SGOT) ≤ 2.5 X institutional upper limit of normal 


CASE 1216 
 
 
 
Page 46  
 
 
Version date: 12/16/2020 
 
 
▪   ALT (SGPT) ≤ 2.5 x institutional upper limit of normal 
 
 
 
4.1.5 Patients must be able to swallow pills. 
 
 
 
4.1.6  Patients must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
 
 
4.1.7 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 during the study and for a minimum of 3 months 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 months following the last dose of study drug if sexually active with a female 
of childbearing potential. 
 
4.2 
Phase II Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
 
 
4.2.1  Patients must have histologically or cytologically confirmed, metastatic colorectal 
cancer. PIK3CA mutant status must be confirmed by tumor sequencing conducted in a 
CLIA certified lab.  Genetic sequencing performed on tissue specimens or circulating DNA 
from peripheral blood samples are allowed.  Abnormalities in PIK3CA considered to be 
variants of unknown significance (VUS) will not be eligible.  
 
 
4.2.2  Patients must have measureable disease according to RECIST 1.1 criteria that is 
amenable to biopsy and be willing to undergo pre- and post-treatment tumor biopsies. 
Lesions to be biopsied do not have to be those used for measurement. 
 
 
 
4.2.3 Patients must have received and progressed on fluoropyrimidine or 
fluoropyrimidine based therapy.  Patients must have a history of disease progression during 
treatment with fluoropyrimidine, or within 3 months of a dose of a fluoropyrimidine-
containing regimen. Patients who have only progressed during treatment holiday of 3 
months or greater will not be eligible. Receipt of either oxaliplatin or irinotecan in 
combination with a fluoropyrimidine is required in the front line setting unless either of 
these agents are otherwise contraindicated in the opinion of the treating physician, in which 
case a fluoropyrimidine only may be used. Prior regorafenib or TAS-102 therapy is not 
required. 
 
 
 
4.2.4  Patients must be >18 years of age. 
  
 
 
4.2.5  Patients must have an ECOG performance status of 0-1 (See Appendix 1).  
 
 
 
4.2.6 Patients must have normal organ and marrow function as defined below:   
▪   Hemoglobin ≥ 9.0 g/dl 
▪   Leukocytes ≥ 3,000/mcL 


CASE 1216 
 
 
 
Page 47  
 
 
Version date: 12/16/2020 
 
 
▪   Absolute neutrophil count ≥ 1,500/mcL 
▪   Platelet count ≥ 100,000/mcL 
▪   Serum creatinine < 1X institutional upper limit of normal  
▪   Total bilirubin ≤ 1.5 mg/dL 
▪   AST (SGOT) ≤ 2.5 X institutional upper limit of normal 
▪   ALT (SGPT) ≤ 2.5 X institutional upper limit of normal 
 
 
 
4.2.7 Patients must be able to swallow pills. 
 
 
 
4.2.8  Patients must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
 
 
4.2.9 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 during the study and for a minimum of 3 months 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 months following the last dose of study drug if sexually active with a female 
of childbearing potential. 
 
4.3 
Phase I and II Exclusion Criteria 
 
The presence of any of the following will exclude a patient from study enrollment. 
 
 
 
4.3.1  Patients with ongoing toxicities > grade 1 according to NCI CTCAE Version 4.0 
(excluding alopecia) due to prior anti-cancer therapy. 
 
 
 
4.3.2 Patients receiving any other investigational agents or whom have received recent 
treatment for colorectal cancer (radiation within the previous two weeks, chemotherapy or 
investigational therapy within the previous four weeks).  
 
 
 
4.3.3  Patients with untreated brain metastases/CNS disease will be excluded due to their 
poor prognosis and because they often develop progressive neurologic dysfunction that 
would confound the evaluation of neurologic and other adverse events. 
 
 
 
4.3.4  Patients with a history of allergic reactions attributed to or intolerance to 
compounds of similar chemical or biologic composition to either CB-839 or 
capecitabine. If capecitabine has been received previously, must have tolerated at least 
an equivalent dose to the dose to be administered at their assigned dose level. 
 
 
 
4.3.5 Patients who are unable to swallow pills or who have undergone surgery that 
prohibits the absorption of pills in the stomach. 
 
 
 
4.3.6  Patients with uncontrolled intercurrent illness including, but not limited to ongoing 
or active infection, symptomatic congestive heart failure (i.e., NYHA Class II), unstable 


CASE 1216 
 
 
 
Page 48  
 
 
Version date: 12/16/2020 
 
 
angina pectoris or myocardial infarction within prior 6 months, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.  
 
 
 
4.3.7 Patients who are pregnant or breastfeeding will be excluded from the study due to 
the potential teratogenic or abortifacient effects that may results from CB-839 and/or 
capecitabine. Because there is an unknown, but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with CB-839 and/or capecitabine, 
breastfeeding should be discontinued if the mother is treated with CB-839 and/or 
capecitabine. These potential risks may also apply to other agents used in this study. 
 
 
 
4.3.8 Patients known to be HIV positive who are not receiving anti-retroviral therapy will 
be excluded due to the marrow suppressive therapy involved in administration of the study 
treatment. 
 
4.4 
Inclusion of Women and Minorities  
 
Men, women and members of all races and ethnic groups are eligible for this trial. 
 
5.0 
REGISTRATION 
 
All patients who have been consented are to be registered in the OnCore™ Database. For those 
patients who are consented, but not enrolled, the reason for exclusion must be recorded. 
 
All patients will be registered through University Hospitals Cleveland Medical Center/Seidman 
Cancer Center and will be provided a study number by contacting the study coordinator. 
 
6.0  
TREATMENT PLAN 
 
6.1 
Treatment Regimen Overview 
 
6.1.1 Phase I: Patients will receive combination therapy with CB-839 and capecitabine for 21 
day cycles and will remain on treatment until either disease progression, development of 
unacceptable toxicity or discontinuation per patient/physician preference. Patients will 
receive CB-839 orally twice daily for 21 days (continuous administration) and capecitabine 
orally twice daily for the first 14/21 days.  
 
A standard 3+3 dose escalation schema will be used to conduct this phase I study. Patients 
will be treated in cohorts of 3 patients starting with dose level 1, with escalating doses of 
both CB-839 and capecitabine. Escalation will continue through all dose levels until the 
MTD has been determined. The dose escalation strategy is as follows: 
 
DOSE ESCALATION SCHEDULE 
Dose Level 
CB-839 (mg) orally twice 
daily x 21 days 
Capecitabine (mg/m2) orally 
twice daily for 14/21 days 
-1 
400 
500 
1 
400 
750 


CASE 1216 
 
 
 
Page 49  
 
 
Version date: 12/16/2020 
 
 
2 
600 
750 
3 
600 
1000 
4 
800 
1000 
 
3A 
400 
1000 
 
 
 
*3A to be conducted only if dose level 3 is too toxic* 
 
6.1.2 Phase II: Patients will receive combination therapy with CB-839 and capecitabine for 21 
day cycles and will remain on treatment until either disease progression, development of 
unacceptable toxicity or discontinuation per patient/physician preference. Patients will 
receive CB-839 800 mg orally twice daily for 21 days (continuous administration) and 
capecitabine 1000 mg/m2 orally twice daily for the first 14/21 days as was determined 
during the phase I portion of the study. Additionally, given that there are ongoing studies, 
the safety profile will continue to be monitored in these studies and the RP2D could be 
adjusted based on emerging safety and tolerability data. 
 
6.2 
General Agent Administration Guidelines 
 
As capecitabine involves a weight based administration, dosing will be based on actual body 
weight. Dose changes (beyond cycle 1) should be made only if there is a > 10% change in body 
weight as calculated by the Mosteller formula. 
 
As CB-839 is administered as a fixed dose, the CB-839 dose does not need to be altered due to 
changes in body weight. 
 
CB-839 will be supplied as 200 mg tablets. Capecitabine will be supplied as 500 mg tablets 
depending on the dose required. Capecitabine dose should be rounded to the closest 500 mg and 
the total dose should not exceed the calculated dose by more than 5%. If an odd number of 500 
mg tablets are needed, the dose may be split between the morning and evening doses (example: if 
2500 mg are required for the total daily dose, 1500 mg may be administered in the morning and 
1000 mg may be administered in the evening). 
 
Dose of up to 5% higher than the calculated BSA-based dose of capecitabine may be given when 
rounding down would result in significant under-dosing as determined by the treating physician.  
Any doses higher than the calculated BSA-based dose should be reviewed by the study PI.  Total 
daily doses higher than 105% of the BSA-based dose should not be given.   
 
As an example: a patient with a BSA of 1.97 would have a total calculated daily dose of 
capecitabine of 3940 mg but may receive 4000 mg total.  In this case the dispensed (rounded) dose 
would be 1.5% higher than the BSA-calculated dose.  If instead the dose was rounded down the 
patient would receive 3500 mg daily which would be 11% lower than the calculated dose.  The 
lower dose should be used if the higher dose is more than 5% above the calculated dose.   
Dose reductions for toxicity should be considered similarly with up to 80% of initial dose being 
allowed at the -1 dose level and up to 55% of initial dose being allowed at the -2 dose level (see 
section 7.2 below).   


CASE 1216 
 
 
 
Page 50  
 
 
Version date: 12/16/2020 
 
 
 
Both CB-839 and capecitabine pills should be swallowed whole and may not be crushed. 
 
A missed or vomited dose of either CB-839 or capecitabine should not be replaced. The patient 
should be instructed to take the next scheduled dose at the regularly scheduled time. 
 
Treatment will continue until development of progressive disease (as defined by section 12.4) or 
unacceptable toxicity. 
 
Appropriate dose modifications for CB-839 and capecitabine are described in Section 7.0 
 
Reported adverse events and potential risks of CB-839 and capecitabine as well as reporting 
requirements for adverse events are described in Section 8.0.  
 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
6.2.1 CB-839 Administration 
 
CB-839 will be given orally twice daily in combination with capecitabine chemotherapy during a 
21 day treatment cycle. Administration of CB-839 will be continuous throughout the 21 day 
treatment cycle. During the phase I component of the study, the dose of CB-839 administered will 
be dictated by the dose escalation table. During the phase II component of the study, the dose of 
CB-839 administered will be 800 mg by mouth twice daily as was determined during the phase I 
portion of the study. 
 
CB-839 should be taken with food—the first dose of the day should be taken with breakfast and 
the second dose of the day should be taken with dinner. 
 
6.2.2 Capecitabine Administration 
 
Patients will receive capecitabine chemotherapy orally by mouth twice daily for the first 14 days 
of each 21 day treatment cycle. During the phase I component of the study, the dose of capecitabine 
administered will be dictated by the dose escalation table. During the phase II component of the 
study, the dose of capecitabine administered will be 1000 mg/m2 twice daily on days 1-14 of a 21 
day treatment cycle as was determined during the phase I component of the study. 
 
Capecitabine tablets should be taken whole with water within 30 minutes following a meal. Doses 
will be taken approximately 12 hours apart at the end of a meal. 
 
6.3 
Phase I Dose Escalation 
 
Dose escalation will proceed within each cohort according to the following scheme.  
 
DOSE ESCALATION SCHEDULE 
Dose Level 
CB-839 (mg) orally twice 
Capecitabine (mg/m2) orally 


CASE 1216 
 
 
 
Page 51  
 
 
Version date: 12/16/2020 
 
 
daily x 21 days 
twice daily for 14/21 days 
-1 
400 
500 
1 
400 
750 
2 
600 
750 
3 
600 
1000 
4 
800 
1000 
 
3A 
400 
1000 
 
 
 
*3A to be conducted only if dose level 3 is too toxic* 
 
For each cohort, 3 patients will be entered sequentially to each dose level. Dose-limiting toxicity 
(DLT) is defined in section 6.4.  
 
• If none of the 3 patients at a dose level experience dose limiting toxicity (DLT) during the 
first cycle (21 day treatment period), new patients may be entered at the next dose level. 
• If 1/3 patients experiences a DLT during the first cycle, up to 3 more patients will be treated 
at the same dose level.  
• If 2 or more experience a DLT during the first cycle, no further patients are started at that 
dose and the MTD is the highest dose level in which <2 (of 6) patients develop a DLT. 
• For the dose level deemed the MTD, 6 patients will be treated at this dose level, even if a 
DLT has not been observed. 
• If at any time 2 or more DLTs are seen in 3 or 6 patients an any given dose level, the 
preceding dose level will be declared the MTD (Maximum Tolerated Dose) and 
recommended phase II dose. MTD is defined as the highest dose level at which < 33% of 
6 patients experience a DLT. If 1 DLT is seen out of 6 patients at a given dose level, new 
patients may be entered at the next dose level. 
• If dose level -1 exceeds the MTD definition, then the study will be suspended and 
additional dose levels will be considered. 
 
For Dose Level -2, -1, 1 and 2 
Number of 
Observed DLTs
Action 
0/3 
Escalate next 3 patients to next dose level 
1/3 
Add 3 more patients to current dose level 
≤ 1/6 
Escalate next 3 patients to next dose level 
≥ 2/3 
Suspend accrual, next lowest dose level is deemed the MTD 
≥ 2/6 
Suspend accrual, next lowest dose level is deemed the MTD 
 
If the final dose level is achieved, a total of 6 patients must be treated at this dose level 
even if no DLTs are observed. 
 
 
6.4 
Definition of Dose-Limiting Toxicity  
 
Patients must receive at least 75% of the planned CB-839 and capecitabine administrations in the 


CASE 1216 
 
 
 
Page 52  
 
 
Version date: 12/16/2020 
 
 
first treatment cycle to be considered evaluable for DLT, unless the patient experiences a DLT or 
has the study drug held for an AE that may herald a 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.  
 
A DLT is defined as any AE that cannot be determined to be unrelated to study treatment, occurs 
within the first treatment cycle (i.e., Cycle 1), and that meets at least one of the non-hematologic 
or hematologic criteria below: 
 
Non-Hematologic DLT: 
• ≥ Grade 3 non-hematologic toxicity according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4 except the following: 
o Nausea, vomiting, or diarrhea lasting < 48 hours and controlled by optimal 
antiemetic/antidiarrheal therapy 
o Grade 3 hyperglycemia lasting < 72 hours with standard anti-diabetic therapy 
o Clinical laboratory abnormalities that are reversible to ≤ Grade 1 or baseline 
status within 72 hours with outpatient care and/or monitoring, or that are 
considered not clinically significant by the Principal Investigator 
• Grade 4 hyperglycemia (>500 mg/dL; 27.8 mmol/L; life threatening consequences) 
• Grade 4 hypoglycemia (<30 mg/dL; <1.7 mmol/L; life threatening consequences) 
• Grade 4 AST (>20.0 x the upper limit of normal) 
• Grade 4 ALT (>20.0 x the upper limit of normal) 
• Grade 3 AST or ALT elevation (>5.0 – 20.0 x the upper limit of normal; >5 x the upper 
limit of normal for >2 weeks) with concomitant Grade 2 increase in total bilirubin (>1.5 
– 3.0 x the upper limit of normal) 
 
Events involving elevation in the AST, ALT or bilirubin with a clear alternative explanation (such 
as progressive disease within the liver) can be exempt from being considered a DLT-defining 
event. 
 
Hematologic DLT: 
• Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 x 109/L] 
• Grade 3 febrile neutropenia (ANC < 1.0 x 109/L with a fever ≥ 38.3 degrees C) 
• Grade 4 thrombocytopenia (< 25.0 x 109/L)  
• Grade ≥ 3 thrombocytopenia associated with Grade ≥ 3 bleeding 
 
In addition, any other AE that is felt to be treatment-limiting in the medical opinion of the Principal 
Investigator may be considered a DLT. 
 
Management and dose modifications are outlined in Section 7. 
 
6.5 
General Concomitant Medications and Supportive Care Guidelines 
 
All supportive measures consistent with optimal patient care will be given throughout the study. 


CASE 1216 
 
 
 
Page 53  
 
 
Version date: 12/16/2020 
 
 
Anxiolytics, anti-emetics, analgesics and antibiotics may be provided at the discretion of the 
treating physician. 
 
6.5.1 Use of Imodium and/or Lomotil should be implemented immediately to prevent 
dehydration should diarrhea develop. 
 
6.5.2 The use of growth factors (filgrastim) is permitted and should be administered in 
accordance with ASCO guidelines (20). Growth factors are not permitted, however, in the first 
treatment cycle of the phase I portion of the study unless the patient experiences a hematologic 
DLT. 
 
6.5.3 The use of erythropoietin stimulating agents is NOT permitted. Anemia may be managed 
with blood transfusions as indicated. 
 
6.5.4 Caution should be taken when capecitabine or CB-839 is co-administered drugs that are 
highly dependent on CYP2C9 for metabolism. 
 
6.5.5 Prophylactic anticoagulation will be allowed during therapy provided the activity of the 
agent used is reflected in either INR or aPTT and that those parameters remain as follows: INR < 
1.5 or aPTT within normal limits. Anticoagulation for therapeutic use of DVT or PE is allowed. 
Caution should be taken in patients receiving Coumadin (which is permitted). Coumadin levels 
should be monitored and the dose of Coumadin may need to be reduced. 
 
6.5.6 Caution should be taken in patients receiving phenytoin. Phenytoin levels should be 
monitored and the phenytoin dose may need to be reduced. 
 
6.5.7 Proton pump inhibitors are not permitted while on study due to their interference with CB-
839 that results in lower CB-839 drug exposure levels. H2 blockers may be used as an acceptable 
alternative. In the event that a patient is not able to tolerate an H2-blocker as an alternative, 
please contact the study principal investigator. Preliminary PK data generated in concurrent 
phase I studies suggest that concomitant use of agents that increase gastric pH (e.g., proton pump 
inhibitors, H2-receptor antagonists, antacids, etc.) may reduce absorption of CB-839, resulting in 
decreased systemic exposure. Note: these agents are NOT CONTRAINDICATED but rather 
discontinuation is recommended whenever possible. Based on emerging PK data from other CB-
839 studies, the PI may allow concomitant use of a PPI with modified guidance regarding the 
administration of CB-839 (e.g., administer CB-839 with an acidic beverage or dietary supplement). 
In the event that a patient needs to resume proton pump inhibitor therapy, a PK sampling pre-dose 
and at 0.5, 1, 2 and 4 hours are required at a point 2-4 weeks after initiation of PPI therapy. 
 
