Conditions: Acute Myeloid Leukemia With Multilineage Dysplasia Blasts 20-30 Percent of Bone Marrow Nucleated Cells Blasts 20-30 Percent of Peripheral Blood White Cells Chronic Myelomonocytic Leukemia High Risk Myelodysplastic Syndrome IPSS Risk Category Intermediate-2 Myelodysplastic Syndrome
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects of glutaminase inhibitor CB-839 in combination with azacitidine in treating patients with myelodysplastic syndrome that has spread to other places in the body. Glutaminase inhibitor CB-839 and azacitidine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety, tolerability and clinical activity of glutaminase inhibitor CB-839 (CB-839) in combination with azacitidine (AZA) for patients with advanced myelodysplastic syndrome (MDS).

SECONDARY OBJECTIVES:

I. To explore the pharmacokinetics (PK) of CB-839 in combination with AZA. II. To explore the pharmacodynamics (PDn) of CB-839 in combination with AZA. III. To assess overall survival, event-free survival and duration of response of CB-839 in combination with AZA.

OUTLINE:

Patients receive glutaminase inhibitor CB-839 orally (PO) twice daily (BID) on days 1-28 and azacitidine subcutaneously (SC) or intravenously (IV) over 10-40 minutes on days 1-7.

After completion of study treatment, patients are followed up at 28 days.

Arms:
arm 1: Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28 and azacitidine SC or IV over 10-40 minutes on days 1-7.

Interventions: intervention 1: Azacitidine intervention 2: Glutaminase Inhibitor CB-839
Intervention descriptions: intervention 1: Given IV or SC intervention 2: Given PO

Protocol document:
Prot_SAP_001.pdf: 
Protocol 2016-0636 
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Phase Ib/II study of the glutaminase inhibitor telaglenastat (CB-839) in 
combination with azacitidine in subjects with advanced myelodysplastic 
syndrome 
MDACC Protocol #: 
2016-0636 
Principal Investigator:  
Courtney DiNardo, MD, MSCE 
Co-Principal Investigator: 
Marina Konopleva, MD, PHD 
Scientific Collaborator: 
Amit Verma, MBBS 
Biostatistical Collaborators: 
Hsiang-Chun Chen 
Jing Ning 
Address: 
1515 Holcombe Blvd, Unit 428 
Houston, TX 77030 
Phone: 
713) 794-1141
Fax: 
713) 792-0319
Email: 
cdinardo@mdanderson.org 
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 TABLE OF CONTENTS 
Page 
1.  Objectives ................................................................................................................. 3 
2.  Background .............................................................................................................. 4 
3.  Subject Eligibility ................................................................................................... 11 
4.  Treatment Plan ....................................................................................................... 11 
5.  Study Procedures ................................................................................................... 18 
6.  Response Definitions ............................................................................................. 21 
7.  Regulatory and Reporting Requirements ............................................................ 27 
8.  Statistical Considerations ..................................................................................... 30 
References ................................................................................................................... 33 
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1. OBJECTIVES
1.1 Primary Objectives 
The primary objectives of this study are to determine the safety, tolerability and clinical 
activity of telaglenastat (CB-839) in combination with azacitidine (AZA) for patients with 
advanced MDS. 
1.2 Secondary Objectives 
The secondary objectives of the study are: 
1.2.1. To explore the pharmacokinetics (PK) of telaglenastat in combination with AZA 
1.2.2. To explore the pharmacodynamics (PDn) of telaglenastat in combination with 
AZA 
1.2.3. To assess overall survival, event-free survival and duration of response of 
telaglenastat  in combination with AZA 
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2. BACKGROUND AND SCIENTIFIC RATIONALE
2.1  Background 
Myelodysplastic syndromes (MDS) are malignant clonal disorders characterized by 
ineffective hematopoiesis, bone marrow dysplasia, peripheral cytopenias including 
thrombocytopenia, and a propensity to transform into acute myeloid leukemia (AML).(1, 
2) Classically, MDS is associated with apoptosis and excessive proliferation, resulting in
a paradoxical combination of a hyper-cellular marrow and peripheral cytopenias.(3)  The
incidence of MDS in the United States is rising, with approximately 20,000 to 30,000
new cases of MDS diagnosed annually, and a median age at diagnosis of 70 years.(3,
4)
Over the past decade, clinical use of the hypomethylating agent azacitidine has been 
shown to improve patient quality of life, decrease transfusion requirements, and improve 
outcome parameters in MDS patients, and is now a standard of care for MDS patients 
requiring therapy.  With current HMA regimens, achievement of an ORR is estimated at 
28-70%, with a CR rate of only 6-34% in patients with MDS treated with front-line HMA
therapy, and with a median length of response in the HMA-responders of only 8 to 10
months.(5-10)
MDS patients requiring therapy include those with intermediate-2 or High-risk disease 
by IPSS, or high or very-high risk by R-IPSS.(11)  In addition, patients with otherwise 
intermediate MDS with high-risk molecular features including TP53, ASXL1, EZH2, 
and/or RUNX1 mutations have been identified as a subgroup that may benefit from 
early therapeutic intervention.(12)   
2.2 Rationale for Glutaminase Inhibition: 
Tumor cells including MDS cells exhibit an altered metabolic profile compared with 
normal cells, presumed to favor rapid growth and proliferation as well as augmented 
survival in hypoxic environment.  As first noted by Warburg in 1924, tumor cells display 
“aerobic glycolysis” in lieu of oxidative phosphorylation, and thereby generate limited 
ATP from glucose.  Consequently, many tumor cells require a continuous supply of 
exogenous glutamine (GLN) that is used to fuel the tricarboxylic acid (TCA) cycle for the 
generation of ATP and as a precursor in the generation of amino acids, nucleic acids, 
and fatty acids.  This enhanced utilization of GLN requires the activity of glutaminase, a 
mitochondrial enzyme which converts GLN to glutamate (GLU).  GLU, in turn, has a 
number of important bioenergetic and biosynthetic functions including as an anaplerotic 
intermediate fueling the TCA cycle via conversion to α-ketoglutarate (αKG).  Many 
tumors have been found to have a pronounced upregulation of glutaminase.  These 
tumors are sensitive to withdrawl of GLN from growth medium, usually have a high 
cellular ratio of GLU to GLN, and are very sensitive to the inhibition of glutaminase by 
telaglenastat .   
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Anti-tumor activity of glutaminase knock-down with shRNA or inhibition with small 
molecules has been reported both in vitro and in vivo.(13, 14)  Mutations in the TCA 
cycle enzyme isocitrate dehydrogenase (IDH), either in the cytoplasm (IDH1) or 
mitochondria (IDH2), have been identified in both AML and MDS.  These mutations 
result in conversion of the TCA cycle intermediate aKG into 2-hydroxyglutarate (2HG).  
2HG, considered an oncometabolite, accumulates in the cell resulting in dioxygenase 
blockade, DNA and histone hypermethylation, and ultimately, impaired cell 
differentiation.   
 
 
 