6.5.8 Emollients and/or urea based creams are recommended for use at the first sign of palmar-
plantar erythrodysesthesia syndrome (hand and foot rash) and should be used liberally before 
making a dose modification based on this AE. 
 
6.6 
Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse events, treatment may continue until one of the 


CASE 1216 
 
 
 
Page 54  
 
 
Version date: 12/16/2020 
 
 
following criteria applies: 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• The investigator considers it, for safety reasons, to be in the best interest of the 
patient 
• Unacceptable treatment related toxicity, NCI CTCAE version 4, grade 3 or 4 
that fails to recover to baseline or < grade 3 in the absence of treatment within 
4 weeks 
• Patient decision to withdraw from treatment (partial consent) or from the study 
(full consent) 
• Pregnancy during the course of the study for a child-bearing participant 
• Death 
• Sponsor reserves the right to temporarily suspend or prematurely discontinue 
the study 
 
The date and reason for discontinuation must be documented. Every effort should be made to 
complete the appropriate assessments.  
 
6.7 
Duration of Follow Up 
 
Patients will be followed for toxicity for 30 days after treatment has been discontinued (or longer 
if treatment related toxicities have not resolved to at least a grade 1) or until death, whichever 
occurs first.  
 
The clinical course of each adverse event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause. 
 
Serious adverse events that are still ongoing at the end of the study period will necessitate follow-
up to determine the final outcome. Any serious adverse event that occurs after the study period 
and is considered to be possibly related to the study treatment or study participation will be 
recorded and reported immediately. 
 
Patients will be followed every 3 months for up to 2 years from study drug discontinuation. 
 
7.0  
DOSE DELAYS/DOSE MODIFICATIONS 
 
Once a patient undergoes a dose modification, neither CB-839 nor capecitabine may be re-
escalated in that patient. 
 
Dose reductions may be implemented for either one agent or both agents depending on the treating 
physician’s assessment of causality. 
 
Patients requiring > 2 dose modification will be taken off protocol therapy. 
 
Patients must receive at least 75% of the total assigned CB-839 and capecitabine doses in order to 
be evaluable for a DLT in the phase I portion of the study. Missed doses must be for reasons other 


CASE 1216 
 
 
 
Page 55  
 
 
Version date: 12/16/2020 
 
 
than toxicity. 
 
For patients in the phase I portion of the study, dose reductions of CB-839 and capecitabine will 
be permitted during the first cycle (21 days) only if a patient experiences a toxicity that results in 
a DLT. If a patient experiences a DLT, treatment continuation at a lower dose of CB-839 and/or 
capecitabine will be permitted as long as the toxicity has returned to ≤ Grade 1 or baseline within 
14 days. Upon recovery, patients may restart at one CB-839/capecitabine dose level lower. Patients 
who do not recover within 14 days will not be eligible for resumption of treatment with CB-839 
or capecitabine.  
 
After cycle 1, dose reductions or interruptions for adverse events may take place at any time at the 
discretion of the Principal Investigator. Dose interruptions for grade 2 non-hematologic toxicity 
for up to 5 days can be implemented at the discretion of the treating physician to manage clinically 
significant toxicity. No dose reduction is required when resuming treatment. Dose interruptions of 
> 5 days should be discussed with the PI. Patients whose dose is interrupted for > 21 days for any 
reason must be withdrawn from the study unless prior approval from the PI has been obtained for 
study continuation. 
 
Adequate medical management for reversible symptoms using supportive medications must be 
used prior to making a dose modification for these symptoms. 
 
7.1 
CB-839 Dose Modifications 
 
CB-839 will be initiated at the dose per the assigned dose level and will be given in 
combination with capecitabine twice daily throughout the 21 day treatment cycle. 
 
7.1.1 CB-839 Dose Modification Table 
 
Starting CB-839 dose 
(mg) by mouth twice 
daily 
1st Dose Modification 
(mg) by mouth twice 
daily 
2nd Dose Modification 
(mg) by mouth twice 
daily 
400 
200 
discontinue 
600 
400 
200 
800 
600 
400 
 
7.1.2 Hematologic and Non-Hematologic Toxicities (except for liver function changes) 
 
 
 Toxicity 
Grade 
CB-839 Dose Changes 
During Current Treatment 
Period 
Dose Adjustments for  
Resumption of Treatment 
2 (or, for 
baseline grade 
2, worsening to 
grade 3) 
Hold study drug and 
provide supportive care 
Restart at the same dose level upon 
resolution to ≤ Grade 1 or baseline 
3 or 4 
Hold study drug and 
provide supportive care 
Reduce to the next lower dose level 
upon resolution of ≤ Grade 1 or 


CASE 1216 
 
 
 
Page 56  
 
 
Version date: 12/16/2020 
 
 
 
baseline 
 
If symptoms persist for > 14 days 
despite dose interruption, the 
patient must be withdrawn from the 
study 
 
 
7.1.3 Abnormal liver function tests (AST, ALT, bilirubin) 
 
Grade 
CB-839 Modification 
1 
No change in dose 
2 
Reduce CB-839 to the next lower dose level 
≥ 3 
Hold CB-839 until ≤ Grade 1 and resume at the next 
lower dose level 
≥ 3 after resumption of 
treatment 
Hold CB-839 until ≤ Grade 1 and resume at the next 
lower dose level 
 
7.1.4 Non-hematologic Toxicity 
 
 
For other non-hematologic toxicities, dose reductions of CB-839 will be at the discretion 
of the investigator. A dose reduction of 200 mg must be performed with each dose 
reduction. A maximum of 2 dose reductions are permitted. 
 
7.2 
Capecitabine Dose Modifications 
 
 
Capecitabine will be initiated at the dose per the assigned dose level and will be given twice 
daily for the first 14 days out of a 21 day treatment cycle. 
 
Dose modifications should be made according to the following table: 
 
7.2.1  Dose Modification Table 
 
 
Toxicity Grade 
 
During a Course of Therapy 
Dose Adjustment 
for Next Cycle (% 
of starting dose) 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
   1st appearance 
Interrupt until resolved to grade 0-1 
100% 
   2nd appearance 
Interrupt until resolved to grade 0-1 
75% 
   3rd appearance 
Interrupt until resolved to grade 0-1 
50% 
   4th appearance 
Discontinue treatment permanently 
 
Grade 3 
   1st appearance 
Interrupt until resolved to grade 0-1 
75% 
   2nd appearance 
Interrupt until resolved to grade 0-1 
50% 
   3rd appearance 
Discontinue treatment permanently 
 


CASE 1216 
 
 
 
Page 57  
 
 
Version date: 12/16/2020 
 
 
 
 
7.2.2 Hematologic Toxicities 
 
ANC (/mm3) 
 
Platelets (/mm3) 
Modification 
< 1500/mm3 
and/or 
< 100,000/mm3 
Hold until ANC ≥ 
1500/mm3 and platelets 
are ≥ 100,000/mm3, 
resume per dose 
modification table 
≥ 1500/mm3 
and 
≥ 100,000/mm3 
No dose modification 
 
 
7.2.3 Nausea and Vomiting 
 
 
**Adequate medical management for these conditions should be implemented before a 
dose modification is made for one of these symptoms** 
Grade 
Modification 
1 
No change in dose 
2 
Hold until ≤ grade 1; resume at same dose level 
3 
Hold until ≤ 1; resume per dose modification table 
4 
Off protocol therapy 
 
7.2.4 Mucositis, Diarrhea and Esophagitis 
 
 
 
**Adequate medical management for these conditions should be implemented before a 
dose modification is made for one of these symptoms** 
Grade 
Toxicities/Symptoms 
Modification 
1 
Mucositis, esophagitis or diarrhea 
No dose modification 
2 
Diarrhea 
No dose modification 
2 
Mucositis or esophagitis 
Hold until ≤ grade 1 and 
resume per dose 
modification table 
3 
Diarrhea 
Hold until ≤ grade 1; 
resume per dose 
modification table 
3/4 
Mucositis or esophagitis 
Hold until ≤ grade 1; 
resume per dose 
modification table 
 
 
7.2.5 Palmar-Plantar Erythrodysesthesia Syndrome (Hand and Foot Rash) 
 
 
Grade 
Modification 
1 
No dose modification 
2 
Hold until symptoms resolve to grade 0 or 1. 
Resume per dose modification table. 
≥ 3 
Hold until symptoms resolve to grade 0 or 1. 
Resume per dose modification table. 


CASE 1216 
 
 
 
Page 58  
 
 
Version date: 12/16/2020 
 
 
 
 
7.2.6 Hyperbilirubinemia 
 
 
If grade 3 or 4 hyperbilirubinemia occurs that is thought to be related to capecitabine, 
capecitabine should be held until the bilirubin improves to ≤ 3.0 x institutional ULN. When 
ready, resume capecitabine according to the capecitabine dose modification table (Section 
7.2.1) where each episode of grade 3 toxicity results in a dose modification. Discontinue 
treatment permanently for the third grade 3 incident. If the patient has already had a dose 
modification for another toxicity, the new dose level should be used as the baseline for 
making these adjustments. 
 
 
For grade 4 toxicity, resume capecitabine at 50% of the original starting dose for the first 
incident and discontinue treatment permanently for any subsequent incident. If the patient 
has already had a dose modification for another toxicity, the new dose levels should be 
used as the baseline for making these adjustments. 
 
 
 


CASE 1216 
 
 
 
Page 59  
 
 
Version date: 12/16/2020 
 
 
7.2.7 Non-hematologic Toxicity 
 
 
For other non-hematologic toxicities, dose reductions of capecitabine will be at the 
discretion of the investigator. Dose modification should be made according to the dose 
modification table. A maximum of 2 dose reductions are permitted. 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS  
 
The following is a list of AEs (section 8.1) and the reporting requirements associated with observed 
AEs (sections 8.3 and 8.4). 
 
The clinical course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause. 
 
Serious adverse events that are still ongoing at the end of the study period will necessitate follow-
up to determine the final outcome. Any serious adverse event that occurs after the study period is 
considered to be possibly related to the study treatment or study participation will be recorded and 
reported immediately. 
 
8.1 
CB-839 
 
The most commonly encountered toxicities include fatigue, nausea, vomiting, elevation in liver 
function tests (including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and 
alkaline phosphatase), elevation in creatinine, constipation, oral pain and photophobia. These have 
generally been mild and reversible. Elevation in gamma-glutamyltransferase, bilirubin, anorexia, 
anemia and dizziness have been observed as adverse events in rare instances (<2%). It should be 
noted that the rate of GGT elevation is more frequent but these elevations are often considered not 
clinically significant. 
 
See section 7.1 for management recommendations and dose modifications. 
 
8.2 
Capecitabine 
 
Known side effects occurring in patients receiving capecitabine include: 
 
 
Hematologic: anemia, neutropenia, thrombocytopenia 
 
 
Cardiovascular: edema, venous thrombosis 
 
 
Constitutional: fatigue, pyrexia, swelling in hands, feet or abdomen, pain, chest pain 
 
 
Dermatologic: hand-foot syndrome, dermatitis, skin discoloration, alopecia 
 
 
Gastrointestinal: diarrhea, nausea, vomiting, stomatitis, abdominal pain, gastro-intestinal 
motility disorder, constipation, taste disturbance, upper GI inflammatory disorders, 
gastrointestinal hemorrhage, ileus 


CASE 1216 
 
 
 
Page 60  
 
 
Version date: 12/16/2020 
 
 
 
Hepatic: hyperbilirubinemia 
 
 
Infections: bacterial or viral 
 
 
Metabolic: appetite decreased, dehydration 
 
 
Musculoskeletal: back pain, arthralgia 
 
 
Neurologic: peripheral sensory neuropathy, headache, dizziness, insomnia 
 
 
Ocular: eye irritation, visual abnormalities 
 
 
Psychiatric disorders: mood alteration, depression 
 
 
Pulmonary: dyspnea, cough, pharyngeal disorder, epistaxis, sore throat 
 
 
Vascular: venous thrombosis 
 
For a comprehensive list of adverse events related to capecitabine, please refer to the FDA-
approved package insert (21). See section 7.2 for management recommendations and dose 
modifications. 
 
8.3 
Definitions  
 
8.3.1 
Adverse Event   
 
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with administration of a test article in a research study. The event can include abnormal 
laboratory findings, symptoms, or disease associated with the investigational agents or procedures 
associated with the research study. The event does not necessarily have to have a causal 
relationship with the investigational agents under study, any risk associated with the research, the 
research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; the 
collection of identifiable private information in the research; an underlying disease, disorder, or 
condition of the patient; and/or other circumstances unrelated to the research or any underlying 
disease, disorder, or condition of the patient.  
 
8.3.2   Serious Adverse Events  
 
A serious adverse event (SAE) is any adverse experience occurring at any dose that results in any 
of the following outcomes:  
• Results in death.  
• Is a life-threatening adverse experience. The term life-threatening in the definition of 
serious refers to an adverse event in which the patient was at risk of death at the time 
of the event. It does not refer to an adverse event which hypothetically might have 


CASE 1216 
 
 
 
Page 61  
 
 
Version date: 12/16/2020 
 
 
caused death if it were more severe.  
• Requires inpatient hospitalization or prolongation of existing hospitalization. Any 
adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may fulfill 
the criteria of “medically important” and as such may be reportable as a serious adverse 
event dependent on clinical judgment. In addition where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedent.  
• Results in persistent or significant disability/incapacity. The definition of disability 
is a substantial disruption of a person’s ability to conduct normal life’s functions. 
• Is a congenital anomaly/birth defect.  
• Is an important medical event. Important medical events that may not result death, be 
life-threatening, or require hospitalization may be considered a serious adverse 
experience when, based upon 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 medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
disease or disorders, or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. The development of a new cancer is 
always considered an important medical event. 
• Clear progression of neoplasia should not be reported as an AE or SAE. Findings that 
are clearly consistent with the expected progression of the underlying cancer should 
not be reported as an adverse event, and hospitalizations due to the progression of 
cancer do not necessarily qualify for an SAE. All deaths should be reported as SAEs 
regardless of the underlying cause. If there is any uncertainly about a finding being due 
solely to progression of neoplasia, the finding should be reported as an AE or SAE as 
appropriate. 
 
8.3.3 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 months after completion of the study treatment must also 
be reported to the investigator. 


CASE 1216 
 
 
 
Page 62  
 
 
Version date: 12/16/2020 
 
 
• Overdose (e.g., a dose higher than that indicated in the protocol) with our without an 
AE. 
• Abuse (e.g., use for nonclinical reasons) with or without an AE. 
• Inadvertent or accidental exposure with or without an AE. 
 
8.3.4 Adverse Event Evaluation  
 
The investigator or designee is responsible for ensuring that all adverse events (both serious and 
non-serious) observed by the clinical team or reported by the patient which occur after the patient 
has signed the informed consent are fully recorded in the patient’s medical records. Source 
documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the patient to withdraw 
from the study, requiring treatment or causing apparent clinical manifestations, result in a delay or 
dose modification of study treatment, or judged relevant by the investigator), should be reported 
as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide the following 
for all adverse events (both serious and non-serious): 
• Event term (as per CTCAE) 
• Description of the event 
• Date of onset and resolution 
• Expectedness of the toxicity 
• Grade of toxicity  
• Attribution of relatedness to the investigational agent- (this must be assigned by an 
investigator, sub-investigator, or treating physician) 
• Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. no 
action, received medication or other intervention, etc. 
• Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4 will be utilized for AE reporting.  
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the patient. 
The event is usually listed in the Investigator Brochure, consent form or research protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the patient.  
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study drug. 
• Probable – The AE is likely related to the study drug. 
• Possible – The AE may be related to the study drug. 


CASE 1216 
 
 
 
Page 63  
 
 
Version date: 12/16/2020 
 
 
• Unlikely – The AE is doubtfully related to the study drug. 
• Unrelated – The AE is clearly NOT related to the study drug. 
 
Attribution should be assigned for individual components of the treatment regimen. 
 
8.4  
SAE Report Form 
 
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported as 
instructed below.  The electronic FDA SAE reporting forms should not be used.   
 
8.5  
Reporting Procedures for Serious Adverse Events 
 
For the purposes of safety reporting, all adverse events will be reported that occur on or after the 
day the first dose of study drug is received through 30 days after the final dose of study drug. 
Adverse events, both serious and non-serious, and deaths that occur during this period will be 
recorded in the source documents. All SAEs should be monitored until they are resolved or are 
clearly determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
Related AEs will be followed until resolution to baseline or grade 1 or stabilization.  
 
8.5.1 SAE Reporting Requirements 
 
• Participating investigators (all sites) must report all serious adverse events to the Lead Site 
Principal Investigator (e.g. Sponsor-Investigator) within 24 hours of discovery or 
notification of the event. The participating investigator must also provide follow-up 
information on the SAE until final resolution. All SAEs should be reported to the study 
principal investigator: 
 
 
 
David Bajor, MD 
 
 
 
 
 
 
 
• The Lead Site Principal Investigator will review the SAE and report the event to the FDA, 
external collaborator(s), and IRB as applicable. Reporting of SAEs by the PI to the IRB 
will be conducted in accordance with the standard operational procedures and policies of 
the IRB and adequate documentation will be maintained to attest to the fact that the IRB 
was properly notified. 
 
• It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL serious 
adverse events that are unexpected and suspected to be related (SUSAR) that occur on the 
study (e.g. ALL SAEs that occur at each enrolling institution) are reported to all 
participating sites. Serious Unexpected and Suspected Adverse Reaction (SUSAR) 
means an event which requires expedited reporting to the Regulatory Authority and is 
suspected (by the Sponsor-Investigator) to be related to the Study Drug, is unexpected (not 
listed in the Sponsor-Investigator’s Brochure), and is serious (as defined in the Protocol 
section 8.3.2). SUSARs are expedited IND safety reports which are required to be reported 
to the relevant Regulatory Authorities within 7 days (fatal or life-threatening event) or 15 


CASE 1216 
 
 
 
Page 64  
 
 
Version date: 12/16/2020 
 
 
days (all other serious events), the detail for FDA reporting requirements is given below. 
 