Figure 1: Metabolic pathway associated with IDH1 and IDH2 mutations.   
Telaglenastat is a potent and selective reversible inhibitor of glutaminase activity.  Two 
alternative splice variants of glutaminase (GLS), GAC and KGA, are found in tumors 
and in normal tissues including lung, liver, heart, kidney, spleen, intestine and brain.  A 
separate gene encodes glutaminase-2 (GLS2), found mainly in the liver.  Telaglenastat 
is an allosteric and noncompetitive inhibitor of both GAC and KGA isoforms of 
glutaminase, but does not inhibit GLS2.  Incubation of recombinant human glutaminase 
with CB-839 results in time-dependent and slowly reversible inhibition of glutaminase 
activity (IC50 = 34 nM with 1 hour pre-incubation).  Glutaminase inhibition is associated 
with antiproliferative activity in a wide range of tumor cell lines.  Pro-apoptotic activity 
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has been observed in triple-negative breast cancer (TNBC), multiple myeloma, 
mesothelioma, and many additional solid and hematologic tumors.   
Recent experimental data suggest that glutamine metabolism is very important for 
leukemic blasts.  Removal of glutamine from the culture media of AML cell lines inhibits 
mTORC1 and induces apoptosis, and shRNA knockdown of SLC1A5, a high-affinity 
transporter for GLN, inhibits tumor formation in mouse AML xenografts.  Leukemic cells 
may be dependent on glutamine utilization pathways to provide carbon skeletons for 
TCA activity (Matre et al, ASH 2013).   
The antiproliferative and pro-apoptotic effect of telaglenastat has been evaluated alone 
and in combination with the hypomethylating agent azacitidine in two different AML cell 
lines (data from OCI-AML3 cell line shown in Figure 2). Both telaglenastat and 
azacitidine showed significant antiproliferative effects in both cell lines. In combination, 
substantially greater inhibition of cell number and induction of apoptosis was observed. 
The mechanism whereby these agents act together has not been fully established. 
However, recent findings indicate that telaglenastat significantly depletes the cellular 
pool of aspartate, which is a substrate for the synthesis of purine and pyrimidine 
nucleotides. In multiple myeloma cells, telaglenastat caused a significant depletion of 
intracellular pools of aspartate, adenylosuccinate and total adenylate. Azacitidine is a 
prodrug that is metabolized to 5-aza-2’-deoxycytidine-triphosphate, which is 
incorporated into DNA and result in DNA damage (Stresemann C and Lyko F, Int. J. 
Cancer 123:8-13 (2008).  The combination of nucleotide depletion and induction of DNA 
damage may result in enhanced impairment of DNA replication. 
Figure 2: Anti-proliferative and pro-apoptotic effects of Telaglenastat and azacitidine in 
AML cell line in vitro.  OCI-AML3 cells were incubated with increasing concentrations of 
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Telaglenastat, azacitidine, or Telaglenastat + azacitidine for 5 days.  The 
antiproliferative effect of single agent or combination treatment was determined by cell 
counting.  The induction of apoptosis was determined by staining with Annexin V.  This 
work was carried out in the laboratory of Dr. Marina Konopleva at MD Anderson Cancer 
Center. 
2.3 In Vivo Pharmacodynamics of telaglenastat : 
Telaglenastat inhibition of cellular glutaminase activity has been assessed in rodents.  
These studies have demonstrated that oral administration of Telaglenastat results in a 
rapid, dose-dependent inhibition of glutaminase in mice bearing established human 
tumor xenografts.  Moreover, all tissues examined with the exception of brain (where 
there is limited exposure) and liver (where GLS2 predominates) showed evidence of 
glutaminase inhibition, although less dramatic than in tumors. 
When telaglenastat was administered to immunocompromised mice bearing established 
human TNBC and myeloma xenografts, there was a significant inhibition of tumor 
growth, both as a single agent and in combination with standard of care 
chemotherapeutics.  Telaglenastat administration was well-tolerated up to 400mg/kg 
BID and resulted in substantial inhibition of tumor growth.   
2.4 PK and PD of telaglenastat in Tumors and Tissues in Mice 
The tissue distribution and PD response to CB-839 was evaluated in mice bearing the 
human TNBC tumor HCC1806 by measurement of drug concentration and glutaminase 
inhibition, respectively.  Telaglenastat was administered as a 200 mg/kg single oral 
dose to female SCID/bg mice.  Excellent exposure to telaglenastat was observed in 
plasma, in the tumor, and in all other tissues examined except brain, where exposure 
was 20-fold lower than in plasma.  GLN concentration increased, while GLU and ASP 
decreased substantially in tumors relative to untreated controls.  GLU and ASP 
remained essentially unchanged in non-tumor tissues, suggesting that despite 
significant exposure to telaglenastat , inhibition of glutaminase does not result in product 
depletion in normal tissues.  Other metabolic pathways appear to resupply the 
intracellular pools of GLU in non-tumor tissues with the exception of the spleen. 
2.5 Nonclinical Metabolism and Pharmacokinetics: 
Please refer to the Investigator’s Brochure (IB) for a more detailed description of the 
nonclinical metabolism and PK. 
Systemic exposure to telaglenastat following oral administration is highly species 
dependent due to significant cross-species differences in absorption and metabolism. 
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Based on the in vitro and in vivo ADME data, good oral exposure of telaglenastat  in 
humans is predicted. 
The oral exposure in female rats was found to be higher than in male rats because of 
more extensive metabolism in male rats. In vitro studies also showed more rapid 
metabolism of telaglenastat in male rat liver microsomes and hepatocytes than in 
female, whereas no differences were observed in vitro using human hepatocytes. Oral 
exposure of telaglenastat in rats was also affected by feeding status. Systemic 
exposure to telaglenastat was higher in fasted rats than in fed rats following oral 
administration. 
 
2.5.1 Absorption 
The apical-to-basolateral permeability of telaglenastat in human Caco-2 monolayers 
was determined to be 9.6 x 10^-6 cm/s and is predictive of good absorption in humans. 
The oral bioavailability of 44-70% in mice and 66-157% in rats demonstrated good 
absorption of telaglenastat in these species.  
 
2.5.2. Distribution: 
 
High in vitro plasma protein binding of telaglenastat was observed in mouse, rat, dog, 
and human plasma using an ultracentrifugation approach. The mean plasma protein 
binding was 98.0, 97.0, 97.9, and 99.1%, respectively. As described in Section 2.4, 
following a single oral dose of 200 mg/kg to SCID/bg mice, telaglenastat was broadly 
distributed to tissues including heart, lung, spleen, muscle, and subcutaneously-
implanted tumors; brain had 20-fold lower telaglenastat levels.  
 
2.5.3. Metabolism: 
 
In vitro metabolic stability of telaglenastat was evaluated using cryopreserved 
hepatocytes derived from mice, rats, dogs, monkeys (cynomolgus, rhesus, and 
marmoset), and humans. Telaglenastat was most stable in human hepatocytes. Gender 
differences were observed only in rats; CB-839 was more stable in rat hepatocytes from 
females. 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. 
 
Two pathways of metabolic transformation of telaglenastat have been identified in vitro 
in hepatocytes and in vivo: amide hydrolysis and P450-mediated hydroxylation. There 
are considerable differences in the mechanism of metabolism across species. All 
metabolites resulting from amide hydrolysis and hydroxylation of CB-839 have a low 
abundance (<10%) in human hepatocyte incubations up to 4 hr. Significant exposure of 
the human metabolites identified thus far is anticipated in the non-clinical GLP toxicity 
studies.  
 