• Safety data will be reported in parallel to Calithera Bioscience’s PharmacoVigilance agent 
according to the Safety Data Exchange Agreement at the following: 
 
 
US Toll Free Fax number: 1 (800) 727-8347 
 
eFax forwarded to calithera@primevigilance.com 
 
Email: calithera@primevigilance.com  
 
Institutional Review Board Reporting Requirements: 
 
• Investigative sites will report adverse events to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events.  
 
FDA Reporting 
 
The University Hospitals Principal Investigator, as holder of the IND, will be responsible for all 
communication with the FDA. In accordance with 21 CFR 312.32, the University Hospitals 
Principal Investigator is responsible for notifying the FDA of SAEs that are serious, unexpected 
(not listed in the Investigator Brochure) and judged to be related (i.e., possible, probably, definite) 
to the study agents. Events meeting the following criteria need to be submitted to the FDA as 
Expedited IND Safety Reports. 
 
7 Calendar Day IND Safety Report 
 
Any unexpected fatal or life-threatening suspected adverse event represent especially important 
safety information and, therefore, must be reported more rapidly to FDA (21 CFR 312.32(c)(2)). 
Any unexpected fatal or life-threatening suspected adverse event must be reported to the FDA no 
later than 7 calendar days after the University Hospitals Principal Investigator initial receipt of the 
information (21 CFR 312.32(c)(2)). University Hospitals Principal Investigator will complete a 
Medwatch Form FDA 3500A and notify the FDA by telephone or facsimile transmission. Such 
reports will be notified in parallel to Calithera Biosciences. 
 
15 Calendar Day IND Safety Report 
 
The timeframe for submitting an IND safety report to FDA and all participating investigators is no 
later than 15 calendar days after the University Hospitals Principal Investigator determines that the 
suspected adverse event or other information qualifies for reporting (21 CFR 312.23(c)(1)). This 
includes any serious, unexpected adverse events considered reasonably or possibly related to the 
investigational agent. University Hospitals Principal Investigator will complete a Medwatch Form 
FDA 3500A and notify the FDA by telephone or facsimile transmission. If FDA requests any 
additional data or information, the University Hospitals Principal Investigator must submit it to 
FDA as soon as possible, but no later than 15 calendar days after receiving the request (21 CFR 
312.23(c)(1)(v)). Such reports will be notified in parallel to Calithera Biosciences. 
 
 
 


CASE 1216 
 
 
 
Page 65  
 
 
Version date: 12/16/2020 
 
 
Follow-up IND Safety Report 
 
Any relevant additional information that the University Hospitals Principal Investigator obtains 
that pertains to a previously submitted IND safety report must be submitted to FDA as a Follow-
up IND Safety Report without delay, as soon as the information is available (21 CFR 312.32(d)(2)). 
The University Hospitals Principal Investigator will maintain records of its efforts to obtain 
additional information. 
 
8.6 
SAEs and OnCore 
 
• All SAEs will be entered into OnCore.   
• A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into 
OnCore. 
 
8.7  
Data Safety and Toxicity Committee 
 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial (internal or 
external) are reported to the Case Comprehensive Cancer Center’s Data and Safety Toxicity 
Committee. This submission is simultaneous with their submission to the sponsor and/or other 
regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per CCCC 
Data and Safety Monitoring Plan. 
  
8.8 
Data and Safety Monitoring Plan (DSMP) 
 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and Safety 
Monitoring Plan in accordance with NCI guidelines.  
 
9.0 
PHARMACEUTICAL INFORMATION  
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Sections 8.1 and 8.2. 
 
9.1  
CB-839 
 
  
Name of Agent: 
CB-839 
 
Other Names:   
NA 
 
Product description: CB-839 is provided as 200 mg opaque Swedish orange gelatin capsules or 
as tablets that are manufactured, packaged, and labeled according to current Good Manufacturing 
Practices (cGMP). 
 
Storage requirements: CB-839 capsules should be stored as will be indicated on the study drug 
label—this should be in a clinical site pharmacy at controlled room temperature, defined as 


CASE 1216 
 
 
 
Page 66  
 
 
Version date: 12/16/2020 
 
 
between 20° and 25°C +/- 5°C (i.e. between 15° and 30°C (59° to 86°F). Stability studies being 
carried out on the phase I clinical supplies support storage for CB-839 capsules for at least 24 
months at room temperature. CB-839 HCl tablets must be stored in a secure area with controlled 
access and separately from commercially available and other investigational drugs, preferably in 
a separate location. Any breach of investigational product storage conditions including 
temperature excursions outside the range 15° and 30°C must be reported to the Sponsor upon 
detection and the IP in question must be quarantined until the Sponsor authorizes usage or 
otherwise. Patients will be instructed to store medication according to storage conditions noted on 
the label, out of reach of children or other cohabitants. 
 
Route of administration: CB-839 will be administered orally twice daily with food. The first 
dose of the day should be taken with breakfast and the second dose of the day should be taken with 
dinner.  
 
Absorption, Distribution, Metabolism and Excretion of CB-839 
 
Systemic exposure to CB-839 following oral administration is highly species dependent due to 
significant cross-species differences in absorption and metabolism. The oral bioavailability was 
good in mice and rates when CB-839 was dosed to animals as a solution; the systemic exposure 
increased less than dose-proportionally. On the other hand, the oral exposure and bioavailability 
in dogs and cynomolgus monkeys was low to modest likely due to extensive first-pass metabolism. 
The oral exposure and bioavailability in marmoset monkeys were also low to moderate likely due 
to poor absorption. Based on the in vitro and in vivo ADME data, good oral exposure of CB-839 
in humans was predicted. Ongoing Phase I studies have demonstrated significant exposure 
following oral dosing. 
 
Absorption: The apical-to-basolateral permeability of CB-839 in Caco-2 monolayers was 
determined to be 9.6 x 10-6 cm/sec and is predictive of good permeation through gut wall 
in humans. The aqueous solubility of CB-839 is pH-dependent, with high solubility under 
low pH and poor solubility at neutral pH. The oral bioavailability of 44-70% in mice and 
66-157% in rats demonstrated good absorption of CB-839 in these species. Oral exposure 
of CB-839 in rats was affected by feeding status. Systemic exposure to CB-839 was higher 
in fasted rats than in fed rats following oral administration. However, in Phase I clinical 
trials most patients demonstrated better CB-839 exposures when taking the drug with food. 
 
Distribution: High in vitro plasma protein binding of CB-839 was observed in mouse, rat, 
dog, and human plasma at 1 and 10 uM using an ultracentrifugation approach; there were 
no significant differences observed among species. The mean plasma protein binding was 
98.0, 97.0, 97.9, and 99.1%, respectively. Following a single oral dose of 200 mg/kg to 
scid/bg mice, CB-839 was broadly distributed to systemic tissues including heart, lung, 
spleen, muscle, and subcutaneously-implanted tumors; brain had 20-fold lower CB-839 
concentration than plasma. 
 
Metabolism: In vitro metabolic stability of CB-839 was evaluated using cryopreserved 
hepatocytes derived from mice, rats, dogs, monkeys (cynomolgus, rhesus, and marmoset), 
and humans. CB-839 was most stable in human hepatocytes. In hepatocytes from marmoset 


CASE 1216 
 
 
 
Page 67  
 
 
Version date: 12/16/2020 
 
 
monkeys, CB-839 was also stable. Gender differences were observed only in rats; CB-839 
was more stable in rat hepatocytes from females than males. CB-839 was considerably less 
stable in the other species tested. The in vitro clearance derived from the hepatocyte 
stability is well correlated with in vivo clearance in mice, rats, dogs, marmoset monkeys, 
and cynomolgus monkeys. The human clearance was predicted to be slow for CB-839 
based upon hepatocyte studies in vitro. Two pathways of metabolic transformation of CB-
839 have been identified in vitro in hepatocytes and in vivo; amide hydrolysis and, to a 
lesser extent, P450-mediated hydroxylation. There are considerable differences in the 
mechanism of metabolism across species. Amide hydrolysis appears to be the predominant 
pathway of metabolism of CB-839 in rat and marmoset monkey hepatocytes. Amide 
hydrolysis also contributes significantly to the metabolism of CB-839 in hepatocytes from 
mice, cynomolgus monkeys, and rhesus monkeys. The relative abundance of metabolites 
in hepatocytes is correlated with those observed in vivo for all species tested (mice, rats, 
dogs, marmoset monkeys, and cynomolgus monkeys). In human hepatocytes, metabolites 
resulting from both amide hydrolysis and hydroxylation of the thiadiazole and pyridazine 
rings were detected. However, all these metabolites have low abundances (<10%) in human 
hepatocyte incubations up to 4 hr and no metabolites unique to human have been observed. 
Based on the in vitro hepatocyte stability and metabolite profiling data, we chose rat and 
marmoset monkey as GLP toxicology species. Significant exposures of major human 
metabolites (the hydrolysis products of CB-839) were observed in the plasma samples from 
both CX-839 clinical Phase I trials and GLP toxicity studies. 
 
Excretion: When CB-839 was dosed orally to bile duct-cannulated rats, thereby not 
allowing bile flow to the intestine, 0.3-1.2% of orally dosed CB-839 appeared in biliary 
excretion predominately in the first 2 hr after dosing. A 41-49% reduction in systemic 
exposure to CB-839 was seen relative to normal rats. Further studies are needed to better 
understand biliary excretion of CB-839 in rats. 
 
Drug-drug interaction: Direct and time-dependent inhibition (TDI) of human cytochrome 
P450 (CYP) enzymes by CB-839 was evaluated in human liver microsomes. CB-839 was 
no an inhibitor for CYP1A2, CYP2B6, CPY2C8, CPY2C19, CYP2D6 and CYP3A. CB-
839 appears to be a moderate inhibitor of CYP2C9 (~40-50% inhibition of 5 uM). Further 
studies are needed to understand the mechanism of inhibition. CB-839 was not an inducer 
of human CYP1A2, 2B6, or 3A4 in cryopreserved hepatocytes from three donors. CB-839 
is a moderate substrate of efflux transporters with an efflux ratio of 6.2 in Caco-2 
monolayers. 
 
Drug Procurement: CB-839 will be supplied for this study by Calithera Biosciences and will be 
stored in the Investigational Pharmacy.  
 
Packaging and labeling: Tablets and capsules are packaged in white plastic bottles with a label 
on the outside identifying the investigational product, capsule strength, storage conditions, 
investigational drug supplier, lot number and date of manufacture. Each bottle is sealed with a 
tamper-evident seal and a child-proof cap. Each bottle contains fifty (50) tablets or capsules. 
  
 
 


CASE 1216 
 
 
 
Page 68  
 
 
Version date: 12/16/2020 
 
 
Drug Accountability: Drug storage, dispensing and accountability will be managed by the 
University Hospitals Seidman Cancer Center Investigational Pharmacy according to standard 
protocol. Patients will be asked to keep a pill diary throughout the duration of treatment (Appendix 
II). 
 
Drug Destruction: At the completion of the study, there will be a final reconciliation of drug 
shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and 
documented prior to return or destruction of unused study drug. Drug destroyed on site will be 
documented in the study files. 
 
Other Information: While receiving CB-839, the following nursing/patient implications apply: 
• Monitor CBC, chemistries and liver function tests prior to drug administration. 
• Symptom management of nausea, vomiting, etc. as needed. 
• Drug should be administered with breakfast and dinner. 
 
9.2  
Capecitabine 
 
  
Name of Agent:  
Capecitabine 
 
Other Names:   
Xeloda 
 
Product description: Capecitabine is supplied as biconvex, oblong film-coated pills, available as 
500 mg pills (peach).  
 
Storage requirements: Capecitabine pills should be stored at 25°C, with excursions permitted to 
15 to 30˚C. 
 
Route of administration: Capecitabine is taken orally and needs to be taken within 30 minutes 
after a meal.  
 
Drug Procurement: Capecitabine is commercially available. The cost of this agent will be the 
patient’s responsibility.  
 
Drug Accountability: Patients will be asked to maintain a pill diary throughout the duration of 
the study (Appendix III). 
  
Other Information: While receiving capecitabine therapy, the following nursing/patient 
implications apply: 
• Monitor CBC and platelet count prior to drug administration. 
• Symptom management of expected nausea, vomiting, diarrhea and hand-foot skin 
syndrome. 
• Drug should be administered at least 12 hours (+/- 2 hours) apart. 
• Capecitabine pills should be swallowed with water within 30 minutes after a meal. 
• Capecitabine pills may not be crushed. 
 


CASE 1216 
 
 
 
Page 69  
 
 
Version date: 12/16/2020 
 
 
10.0 
CORRELATIVE STUDIES 
 
10.1 
Glutaminase Activity Level 
 
The purpose of assessing the change in glutaminase activity level is to determine if administration 
of CB-839 results in a decrease in glutaminase activity in post-treatment platelets and biopsy 
specimens as compared to prior to CB-839 treatment using a glutaminase inhibition assay. 
 
10.1.1 Background  
 
As is outlined in section 1.1, PIK3CA mutant cancer cells are dependent on glutamine for survival. 
To enter the TCA cycle, glutamine is first deaminated by glutaminase (GLS) to generate glutamate. 
Glutamate is then converted to alpha-ketoglutarate (alpha-KG), a TCA cycle intermediate, by 
either an aminotransferase (e.g. GPTs and GOTs) or a glutamate dehydrogenase. Glutamine 
metabolites are utilized to produce ATP, lipids and other macromolecules, thereby promoting 
tumor growth (4). CB-839 is a glutaminase inhibitor that we hypothesize will starve colorectal 
cancer tumors that are PIK3CA mutant of glutamine, thereby inhibiting growth. To assess if CB-
839 is producing a pharmacodynamic effect in both platelets and tumors, glutaminase activity may 
be measured via a glutaminase inhibition assay as has been previously described (17,19). 
 
10.1.2   Rationale for Analysis 
 
Demonstration of glutaminase inhibition in both platelets and tumor specimens following 
treatment with single agent CB-839 as compared to prior to initiation of treatment will provide a 
pharmacodynamic marker indicating that CB-839 is reaching its intended target. If correlation is 
seen between platelets and tumor specimens in regard to level of inhibition, it may be necessary to 
assess platelets only in regard to glutaminase inhibition in subsequent studies. See section 14.4 for 
statistical plan. 
 
10.1.3 Collection of Specimens 
 
During the phase II component of the study, patients will undergo either CT or US guided biopsy 
of a metastatic focus both prior to the initiation of treatment and 10-15 days following initiation 
of treatment. The pre-treatment biopsy may be performed up to 14 days prior to the initiation of 
treatment.  The pre-treatment biopsy must be done after the 4-week washout from previous 
systemic therapy. 
 
Tumor Biopsies: Patients will undergo biopsy in the University Hospitals Cleveland Medical 
Center (UHCMC) Department of Radiology. If being treated at the Taussig Cancer Institute (TCI) 
of the Cleveland Clinic, patients will undergo biopsy in the Cleveland Clinic Department of 
Radiology. Use of CT or US guidance for each biopsy will be per the discretion of the physician 
performing the biopsy and the same metastatic focus of tumor will be biopsied at baseline and 10-
15 days following initiation of treatment. If for whatever reason the same lesion cannot be 
biopsied, a second lesion may be biopsied but this must be noted and recorded. Biopsies will be 
conducted according to standard practice. Four core biopsies will be obtained for each patient 
during each biopsy. Fine needle aspiration biopsies are NOT appropriate. Three RNA cryovials 


CASE 1216 
 
 
 
Page 70  
 
 
Version date: 12/16/2020 
 
 
will be labeled with the date, patient initials, patients study number and vial number. All study 
personnel, particularly those handling RNA cryovials, must wear clean gloves. Each of the three 
core biopsies will be placed in its own cryovial. Two cryovials should contain approximately 1.5 
ml sterile PBS for placement of a fresh specimen and then will be placed on wet ice (see section 
10.4 for further details). The remaining two cryovials will immediately be placed in dry ice or 
liquid nitrogen. Biopsies collected at UHCMC will be transported to the Case Comprehensive 
Cancer Center, Translational Research Shared Resource for the Wang lab to pick up. Biopsies 
collected at TCI will be transported to the Cleveland Clinic Central Biorepository for the Wang 
lab to pick up. Biopsies collected at Weill Cornell College of Medicine will be transported to the 
Laboratory of Dr. Manish Shah for processing. The frozen specimens will be processed 
individually with the second specimen being processed only if insufficient nucleic acid is 
recovered or if histologic review identifies the presence of necrotic tumor in the first specimen. 
The remaining fresh frozen specimens will be stored for later use.  
 
Platelets: Approximately 24ml of whole blood will be collected via peripheral venipuncture into 
3, 10 ml yellow top ACD-A (Acid Citric Dextrose (ACD) Solution A) tubes for analysis of 
glutaminase activity in platelets. Whole blood samples will be collected on wet ice and transported 
to the Translational Research Shared Resource for processing and storage. Specimens will be 
collected at the time of the pre-treatment tissue biopsy as well as 10-15 days following initiation 
of treatment (obtained on the same day as the tissue biopsy). 
 
10.1.4 Handling of Specimens 
 
10.2.4.1 
Handling of Specimens at UHCMC 
 
The vials containing PBS will be placed on wet ice (>5 lb), and the other two cryovials will 
immediately be placed in dry ice (>5 lb). Personnel from the Case Comprehensive Cancer Center, 
Translational Research Shared Resource will then be contacted (see below) for transportation, 
tracking and storage. Upon acquisition, TRSR personnel will contact the Wang Lab to pick up the 
PBS containing vial for organoid culture and analyses as described in the Laboratory Manual and 
the frozen specimens for storing at -80°C. 
 