2.5.4. Excretion: 
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About 0.3-1.2% of orally dose CB-839 was eliminated via biliary excretion in bile duct-
cannulated rats. And biliary excretion happened predominately in the first 2 hr after 
dosing. On the other hand, when CB-839 was dosed orally to bile duct-cannulated rats, 
41 to 49 reduction in systemic exposure to CB-839 was seen relative to normal rats, 
suggesting a significant amount of CB-839 is flowing through the bile, and perhaps 
undergoing enterohepatic recirculation in normal animals. Further studies are needed to 
better understand biliary excretion of CB-839 in rats.  
2.5.5. Drug-drug interaction 
Direct and time-dependent inhibition (TDI) of human cytochrome P450 (CYP) enzymes 
by telaglenastat was evaluated in human liver microsomes (HLM). CB-839 was not an 
inhibitor for CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A. CB-839 
appears to be an inhibitor of CYP2C9 with an IC50 of 1.8 - 6.7 μM. Further studies are 
needed to understand the time-dependency of inhibition. Telaglenastat was not an 
inducer of human CYP1A2, 2B6, or 3A4 in cryopreserved hepatocytes from three 
donors. Telaglenastat is a moderate substrate of efflux transporters with an efflux ratio 
of 6.2 in Caco-2 monolayers. 
2.6 Genotoxicity 
The genotoxicity of telaglenastat in bacteria was evaluated in a GLP-compliant Ames 
test.  There were no findings of mutagenicity of telaglenastat . 
2.7 Clinical Data 
The safety, pharmacokinetics (PK), and pharmacodynamics (PDn) following oral 
administration of telaglenastat is being evaluated in three ongoing Phase 1 clinical trials 
in CX-839-001 (solid tumors), CX-839-002 (MM and NHL), and CX-839-003 (acute 
leukemia). Increasing doses of telaglenastat resulted in an increase in plasma 
concentration of telaglenastat and in inhibition of glutaminase activity in platelets and in 
tumors.  As of January 26, 2016, 147 subjects have been treated with telaglenastat 
monotherapy across the 3 studies, at doses of 100 – 1000 mg orally TID fasted, or 600 
– 1000 mg BID orally with food.  To date, 2 DLT events (elevated creatinine and
elevated LFTs) have been reported for the monotherapy.  Although a maximum
tolerated dose (MTD) has not been defined, 800 mg BID is the highest dose that is
confirmed to be safe and well tolerated as monotherapy.  The most frequent drug-
related grade 3-4 toxicity has been reversible elevations in liver function tests, primarily
ALT, AST and GGT, although the frequency of Grade 3/4 LFT elevations is substantially
reduced with BID dosing with food as compared to the original TID regimen.  CB-839
has been evaluated at doses up to 1000 mg TID in patients with hematologic
malignancies.
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In the CX-839-003 study the safety and tolerability of telaglenastat is being evaluated in 
patients with hematological malignancies (acute myelogenous leukemia (AML), acute 
lymphocytic leukemia (ALL), or myelodysplastic syndrome (MDS) either as 
monotherapy or in combination with azacitidine.   A total of 11 leukemia patients have 
received telaglenastat as monotherapy on the BID schedule with food and treatment 
related AEs are presented in TABLE 1. Overall, 81.8% of patients experienced an AE 
that was considered at least possibly related to CB-839.  The most frequent CB-839-
related AEs were hematological (thrombocytopenia and anemia) with other AEs 
including Grade 1/2 elevated AST, elevated creatinine, constipation and dyspnea.  The 
hematological AEs were all Grade 3/4 whereas the non-hematological AEs were 
typically mild to moderate in intensity (Grade 1/2), reversible and manageable without 
dose interruption or modification.  No Grade 3/4 elevations in LFTs were noted.  CB-
839-related Grade 3/4 events included thrombocytopenia (4), neutropenia (2), anemia
(2), lymphopenia (1), hyponatremia (1) and stomatitis (1).
Table 1:  CX-839-003 Treatment-Related Adverse Events in ≥ 2 patients – BID fed 
BID Monotherapy (N=11) 
MedDRA Preferred Term 
Number (%) of 
patients 
All 
Grades 
≥Grade 
3 
Patients with Any CB-839-Related AE 
9 (81.8) 
5 (45.5) 
THROMBOCYTOPENIA 
4 (36.4) 
4 (36.4) 
ASPARTATE AMINOTRANSFERASE 
INCREASED 
2 (18.2) 
0 
BLOOD CREATININE INCREASED 
2 (18.2) 
0 
CONSTIPATION 
2 (18.2) 
0 
DYSPNOEA 
2 (18.2) 
0 
NEUTROPENIA 
2 (18.2) 
2 (18.2) 
Reductions in blast counts were achieved in 2 patients with AML receiving monotherapy 
telaglenastat including one with CRi. 
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On the CX-839-003 study telaglenastat also is being evaluated at escalating doses (400 
mg BID – 800 mg BID) in combination with standard dose azacitidine (75 mg/m2 dosed 
IV or SC for 7 days of every 28-day cycle).  As of the data cutoff for this document 4 
patients have received telaglenastat in the 400 mg BID dose cohort in combination with 
azacitidine   One of 4 patients has experienced a treatment-related AE considered at 
least possibly related to telaglenastat .  To date, no DLTs have occurred.  Efficacy data 
are not yet available for patients receiving telaglenastat in combination with azacitadine. 
 
 
3. STUDY ELIGIBILITY 
 
3.1 Inclusion Criteria 
 
1.  Signed, informed consent must be obtained prior to any study specific 
procedures. 
 
2. Subjects must be > 18 years of age at the time of informed consent 
 
3. Subjects with a histologically confirmed diagnosis of MDS, including both MDS 
and RAEB-T (AML with 20-30% blasts and multilineage dysplasia by FAB 
criteria) by World Health Organization (WHO) and chronic myelomonocytic 
leukemia (CMML) are eligible. 
 
4. Subjects with high-risk MDS (i.e. IPSS Intermediate-2 or high-risk; or R-IPSS 
high or very-high risk).  Patients with Intermediate-1 risk by IPSS or Intermediate 
risk by R-IPSS and with IDH1 or IDH2, or high-risk molecular features including 
TP53, ASXL1, EZH2, and/or RUNX1 mutations are also eligible. 
 
5. Subjects with prior hypomethylating agent therapy exposure may be eligible 
based on discussion with the PI. 
 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. 
 
7. Adequate liver function, as evidenced by a serum bilirubin < 2x the ULN (except 
for patients with Gilbert’s disease) and ALT or AST < 3x the laboratory ULN. 
8. Adequate renal function including creatinine clearance > 30 mL/min based on the 
Cockcroft-Gault equation.   
 
9. Able to understand and voluntarily sign a written informed consent, and willing 
and able to comply with protocol requirements. 
 
10.  Resolution of all clinically significant treatment-related, non-hematological 
toxicities, except alopecia, from any previous cancer therapy to < Grade 1 prior to 
the first dose of study treatment 
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11. Female patients of childbearing potential must have a negative serum or urine
pregnancy test within 3 days of 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.
3.2 Exclusion Criteria: 
1. Any prior or coexisting medical condition that in the investigator’s judgment will
substantially increase the risk associated with the subject’s participation in the
study.
2. Psychiatric disorders or altered mental status precluding understanding of the
informed consent process and/or completion of the necessary study procedures
3. Active uncontrolled infection at study enrollment including known diagnosis of
human immunodeficiency virus or chronic active Hepatitis B or C infection.
4. Clinically significant gastrointestinal conditions or disorders that may interfere
with study drug absorption, including prior gastrectomy.
5. Patients with known active CNS disease, including leptomeningeal involvement.
6. Impaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant
cardiac disease including the following: a) New York Heart Association Grade III
or IV congestive heart failure, b) myocardial infarction within the last 6 months
7. Subjects with a QTc > 480 ms (QTc > 510 msec for subjects with a bundle
branch block at baseline).
8. Nursing or pregnant women.
9. Subjects with known hypersensitivity to study drugs or their excipients.
4. TREATMENT PLAN
4.1 Study Design 
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This is a Phase 1b/II clinical trial designed to assess the safety, tolerability and efficacy 
of telaglenastat in combination with AZA for the treatment of advanced MDS.  Patients 
will be treated with standard AZA (IV or SQ 75mg/m2 IV daily x 7 days) and 
telaglenastat orally twice daily continuously for 28 days per treatment cycle.  A cycle will 
consist of 28 days of dosing.  Patients will continue on study therapy unless they have 
evidence of progressive disease or unacceptable toxicity.  Other objectives include 
exploring the PK and PDn of telaglenastat  in combination with AZA. 
4.1.1. Phase 1b: 
In the Phase 1b portion, telaglenastat will be administered at the goal starting dose level 
0 of 600mg BID continuously.  The MTD is defined as the highest dose level with </= 1 
out of 6 patients experiencing a DLT during the first cycle. 
The first 6 patients will be treated at dose level 0.  If </= 1 out of the 6 patients 
experience a DLT during the first cycle, this level will be identified as the RP2D and the 
study will progress to the Phase II portion.  If > 2 out of the 6 patients experience a DLT 
during the first cycle, this dose level would exceed the MTD, and an additional 6 
patients will be treated at the next lower dose level.  Reduced dose level -1 is defined in 
Table 1 below.  Patients treated in the Phase 1b portion that are removed from study 
before day 28 for any reason other than toxicity, and have not experienced DLT, will be 
replaced.   
AZA will be administered subcutaneously (SQ) or intravenously (IV) for 7 days of every 
cycle (days 1-7) as determined by the treating physician.  Both SQ and IV forms of 
administration are FDA-approved and are considered interchangeable, based on patient 
and physician preference. 
Table 1:  Dose de-escalation for telaglenastat and AZA 
Dose Level
CB-839 (oral)
AZA (IV or SQ)
0
600 mg BID days 1-28
75 mg/m2 days 1-7
-1
400 mg BID days 1-28
75 mg/m2 days 1-7
Dose reductions beyond those mentioned in this table or different to the doses specified 
should be discussed with the PI and documentation of the justification recorded in the 
medical record. 
4.1.1.2. Dose De-escalation Procedures: 
A dose-limiting toxicity (DLT) is defined as any Grade 3 or higher non-hematologic 
adverse event or abnormal laboratory value occurring during the first cycle (i.e. the first 
28 days) on study except those that are clearly and incontrovertibly due to disease 
progression or extraneous causes,  with the following exceptions: 
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 CTCAE v4.03 Grade 3 AST or ALT that resolves to < Grade 2 within 14 days 
without an associated rise in bilirubin 
 Grade 3 nausea, vomiting or diarrhea that can be managed to < Grade 2 with 
standard antiemetic or antidiarrheal medications  
 Grade > 3 electrolyte abnormality that lasts < 24 to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions  
 Grade 3 biochemical abnormalities of amylase or lipase without clinical evidence 
of pancreatitis 
 
Hematologic DLT is defined as Grade > 3 neutropenia and/or thrombocytopenia with a 
hypocellular bone marrow lasting for 6 weeks or more after the start of a course in the 
absence of underlying MDS.  Anemia will not be considered for the definition of DLT. 
 
4.1.1.3. The first 6 patients will be treated at dose level 0.  If DLT occurs in > 2/6 
evaluable patients, this dose level would exceed the MTD, and an additional 6 patients 
will be treated at the lower dose level.  The highest dose level at which 0-1/6 patients 
experience DLT will be used as the RP2D.  Should >2/6 DLTs occur in dose level -1, 
the combination may be considered too toxic in this indication and the study may be 
discontinued. 
 
 
4.1.2. Phase II: 
 
The Phase II portion will open after determination of the RP2D of the combination of 
telaglenastat and AZA from the Phase 1b portion.  The RP2D will be selected based on 
the totality of the clinical data (safety, tolerability, PK, PDn, and efficacy) and will not 
exceed the MTD.  A total of 28 evaluable MDS patients, which includes 22 Phase II 
patients and 6 patients treated at the RP2D from Phase 1, will be enrolled.  
We will enroll 16 patients in the first stage. If 6 or fewer patients achieve response, 
enrollment will be halted.  If 7 or more out of the first 16 patients achieve response, 
accrual will continue until a total of 28 patients have been enrolled.  If 15 or more out of 
these 28 patients achieve response, the treatment will be considered efficacious and 
worthy of further investigation. Toxicities will be monitored closely using the method of 
Thall et al (1995) in Section 8.1.3.  
4.2. Study Duration: 
 
4.2.1. All subjects must complete a screening visit, day 1 visits for each new cycle, and 
an end-of-treatment visit. 
 
4.2.2. Treatment will continue until discontinuation due to relapse, unacceptable toxicity, 
or disease progression as defined by the IWG 2006 criteria for MDS.  This includes: 
 
- 
clinically significant progressive disease at any time, or 
 
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- 
a lack of clinical benefit after 5 cycles of treatment at the highest dose of study 
medication, or 
 
- 
Possibility of undergoing allogeneic stem cell transplantation 
 
- 
discontinuation of study drug for more than 6 weeks, or 
 
- 
intercurrent illness that prevents further administration of treatment, or 
 
- 
unacceptable adverse event(s), or 
 
- 
patient decision for study withdrawal, or 
 
- 
general or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
Patients may remain on study for up to 12 cycles if the patient demonstrates clinical 
benefit and no excessive toxicity (i.e. no clinically significant study-drug related grade > 
3 toxicity).  Patients who are experiencing clinical benefit and have not experienced 
excessive toxicity may be eligible to continue therapy after discussion with the PI and 
the discussion documented in the patient’s medical record. 
 
If one of the study agents is discontinued due to toxicity, the patient may remain on 
study until the occurrence of significant disease progression, severe toxicity that 
requires all study agents to be permanently discontinued, or at the discretion of the PI. 
 
4.2.3. Cycle Length: 
 
Study cycles will be administered every 28 days + 5 days or upon resolution of any 
clinically significant study drug related AE to grade 0-2, whichever occurs first.  
 
4.2.4. Cycle Administration: 
 
4.2.4.1. AZA may be administered by MDACC or local physician, inclusive of the 
regional care centers.  Commercial supplies and institutional standards for 
administration of AZA will be used and records will be obtained from the local physician 
as indicated in the Dear Doctor Letter.  Institutional standards include administration of 
AZA on the “5-2-2” schedule. 
 
4.2.4.2. Telaglenastat should be taken orally twice daily with food.  The first 
telaglenastat dose of the day will be administered immediately after breakfast.  The 
evening/second dose should be taken with a meal approximately 12 hours (+/- 2 hours) 
after the morning dose.   
 
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4.2.4.3. Telaglenastat will be self-administered primarily on an outpatient basis; but may 
be administered as an inpatient.   
 
4.2.4.4. Patient compliance will be documented using the MDACC Research Medication 
Diary and will be assessed at each study visit.   
 
4.2.4.5. Missed doses should be skipped.  If a patient forgets to take a dose of study 
drug and they are outside the allotted protocol window (+/- 6 hours) they should be 
instructed NOT to take extra study drug at their next administration.  If a dose is delayed 
by <6 hours, they should be instructed to take the dose and then to take the next dose 
at the normal time. 
 
 
4.3. Identity of Investigational Product: 
 
 
International Non-proprietary name 
Telaglenastat  
Manufacturer  
 
 
 
Calithera 
Dose  
 
 
 
 
As per protocol 
Route of Administration 
 
 
oral 
Formulation 
Capsule or tablet formulation (200 mg)  
 
Telaglenastat will be provided by Calithera. 
 
For oral administration only 
Store at room temperature 15-300C (59-860 F). Do not refrigerate or 
freeze. Keep bottle tightly closed.   
The Expiry date will be provided by Calithera (based on Certificate of 
Analysis) 
 
 
 
 
4.4 Supportive Care Guidelines and Concomitant Medications: 
 
4.4.1. Concomitant treatment is permitted if the medication is not expected to interfere 
with the evaluation of safety or efficacy of the study drug.  During the study, if the use of 
any concomitant treatment becomes necessary (e.g., for treatment of an adverse 
event), the treatment must be recorded on the eCRF, including the reason for treatment, 
name of the drug, dosage, route, and start and stop dates of administration 
 
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4.4.2. Supportive measures including blood and platelet transfusions, antimicrobials, 
and analgesics are permitted. 
 
4.4.3. The administration of anticancer therapies, other investigational cytotoxic agents, 
or prophylactic use of hematopoietic colony stimulating factors are not permitted. 
 
4.4.4. Erythropoietin or hematopoietic colony stimulating factors for treatment of 
cytopenias are discouraged.  If administered, the subject will not be eligible for a HI 
response assessment within one week of the receipt of epoetin alfa or filgrastim, tbo-
filgrastim, filgrastim-sndz, or for one month after receipt of pegfilgrastim or darbopoetin. 
 
4.4.5. Telaglenastat is metabolized by human hepatocytes primarily through amide 
hydrolysis.  Telaglenastat does not appear to induce CYP drug-metabolizing enzymes 
and only weakly inhibits CYP2C9 (IC50 1.8-6.7 µM) in vitro.  Therefore, drug-drug 
interactions are not expected.  Although CB-839 is not expected to inhibit CYP2C9 at 
the exposure levels planned, caution is warranted when administering CB-839 to 
patients taking drugs that are highly dependent on CYP2C9 for metabolism and have a 
narrow therapeutic index.  (See Appendix A). 
 
Preliminary PK data generated in this and concurrent Phase 1 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 telaglenastat , resulting 
in decreased systemic exposure. Although patients are not required to discontinue their 
use of these agents, discontinuation is recommended whenever possible.  
 
 
4.5 Dosing Delays and Dose Modifications: 
 
4.5.1. Dose Adjustments: 
 
The doses of telaglenastat and AZA will be adjusted according to the guidelines shown 
in the following tables for study drug-related clinically significant toxicity.  If toxicity is not 
covered in the table, doses may be reduced or held at the discretion of the investigator 
for the patient’s safety.  
 
Patients will be withdrawn from the study if they fail to recover to CTCAE v4.03 grade 0 
to 1 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from a 
clinically significant non-hematologic treatment-related toxicity within 6 weeks (leading 
to treatment delay of > 4 weeks) unless the investigator feels that the patient should 
remain in the study because of evidence that the patient is/may continue deriving 
benefit from continuing study treatment. Such instances will be discussed with the 
principal investigator on a case by case basis and the discussion documented in the 
medical record. 
 
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Patients with study-drug related toxicities that are manageable with supportive therapy 
may not require dose reductions. For patients with other drug-related toxicities, the 
following dose adjustment rules apply: 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.5.2. 
Administration of subsequent cycles should be administered when neutrophils recover 
to > 1 x 10^9/L and platelets to >30 x 10^9/L, or to baseline levels prior to the start of 
the last cycle of therapy.  Patients with residual disease may start the next cycle with 
neutrophil and/or platelet counts lower than these if judged to be in the best interest of 
the patient.  The decision to treat should be documented in the patient’s medical record. 
 
5. STUDY PROCEDURES 
 
5.1 Screening (Visit 1) 
 
The following procedures are performed during screening, staging and workup.  These 
procedures are to be performed within 4 weeks prior to study drug administration, 
except where indicated.  All procedures for the Phase 1b and Phase 2 are 
interchangeable. 
 