Translational Research Shared Resource Contact Information (UH Seidman) 
ATTN: Erin Hohler 
University Hospitals Cleveland Medical Center 
11100 Euclid Avenue 
Seidman Cancer Center,
 
Cleveland, OH 44106 
 
 
 
 
Wang Lab Contact Information: 
Yiqing Zhao 
 
 


CASE 1216 
 
 
 
Page 71  
 
 
Version date: 12/16/2020 
 
 
Email: 
 
 
John Wang 
 
 
 
 
Wolstein Research Building 
 
2013 Cornell Road 
Cleveland, OH 44106 
 
10.1.4.2 
Handling of Specimens at TCI 
 
The fresh biopsy vials (containing PBS) will be placed on wet ice (>5 lb), and the other two 
cryovials will immediately be placed in dry ice (>5 lb). Personnel from the Cleveland Clinic 
Central Biorepository will then be contacted (see below) for transportation, tracking and storage. 
Upon acquisition, the Cleveland Clinic Central Biorepository personnel will contact the Wang Lab 
to pick up the PBS containing vial for organoid culture and analysis as described in the Laboratory 
Manual and the frozen specimens for storing at -80°C. 
 
The Cleveland Clinic Central Biorepository contact information 
ATTN: Brad Skilton 
Cleveland Clinic Central Biorepository 
Department of Pathology—Tissue Procurement 
 
 
 
Wang Lab Contact Information: 
Yiqing Zhao 
 
 
 
 
John Wang 
 
 
 
 
Wolstein Research Building 3204 
2013 Cornell Road 
Cleveland, OH 44106 
 
10.1.4.3 
Handling of Specimens at Weill Cornell College of Medicine 
 
The fresh biopsy vials (containing PBS) will be placed on wet ice (>5 lb), and the other two 
cryovials will immediately be placed in dry ice (>5 lb). Personnel from the Laboratory of Dr. 


CASE 1216 
 
 
 
Page 72  
 
 
Version date: 12/16/2020 
 
 
Manish Shah will then be contacted (see below) for processing. The PBS containing vial will be 
cultured as organoids in the Shah lab. The frozen specimens will be shipped to the Wang laboratory 
according to procedures described in the Laboratory Manual. 
 
Shah Lab Contact Information 
 
Laboratory of Dr. Manish Shah 
 
510 East 70th Street 
Weill Cornell Medical College 
New York, New York 10065 
 
10.1.5 Analytical Laboratory 
 
Personnel in the Wang Lab will process fresh frozen specimens. One core biopsy per patient will 
be divided on a metal plate that is kept cold with dry ice. Additional biopsies will be archived and 
used on an as needed basis (see section 10.1.3). Each biopsy will be sectioned into 5 sections. 
Light microscopy to confirm the histologic presence of viable cancer tissue will be conducted on 
peripheral sections (H&E staining). Tissue sections immediately adjacent to and internal to the 
microscopy confirmed sections will be used for subsequent pharmacodynamic analysis 
(glutaminase activity, nucleotide levels, DNA extraction, RNA extraction) (22). 
 
Wang Lab Contact Information: 
Yiqing Zhao  
 
 
 
  
John Wang 
 
  
 
 
Wolstein Research Building 
 
2013 Cornell Road 
Cleveland, OH 44106 
 
Histologically confirmed fresh frozen specimens will be used by the Translational Research 
Shared Resource or the Wang Lab for conduct of the glutaminase assay. 
 
Translational Research Shared Resource 
ATTN: Erin Hohler 
University Hospitals Cleveland Medical Center 
11100 Euclid Avenue 
Seidman Cancer Center, 
 
Cleveland, OH 44106 
 


CASE 1216 
 
 
 
Page 73  
 
 
Version date: 12/16/2020 
 
 
 
 
 
10.1.6   Methods  
 
Glutaminase activity level will be measured using a glutaminase inhibition assay in both solid 
tumors and platelets.  
 
Tumor Biopsy Specimens: The glutaminase inhibition assay will be conducted during the phase II 
portion of the study and will require fresh frozen biopsy specimens. These will be obtained as 
described in section 10.1.3. Patients will undergo a pretreatment biopsy up to 14 days prior to the 
initiation of treatment, then will undergo a second biopsy on day 10-15 of treatment. Only the post-
treatment tumor biopsy will be used for the glutaminase activity assay. Samples will be frozen in 
liquid nitrogen and transferred to the Translational Research and Pharmacology Core on dry ice. 
Specimens will be evaluated for glutaminase activity per the Glutaminase Activity Assay Protocol 
for Platelets and Tumor Biopsy Samples (methods provided in laboratory manual). 
 
Platelets: The glutaminase inhibition assay will be conducted during the phase II portion of the 
study. 24ml of blood will be collected from each patient on day 10-15 of treatment and will be 
collected on the same day as the post-treatment tissue biopsy. Specimens will be evaluated for 
glutaminase activity per the Glutaminase Activity Assay Protocol for Platelets and Tumor Biopsy 
Samples (methods provided in laboratory manual). Processing of samples will be done for each of 
the sites as outlined in section 10.2.4 and per the laboratory manual. 
 
10.2 
Pharmacokinetic analysis of CB-839 
 
The purpose of conducting a pharmacokinetic analysis of CB-839 is to determine if there is a 
correlation seen between plasma trough levels of CB-839 and both glutaminase activity levels (in 
tumors and platelets) and UPP1 gene expression. 
 
10.2.1  Background  
 
Pharmacokinetic sampling was performed on Cycle 1, Day 1 (C1D1), C1D15 and D1 of each 
subsequent treatment cycle in each of the previously conducted phase I studies (17,18). A dose 
dependent relationship was observed with CB-839 exposure increasing with dose. The half-life of 
CB-839 was determined to be 4 hours. Additional pharmacokinetic parameters (AUC, Cmax and 
Cmin) demonstrated greater variability with TID dosing than with BID dosing. Additionally, Cmin 
fell below a target concentration of 200 ng/mL in 46% of patients receiving 400 mg or higher TID 
regimens while all patients receiving BID dosing with 600 mg maintained a Cmin greater than the 
200 ng/mL target concentration. 
 
Pharmacodynamics of CB-839 were also assessed in both previously conducted phase I studies. 
Glutaminase activity was measured in circulating platelets as well as tumor biopsy specimens. 
Blood samples collected at baseline and four hours following CB-839 treatment were assessed for 
glutaminase inhibition and demonstrated a dose dependent relationship. At a CB-839 treatment 
dose of 600 mg BID, greater than 90% glutaminase inhibition should be observed even at Cmin. 


CASE 1216 
 
 
 
Page 74  
 
 
Version date: 12/16/2020 
 
 
Glutaminase activity within tumor specimens also demonstrated a dose-response relationship. 
 
10.2.2  Rationale for Analysis 
 
Pharmacokinetic analysis of patients receiving CB-839 at each dose level will allow for 
correlations to be made between trough levels of CB-839 and glutaminase activity level. 
 
10.3.3  Collection of Specimens 
 
Approximately 2ml of blood will be collected via peripheral venipuncture into an EDTA tube 
(lavender top). This blood sample will be used to measure concentrations of CB-839 of each 
pharmacokinetic blood collection. The exact actual time of collection must be noted in the source 
documents and eCRFs.  
 
For collecting specimens, the following protocol should be followed: 
• Label a 3.0 mL K2EDTA vacutainer tube. 
• Label 2 cryovials. 
• Prepare an ice bucket. 
• Draw blood into the 3.0 mL vacutainer tube. Ensure that tube is filled with a minimum 
of 2 mL of blood. 
• Samples should be thoroughly mixed by completely and gently inverting the tube 8 
times. If a complete 2 mL volume of blood was not obtained, please discard sample 
and re-collect with a fresh vacutainer. 
• The whole blood samples should be placed on ice immediately after collection. Try not 
to wet the label. 
• Plasma should be prepared within 30 minutes of collection by centrifuging the blood 
samples at 2000 x g for 10 minutes at 4˚C. 
• Split the resultant plasma into two aliquots of approximately equal amounts (at least 
0.3 mL) and transfer into the two labeled cryovials. 
• Place each of the three samples immediately into the cryobox and store at -70˚C until 
shipment. 
 
Note: PK assay will be conducted at a central laboratory where the assay for CB-839 has 
been validated. Details are given below and in the laboratory manual: 
 
 
 
 
 
Intertek Pharmaceutical Services 
 
 
 
 
 
 
 
 
 
10420 Wateridge Circle 
 
 
 
 
San Diego, CA 92121 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 14.0 for statistical plan.  
 
10.2.4  Handling of Specimens 


CASE 1216 
 
 
 
Page 75  
 
 
Version date: 12/16/2020 
 
 
 
See section 10.1.4 for handling of specimens. PK specimens will be shipped to Intertek 
Pharmaceutical Services as outlined (see section 10.2.5). 
 
10.2.5  Analytical Laboratory 
 
Pharmacokinetic analysis will be carried out by central lab 
 
 
 
 
 
Intertek Pharmaceutical Services 
 
 
 
 
 
 
 
 
 
10420 Wateridge Circle 
 
 
 
 
San Diego, CA 92121 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.2.6  Methods 
 
All plasma samples will be analyzed for CB-839 by using a validated liquid chromatography 
tandem mass spectrometry (LC-MS/MS) method of appropriate specificity and sensitivity 
according to Good Laboratory Practices (GLPs). 
 
10.3 
Additional Pharmacodynamic Analyses 
 
An evaluation of nucleotide levels as well as a whole exome analysis and an RNA seq analysis 
will be conducted on baseline and post-treatment tissue biopsies to determine the 
pharmacodynamic effect of CB-839 and capecitabine on PIK3CA mutant colorectal cancer. This 
will be conducted during the phase II portion of the trial.  
 
10.3.1 Background and Rationale 
 
Glutamine can be deaminated to generate ammonia as a nitrogen donor for nucleotide synthesis. 
Since CB-839 blocks glutamine deamination, it should impact nucleotide synthesis. On the other 
hand, the 5-FU metabolite, FdUMP, inhibits thymidylate synthase and blocks production of dTTP, 
thereby perturbing levels of other nucleotides through various feedback mechanisms. Taken 
together, these observations suggest that the combination of CB-839 with 5-FU may have additive 
or synergistic effects on cellular nucleotide pools. As such, we will determine nucleotide levels in 
pre- and post-treatment biopsy specimens to determine the impact of CB-839 and capecitabine on 
nucleotide levels. 
 
Genome wide changes are anticipated to occur with the administration of CB-839 and capecitabine 
on both the DNA and RNA level. We will therefore use tumor tissue to determine changes 
occurring in DNA with pre- and post-treatment assessments of the genome via whole genome 
sequencing and also changes in tumor tissue at the expression level by performing pre- and post-
treatment RNA seq analyses. 
10.3.2 Collection and Handling of Specimens 


CASE 1216 
 
 
 
Page 76  
 
 
Version date: 12/16/2020 
 
 
 
See sections 10.1.3 and 10.1.4 for collection and handling of specimens. 
 
10.3.3  Analytical Laboratory 
 
Nucleotide levels will be measured in the Proteomics Shared Resource by Dr. Yan Xu as outlined 
in the laboratory manual.  
 
Specimens will be processed for whole exome sequencing and RNA seq by the Wang Lab: 
 
Wang Lab Contact Information: 
Yiqing Zhao  
 
 
 
  
John Wang 
 
  
 
 
Wolstein Research Building 
 
2013 Cornell Road 
Cleveland, OH 44106 
10.3.4 Methods 
 
Please see the Laboratory Manual for methods on measurement of nucleotide levels, whole exome 
sequencing and RNA seq. 
 
10.4 
Generation of Organoids 
 
10.4.1 Background  
 
The purpose of generating organoids from patient tissue specimens is to allow for a sustained 
source of genetic material upon which additional pharmacodynamic assessments may be 
performed. This could be either due to limited tissue being available to perform the planned 
assessments or for material to remain available for future assessments and additional research is 
conducted. 
 
10.4.2   Rationale for Analysis 
 
Given the limited material available for molecular analyses, the generation of organoids from 
patient tissue specimens is a way to generate additional molecular material that will allow for 
completion of the planned assessments. 
 
10.4.3 Collection of Specimens 


CASE 1216 
 
 
 
Page 77  
 
 
Version date: 12/16/2020 
 
 
 
During the phase II component of the study, patients will undergo either CT or US guided biopsy 
of a metastatic focus both prior to the initiation of treatment and 10-15 days following initiation 
of treatment. The pre-treatment biopsy may be performed up to 14 days prior to the initiation of 
treatment. 
 
Tumor Biopsies: Patients will undergo biopsy in the University Hospitals Cleveland Medical 
Center (UHCMC) Department of Radiology. If being treated at the Taussig Cancer Institute (TCI) 
of the Cleveland Clinic, patients will undergo biopsy in the Cleveland Clinic Department of 
Radiology. If being treated at the Weill Cornell College of Medicine, patients will undergo biopsy 
in the Weill Cornell College of Medicine Department of Radiology. Use of CT or US guidance for 
each biopsy will be per the discretion of the physician performing the biopsy and the same 
metastatic focus of tumor will be biopsied at baseline and 10-15 days following initiation of 
treatment. If for whatever reason the same lesion cannot be biopsied, a second lesion may be 
biopsied but this must be noted and recorded. Biopsies will be conducted according to standard 
practice. Three core biopsies will be obtained for each patient during each biopsy. Fine needle 
aspiration biopsies are NOT appropriate. Three RNA cryovials will be labeled with the date, 
patient initials, patients study number and vial number. All study personnel, particularly those 
handling RNA cryovials, must wear clean gloves. Each of the three core biopsies will be placed in 
its own cryovial. One cryovial, should contain approximately 1.5 ml of sterile PBS for placement 
of a fresh specimen and then will be placed on wet ice (see section 10.4 for further details). The 
remaining two cryovials will immediately be placed in dry ice or liquid nitrogen. Biopsies 
collected at UHCMC will be transported to the Case Comprehensive Cancer Center, Translational 
Research and Pharmacology Core Facility for the Wang lab to pick up. Biopsies collected at TCI 
will be transported to the Cleveland Clinic Central Biorepository for the Wang lab to pick up. 
Biopsies collected at Weill Cornell College of Medicine will be transported to the laboratory of 
Dr. Manish Shah for processing. The frozen specimens will be processed individually with the 
second specimen being processed only if insufficient nucleic acid is recovered or if histologic 
review identifies the presence of necrotic tumor in the first specimen. The remaining fresh frozen 
specimens will be stored for later use. 
 
10.4.4 Handling of Specimens 
 
10.4.4.1 
Handling of Specimens at UHCMC 
 
The vial containing PBS will be placed on wet ice (>5 lb). Personnel from the Case Comprehensive 
Cancer Center, Translational Research Shared Resource will then be contacted (see below) for 
transportation, tracking and storage. Upon acquisition, TRSR personnel will contact the Wang Lab 
to pick up the PBS containing vial for organoid culture and analyses as described in the Laboratory 
Manual. 
 
Translational Research Shared Resource Contact Information (UH Seidman) 
ATTN: Erin Hohler  
University Hospitals Case Medical Center  
11100 Euclid Avenue  
Seidman Cancer Center,
  


CASE 1216 
 
 
 
Page 78  
 
 
Version date: 12/16/2020 
 
 
Cleveland, OH 44106  
  
  
  
 
Wang Lab Contact Information: 
Yiqing Zhao  
 
 
 
  
John Wang 
 
  
 
 
Wolstein Research Building 
 
2013 Cornell Road 
Cleveland, OH 44106 
 
10.4.4.2 Handling of Specimens at TCI 
 
The vial containing PBS will be placed on wet ice (>5 lb). Personnel from the Cleveland Clinic 
Central Biorepository will then be contacted (see below) for transportation, tracking and storage. 
Upon acquisition, the Cleveland Clinic Central Biorepository personnel will contact the Wang Lab 
to pick up the PBS containing vial for organoid culture and analyses as described in the Laboratory 
Manual. 
 
The Cleveland Clinic Central Biorepository contact information 
ATTN: Brad Skilton 
Cleveland Clinic Central Biorepository 
 
 
 
 
Wang Lab Contact Information: 
Yiqing Zhao  
 
 
 
  
John Wang 
 
  
 
Wolstein Research Building 
 


CASE 1216 
 
 
 
Page 79  
 
 
Version date: 12/16/2020 
 
 
2013 Cornell Road 
Cleveland, OH 44106 
 
10.4.4.3 Handling of Specimens at Weill Cornell College of Medicine 
 
The vial containing PBS will be placed on wet ice (>5 lb). Personnel from the Laboratory of Dr. 
Manish Shah for processing (see below).  The PBS containing vial will be cultured as organoids 
in the Shah lab. The frozen specimens will be shipped to the Wang laboratory according to 
procedures described in the Laboratory Manual. 
 
Shah Lab Contact Information 
Attn: Kyle Bocchino 
Laboratory of Dr. Manish Shah 
 
510 East 70th Street 
Weill Cornell Medical College 
New York, New York 10065 
 
10.4.5 Analytical Laboratory 
 
Fresh specimens at UHCMC and TCI will be processed in the laboratory of Zhenghe (John) Wang. 
 
Wang Lab Contact Information: 
Yiqing Zhao  
 
 
 
  
John Wang 
 
  
 
 
Wolstein Research Building 
 
2013 Cornell Road 
Cleveland, OH 44106 
 
Fresh specimens at Weill Cornell College of Medicine will be processed in the laboratory of Dr. 
Manish Shah. 
 
Weill Cornell Medical College 
Attn: Kyle Bocchino 
Laboratory of Dr. Manish Shah 
 
510 East 70th Street 
New Yor, NY 10065 
 
10.4.6   Methods  


CASE 1216 
 
 
 
Page 80  
 
 
Version date: 12/16/2020 
 
 
 
The generation of organoids will be conducted during the phase II portion of the study. And will 
require fresh biopsies. These will be obtained as described in section 10.4.3. Patients will undergo 
a pretreatment biopsy up to 14 days prior to the initiation of treatment, then will undergo a second 
biopsy on day 10-15 of treatment. Samples will be placed fresh in sterile PBS and placed on wet 
ice and will be transferred to the laboratory of Dr. Zhenghe Wang for processing. Organoids will 
be generated as outlined in the laboratory manual. 
 
11.0  STUDY PARAMETERS AND CALENDAR  
 
11.1 
Phase I Study Parameters 
 
11.1.1 Screening Evaluation  
 
Screening studies and evaluations will be used to determine the eligibility of each patient for study 
inclusion. All evaluations must be completed ≤ 21 days prior to administration of protocol therapy. 
 