A signed and dated IEC/IRB approved informed consent form must be obtained before 
any study specific procedures are performed.  Procedures that are part of routine care 
are not considered study specific procedures.  All subjects will be screened for eligibility 
before enrollment.  Once the subject has met all inclusion criteria, they will be enrolled 
onto the study. 
 
Table 2: Procedures during Screening, Staging and Workup 
NCI  CTCAE v4.03 Grade 
Action 
Grade 0-2 non-hematological 
toxicity 
No dose reduction. 
For grade 2 toxicities that are 
persistent and/or intolerable 
(e.g. stomatitis) patients may 
have a treatment interruption 
or dose reductions to the next 
lower dose level. 
Grade 3-4 clinically significant 
non-hematological toxicity† 
Hold until recover to NCI CTC 
AE grade 0-1 
If recovery occurs within 4 
weeks after treatment has 
been held, dose should be 
reduced to –1 dose level, if 
applicable.   
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Procedures 
Specifics 
Informed consent
Full History and Physical 
Examination 
History – present illness, prior 
surgeries, other medical illnesses, 
review of systems, allergies, prior 
therapy for cancer and concurrent 
meds;  
 
Physical exam – record weight, 
and note abnormalities in any 
major organ system (including but 
not limited to neurologic, head and 
neck, lymph nodes, 
cardiovascular, pulmonary, 
abdomen, extremities), note and 
measure sites of disease
Concomitant Medications
Vital signs (including temperature, 
pulse, and blood pressure) 
 
ECOG performance status
Urine or blood pregnancy test 
(females of child-bearing potential 
only)
Within 7 days prior to first dose 
Disease status  (IPSS classification 
and WHO disease classification) 
 
Note: Bone marrow aspirate and/or 
biopsy within 4 weeks prior to first 
dose of drug in all patients.
Staging with bone marrow aspiration
and biopsy for disease assessment. 
 
Serum chemistries (repeat if 
screening chemistries completed 
greater than 72 hours prior to the 
first dose) 
Sodium, potassium, blood urea 
nitrogen, creatinine, glucose, 
calcium, phosphate, magnesium, 
AST and/or ALT, total bilirubin, 
alkaline phosphatase, uric acid, 
amylase and  lipase
CBC with differential (repeat if 
screening test completed greater 
than 72 hours prior to the first dose)
Differential may be omitted if WBC 
≤0.5 x109/L 
Standard 12-lead EKG with QTc 
calculation
 
 
5.2 On-Study Procedures 
 
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5.2.1. Cycle 1 Day 1: 
 
Pretreatment baseline procedures are acceptable if performed within 3 days prior to 
C1D1 except vital signs, serum chemistries, and hematology labs.  Vital signs must be 
taken prior to dosing on C1D1.  Patients should be instructed not to eat breakfast prior 
to their clinic visit on C1D1. During the C1D1 visit, patients will undergo the following 
procedures prior to dosing: 
 
1. Symptom-directed physical exam including vital signs and weight. This is a focused 
exam performed based upon observed clinical signs and patient complaints. System 
exams are only required as clinically indicated. 
2. Clinical laboratory evaluation  
3. Pre-dose plasma sample collection for PK and correlative studies 
4. Pre-dose bone marrow aspirate and/or biopsy for correlative studies (obtained after 
study consent is signed). 
5. Recording of concomitant medications 
 
Telaglenastat should be administered after pre-dose procedures have been completed 
and the patient has consumed breakfast.  Azacitidine will be administered SC or IV after 
all safety evaluations have been performed and the appropriate premedication has been 
administered.  Note: If institutional guidelines for pre-medication include a proton pump 
inhibitor (PPI), the treatment should only be administered > 1 hour after dosing with 
telaglenastat .  Following receipt of telaglenastat , the patients will undergo the 
following: 
 
1. AE monitoring 
2. ECG with QTcF (in duplicate) between 2-4 hr post-dose 
 
Subsequent doses of telaglenastat will be self-administered by the patient per dosing 
instructions after all study procedures have been completed. 
 
 
 
 
 
5.2.2. Cycle 1 Days 2-7: 
 
During Cycle 1 and all subsequent cycles, Days 2-7, patient will undergo vital signs prior 
to azacitidine administration.  Patients may take their telaglenastat doses prior to, 
during, or after their AZA according to their usual dosing schedule. 
 
5.2.3. Cycle 1 Day 8, Day 15, Day 22 (+/- 3 days) 
 
At these Cycle 1 mid-cycle assessments, patients will return to clinic to undergo the 
following procedures: 
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1. AE monitoring 
2. Recording of concomitant medications 
3. Vital signs and weight 
4. Symptom-directed physical exam 
5. Clinical laboratory evaluation (hematology, serum chemistries) 
6. Plasma samples for PK analysis pre-dose on C1D15 
*Patients may take their telaglenastat doses prior to, during, or after their clinic visit 
according to their usual dosing schedule because there are no specified pre-dose 
procedures with the exception of C1D15 where the patient should not take their 
telaglenastat dose prior to arrival due to pre-dose PK sample. 
 
5.2.4. Cycle 2 Day 1 (+/- 5 days) and all subsequent cycles on Day 1 
 
Patients may take their telaglenastat doses prior to, during, or after their clinic visit 
according to their usual dosing schedule because there are no specified pre-dose study 
procedures with the exception of C2D1 and C3D1 due to pre-dose PK samples. 
1. Vital signs and weight 
2. AE monitoring 
3. Recording of concomitant medications 
4. Symptom-directed physical exam 
5. Clinical laboratory values (hematology, serum chemistry) 
6. Plasma sample for exploratory biomarker analysis 
7. Bone marrow evaluation of tumor/disease burden is required for all patients receiving 
telaglenastat  on cycle 2 day 1, cycle 4 day 1, cycle 6 day 1, and every 3 cycles 
thereafter, +/- 5 days for all above assessments.  Additional evaluations are acceptable 
as clinically indicated.  
8. Bone marrow sample for biomarker and pharmacodynamics analysis during above 
protocol-defined time points.  
9. Plasma samples for correlative analysis on same day as bone marrow sample 
timepoints are collected 
10. Plasma samples for PK analysis prior to the administration of study drug, on C2D1 
and C3D1. 
 
5.3. End of Study Visit: 
 
Subjects will undergo an End of Treatment (EOT) Visit within 28 days of discontinuation 
of telaglenastat .  The following EOT procedures are recommended: 
 
1. AE monitoring 
2. Recording of concomitant medications 
3. Vital signs and weight 
4. Complete physical examination 
5. ECOG performance status evaluation 
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6. Clinical laboratory values (hematology, chemistry) 
7. Serum or urine pregnancy test for women of child-bearing potential 
8. 12-lead ECG with QTcF 
9. Bone marrow sample for biomarker and/or PDn analysis. This is only required if the 
reason for treatment discontinuation is relapse/disease progression following a PR or 
better. Patients with adequate numbers of leukemic blasts circulating in the peripheral 
blood may submit a whole blood sample instead of a bone marrow sample 
 
5.4 Long Term Follow Up 
 
All patients discontinued from study treatment for any reason other than withdrawal of 
consent for treatment and follow-up will continue to be assessed for survival.  Survival 
information (i.e. the date and cause of death) will be collected via quarterly 
telephone calls and/or clinical visits for a period of 5 years after the last subject 
has enrolled on the study. 
 
 
6. RESPONSE DEFINITIONS 
 
6.1 Study Endpoints: 
 
6.2.1. Efficacy Analysis:  Clinical activity of telaglenastat + AZA will be assessed 
based on Modified IWG Response Criteria for MDS (Cheson et al, 2006). 
 
Proposed Modified International 
Working Group Response Criteria for 
Altering Natural History of MDS 
Category 
Response criteria  
(Responses must last at least 4 weeks) 
Complete remission  
Bone marrow: ≤5% myeloblasts with 
normal maturation of all cell lines* 
Persistent dysplasia will be noted*† 
Peripheral blood‡ Hgb ≥11 g/dL Platelets 
≥100 × 109/L Neutrophils ≥1.0 × 109/L† 
Blasts = 0% 
Partial remission  
All CR criteria if abnormal before 
treatment except: Bone marrow blasts 
decreased by ≥50% over pretreatment 
but still >5% Cellularity and morphology 
not relevant 
Marrow CR†  
Bone marrow: ≤5% myeloblasts and 
decrease by ≥50% over pretreatment† 
Peripheral blood: if HI responses, they will 
be noted in addition to marrow CR† 
Stable disease  
Failure to achieve at least PR, but no 
evidence of progression for >8 wks 
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Failure  
Death during treatment or disease 
progression characterized by worsening 
of cytopenias, increase in percentage of 
bone marrow blasts, or progression to a 
more advanced MDS FAB subtype than 
pretreatment 
Relapse after CR or PR  
At least 1 of the following: Return to 
pretreatment bone marrow blast 
percentage Decrement of ≥50% from 
maximum remission/response levels in 
granulocytes or platelets Reduction in 
Hgb concentration by ≥1.5 g/dL or 
transfusion dependence 
Cytogenetic response  
Complete: Disappearance of the 
chromosomal abnormality without 
appearance of new ones Partial: At least 
50% reduction of the chromosomal 
abnormality 
Disease progression  
For patients with: Less than 5% blasts: 
≥50% increase in blasts to >5% blasts 
5%-10% blasts: ≥50% increase to >10% 
blasts 10%-20% blasts: ≥50% increase to 
>20% blasts 20%-30% blasts: ≥50% 
increase to >30% blasts  
Any of the following: At least 50% 
decrement from maximum 
remission/response in granulocytes or 
platelets Reduction in Hgb by ≥2 g/dL 
Transfusion dependence 
Survival  
Endpoints: Overall: death from any cause 
Event free: failure or death from any 
cause PFS: disease progression or death 
from MDS DFS: time to relapse Cause-
specific death: death related to MDS 
Source: (Cheson, et al. 2006) Abbreviations: MDS = myelodysplastic syndromes; CR 
= complete remission; Hgb = hemoglobin; HI = hematologic improvement; PR = partial 
remission; FAB = French-American-British; AML = acute myeloid leukemia; PFS = 
progression-free survival; DFS = disease-free survival. Note: Deletions to IWG 
response criteria are not shown. Note: To convert hemoglobin from g/L to g/dL, divide 
g/L by 10. *Dysplastic changes should consider the normal range of dysplastic 
changes (modification).  
†Modification to IWG response criteria (Cheson, et al. 2003) ‡In some circumstances, 
protocol therapy may require the initiation of further treatment (e.g., consolidation, 
maintenance) before the 4-week period. Such subjects can be included in the 
response category into which they fit at the time the therapy is started. Transient 
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cytopenias during repeated chemotherapy courses should not be considered as 
interrupting durability of response, as long as they recover to the improved counts of 
the previous course.  
 
6.2.2. Hematologic Improvement Response Criteria:   
 
*Responses must last at least 8 weeks 
 
Proposed Modified International 
Working Group Response Criteria for 
Hematologic Improvement 
Hematologic improvement* 
Response criteria  
(Responses must last at least 8 
weeks)†  
Erythroid response (pretreatment, < 11 
g/dL)  
Hgb increase by ≥1.5 g/dL Relevant 
reduction of units of RBC transfusions by 
an absolute number of at least 4 RBC 
transfusions/8 wk compared with the 
pretreatment transfusion number in the 
previous 8 wk. Only RBC transfusions 
given for a Hgb of ≤9.0 g/dL pretreatment 
will count in the RBC transfusion 
response evaluation† 
Platelet response (pretreatment, < 100 × 
109/L)  
Absolute increase of ≥30 × 109/L for 
patients starting with >20 × 109/L 
platelets Increase from <20 × 109/L to 
>20 × 109/L and by at least 100%† 
Neutrophil response (pretreatment, < 1.0 
× 109/L) 
At least 100% increase and an absolute 
increase >0.5 × 109/L† 
Progression or relapse after HI‡  
At least 1 of the following:  
At least 50% decrement from maximum 
response levels in granulocytes or 
platelets  
Reduction in Hgb by > 1.5 g/dL  
Transfusion dependence 
Source: (Cheson, et al. 2006) Abbreviations: Hgb indicates hemoglobin; RBC: red 
blood cell; HI: hematologic improvement. Note: Deletions to the IWG response criteria 
are not shown. Note: To convert hemoglobin from g/L to g/dL, divide g/L by 10. 
*Pretreatment counts averages of at least 2 measurements (not influenced by 
transfusions) ≥1 week apart (modification).  
†Modification to IWG response criteria (Cheson, et al. 2003) ‡In the absence of 
another explanation, such as acute infection, repeated courses of chemotherapy 
(modification), gastrointestinal bleeding, hemolysis, and so forth.  
 
For each subject, response to therapy, duration of response, event-free survival, and 
overall survival will be calculated. The duration of response is defined as the number of 
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days from the date of initial response (PR or better) to the date of first documented 
disease progression/relapse or death, whichever occurs first. Event-free survival is 
defined as the number of days from the date of treatment initiation (i.e., C1D1) to the 
date of documented treatment failure, relapses from CR, or death from any cause, 
whichever occurs first, and will be calculated for all patients. In the event that neither 
disease progression or death is documented prior to study termination, analysis cutoff, 
or the start of confounding anticancer therapy, these endpoints will be censored at the 
date of last tumor assessment date. 
 
In addition, relationships between anti-tumor activity, PDn markers, exploratory 
biomarkers, and drug exposure levels will be explored. 
 
6.2.3. Primary Safety Endpoint 
 
Primary safety endpoint: The overall incidence and severity of all adverse events using 
Common Toxicity Criteria v 4.0.   
 
An adverse event is any untoward medical occurrence that may present during treatment 
with a pharmaceutical product but which does not necessarily have a causal relationship 
with this treatment.  Adverse events (AEs) will be collected using the Leukemia AE 
guidelines. 
Adverse drug reaction is a response to a drug which is noxious and unintended and which 
occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease 
or for the modification of physiologic function. 
All “suspected adverse reactions” (as defined in 21 CFR 312.32(a)) will be captured in 
the case report forms.  For abnormal chemical values grade 3 or 4, the apogee will be 
reported per course in the CRF. 
Assessing causal connections between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a 
contributory cause of an adverse event if, had the drug not been administered, 1) the 
event would not have happened at all, 2) the event would have occurred later than it 
actually did, or 3) the event would have been less severe. 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial.   
 
 
6.2.4. Serious Adverse Event Reporting (SAEs) 
 
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An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
- 
Death 
- 
A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred.  It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
- 
Inpatient hospitalization or prolongation of existing hospitalization 
- 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
- 
A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject 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 dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
- 
Important medical events as defined above may also be considered serious 
adverse events.  Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, IND 
office. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
Only unexpected AEs will be recorded in the Case Report Form (CRF).  The Principal 
Investigator will sign and date the PDMS or CORE Case Report Form toxicity pages per 
each patient at the completion of each course.  Following signature, the Case Report 
Form will be used as source documentation for the adverse events for attribution. 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office.   
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. MDACC.  
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Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery 
is complete and laboratory tests have returned to baseline, progression of the 
event has stabilized, or there has been acceptable resolution of the event. 
Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
The following SAEs are not subject to expedited reporting, but would still be included in 
the annual report via the SAE log. 
a. Infection or cytopenias leading to hospitalization or prolongation of hospitalization 
Disease progression leading to death, life-threating AE, hospitalization or 
prolongation of hospitalization, or disability.  
Reporting to FDA: 
- 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32 
 
- 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy. 
 
6.2.5. Procedure in Case of Pregnancy 
 
If a female subject or partner of a male subject becomes pregnant during the study 
dosing period or within 3 months from the discontinuation of dosing, the investigator 
should report the information to the study supporter as if it is an SAE. The expected 
date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated fertility date, pregnancy result and neonatal data etc., should be included in 
this information.  The investigator will follow the medical status of the mother, as well as 
the fetus, as if the pregnancy is an SAE. 
 
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous 
abortion, induced abortion, stillbirth, death of newborn, congenital anomaly (including 
anomaly in a miscarried fetus)], the investigator should respond in accordance with the 
report procedure for SAEs. Additional information regarding the outcome of a pregnancy 
(which is categorized as an SAE) is mentioned below. 
- 
"Spontaneous abortion" includes abortion and missed abortion. 
- 
Death of an infant within 1 month after birth should be reported as an SAE 
regardless of its relationship with the study drug. 
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- 
If an infant dies more than 1 month after the birth, it should be reported if a 
relationship between the death and intrauterine exposure to the study drug is 
judged as "possible" by the investigator. 
- 
In the case of a delivery of a living newborn, the "normality" of the infant is 
evaluated at the birth. 
- 
"Normality" of the miscarried fetus is evaluated by visual examination unless test 
results which indicate a congenital anomaly are obtained prior to miscarriage. 
 