The following should be obtained at baseline: 
-   Informed consent 
-   Demographics 
-   Medical History 
-   Complete physical examination 
-   Height 
-   Weight 
-   Vital signs including temperature, heart rate, blood pressure and respiratory rate 
-   Concomitant medications including all over the counter medications and supplements 
(note that if patients are on a PPI, transition to an H2 blocker prior to treatment is required) 
-   ECOG performance status 
-   Baseline symptom/adverse event assessment 
-   Laboratory studies 
 
-   Complete blood count (CBC) with differential 
 
-   Comprehensive metabolic panel 
 
-   Calculated creatinine clearance if creatinine and/or BUN are abnormal 
 
-   Pregnancy test (if female of reproductive age) 
-   CT of the chest, abdomen and pelvis 
-   Baseline CT/US guided tumor biopsy 
 
11.1.2 Treatment Period 
 
CB-839 and Capecitabine, Cycle 1, Day 1 
All assessments may be performed up to 24 hours prior to treatment. 
 
-   Physical examination 
 
-   Weight 
 
-   Vital signs including temperature, heart rate, blood pressure and respiratory rate 
 
-   Concomitant medications including over the counter medications and supplements 
 
-   ECOG performance status 


CASE 1216 
 
 
 
Page 81  
 
 
Version date: 12/16/2020 
 
 
 
-   Symptom/adverse event assessment 
 
-   Laboratory studies  
 
 
-   Complete blood count (CBC) with differential 
 
 
-   Comprehensive metabolic panel 
 
 
-   Calculated creatinine clearance if creatinine and/or BUN are abnormal 
 
-   Administration of CB-839 by mouth twice daily for a 21 day treatment cycle 
 
-   Administration of capecitabine by mouth twice daily for first 14 days of 21 day cycle 
 
CB-839 and Capecitabine, Cycle 1, Day 8 and Day 15 
Labs may be obtained +/- one day. 
 
-   Symptom/adverse event assessment 
-   Laboratory studies 
 
 
-   Complete blood count (CBC) with differential 
 
 
-   Comprehensive metabolic panel 
 
 
-   Calculated creatinine clearance if creatinine and/or BUN are abnormal 
 
 
-   Pharmacokinetic assessment prior to morning dose of CB-839 (day 15 only) 
 
CB-839 and Capecitabine, Cycle 2 and beyond, Day 1 
All assessments may be performed +/- one day 
 
-   Physical examination 
 
-   Weight 
 
-   Vital signs including temperature, heart rate, blood pressure and respiratory rate 
 
-   Concomitant medications including over the counter medications and supplements 
 
-   ECOG performance status 
 
-   Symptom/adverse event assessment 
 
-   Laboratory studies  
 
 
-   Complete blood count (CBC) with differential 
 
 
-   Comprehensive metabolic panel 
 
 
-   Calculated creatinine clearance if creatinine and/or BUN are abnormal 
 
-   Administration of CB-839 by mouth twice daily for a 21 day treatment cycle 
 
-   Administration of capecitabine by mouth twice daily for first 14 days of 21 day cycle 
 
CB-839 and Capecitabine, Cycle 3, sometime between days 15-21 of treatment cycle 
 
-   CT of the chest, abdomen and pelvis for restaging evaluation 
 
Subsequent CT imaging of the chest, abdomen and pelvis should be performed on an every 
9 week basis +/- one week for as long as patient is receiving study treatment. 
 
11.2 
Phase II Study Parameters 
 
11.2.1 Screening Evaluation  
 
Screening studies and evaluations will be used to determine the eligibility of each patient for study 
inclusion. All evaluations must be completed ≤ 21 days prior to administration of protocol therapy 
(with the exception of the PIK3CA status which may be obtained at any time). 
The following should be obtained at baseline: 


CASE 1216 
 
 
 
Page 82  
 
 
Version date: 12/16/2020 
 
 
-   Informed consent 
-   Demographics 
-   Medical History 
-   Complete physical examination 
-   Height 
-   Weight 
-   Vital signs including temperature, heart rate, blood pressure and respiratory rate 
-   Concomitant medications including all over the counter medications and supplements 
(note that if patients are on a PPI, transition to an H2 blocker prior to treatment is required) 
-   ECOG performance status 
-   Baseline symptom/adverse event assessment 
-   Laboratory studies 
 
-   Complete blood count (CBC) with differential 
 
-   Comprehensive metabolic panel 
 
-   Calculated creatinine clearance if creatinine and/or BUN are abnormal 
 
-   CEA (carcinoembryonic antigen) blood test 
 
-   Pregnancy test (if female of reproductive age) 
-   CT of the chest, abdomen and pelvis 
-   Baseline CT/US guided tumor biopsy 
 
11.2.2 Treatment Period 
 
CB-839 and Capecitabine, Cycle 1, Day 1 
All assessments other than tumor biopsy and pharmacokinetics may be performed up to 24 hours 
prior to treatment. 
 
-   Physical examination 
 
-   Weight 
 
-   Vital signs including temperature, heart rate, blood pressure and respiratory rate 
 
-   Concomitant medications including over the counter medications and supplements 
 
-   ECOG performance status 
 
-   Symptom/adverse event assessment 
 
-   Laboratory studies  
 
 
-   Complete blood count (CBC) with differential 
 
 
-   Comprehensive metabolic panel 
 
 
-   Calculated creatinine clearance if creatinine and/or BUN are abnormal 
 
-   Administration of CB-839 by mouth twice daily for a 21 day treatment cycle 
 
-   Administration of capecitabine by mouth twice daily for first 14 days of 21 day cycle 
 
CB-839 and Capecitabine, Cycle 1, Day 8 and Day 15 
Labs may be obtained +/- one day. 
 
-   Symptom/adverse event assessment 
-   Laboratory studies 
 
 
-   Complete blood count (CBC) with differential 
 
 
-   Comprehensive metabolic panel 
 
 
-   Calculated creatinine clearance if creatinine and/or BUN are abnormal 
CB-839 and Capecitabine, Cycle 1, Day 10-15 


CASE 1216 
 
 
 
Page 83  
 
 
Version date: 12/16/2020 
 
 
 
-   CT/US guided tumor biopsy 
 
-   Platelet glutaminase assay (to be obtained the same day as the tumor biopsy) 
 
-   Pharmacokinetic assessment prior to morning dose of CB-839 (day 15 only) 
 
CB-839 and Capecitabine, Cycle 2 and beyond, Day 1 
All assessments may be performed +/- one day 
 
-   Physical examination 
 
-   Weight 
 
-   Vital signs including temperature, heart rate, blood pressure and respiratory rate 
 
-   Concomitant medications including over the counter medications and supplements 
 
-   ECOG performance status 
 
-   Symptom/adverse event assessment 
 
-   Laboratory studies  
 
 
-   Complete blood count (CBC) with differential 
 
 
-   Comprehensive metabolic panel 
 
 
-   Calculated creatinine clearance if creatinine and/or BUN are abnormal 
-   CEA (carcinoembryonic antigen) blood test 
 
-   Administration of CB-839 by mouth twice daily for a 21 day treatment cycle 
 
-   Administration of capecitabine by mouth twice daily for first 14 days of 21 day cycle 
 
CB-839 and Capecitabine, Cycle 3, sometime between days 15-21 of treatment cycle 
 
-   CT of the chest, abdomen and pelvis for restaging evaluation 
 
Subsequent CT imaging of the chest, abdomen and pelvis should be performed on an every 
9 week basis +/- one week for as long as patient is receiving study treatment 
 
 
 
 






CASE 1216 
 
 
 
Page 86  
 
 
Version date: 12/16/2020 
 
 
12.0  MEASUREMENT OF EFFECT  
 
Although response is not the primary endpoint of the phase I portion of this trial, patients will be 
assessed by standard criteria. Response rate is the primary endpoint for the phase II portion of the 
trial. For the purposes of this study, patients should be re-evaluated every 9 weeks in addition to 
undergoing a baseline scan. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (23). Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
12.1 
Definitions 
 
Evaluable for toxicity: All patients who receive at least one dose of study drug (either CB-839 or 
capecitabine) will be included in the analysis of safety regardless of the duration of treatment. 
 
Evaluable for objective response: Only those patients who have measureable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified according 
to the definitions stated below. Note: Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable. 
 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable, but do not meet the definitions of measureable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
 
12.2 
Disease Parameters 
 
Measurable Disease: Measureable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter for non-nodal lesions and short axis for nodal lesions to 
be recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm with calipers by 
clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). Tumor lesions that are situated in a previously irradiated area will not be considered 
measureable. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measureable, 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 followup, only the short axis will be measured and 
followed. 
 
Non-measureable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) are considered 


CASE 1216 
 
 
 
Page 87  
 
 
Version date: 12/16/2020 
 
 
non-measureable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI) are considered as non-measureable. 
 
Note: Cystic 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 measureable 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. 
 
Target lesions: All measureable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and 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. 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. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesion) 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 
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. 
 
Non-target lesions: All other lesions (or sites of disease) including any measureable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurement of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout followup. 
 
12.3 
Methods for Evaluation of Measureable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during followup. Imaging-based evaluation is 
preferred to evaluation by 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 measureable when they are superficial 
(e.g. skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g. 
skin nodules). In the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measureable lesions when they are clearly 


CASE 1216 
 
 
 
Page 88  
 
 
Version date: 12/16/2020 
 
 
defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesion on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measureable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at followup should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-holding techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data, which may bias an investigator if it is not routine or serially performed. PET may 
not be used for making determinations regarding response to treatment. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and because they are operator dependent, it cannot be guaranteed 
that the same technique and measurements will be taken from one assessment to the next. If new 
lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathologic response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. 
 
Cytology, Histology: These techniques can be used to differentiated between partial responses 


CASE 1216 
 
 
 
Page 89  
 
 
Version date: 12/16/2020 
 
 
(PR) and complete responses (CR) in rare cases (e.g. residual lesions in tumor types, such as germ 
cell tumors where known residual benign tumors can remain). 
 
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 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
12.4 
Response Criteria 
 
Evaluation of Target Lesions 
 
Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any 
pathologic 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 of 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. 
 
Evaluation of Non-Target lesions 
 
Response 
Evaluation of Non-Target Lesions 
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). 
Note: If tumor markers are initially above 
the upper normal limit, they must normalize 
for a patient to be considered in complete 
clinical response. 


CASE 1216 
 
 
 
Page 90  
 
 
Version date: 12/16/2020 
 
 
Non-CR/Non-PD 
[Incomplete response/Stable Disease (SD)] 
Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target 
lesions. 
Unequivocal 
progression should not normally trump 
target lesion status. It must be representative 
of overall disease status change, not a single 
lesion increase. 
 
Although a clear progression of ‘non-target’ 
lesions only is exceptional, the opinion of 
the treating physician should prevail in such 
circumstances, and the progression status 
should be confirmed at a later time by the 
review panel (or PI). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measureable Disease (e.g. Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-
PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not 
evaluated 
No 
PR 
SD 
Non-PD***/not 
evaluated 
No 
SD 
Documented at least once 
≥ 8 wks. from study entry
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
***PD in non-target lesions should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase. Please refer to 
the Evaluation of Non-Target Lesions – Progressive Disease (Section 12.2) for further 


CASE 1216 
 
 
 
Page 91  
 
 
Version date: 12/16/2020 
 
 
explanation. 
NOTE: 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 the 
objective progression even after discontinuation of treatment. 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). The duration of overall 
CR is measured from the time measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
12.5 
Progression Free Survival 
 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first. 
 
13.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
The OnCore™ Database will be utilized, as required by the Case Comprehensive Cancer Center, 
to provide data collection for both accrual entry and trial data management. OnCore™ is a Clinical 
Trials Management System housed on secure servers maintained at Case Western Reserve 
University. OnCore™. Access to data through OnCore™ is restricted by user accounts and 
assigned roles. Once logged into the OnCore™ system with a user ID and password, OnCore™ 
defines roles for each user which limits access to appropriate data. User information and password 
can be obtained by contacting the OnCore™ Administrator at OnCore-registration@case.edu. 
 
OnCore™ is designed with the capability for study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification. This study will utilize electronic Case Report 
Form completion in the OnCore™ database. A calendar of events and required forms are available 
in OnCore™. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
 
 


CASE 1216 
 
 
 
Page 92  
 
 
Version date: 12/16/2020 
 
 
 
13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures. The 
Principal Investigator will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
patient’s financial responsibility. Patients must also be notified that they are free to discontinue 
from the study at any time. The patient should be given the opportunity to ask questions and be 
allowed time to consider the information provided.  
 
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the patient. Additionally, documentation of the 
consenting process should be located in the research chart. 
 
13.2.2 Patient Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a patient 
must sign an authorization to release medical information to the sponsor and/or allow the sponsor, 
a regulatory authority, or Institutional Review Board access to patient’s medical information that 
includes all hospital records relevant to the study, including patients’ medical history.  
 
13.2.3  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with local, national and international regulations. 
No records will be destroyed until the Principal Investigator confirms destruction is permitted.  
 
13.2.4  Audits and inspections  
Authorized representatives of the sponsor, sponsor’s collaborators, a regulatory authority, an 
Independent Ethics Committee (IEC) or an Institutional Review Board (IRB) may visit the site to 
perform audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonization (ICH), and any applicable regulatory 
requirements.  For multi-center studies, participating sites must inform the sponsor-investigator of 
pending audits.  
 
14.0   STATISTICAL CONSIDERATIONS  
 
14.1 
Study Design/Endpoints 
 
14.1.1 Definition of Primary Endpoint 
 
Phase I: Safety, tolerability and recommended phase II dose (RP2D) of combination 
therapy with CB-839 and capecitabine chemotherapy in patients with no remaining 
treatment options or patients for whom single agent capecitabine is an acceptable therapy.  


CASE 1216 
 
 
 
Page 93  
 
 
Version date: 12/16/2020 
 
 
 
Phase II: : Progression free survival (PFS) on combination CB-839 and capecitabine as 
determined by clinical assessment and RECIST criteria in patients with metastatic PIK3CA 
mutant colorectal cancer who are refractory to fluoropyrimidine based therapy.  
Progression free survival is defined as the time from randomization to documented 
progression or death without progression. 
 
14.1.2 Definition of Secondary Endpoints 
 
Phase I: Dose-limiting toxicities as assessed by CTCAE version 4 of combination CB-839 
and capecitabine in patients with advanced solid tumors with no remaining treatment 
options or patients for whom single agent capecitabine is an acceptable therapy. 
 
Phase I: Response rate as assessed by RECIST criteria of combination CB-839 and 
capecitabine chemotherapy in patients with advanced solid tumors with no remaining 
treatment options or patients for whom single agent capecitabine is an acceptable therapy. 
 
Phase II: Response rate as assessed by RECIST criteria of combination CB-839 and 
capecitabine chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer 
who are refractory to fluoropyrimidine based therapy.  
 
Phase II: Overall survival of patients with metastatic PIK3CA mutant colorectal cancer 
who are refractory to fluoropyrimidine based therapy following treatment with CB-839 and 
capecitabine chemotherapy. Overall survival is defined as the time from randomization to 
death from any cause. 
 
14.1.3 Definition of Correlative Endpoints 
 
Phase I: Post-CB-839 pharmacokinetics as assessed by CB-839 drug levels following 
combination therapy with CB-839 and capecitabine in patients with advanced solid tumors 
for whom there are no further treatment options or patients for whom single agent 
capecitabine is an acceptable treatment option. 
 
Phase II: Change in glutaminase activity level as assessed by a glutaminase inhibition assay 
in both colorectal tumor specimens as well as platelets from patients whom have metastatic 
PIK3CA mutant colorectal cancer and are refractory to fluoropyrimidine based therapy and 
who have received treatment with CB-839 and capecitabine chemotherapy. 
 
Phase II: Reduction in nucleotide levels as assessed by HPLC in tumor specimens of 
patients with metastatic PIK3CA mutant colorectal cancer who are refractory to 
fluoropyrimidine based therapy and who have received treatment with CB-839 and 
capecitabine chemotherapy. 
 
Phase II: Change in cellular genome as assessed by whole exome sequencing of tumor 
specimens of patients with metastatic PIK3CA mutant colorectal cancer who are refractory 
to fluoropyrimidine based therapy and who have received treatment with CB-839 and 


CASE 1216 
 
 
 
Page 94  
 
 
Version date: 12/16/2020 
 
 
capecitabine chemotherapy. 
Phase II: Change in cellular gene expression as assessed by RNA seq of tumor specimens 
of patients with metastatic PIK3CA mutant colorectal cancer who are refractory to 
fluoropyrimidine based therapy and who have received treatment with CB-839 and 
capecitabine chemotherapy. 
 
Phase II: Correlation between plasma trough levels of CB-839 and biomarkers of interest 
in both tumors and platelets in patients with metastatic PIK3CA mutant colorectal cancer 
who are refractory to fluoropyrimidine based therapy and who have received treatment 
with CB-839 and capecitabine chemotherapy. 
 
Phase II: Correlation between clinical response to treatment and biomarkers of interest in 
patients with metastatic PIK3CA mutant colorectal cancer who are refractory to 
fluoropyrimidine based therapy and who have received treatment with CB-839 and 
capecitabine chemotherapy. 
 
14.2 
Analytic Plan for Primary Objectives 
 
The phase I component of this study is a dose-escalation trial of CB-839 and capecitabine in 
patients with advanced solid tumors for whom there are no remaining treatment options or for 
whom capecitabine is an acceptable treatment. It has been designed to define the recommended 
phase II dose of CB-839 and capecitabine. A traditional 3+3 dose escalation design will be 
adopted. Nine to twenty-four patients are expected to be enrolled, depending on the number of 
dose escalations and assuming that a total of 6 patients will be treated at the final recommended 
phase II dose level. Patients who complete the first 21 day treatment cycle of CB-839 and 
capecitabine chemotherapy will be included in the analysis. Patients who do not complete the first 
21 day treatment cycle or who fail to receive at least 75% of the doses of both CB-839 and 
capecitabine for reasons unrelated to toxicity will not be included and must be replaced.  
 