6.2.6. SAE Reporting to Calithera 
 
Any serious adverse events which occur during the clinical study or within 30 days of 
receiving the last dose of study medication, whether or not related to the study drug, 
must be reported by the investigator.  In addition, any SAEs which occur as a result of 
protocol specific diagnostic procedures or interventions must also be reported. 
 
All serious adverse events must be reported within 5 working days of knowledge of the 
event (within 24 hours for life threatening or fatal events) to Calithera Bioscience’s 
PharmacoVigilance agent according to the Safety Data Exchange Agreement at the 
following: 
 
US Toll Free Fax #: 1 (800) 727-8347 
 
eFax forwarded to calithera@primevigilance.com 
 
email: calithera@primevigilance.com 
 
 
The SAE report should comprise a full written summary, detailing relevant aspects of 
the adverse events in question.  Where applicable, information from relevant hospital 
case records and autopsy reports should be included.  Follow-up information should be 
forwarded to Calithera within 24 hours. 
 
SAEs brought to the attention of the investigator at any time after cessation of 
telaglenastat and considered by the investigator to be related or possibly related to 
telaglenastat must be reported to Calithera if and when they occur.  Additionally, in 
order to fulfill international reporting obligations, SAEs that are related to study 
participation (e.g., procedures, invasive tests, change from existing therapy) or are 
related to a concurrent medication will be collected and recorded from the time the 
subject consents to participate in the study until he/she is discharged. 
 
 
6.3. Secondary and Exploratory Endpoints: 
 
 
6.3.1. Pharmacokinetic Analysis 
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PK studies will be performed on plasma to assess steady-state levels of telaglenastat 
over time, and drug accumulation over time. PK sampling will occur on C1D15, C2D1, 
and C3D1.  
PK assay will be conducted at a central laboratory where the assay for telaglenastat has 
been validated. Details are given below and in the laboratory manual: 
 
Intertek Pharmaceutical Services 
 
Attn:   
Sample Accessioning 
Address:  
10420 Wateridge Circle 
San Diego, CA 92121 
Phone:  
(858) 558-2599 
Fax:   
(858) 558-2600 
Email:  
sd.accessioning@intertek.com 
 
 
6.3.2. Pharmacodynamic Analysis 
 
Pharmacodynamic effects of telaglenastat will be measured in MDS CD34+ and in bone 
marrow stromal cells isolated before treatment and at all bone marrow study timepoints. 
These include measurements of intracellular metabolism; RNA expression of GLS and 
other metabolic genes; DNA methylation and hyddroxymethylation studies; quantitation 
of phenotypically defined MDS stem cells. These PD analyses will be performed in the 
laboratory of Dr Konopleva and Dr Amit Verma. 
 
No formal statistical analysis of PDn endpoints will be performed. PDn data from each 
assay will be listed, and possible relationships between PK and PDn variables will be 
explored. Any biological activity will be described. 
 
 
7. Regulatory and Reporting Requirements: 
 
7.1. Informed Consent: 
 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any 
investigational products are administered.  A legally acceptable representative is an 
individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study. 
 
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The acquisition of informed consent should be documented in the subject’s medical 
records, and the informed consent form should be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  The original signed informed consent form should be 
retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject or legally acceptable representative. 
 
7.2. Independent Ethics Committee/Institutional Review Board 
 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IEC/IRB 
for written approval. A copy of the written approval of the protocol and informed consent 
form must be received by Calithera before recruitment of subjects into the study and 
shipment of investigational product. 
 
The investigator must submit and, where necessary, obtain approval from the IEC/IRB 
for all subsequent protocol amendments and changes to the informed consent form. 
The investigator should notify the IEC/IRB of deviations from the protocol or serious 
adverse events occurring at the site and other adverse event reports received from 
Calithera, in accordance with local procedures. 
 
The investigator will be responsible for obtaining annual IEC/IRB approval/renewal 
throughout the duration of the study. Copies of the investigator’s reports and the 
IEC/IRB’s continuance of approval must be sent to Calithera. 
 
7.3 Subject Confidentiality 
 
The investigator must ensure that the subject’s confidentiality is maintained. On 
documents submitted to Calithera, subjects should be identified by their study number 
only. Documents that are not for submission to Calithera (eg, signed informed consent 
forms) should be kept in strict confidence by the investigator. 
 
In compliance with ICH GCP Guidelines, it is required that the investigator and 
institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the subject’s original medical 
records for verification of study-related procedures and data. Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are 
important to the evaluation of the study. The investigator is obligated to inform and 
obtain the consent of the subject to permit named representatives to have access to 
his/her study-related records without violating the confidentiality of the subject. 
 
7.4. Study Termination 
 
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Both Calithera and the investigator reserve the right to terminate the study according to 
the study contract. The investigator should notify the IEC/IRB in writing of the study’s 
completion or early termination and send a copy of the notification to Calithera. 
 
Subjects may be eligible for continued treatment with investigational product by 
extension protocol or as provided for by the local country’s regulatory mechanism. 
However, Calithera reserves the unilateral right to determine whether to supply the 
investigational product, and by what mechanism, after termination of the trial and before 
it is available commercially. 
 
7.5. Study Documentation and Archival 
 
The investigator should maintain a list of appropriately qualified persons to whom 
he/she has delegated study duties. All persons authorized to make entries and/or 
corrections on case report forms will be included on the Delegation of Authority Form. 
 
Source documents are original documents, data, and records from which the subject’s 
case report form data are obtained. These include but are not limited to hospital 
records, clinical and office charts, laboratory and pharmacy records, diaries, 
microfiches, radiographs, and correspondence. Case report form entries may be 
considered source data if the CRF is the site of the original recording (ie, there is no 
other written or electronic record of data). In this study, case report forms calculating 
IPSS may be used as source documents for IPSS risk category assignment. 
 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Calithera and/or applicable regulatory 
authorities. Elements should include: 
 
- 
Subject files containing completed case report forms, informed consent forms, 
and subject identification list 
 
- 
Study files containing the protocol with all amendments, investigator’s brochure, 
copies of prestudy documentation and all correspondence to and from the IEC/IRB 
and Calithera 
 
- 
Proof of receipt, Investigational Product Accountability Record, Return of 
Investigational Product for Destruction, Final Investigational Product Reconciliation 
Statement, and all drug-related correspondence 
 
 
In addition, all original source documents supporting entries in the case report forms 
must be maintained and be readily available.  No study document should be destroyed 
without prior written agreement between Calithera and the investigator. Should the 
investigator wish to assign the study records to another party or move them to another 
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location, he/she must notify Calithera in writing of the new responsible person and/or 
the new location. 
7.6. Serious Adverse Event Reporting (SAE): 
See Section 6.2.4 for detailed information regarding SAE definitions. 
It is the responsibility of the PI and the research teams to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.   Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to Calithera, regardless of attribution (see Section 6.2.2.3).  SAE 
reporting will be done according to 21 CFR 312.32(c)(1)(iv) (“Sponsor must report any 
clinically important increase in the rate of a serious adverse reaction over that listed in 
the protocol or investigator brochure.”).  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for adverse event 
reporting. (http://ctep.cancer.gov/reporting/ctc.html).   
7.7 IND Summaries: 
A Toxicity Summary will be submitted to the IND Office Medical Monitor after the first six 
evaluable patients complete cycle one of study treatment, prior to the Dose modification 
or Phase II. 
A Toxicity Summary will be submitted to the IND Office Medical Monitor after the first 7 
evaluable patients and every 7 evaluable patients thereafter. 
A Response Summary will be submitted to the IND Office Medical Monitor after 16 
evaluable patients complete 6 cycles of study treatment. 
8. STATISTICAL CONSIDERATIONS:
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8.1. Statistical Design 
 
This is a single institution phase Ib/II study to determine the safety, tolerability and 
clinical activity of telaglenastat in combination with azacitidine (AZA) for patients with 
advanced MDS.  Up to 40 patients will be enrolled from MDACC, allowing 6 patients 
treated in the Phase 1b portion that are removed from study before day 28 for any 
reason other than toxicity and have not experienced DLT, or considered non-evaluable 
for DLT or response. 
 
 
8.1.1 Phase Ib: 
The Phase Ib part of the study is performed to assess the safety of telaglenastat in 
combination with AZA.  We will first enroll 6 patients at dose level 0.  If only 0 or 1 of 6 
patients experiences a DLT, the dose level will be identified as the RP2D.  If at least 2 
of 6 patients experience DLTs, then the MTD has been exceeded and 6 patients will be 
treated at the lower dose level (i.e. dose level -1).  If at least 2 of 6 patients experience 
DLTs in dose level -1, the combination may be considered too toxic in this indication 
and the study may be discontinued.  The 6 patients treated at the RP2D level will be 
evaluated in the Phase II portion.  A maximum of 12 patients will be enrolled in the 
Phase 1b part of the study. 
 