In the phase II component of this study, the primary endpoint is progression free survival rate at 6 
months with a null hypothesis of 18% vs. a target of 36%. Employing a 2-stage design, and 
assuming 80% power and a 0.05 significance level, 40 total patients will be required with 18 in 
the first stage and the probability of early stopping if the null hypothesis is correct (<3/18 patients 
with stable disease at 6 months) will be 0.589. If at least 3 patients in 18 has stable disease or better 
at 6 months, an additional 22 patients will be treated (total of 40 patients). If antitumor activity is 
identified in the PIK3CA mutant population, we will consider amending the phase 2 trial to assess 
an additional cohort of patients with wild-type PIK3CA. The statistical considerations will follow 
the same rules as in the original mutant cohort. Response rate will be determined using RECIST 
criteria. 
  
14.3 
Analytic Plan for Secondary Objectives 
 
All toxicities will be summarized as the percentage of patients experiencing each type and grade 
of event according to dose level. Patients who receive at least one dose of treatment will be 
included in the analysis. 
 


CASE 1216 
 
 
 
Page 95  
 
 
Version date: 12/16/2020 
 
 
In the phase I portion of the study, response rate will be summarized using frequencies and 
proportions by dose level. Response to treatment will be determined using RECIST criteria. 
 
14.4 
Analytic Plan for Correlative Objectives 
 
All correlative studies will be performed in biospecimens from the intent to treat population of 18-
40 patients from the phase II portion of the study. Pre- and post-treatment tumor samples from the 
same patients will be used for assessments, except glutaminase activity, which will be performed 
on post-treatment samples only (tumor samples and platelet samples). All correlative continuous 
measurements will be summarized using mean +/- SEM, range and median; all categorical 
measurements will be summarized using frequencies and proportions. Change in these 
measurements in tumors before and after therapy will be assessed using paired Wilcoxon tests. 
Unpaired Wilcoxon tests will be used for assessment of glutaminase actively in post-treatment 
samples only.  Assuming a maximum of 40 patients (2-sided test with 0.05 significance level and 
80% power), for the paired T-test we can detect normalized differences of 4.5 to 18.2% for 
standard deviations of the difference between pairs ranging from 0.10 to 0.40. Correlations of 
plasma trough levels and platelet glutaminase activity will be calculated using Spearman 
correlation coefficients. Assuming a maximum of 40 patients, 2-sided test with 0.05 significance 
level, we have >98% power to detect a Spearman correlation coefficient of 0.60 or higher. 
 
 
Whole exome sequencing and RNA sequencing will be performed on pre and post treatment tissue 
samples and compared for differences for all patients (n=40 patients maximum).  All of these 
analyses are exploratory, hence no power calculations are shown.   
 
14.5 
Sample Size Justification 
 
The phase I component of the trial will be conducted using a standard 3+3 dose escalation design. 
As there are four dose levels to be assessed (and two minus dose levels if needed), a total of 9-24 
patients will be needed to complete the study. 
 
In the phase II portion of the study, disease control rate is the primary endpoint and the study will 
be conducted using a Simon two-stage design. As outlined in section 14.2, a minimum of 18 and 
a maximum of 40 patients will be required. 
 
14.6 
Accrual Rate Estimate 
 
Accrual for this study will occur at the University Hospitals Seidman Cancer Center and the 
Cleveland Clinic Taussig Cancer Institute, both of the Case Comprehensive Cancer Center. For 
the phase I portion of the trial, we anticipate that it will take approximately 6-7 months to complete 
this portion of the trial if all doses levels need to be evaluated. For the phase II portion of the study, 
between the two institutions, 719 colorectal cancer patients are seen annually. We estimate that 
approximately 30% of our patients will have measureable, metastatic disease and that 15% of 
patients will have a PIK3CA mutation, resulting in 32 eligible patients per year. Based on our 
proposed sample size of 18-40 patients, we anticipate that it will take approximately 18-40 months 
to accrue to the phase II portion of the trial. 


CASE 1216 
 
 
 
Page 96  
 
 
Version date: 12/16/2020 
 
 
 


CASE 1216 
 
 
 
Page 97  
 
 
Version date: 12/16/2020 
 
 
REFERENCES 
1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2015. CA Cancer J Clin 2015;65:5-29. 
2. National Comprehensive Cancer Network Colon Cancer Guidelines, version 3.2015. 
3. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations on the PIK3CA gene in 
human cancers. Science, 2004;304:554. 
4. Dang CV. Links between metabolism and cancer. Genes Dev 2012;26:877-890. 
5. Patra KC, Hay N. Hexokinase 2 as oncotarget. Oncotarget 2013;4:1862-1863. 
6. Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to 
disruption. Nature 2012;491:364-373. 
7. Abraham RT, Eng CH. A metabolic (re-)balancing act. Molecular Cell 2010;38:481-482. 
8. Samuels Y, Diaz LA, Jr., Schmidt-Kittler O, et al. Mutant PIK3A promotes cell growth and 
invasion of human cancer cells. Cancer Cell 2005;7:561-573. 
9. Son J, Lyssiotis CA, Ying H, et al. Glutamine supports pancreatic cancer growth through a 
KRAS-regulated metabolic pathway. Nature 2013;496:101-105. 
10. Yun J, Rago C, Cheong I, et al. Glucose deprivation contributes to the development of KRAS 
pathway mutations in tumor cells. Science 2009;325:1555-1559. 
11. Huang F, Zhang Q, Ma H, et al. Expression of glutaminase is upregulated in colorectal cancer 
and of clinical significance. International journal of clinical and experimental pathology 
2014;7:1093-1100. 
12. Gross MI, Demo SD, Dennison JB, et al. Antitumor activity of the glutaminase inhibitor CB-
839 in triple-negative breast cancer. Mol Cancer Ther 2014;13:890-901. 
13. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical 
strategies. Nature Reviews Cancer 2003;3:330-338. 
14. Cao D, Pizzorno G. Uridine phosphorylase: an important enzyme in pyrimidine metabolism 
and fluoropyrimidine activation. Drugs of Today 2004;40:431-443. 
15. Cao D, Russell RL, Zhang D, et al. Uridine phosphorylase (-/-) murine embryonic stem cells 
clarify the key role of this enzyme in the regulation of the pyrimidine salvage pathway and in 
the activation of fluoropyrimidines. Cancer Research 2002;62:2313-2317. 
16. Im YS, Shin HK, Kim HR, et al. Enhanced cytotoxicity of 5-FU by bFGF through up-
regulation of uridine phosphorylase 1. Molecules and Cells 2009;28:119-124. 
17. Harding JJ, Telli ML, Munster PN, et al. Safety and tolerability of increasing doses of CB-839, 
a first-in-class, orally administered small molecule inhibitor of glutaminase, in solid tumors. J 
Clin Oncol 2015 (suppl; abstr 2512). 
18. Meric-Bernstam F, DeMichele A, Telli ML, et al. Phase I study of CB-839, a first-in-class, 
orally administered small molecule inhibitor of glutaminase in patients with refractory solid 
tumors. Abstract C49: AACR-NCI-EORTC International Conference: Molecular Targets and 
Cancer Therapeutics; November 5-9, 2015; Boston, MA. 
19. Konopleva MY, Flinn IW, Wang ES, et al. Phase I Study: Safety and tolerability of increasing 
doses of CB-839, on orally administered small molecule inhibitor of glutaminase in acute 
leukemia. European Hematology Association, 20th Congress, June 2015; poster 99749. 
20. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: 
American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2015; 
pii: JCO.2015.62.3488. 
21. Capecitabine package insert. 
22. Dowlati A, Haaga J, Remick SC, et al. Sequential tumor biopsies in early phase clinical trials 
of anticancer agents for pharmacodynamics evaluation. Clin Cancer Res 2001;7:2971-2976. 


CASE 1216 
 
 
 
Page 98  
 
 
Version date: 12/16/2020 
 
 
23. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CASE 1216 
 
 
 
Page 99  
 
 
Version date: 12/16/2020 
 
 
APPENDIX I 
 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade
Description 
Percent 
Description 
 
0 
 
Normal activity. Full active, able to 
carry on all pre-disease performance 
without restriction.  
 
100 
 
Normal, no complaints, no 
evidence of disease. 
 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work.  
 
2 
In bed < 50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% if waking hours. 
 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
 
50 
Requires considerable assistance 
and frequent medical care. 
 
3 
In bed > 50% of the time.  Capable 
of only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
 
40 
 
Disabled, requires special care 
and assistance. 
 
30 
 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care. Totally confined to bed or 
chair. 
 
20 
Very sick, hospitalization 
indicated. Death not imminent.  
 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 





ICF_001.pdf: 
CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
1
CONSENT FOR CANCER RESEARCH
Project Title: CASE 1216, “Phase I/II Study of CB-839 and Capecitabine in Patients with Advanced Solid 
Tumors and Fluoropyrimidine Resistant PIK3CA Mutant Colorectal Cancer”
Sponsor: Case Comprehensive Cancer Center
University Hospitals’ Principal Investigator:  David Bajor, MD 
Phase 1 consent
Cancer research studies are coordinated by physicians and scientists from Cleveland Clinic, University 
Hospitals and Case Western Reserve University (CWRU) through the NIH National Cancer Institute (NCI) 
designated Case Comprehensive Cancer Center (Case CCC).  The goal of this collaboration is to enhance 
cancer treatment and research in Northeast Ohio. This study is being offered at University Hospitals (UH).
What is the usual approach to my cancer?
You are being asked to take part in a clinical research study sponsored by the Case Comprehensive Cancer 
Center that tests CB-839, an investigational drug, in combination with capecitabine, a standard medication 
used for colon and rectal cancer. 
You are being asked to take part in this study because you have a solid tumor cancer and have no 
remaining effective treatments for your disease. The usual approach to your cancer would be to provide 
you with comfort or palliative care rather than treatment.
 If you have colon or rectal cancer, you are being asked to take part in this study because the first standard 
drugs you received (capecitabine or its sister drug 5-fluorouracil or 5-FU and either oxaliplatin or 
irinotecan) are no longer effective treatment for your disease. The usual next approach to your cancer 
would be for you to receive another standard treatment for colon or rectal cancer. This may include either 
oxaliplatin or irinotecan if you haven’t had them before, regorafenib or TAS-102. These are all standard 
medications used to treat colon and rectal cancer. By taking part in this study, you may be choosing to 
receive the study treatment instead of standard treatment, which may work better.
What are my other choices if I do not take part in this study?
If you decide not to take part in this study, you have other choices. For example:
you may choose to have the usual approach described above
you may choose to take part in a different study, if one is available
or you may choose not to be treated for cancer, for example, with comfort/palliative care
Why is this study being done?
This study has two portions. The main goal of the Phase I portion of this research study is to see what 
doses of CB-839 and capecitabine can safely be given to subjects without having too many side effects. 
Other purposes of this research study will be to determine what side effects are seen with this 
combination of medicines. The Phase II portion of the study will test how many subjects show shrinkage 
in their tumor with this combination of medicines and what changes occur inside the cancer cells and 
blood cells after treatment. You are being asked to participate in the Phase I portion of this research study. 
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
2
CB-839 is an investigational (experimental) anti-cancer agent that has not been approved by the Food and 
Drug Administration (FDA) for use in patients with cancer. CB-839 blocks one of the pathways that cancer 
cells use to metabolize nutrients. Blocking this process may block the cancers energy supply and keep it 
from growing.
Capecitabine is an anti-cancer agent that is commonly used for patients with colon cancer, rectal cancer, 
and breast cancer and is approved by the Food and Drug Administration for treatment of these types of 
cancer. If you have had colon cancer, rectal cancer, or breast cancer, most likely you have had this 
medicine or a similar type of medicine as part of your treatment. It is possible that when CB-839 is given 
with capecitabine, it will help the capecitabine work better, even if it had stopped working in the past, 
although this has not been proven.
What are the study groups? 
The research study you are being asked to take part in is a Phase I study. Phase I studies test drugs or drug 
combinations that have not been studied in humans or have only been tested in a few human studies. The 
purpose of this phase I study is to determine the highest dose of CB-839 and capecitabine that can be 
given together safely to subjects with advanced solid tumor cancers. This dose is called the maximum 
tolerated dose (MTD). To determine the MTD, different subjects will receive different amounts of both 
CB-839 and capecitabine.  
Because this study is designed to determine the largest dose of CB-839 and capecitabine that can be given 
safely, you may not receive the same dose of the drug as other subjects enrolled in the study. At the 
beginning of the study, 3-6 subjects will be treated with a low dose of CB-839 and capecitabine. 
If no serious side effects are reported, the next set of 3-6 subjects enrolled in the study will receive a 
higher dose of CB-839 and capecitabine. Again, if no serious side effects occur, another set of subjects in 
the study will be enrolled at the next higher dose level.  This will continue as long as CB-839 and 
capecitabine are tolerated by subjects or until the maximum doses of each individual drug are reached.
The dose level of the study drug you receive will depend on when you enter the study, and whether 
subjects enrolled before you had any serious side effects at their dose levels. Neither you nor your doctor 
will be able to choose which dose of CB-839 and capecitabine you receive. If serious side effects are seen 
indicating that the dose used is not tolerated, the dose of the study drug may be lowered.
A total of 9-24 subjects (men and women who are 18 years and older) will be enrolled in the Phase I 
portion of this trial. 
How long will I be in this study?
You will receive study drugs until any of the following happen:

your doctor has determined that your cancer has progressed, 

the study treatment becomes intolerable,

the completion or termination of the study,

severe side effects occur, 

you or your physician wishes to discontinue treatment, or

the study Sponsor finds it necessary to limit or end this study.  
After you are finished with the study treatment, the study doctor will ask you to visit the office for a 
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
3
treatment completion visit described below within 30 days after your last dose of study treatment.
What extra tests and procedures will I have if I take part in this study?
Most of the exams, tests, and procedures you will have are part of the usual approach for your cancer. 
However, there may be some extra procedures that you will need to have if you take part in this study. 
Neither you nor your health care plan/insurance carrier will be billed for the collection of the research-
only samples and procedures that will be collected/done for this study.
Pharmacokinetic (PK) studies measure the amount of CB-839 that you have in your blood at any point in 
time after starting CB-839 treatment. These PK tests will study how your body processes the drugs. This 
will only be checked one time during the study and this will be on the morning of the 15th day of treatment. 
This will be after CB-839 and capecitabine have been taken twice a day for 2 weeks. At this time point, 
about half a teaspoon of blood will be drawn for research purposes. These PK samples will be sent to a 
central laboratory for analysis. 
During The Study
The study treatment is divided up into cycles. Each cycle is 21 days long. You will take CB-839 twice a day 
for each day of a cycle. You will take capecitabine twice a day but only for the first 14 days of each cycle.
On Cycle 1, Day 15, do not take your morning dose of CB-839 at home. You will take it in clinic instead, 
right after the PK blood sample is drawn.
Because both of the medicines in this study are taken by mouth, you will be responsible for keeping a 
diary of when you take your medicines. A diary will be given to you by the study team and the study team 
will show you how to fill it out. You will need to bring your study diary with you to every visit.
Neither of the study medications should be crushed and need to be swallowed whole. You should keep 
your medications out of reach of children and away from other people living in your home.
The CB-839 capsules should be taken twice a day with food. You should take your first dose of the day 
with breakfast and your second dose of the day with dinner. 
The capecitabine tablets should also be taken twice a day but on a slightly different schedule. You should 
take your capecitabine tablets within 30 minutes after eating breakfast and within 30 minutes after eating 
dinner. 
If you miss a dose it should not be made up. If you have any questions about how to take your medications 
you should contact your study doctor.
What possible risks can I expect from taking part in this study?
If you choose to take part in this study, there is a risk that: 
 You may lose time at work or home and spend more time in the hospital or doctor’s office than 
usual 
 You may be asked sensitive or private questions which you normally do not discuss 
 There is a risk someone could get access to the personal information in your medical records or 
other information researchers have kept about you. Someone might be able to trace this 
information back to you. The researchers believe the chance that someone will identify you is very 
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
4
small, but the risk may change in the future as people come up with new ways of tracing 
information. In some cases, this information could be used to make it harder for you to get or 
keep a job. There are laws against misuse of genetic information, but they may not give full 
protection. The researchers believe the chance these things will happen is very small, but cannot 
promise that they will not occur. 
The CB-839 and capecitabine used in this study may affect how different parts of your body work such as 
your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health. 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
Here are important points about side effects: 
 The study doctors do not know who will or will not have side effects. 
 Some side effects may go away soon, some may last a long time, or some may never go away. 
 Some side effects may interfere with your ability to have children. 
 Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a problem: 
 Tell the study doctor if you notice or feel anything different so they can see if you are having a side 
effect. 
 The study doctor may be able to treat some side effects. 
 The study doctor may adjust the study drugs to try to reduce side effects. 
The tables below show the most common and the most serious side effects that researchers know about. 
There might be other side effects that researchers do not yet know about, including side effects of 
combining CB-839 and capecitabine. If important new side effects are found, the study doctor will discuss 
these with you. 
Risks of CB-839:
Likely (occurs in more than 10% of people—more than 10 out of 100 people)

feeling tired

abnormal liver function tests which may indicate liver damage

nausea

temporary sensitivity to light or discomfort with light
Less likely (occurs in 5% to 10% of people—from 5 to 10 out of 100 people)

vomiting

decreased appetite
Findings from safety studies with the study drug in animals include reversible abnormalities in some tests 
of liver and gallbladder function.
Increases in liver enzymes, which could be a sign of liver damage, have been observed in participants 
treated with CB-839. Changes to date have been reversible and have not generally recurred on dose 
reduction.
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
5
If you do not understand any of these side effects, please ask the study doctor or study staff to explain 
these terms to you.
Risks of Capecitabine:
Likely (occurs in more than 20% of people – more than 20 out of 100 people)

swelling of the body

blisters on the skin

redness, pain or peeling of palms and soles

pain

diarrhea, loss of appetite, nausea, vomiting

sores in mouth which may cause difficulty swallowing

anemia which may require blood transfusions

infection, especially when white blood cell count is low

bruising, bleeding

feeling of “pins and needles” in arms and legs

tiredness

fever
Less likely (occurs in 3% to 20% of people – from 3 to 20 out of 100 people)

blurred vision, dry or itchy eyes

muscle spasms, body aches

abnormal heartbeat

restlessness, irritability

swelling of face, fingers and lower legs

constipation

confusion

difficulty with balancing
Rare, but serious (occurs in less than 3% of people – less than 3 out of 100 people)

allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat

difficulty speaking, walking or seeing

internal bleeding which may cause blood in vomit or black tarry stools

damage to the heart
The following should be avoided, if at all possible while you are on the study drug:

There are many drugs that both CB-839 and capecitabine could potentially interact with, so you 
must discuss your medications with your study doctor. You must also inform your study doctor of 
any new medications you start while on this study. This includes over-the-counter medications, 
alternative therapies, or herbal medications.
Potential Risk or Discomfort from Procedures:
Blood Draws
The insertion of the needle to draw blood is painful; however, the discomfort is brief. For most people, 
needle punctures to get blood samples do not cause any serious problems; however, they may cause 
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
6
bleeding, bruising, discomfort, infections, dizziness, or fainting.
Reproductive Risks
Women who are pregnant or breastfeeding cannot take part in this study because we do not know what 
effect CB-839 or capecitabine will have on an unborn child or whether the drugs are passed to a baby 
through mother’s milk. To avoid risk to the fetus, it is important that you not be pregnant while 
participating in this study. If applicable, you must stop breastfeeding if you are being treated with the 
study drug. If you are a woman capable of having children, you will be given a pregnancy test before you 
begin the study, which must be negative in order for you to take part. 
Women
If you are a woman capable of having children and choose to have sex, you must use two forms of 
acceptable contraception, including one barrier method (e.g. latex condom, diaphragm or cervical/vault 
cap when used with spermicidal foam/gel/cream/film/suppository), while you are in this study and for 3 
months after your last dose of the study drug. One of the acceptable methods of contraception is the use 
of a condom along with a diaphragm with spermicidal agent (foam/gel/cream/film/suppository).
Additional methods are:

IUD or IUS (intrauterine devices or intrauterine system, except IUD progesterone T) in addition to 
a barrier method with spermicide.

Vasectomy by sole male partner.

Use of approved oral, injected, or implanted hormonal methods of contraception in addition to a 
barrier method with spermicide. This must be approved by your study doctor before you begin 
taking the study drug.
Even if you use birth control during the study, there is still a chance you could become pregnant. If you 
become pregnant or you think you may be pregnant during the study, you must immediately stop taking 
the study drug and tell your study doctor. If you become pregnant during the study, the pregnancy will be 
followed to determine the outcome. If you become pregnant during the study, the study drug may involve 
unforeseeable risks to the unborn baby.
Men
Men who are able to father children must use adequate contraception. If you are a man you must:

Prevent pregnancy in a female partner.

Prevent exposure of a partner to semen by any means (not just intercourse).

Prevent the possible exposure of a pregnant female to the study drug from your semen.

You should inform your partner of the potential for harm to an unborn child. She should know 
that if pregnancy occurs, she should promptly notify her doctor.
You should not donate sperm for 3 months after your last dose of study drug. In addition, acceptable 
methods of birth control include using one of the following while you are in this study and for 3 months 
after your last dose of the study drug (due to the unknown effects of the study drug on the sperm):

Abstinence (no sex)

Condom plus spermicidal agent (foam/gel/cream/film/suppository)

Vasectomy
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
7
What possible benefits can I expect from taking part in this study?
There is no guarantee that you will receive any benefits from this study, and taking part in this study may 
or may not cause your health to improve. Information from this study may help doctors learn more about 
CB-839 and capecitabine. This information may benefit other patients with cancer in the future.
Can I stop taking part in this study?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the study 
doctor know as soon as possible so you can stop safely. If you stop, you can decide whether or not to let 
the study doctor continue to provide your medical information to the organization running the study.
The study doctor will tell you about new information or changes in the study that may affect your health 
or your willingness to continue in the study.
The study doctor may take you out of the study:

If your health changes and the study is no longer in your best interest

If new information becomes available

If you do not follow the study requirements

If the study is stopped by the sponsor, Institutional Review Board (IRB) or FDA.
What are my rights in this study?
Taking part in this study is your choice. No matter what decision you make, and even if your decision 
changes, there will be no penalty to you. You will not lose medical care or any legal rights. 
What are the costs of taking part in this study?
Your involvement in this research study is voluntary and you will not be paid for your participation.
The investigational study agent, CB-839, will be provided free of charge and capecitabine will be billed to 
your insurance while you are participating in this study. Depending on your insurance, there may be a cost 
involved for the capecitabine. Neither you nor your insurance provider will be responsible for the costs of 
any research-only PK tests. The blood work for research purposes will not be charged to you. It will be 
paid for by the research study.  
You and/or your health plan/insurance company will need to pay for some or all of the costs of treating 
your cancer in this study (i.e., medical history, review of medications, physical exams, performance status, 
routine blood tests, pregnancy test, x-rays and/or scans for tumor measurement). Some health plans will 
not pay these costs for people taking part in studies. Check with your health plan or insurance company 
to find out what they will pay for. Taking part in this study may or may not cost your insurance company 
more than the cost of getting regular cancer treatment.
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
Web site at http://www.cancer.gov/clinicaltrials/learningabout.
Notice for Managed Care (Medicare Advantage Plan) Beneficiaries
Certain services that are required for your care as a participant in a clinical trial can be billed to, and paid 
by, your medical insurance. These services are referred to as “covered” clinical trial services. However, if 
you have a Medicare Advantage Plan as part of your medical insurance, this insurance cannot be billed for 
covered clinical trial services. Instead, traditional Medicare will be billed, and will pay for those services. 
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
8
This has an impact to you. When traditional Medicare pays for such services, you will be responsible for 
paying the coinsurance amounts applicable to these services, in addition to any other deductibles or co-
insurance you may have on your other health coverage. Please speak with a financial counselor to 
understand what the specific financial impact will be for you associated with participating in this clinical 
trial.
What happens if I am injured or hurt because I took part in this study?
If you believe that you are injured as a result of the research procedures being performed, please 
immediately contact the study doctor.
If injury occurs as a result of your involvement in this research, medical treatment is available from 
University Hospitals or another medical facility but you/your medical insurance will be responsible for the 
cost of this treatment. A research injury is an injury that happens as a result of taking part in this research 
study. If you are injured by a medical treatment or procedure that you would have received even if you 
weren’t in the study, that is not considered a “research injury.” There are no plans for payment of medical 
expenses or other payments, including lost wages, for any research related injury. To help avoid injury, it 
is very important to follow all study directions.
Further information about research-related injuries is available by contacting the University Hospitals 
Cleveland Medical Center’s Research Subject Rights phone line at 
HIPAA AUTHORIZATION
Authorization to Use or Disclose (Release) Health Information that Identifies You for a Research Study 
If you volunteer to participate in this research, your protected health information (PHI) that identifies you 
will be used or disclosed to David Bajor, MD, and the research study staff at University Hospitals for the 
purposes of this research and to Case Western Reserve University for administration.
The PHI that we may use or disclose (release) for this research may include your name, address, phone 
number, date of birth, Social Security number, information from your medical record, lab tests, or certain 
information relating to your health or condition.
Some of the tests and procedures done solely for this research study may also be placed in your medical 
record so other doctors know you are in this study. Upon completion of the study, you may have access 
to the research information that is contained in your medical record.  
In addition to the investigators and research staff listed above, your PHI may be looked at by other groups 
involved with the study such as the University Hospitals Institutional Review Board and the Case 
Comprehensive Cancer Center Protocol Review and Monitoring Committee. Your PHI may also be used by 
and/or disclosed (released) to:

Calithera Biosciences (the company who makes CB-839), its study monitors and 
representatives;

Calithera Biosciences’ collaborators and licensees (people and companies who partner with 
Calithera);

The Food and Drug Administration;
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
9

The Department of Health and Human Services;

The National Cancer Institute (NCI);

Other Institutional Review Boards; 

Data Safety and Monitoring Boards;

The Office for Human Research Protections (OHRP);

Other staff from the Principal Investigator’s medical practice group; University Hospitals, including 
the Center for Clinical Research and the Law Department; Government representatives or Federal 
agencies, when required by law. 
Once your personal health information is released it may be re-disclosed and no longer protected by 
privacy laws.
Your research information may be used and disclosed indefinitely, but you may stop these uses and 
disclosures at any time by writing to:
David Bajor, MD
Case Comprehensive Cancer Center
University Hospitals Cleveland Medical Center
11100 Euclid Ave.
Cleveland, OH 44106
Your participation in the research will stop, but any information previously recorded about you cannot be 
removed from the records and will continue to be used as part of this research.  Also, information already 
disclosed outside the Cleveland Clinic and/or University Hospitals cannot be retrieved.  This will not affect 
your rights to treatment or benefits outside the research study.   
University Hospitals will not use your information collected in this study for another research purpose 
without your written permission; unless the University Hospitals Institutional Review Board assures your 
privacy and confidentiality is protected.  The IRB is a committee whose job it is to protect the safety and 
welfare of research subjects.
By signing this informed consent form, you are authorizing such access to your research and medical 
record information.  If you choose not to sign this consent form, you will not be able to participate in this 
research study.  This Authorization does not have an expiration date.
Voluntary Participation
Your participation in this research study is voluntary. Choosing not to participate will not alter your usual 
health care or involve any penalty or loss of benefits to which you are otherwise entitled. If you decide to 
join the study, you may withdraw at any time and for any reason without penalty or loss of benefits. If 
information generated from this study is published or presented, your identity will not be revealed.  
In the event new information becomes available that may affect the risks or benefits associated with this 
study or your willingness to participate in it, you will be notified so that you can decide whether or not to 
continue participating.  
If you decide to withdraw from the study and do not request that your samples be destroyed, they will 
continue to be analyzed as planned.
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
10
Questions about the Research
If you have any questions, you can ask the Principal Investigator and/or research staff at 
.
Emergency or after-hours contact information 
If you are a University Hospitals patient, and you need to contact study staff outside normal business 
hours, you may contact 
and you will be transferred to the answering service, which can put 
you in contact with David Bajor, MD, or the oncologist (cancer doctor) on call. 
 
Where Can I Get More Information?
If the researchers cannot be reached, or if you would like to talk to someone other than the researcher(s) 
about: concerns regarding the study, research participant’s rights; research-related injury; or other human 
subjects’ issues, you may contact the University Hospitals Cleveland Medical Center’s Research Subjects 
Rights Phone line at 
. 
You may call the National Cancer Institute's Cancer Information Service at:
1-800-4-CANCER (1-800-422-6237) 
You may also visit the NCI Web site at http://cancer.gov/

For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/

For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.  If you want more information about this study, ask your study doctor.  
US National Institutes of Health (NIH) Clinical Trial Database:   
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, if applicable, as 
required by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
Signature
Signing below indicates that you have been informed about the research study in which you voluntarily 
agree to participate; that you have asked any questions about the study that you may have; and that the 
information given to you has permitted you to make a fully informed and free decision about your 
participation in the study.  By signing this consent form, you do not waive any legal rights, and the 
investigator(s) or sponsor(s) are not relieved of any liability they may have.  A copy of this consent form 
will be provided to you.
Signature of Participant
Date
Printed Name of Participant
Signature of Witness
Date
Printed Name of Witness
(To be used if the participant is illiterate, blind or cannot physically sign but is able to provide informed 
consent.)
I have discussed the information contained in this document with the participant and it is my opinion that 
the participant understands the risks, benefits, alternatives and procedures involved with this research 
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
11
study.
Signature of Person Obtaining Consent
Date
Printed Name of Person Obtaining Consent
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 1
Protocol version 01/30/18
Consent version 01/30/18
12
Study Calendar 
Cycle 1 
Study Days
Pre-
Study
Day 1
Day 8
Day 15
Cycle 2 and 
beyond, 
Day 1
Cycle 3, 
Day 14-
21
Every 
9 
weeks
30 Day 
Follow-
Up
Informed Consent
X
Demographics
X
Medical History
X
Height
X
Weight 
X
X
X
X
Vitals
X
X
X
X
Physical Examination
X
X
X
X
Medication Assessment
X
X
X
Performance Status
X
X
X
X
Symptom Assessment
X
X
X
X
X
X
Routine blood tests
X
X
X
X
X
X
Pregnancy test (if 
needed)
X
Tumor scans (CT scans)
X
X
X
Research PK blood test
X
CB-839
X
X
X 
X
X
Capecitabine
X
X
X
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
1
CONSENT FOR CANCER RESEARCH
Project Title: CASE 1216, “Phase I/II Study of CB-839 and Capecitabine in Patients with Advanced Solid 
Tumors and Fluoropyrimidine Resistant PIK3CA Mutant Colorectal Cancer”
Sponsor: Case Comprehensive Cancer Center
University Hospitals’ Principal Investigator:  David Bajor, MD
 
Cleveland Clinic Principal Investigator:  Alok Khorana, MD
Phase 2 consent
Cancer research studies are coordinated by physicians and scientists from Cleveland Clinic, University 
Hospitals and Case Western Reserve University (CWRU) through the NIH National Cancer Institute (NCI) 
designated Case Comprehensive Cancer Center (Case CCC).  The goal of this collaboration is to enhance 
cancer treatment and research in Northeast Ohio. This study is being offered at Cleveland Clinic (CC) and 
University Hospitals (UH).
What is the usual approach to my colorectal cancer?
You are being asked to take part in a clinical research study sponsored by the Case Comprehensive Cancer 
Center that tests CB-839 an investigational drug, in combination with capecitabine, a standard medication 
used for colon and rectal cancer. 
You are being asked to take part in this study because you have colon or rectal cancer and the standard 
drug capecitabine (or its sister drug 5-fluorouracil or 5-FU) in combination with either oxaliplatin or 
irinotecan but also sometimes as a single agent is no longer effective treatment for your disease. The usual 
next approach is to receive another standard treatment for colon or rectal cancer. This may include either 
oxaliplatin or irinotecan if you haven’t had either of them before, regorafenib or TAS-102. These are all 
standard medications used to treat colon and rectal cancer. You also have an abnormal feature in your 
colon or rectal tumor (called a PIK3CA mutation) that may make you more likely to respond to the 
combination of medicines used in this study than patients who do not have this abnormality in their colon 
or rectal tumor. By taking part in this study, you may be choosing to receive the study treatment instead 
of standard treatment, which may work better.
What are my other choices if I do not take part in this study?
If you decide not to take part in this study, you have other choices. For example:
you may choose to have the usual approach with described above
you may choose to take part in a different study, if one is available
or you may choose not to be treated for cancer, for example, comfort/palliative care 
Why is this study being done?
This study has two portions. The main goal of the Phase I portion of the study was to find what doses of 
CB-839 and capecitabine could safely be given to subjects without having too many side effects. Other 
purposes were to determine what side effects were seen with this combination of medicines. The Phase 
I portion of the study is now closed. 
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
2
You are being asked to take part in the Phase II portion of the study. The Phase II portion of the study will 
research how many subjects show shrinkage in their tumor with this combination of medicines and what 
changes occur inside the cancer cells and blood cells following treatment.
CB-839 is an investigational (experimental) anti-cancer agent that has not been approved by the Food and 
Drug Administration (FDA) for use in patients with cancer. CB-839 blocks one of the pathways that cancer 
cells use to metabolize nutrients. Blocking this process may block the cancers energy supply and keep it 
from growing.
Capecitabine is an anti-cancer agent that is commonly used for patients with colon cancer, rectal cancer, 
and breast cancer and is approved by the Food and Drug Administration for treatment of these types of 
cancer. Most likely, you have had this medicine or a similar type of medicine as part of your colon or rectal 
cancer treatment. It is possible that when CB-839 is given with capecitabine, it will help the capecitabine 
work better, even if it had stopped working in the past, although this has not been proven.
A total of 18 to 40 subjects (men and women who are 18 years and older) will be enrolled in the Phase II 
portion of this trial.
How long will I be in this study?
You will receive study drugs until any of the following happen:

your doctor has determined that your cancer has progressed, 

the study treatment becomes intolerable,

the completion or termination of the study,

severe side effects occur, 

you or your physician wishes to discontinue treatment, or

the study Sponsor finds it necessary to limit or end this study.  
After you are finished with the study treatment, the study doctor will ask you to visit the office for a 
treatment completion visit described below within 30 days after your last dose of study treatment.
What extra tests and procedures will I have if I take part in this study?
If you agree to take part in the study, there are required research-only studies, which we would like to ask 
you to take part in. This portion of the study will research what changes occur inside the cancer cells and 
blood cells following treatment.
Pharmacokinetic (PK) studies measure the amount of CB-839 that you have in your blood at any point in 
time after starting CB-839 treatment. These PK tests will study how your body processes the drugs. This 
will only be checked one time during the study and this will be between the 10th and 15th day of Cycle 1. 
At this time point, about half a teaspoon of blood will be drawn for research purposes. These PK samples 
will be sent to a central laboratory for analysis.
Pharmacodynamic (PD) studies look at how CB-839 affects your body. At each time point, about 3 
tablespoons of blood will be drawn for research purposes. This will be done before you start your CB-839 
and capecitabine treatment. It will be done a second time between the 10th and 15th day of Cycle 1. 
Research biopsies
Two tumor biopsies will be done to check the characteristics of your tumor. These biopsies are required 
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
3
for you to take part in the study. Your tumor has cells that could be affected by the study drug. A tumor 
biopsy will be done on a tumor that is accessible. Genetic sequencing will be done on these biopsies in 
order to determine tumor genomic changes caused by treatment with CB-839 and capecitabine.
A total of three biopsy cores will be taken each time you have a biopsy procedure. 
Before You Begin This Study:
At any time before taking part in the study, it will need to be determined if your cancer has an abnormal 
feature that would make you a possible patient to be treated as part of this trial. This abnormality is a 
mutation in one of your genes, the PIK3CA gene. This gene is thought to be abnormal in about 15-30% of 
patients with colon or rectal cancer. You should talk with your doctor about how the abnormality may be 
checked in your colon or rectal cancer.
Your first biopsy needs to be done before your first dose of CB-839 and capecitabine and may be done up 
to 2 weeks before you start treatment.
During The Study
If the exams, tests, and procedures show that you can be in the study, and you choose to take part, then 
you will have the following extra research tests and procedures done (please also refer to the Study 
Calendar on the last page). 
The study treatment is divided up into cycles. Each cycle is 21 days long. You will take CB-839 twice a day 
for each day of a cycle. You will take capecitabine twice a day but only for the first 14 days of each cycle.
A biopsy of your tumor will be done again after being on CB-839 and capecitabine treatment for 10-15 
days. 
On Cycle 1, Day 15, do not take your morning dose of CB-839 at home. You will take it in clinic instead, 
right after the PK blood sample is drawn.
Because both of the medicines in this study are taken by mouth, you will be responsible for keeping a 
diary of when you take your medicines. A diary will be given to you by the study team and the study team 
will show you how to fill it out. You will need to bring your study diary with you to every visit.
Neither of the study medications should be crushed and need to be swallowed whole. You should keep 
your medications out of reach of children and away from other people living in your home.
The CB-839 capsules or tablets should be taken twice a day with food. You should take your first dose of 
the day with breakfast and your second dose of the day with dinner. 
The capecitabine tablets should also be taken twice a day but on a slightly different schedule. You should 
take your capecitabine tablets within 30 minutes after eating breakfast and within 30 minutes after eating 
dinner. 
If you miss a dose it should not be made up. If you have any questions about how to take your medications 
you should contact your study doctor.
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
4
What possible risks can I expect from taking part in this study?
If you choose to take part in this study, there is a risk that: 
 You may lose time at work or home and spend more time in the hospital or doctor’s office than 
usual 
 You may be asked sensitive or private questions which you normally do not discuss 
 There is a risk someone could get access to the personal information in your medical records or 
other information researchers have kept about you. Someone might be able to trace this 
information back to you. The researchers believe the chance that someone will identify you is very 
small, but the risk may change in the future as people come up with new ways of tracing 
information. In some cases, this information could be used to make it harder for you to get or 
keep a job. There are laws against misuse of genetic information, but they may not give full 
protection. The researchers believe the chance these things will happen is very small, but cannot 
promise that they will not occur. 
The CB-839 and capecitabine used in this study may affect how different parts of your body work such as 
your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health. 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
Here are important points about side effects: 
 The study doctors do not know who will or will not have side effects. 
 Some side effects may go away soon, some may last a long time, or some may never go away. 
 Some side effects may interfere with your ability to have children. 
 Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a problem: 
 Tell the study doctor if you notice or feel anything different so they can see if you are having a side 
effect. 
 The study doctor may be able to treat some side effects. 
 The study doctor may adjust the study drugs to try to reduce side effects. 
The tables below show the most common and the most serious side effects that researchers know about. 
There might be other side effects that researchers do not yet know about, including the side effects of 
combining the CB-839 and capecitabine. If important new side effects are found, the study doctor will 
discuss these with you.
Risks of CB-839:
More common (seen in 10% or more of patients):

feeling tired

abnormal liver function tests (an increase in specific laboratory tests, such as: alanine 
aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, and alkaline 
phosphatase), which may indicate liver damage

nausea

temporary sensitivity to light or discomfort with light
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
5
Less common (seen in 5% to 10% of patients):

vomiting

decreased appetite

decreased red blood cell count
Findings from safety studies with the study drug in animals include reversible abnormalities in some tests 
of liver and gallbladder function.
Increases in liver enzymes, which could be a sign of liver damage, have been observed in participants 
treated with CB-839. Changes to date have been reversible and have not generally recurred on dose 
reduction.
If you do not understand any of these side effects, please ask the study doctor or study staff to explain 
these terms to you.
Risks of Capecitabine:
Likely (occurs in more than 20% of people – more than 20 out of 100 people)

swelling of the body

blisters on the skin

redness, pain or peeling of palms and soles

pain

diarrhea, loss of appetite, nausea, vomiting

sores in mouth which may cause difficulty swallowing

anemia which may require blood transfusions

infection, especially when white blood cell count is low

bruising, bleeding

feeling of “pins and needles” in arms and legs

tiredness

fever
Less likely (occurs in 3% to 20% of people – from 3 to 20 out of 100 people)

blurred vision, dry or itchy eyes

muscle spasms, body aches

abnormal heartbeat

restlessness, irritability

swelling of face, fingers and lower legs

constipation

confusion

difficulty with balancing
Rare, but serious (occurs in less than 3% of people – less than 3 out of 100 people)

allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat

difficulty speaking, walking or seeing

internal bleeding which may cause blood in vomit or black tarry stools

damage to the heart
The following should be avoided, if at all possible while you are on the study drug:
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
6

There are many drugs that both CB-839 and capecitabine could potentially interact with, so you 
must discuss your medications with your study doctor. You must also inform your study doctor of 
any new medications you start while on this study. This includes over-the-counter medications, 
alternative therapies, or herbal medications.
Potential Risk or Discomfort from Procedures
Blood Draws
The insertion of the needle to draw blood is painful; however, the discomfort is brief. For most people, 
needle punctures to get blood samples do not cause any serious problems; however, they may cause 
bleeding, bruising, discomfort, infections, dizziness, or fainting.
Research Biopsies
Risks associated with biopsies include pain, redness, swelling, low blood pressure, excessive bleeding, 
bruising, or draining at the needle site, abnormal wound healing, fever, infection, and allergic reaction to 
the medication used to numb the skin over the biopsy site. Two to 3% of patients require hospitalization 
after a tumor biopsy.
Reproductive Risks
Women who are pregnant or breastfeeding cannot take part in this study because we do not know what 
effect CB-839 or capecitabine will have on an unborn child or whether the drugs are passed to a baby 
through mother’s milk. To avoid risk to the fetus, it is important that you not be pregnant while 
participating in this study. If applicable, you must stop breastfeeding if you are being treated with the 
study drug. If you are a woman capable of having children, you will be given a pregnancy test before you 
begin the study, which must be negative in order for you to take part. 
Women
If you are a woman capable of having children and choose to have sex, you must use two forms of 
acceptable contraception, including one barrier method (e.g. latex condom, diaphragm or cervical/vault 
cap when used with spermicidal foam/gel/cream/film/suppository), while you are in this study and for 3 
months after your last dose of the study drug. One of the acceptable methods of contraception is the use 
of a condom along with a diaphragm with spermicidal agent (foam/gel/cream/film/suppository).
Additional methods are:

IUD or IUS (intrauterine devices or intrauterine system, except IUD progesterone T) in addition to 
a barrier method with spermicide.

Vasectomy by sole male partner.

Use of approved oral, injected, or implanted hormonal methods of contraception in addition to a 
barrier method with spermicide. This must be approved by your study doctor before you begin 
taking the study drug.
Even if you use birth control during the study, there is still a chance you could become pregnant. If you 
become pregnant or you think you may be pregnant during the study, you must immediately stop taking 
the study drug and tell your study doctor. If you become pregnant during the study, the pregnancy will be 
followed to determine the outcome. If you become pregnant during the study, the study drug may involve 
unforeseeable risks to the unborn baby.
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
7
Men
Men who are able to father children must use adequate contraception. If you are a man you must:

Prevent pregnancy in a female partner.

Prevent exposure of a partner to semen by any means (not just intercourse).

Prevent the possible exposure of a pregnant female to the study drug from your semen.

You should inform your partner of the potential for harm to an unborn child. She should know 
that if pregnancy occurs, she should promptly notify her doctor.
You should not donate sperm for 3 months after your last dose of study drug. In addition, acceptable 
methods of birth control include using one of the following while you are in this study and for 3 months 
after your last dose of the study drug (due to the unknown effects of the study drug on the sperm):

Abstinence (no sex)

Condom plus spermicidal agent (foam/gel/cream/film/suppository)

Vasectomy 
Genetic Information Nondiscrimination Act (GINA) 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), effective May 21, 2010, 
generally makes it illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. This law generally will protect you in the 
following ways: 

Health insurance companies and group health plans may not request your genetic information 
that we get from this research.

Health insurance companies and group health plans may not use your genetic information when 
making decisions regarding your eligibility or premiums. 

Employers with 15 or more employees may not use your genetic information that we get from 
this research when making a decision to hire, promote, or fire you or when setting the terms of 
your employment. 
Be aware that this Federal law does not protect you against genetic discrimination by companies that sell 
life insurance, disability insurance, or long-term care insurance.
What possible benefits can I expect from taking part in this study?
There is no guarantee that you will receive any benefits from this study, and taking part in this study may 
or may not cause your health to improve. Information from this study may help doctors learn more about 
CB-839 and capecitabine. This information may benefit other patients with cancer in the future.
Can I stop taking part in this study?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the study 
doctor know as soon as possible so you can stop safely. If you stop, you can decide whether or not to let 
the study doctor continue to provide your medical information to the organization running the study.
The study doctor will tell you about new information or changes in the study that may affect your health 
or your willingness to continue in the study.
The study doctor may take you out of the study:
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
8

If your health changes and the study is no longer in your best interest

If new information becomes available

If you do not follow the study requirements

If the study is stopped by the sponsor, Institutional Review Board (IRB) or FDA.
What are my rights in this study?
Taking part in this study is your choice. No matter what decision you make, and even if your decision 
changes, there will be no penalty to you. You will not lose medical care or any legal rights. 
What are the costs of taking part in this study?
Your involvement in this research study is voluntary and you will not be paid for your participation.
The investigational study agent, CB-839 will be provided free of charge and capecitabine will be covered 
by your insurance while you are participating in this study. Depending on your insurance, there may be a 
cost involved for the capecitabine as this is a standard medicine used for colon and rectal cancers. Neither 
you nor your insurance provider will be responsible for the costs of any research-only tests or procedures. 
The blood work for research purposes will not be charged to you. It will be paid for by the research study.  
You and/or your health plan/insurance company will need to pay for some or all of the costs of treating 
your cancer in this study (i.e., medical history, review of medications, physical exams, performance status, 
routine blood tests, pregnancy test, x-rays and/or scans for tumor measurement). Some health plans will 
not pay these costs for people taking part in studies. Check with your health plan or insurance company 
to find out what they will pay for. Taking part in this study may or may not cost your insurance company 
more than the cost of getting regular cancer treatment.
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
Web site at http://www.cancer.gov/clinicaltrials/learningabout.
Notice for Managed Care (Medicare Advantage Plan) Beneficiaries
Certain services provided to you as a participant in a clinical trial are allowable to be billed to, and paid 
by, your medical insurance.  These services are referred to as “covered” clinical trial services.  If you have 
a Medicare Advantage Plan as part of your medical insurance, the Centers for Medicare & Medicaid 
Services (CMS) require that traditional Medicare will be billed for those covered clinical trial services.  
When this occurs, you will remain responsible for paying the coinsurance and deductibles according your 
Medicare Advantage Plan.  Your Medicare Advantage Plan should cover any associated cost share related 
to Medicare.  Please speak with a financial counselor to understand what the specific financial impact will 
be for you associated with participating in this clinical trial.
What happens if I am injured or hurt because I took part in this study?
If you believe that you are injured as a result of the research procedures being performed, please 
immediately contact the study doctor.
If injury occurs as a result of your involvement in this research, medical treatment is available from 
University Hospitals, Cleveland Clinic or another medical facility but you/your medical insurance will be 
responsible for the cost of this treatment.  A research injury is an injury that happens as a result of taking 
part in this research study.  If you are injured by a medical treatment or procedure that you would have 
received even if you weren’t in the study, that is not considered a “research injury”. There are no plans 
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
9
for payment of medical expenses or other payments, including lost wages, for any research related injury.  
To help avoid injury, it is very important to follow all study directions.
Further information about research-related injuries is available by contacting the Cleveland Clinic 
Institutional Review Board at (216) 444-2924 or University Hospitals Cleveland Medical Center’s Research 
Subject Rights phone line at (216) 983-4979.
HIPAA AUTHORIZATION
Authorization to Use or Disclose (Release) Health Information that Identifies You for a Research Study 
If you volunteer to participate in this research, your protected health information (PHI) that identifies you 
will be used or disclosed to David Bajor, Alok Khorana, MD, and the research study staff at Cleveland Clinic 
and/or University Hospitals for the purposes of this research and to Case Western Reserve University for 
administration.
The PHI that we may use or disclose (release) for this research may include your name, address, phone 
number, date of birth, Social Security number, information from your medical record, lab tests, or certain 
information relating to your health or condition.
Some of the tests and procedures done solely for this research study may also be placed in your medical 
record so other doctors know you are in this study.  Upon completion of the study, you may have access 
to the research information that is contained in your medical record.  
In addition to the investigators and research staff listed above, your PHI may be looked at by other groups 
involved with the study such as the Cleveland Clinic Institutional Review Board, University Hospitals 
Institutional Review Board and the Case Comprehensive Cancer Center Protocol Review and Monitoring 
Committee.  Your PHI may also be used by and/or disclosed (released) to:

Calithera Biosciences, (the company who makes CB-839), its study monitors and 
representatives;

Calithera Biosciences’ collaborators and licensees (people and companies who partner with 
Calithera);

The Food and Drug Administration;

The Department of Health and Human Services;

The National Cancer Institute (NCI);

Other Institutional Review Boards; 

Data Safety and Monitoring Boards;

The Office for Human Research Protections (OHRP);

Other staff from the Principal Investigator’s medical practice group; University Hospitals, including 
the Center for Clinical Research and the Law Department; Government representatives or Federal 
agencies, when required by law. 
Once your personal health information is released it may be re-disclosed and no longer protected by 
privacy laws.
Your research information may be used and disclosed indefinitely, but you may stop these uses and 
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
10
disclosures at any time by writing to:
David Bajor, MD
or
Alok Khorana, MD
Case Comprehensive Cancer Center
Case Comprehensive Cancer Center
University Hospitals Cleveland Medical Center
Cleveland Clinic
11100 Euclid Ave.
9500 Euclid Ave.
Cleveland, OH 44106
Cleveland, OH 44195
Your participation in the research will stop, but any information previously recorded about you cannot be 
removed from the records and will continue to be used as part of this research.  Also, information already 
disclosed outside the Cleveland Clinic and/or University Hospitals cannot be retrieved.  This will not affect 
your rights to treatment or benefits outside the research study.   
The Cleveland Clinic and/or University Hospitals will not use your information collected in this study for 
another research purpose without your written permission; unless the Cleveland Clinic Institutional 
Review Board (IRB) and/or University Hospitals Institutional Review Board assures your privacy and 
confidentiality is protected.  The IRB is a committee whose job it is to protect the safety and welfare of 
research subjects.
By signing this informed consent form, you are authorizing such access to your research and medical 
record information.  If you choose not to sign this consent form, you will not be able to participate in this 
research study.  This Authorization does not have an expiration date.
Voluntary Participation
Your participation in this research study is voluntary. Choosing not to participate will not alter your usual 
health care or involve any penalty or loss of benefits to which you are otherwise entitled. If you decide to 
join the study, you may withdraw at any time and for any reason without penalty or loss of benefits. If 
information generated from this study is published or presented, your identity will not be revealed.  
In the event new information becomes available that may affect the risks or benefits associated with this 
study or your willingness to participate in it, you will be notified so that you can decide whether or not to 
continue participating.  
If you decide to withdraw from the study and do not request that your samples be destroyed, they will 
continue to be analyzed as planned.
Questions about the Research
If you have any questions, you can ask the Principal Investigator and/or research staff at (216) 844-6003.
Emergency or after-hours contact information 
If you are a University Hospitals patient, and you need to contact study staff outside normal business 
hours, you may contact 
and you will be transferred to the answering service, which can put 
you in contact with David Bajor, MD, or the oncologist (cancer doctor) on call. 
 
If you are a Cleveland Clinic patient, you should contact the page operator at 
 or toll free 
at 
, and ask for the oncologist (cancer doctor) that is on call.
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
11
Where Can I Get More Information?
If the researchers cannot be reached, or if you would like to talk to someone other than the researcher(s) 
about: concerns regarding the study, research participant’s rights; research-related injury; or other human 
subjects issues, you may contact the Institutional Review Board (IRB) at Cleveland Clinic IRB 
 
or the University Hospitals Cleveland Medical Center’s Research Subjects Rights Phone line at 
 
You may call the National Cancer Institute's Cancer Information Service at:
1-800-4-CANCER (1-800-422-6237) 
You may also visit the NCI Web site at http://cancer.gov/

For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/

For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.  If you want more information about this study, ask your study doctor.  
US National Institutes of Health (NIH) Clinical Trial Database:   
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, if applicable, as 
required by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
Signature
Signing below indicates that you have been informed about the research study in which you voluntarily 
agree to participate; that you have asked any questions about the study that you may have; and that the 
information given to you has permitted you to make a fully informed and free decision about your 
participation in the study.  By signing this consent form, you do not waive any legal rights, and the 
investigator(s) or sponsor(s) are not relieved of any liability they may have.  A copy of this consent form 
will be provided to you.
Signature of Participant
Date
Printed Name of Participant
Signature of Witness
Date
Printed Name of Witness
(To be used if the participant is illiterate, blind or cannot physically sign but is able to provide informed 
consent.)
I have discussed the information contained in this document with the participant and it is my opinion that 
the participant understands the risks, benefits, alternatives and procedures involved with this research 
study.
Signature of Person Obtaining Consent
Date
Printed Name of Person Obtaining Consent
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024


CASE 1216 – Phase 2
Protocol version 12/16/2020
Consent 12/16/2020
12
Study Calendar 
Cycle 1
Study Days
Pre-
Study
Pre-
treatment
Day 1
Day 8
Day 15
Cycle 2 and 
beyond, 
Day 1
Cycle 3, 
Day 14-21
Every 9 
weeks
30 Day 
Follow-
Up
Informed 
Consent
X
Demographics
X
Medical History
X
Height
X
Weight 
X
X
X
X
Vitals
X
X
X
X
Physical 
Examination
X
X
X
X
Current 
Medication 
Assessment
X
X
X
Performance 
Status
X
X
X
X
Symptom 
Assessment
X
X
X
X
X
X
Blood tests
X
X
X
X
X
X
Pregnancy test 
(if needed)
X
CT chest, 
abdomen and 
pelvis
X
X
X
Tumor biopsy
X
X 
Research labs
X
X
CB-839
X
X
X
X
Capecitabine
X
X
X
    
        IRB NUMBER: 06-16-28C
        IRB APPROVAL DATE: 10/25/2023
        IRB EFFECTIVE DATE: 10/25/2023
        IRB EXPIRATION DATE: 10/24/2024