A Toxicity Summary will be submitted to the IND Office Medical Monitor after the first six 
evaluable patients complete cycle one of study treatment, prior to the Dose modification 
or Phase II. 
 
 
8.1.2. Phase II: 
The Simon minimax two-stage design will be employed for the Phase II portion.(15)  We 
assume a target response rate of 60% and a response rate of 40% or lower will be 
considered not desirable.  Response is defined as complete remission (CR), partial 
remission (PR), marrow CR (mCR), or Hematologic Improvement (HI) by modified IWG 
criteria for MDS patients.  For example a 29% CR/PR rate was reported in the 
azacitidine arm in the randomized AZA-001 trial, and a 23% CR/PR rate and 60% ORR 
(including 37% HI) was seen in the azacitidine arm of the CALGB 9221 trial.  To 
implement the Simon’s two-stage design, the assessment window for response 
(CR+PR+mCR+HI) is defined as response occurring within the first 6 cycles of 
treatment.  With a type I error rate of 10% and 80% power, we will enroll 16 patients in 
the first stage.  If 6 or fewer patients achieve response, enrollment will be halted.  If 7 or 
more out of the first 16 patients achieve response, accrual will continue until a total of 
28 patients have been enrolled.  If 15 or more out of these 28 patients achieve 
response, the treatment will be considered efficacious and worthy of further 
investigation.  Under this Simon’s minimax two-stage design, the probability of early 
termination is 53% and the expected sample size is 22 if the true response rate is 40%. 
 
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A Toxicity Summary will be submitted to the IND Office Medical Monitor after the first 7 
evaluable patients and every 7 evaluable patients thereafter. 
 
A Response Summary will be submitted to the IND Office Medical Monitor after 15 
evaluable patients complete 6 cycles of study treatment. 
 
8.1.3. Toxicity: 
The method of Thall, Simon and Estey will be used for toxicity monitoring for the Phase 
II part of this study.(16)  For monitoring purposes, toxicity is defined as DLT which 
occurs  during the first cycle.  Denote the probability of toxicity by PT. We assume as a 
priori, PT ~ beta (0.6, 1.4).  Our stopping rule is to stop the trial if Pr(PT > 0.30 | 
data)>0.90.  That is, we will stop the trial for new patient enrollment if at any time during 
the study; we determine that there is more than 90% chance that the toxicity rate is 
more than 30%. This toxicity stopping rule will be applied in cohort size of 7, starting 
from the 7th patient.  Stopping boundaries corresponding to this stopping rule are listed 
in Table 1. The operating characteristics are summarized in Table 2. The design 
software Multc Lean Desktop (version 2.1) developed by the Department of Biostatistics 
at M. D. Anderson Cancer Center (MDACC) was used to generate the toxicity stopping 
boundaries and the operating characteristics table. 
 
Table 1.  Early stopping boundaries for toxicity monitoring 
# of patients ( in 
cohort size of 7, 
starting from the 7th  
patient) 
Stop the trial if there 
are this many 
patients with 
toxicities:  
7 
4-7 
14 
7-14 
21 
10-21 
 
Table 2. Operating characteristics for toxicity monitoring  
True toxicity rate 
Prob(stop the trial early) 
Average sample size 
0.10 
0.0028 
27.94 
0.20 
0.0398 
27.22 
0.30 
0.1817 
24.69 
0.40 
0.4639 
19.91 
0.50 
0.7697 
14.37 
 
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8.2 Analysis Populations: 
 
8.2.1. Safety Population 
All patients who receive at least 1 dose of telaglenastat will be included in the analysis 
of safety regardless of the duration of treatment. Patients who experience adverse 
events during the Screening period but who do not start on study treatment due to 
reasons that include, but are not limited to ineligibility/screen failure, death or withdrawal 
of consent, will not be included in the safety population. 
 
8.2.2. DLT-evaluable: 
Unless doses are missed in Cycle 1 due to DLT(s), a patient must receive at least 85% 
of the planned doses of telaglenastat and at least > 5 doses of azacitidine to be 
considered evaluable for DLTs.  If a patient received fewer doses of telaglenastat or 
AZA in the first 28 days of treatment for reasons other than a DLT, the patient will be 
considered non-evaluable for DLT and replaced. 
 
8.2.3. Efficacy Evaluable Population 
All patients who complete at least one post-baseline disease status assessment or who 
discontinue study medication early due to study drug-related toxicity will be considered 
evaluable for efficacy.  Patients who discontinue and have not received at least 85% of 
the telaglenastat doses and at least 5 doses of azacitidine within the first cycle of 
treatment will be considered non-evaluable for response and may be replaced. 
 
8.3. Analysis Plan: 
During Phase II portion, if 6 or fewer patients out of the first 16 patients achieve 
response, enrollment will be halted.  If 7 or more out of the first 16 patients achieve 
response, accrual will continue until a total of 28 patients have been enrolled.  If 15 or 
more out of these 28 patients achieve response, the treatment will be considered 
efficacious and worthy of further investigation.  The rates of response 
(CR+PR+mCR+HI) to therapy will be estimated along with the 95% confidence interval. 
The Kaplan-Meier method will be used to estimate the probabilities of event-free 
survival (EFS), overall survival (OS) and duration of response. Log-rank tests will be 
used to compare among subgroups of patients in terms of EFS, OS or duration of 
response. Anti-tumor activity, PDn markers, exploratory biomarkers and drug exposure 
levels will be summarized graphically and with descriptive statistics. Safety data will be 
summarized using frequency and percentage, by category and severity.  
 
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References: 
1. 
Doll DC, List AF. Myelodysplastic syndromes. The Western journal of medicine. 
1989 Aug;151(2):161-7. PubMed PMID: 2672599. Pubmed Central PMCID: 1026906. 
Epub 1989/08/01. eng. 
2. 
Albitar M, Manshouri T, Shen Y, Liu D, Beran M, Kantarjian HM, et al. 
Myelodysplastic syndrome is not merely "preleukemia". Blood. 2002 Aug 1;100(3):791-
8. PubMed PMID: 12130488. Epub 2002/07/20. eng. 
3. 
Dansey R. Myelodysplasia. Current opinion in oncology. 2000 Jan;12(1):13-21. 
PubMed PMID: 10687724. Epub 2000/02/25. eng. 
4. 
Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and 
survival in the United States. Cancer. 2007 Apr 15;109(8):1536-42. PubMed PMID: 
17345612. Epub 2007/03/09. eng. 
5. 
Kadia TM, Jabbour E, Kantarjian H. Failure of hypomethylating agent-based 
therapy in myelodysplastic syndromes. Seminars in oncology. 2011 Oct;38(5):682-92. 
PubMed PMID: 21943675. Epub 2011/09/29. eng. 
6. 
Prebet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, et al. Outcome of 
high-risk myelodysplastic syndrome after azacitidine treatment failure. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2011 Aug 
20;29(24):3322-7. PubMed PMID: 21788559. Epub 2011/07/27. eng. 
7. 
Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J, et al. 
Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk 
myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007 Jan 
1;109(1):52-7. PubMed PMID: 16882708. Epub 2006/08/03. eng. 
8. 
Steensma DP, Baer MR, Slack JL, Buckstein R, Godley LA, Garcia-Manero G, et 
al. Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults 
with myelodysplastic syndromes: the alternative dosing for outpatient treatment 
(ADOPT) trial. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2009 Aug 10;27(23):3842-8. PubMed PMID: 19528372. Epub 
2009/06/17. eng. 
9. 
Lee JH, Jang JH, Park J, Park S, Joo YD, Kim YK, et al. A prospective 
multicenter observational study of decitabine treatment in Korean patients with 
myelodysplastic syndrome. Haematologica. 2011 Oct;96(10):1441-7. PubMed PMID: 
21659363. Pubmed Central PMCID: 3186304. Epub 2011/06/11. eng. 
10. 
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et 
al. Efficacy of azacitidine compared with that of conventional care regimens in the 
treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase 
III study. The lancet oncology. 2009 Mar;10(3):223-32. PubMed PMID: 19230772. 
11. 
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. 
Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 
2012 Sep 20;120(12):2454-65. PubMed PMID: 22740453. Epub 2012/06/29. eng. 
12. 
Bejar R, Stevenson KE, Caughey BA, Abdel-Wahab O, Steensma DP, Galili N, et 
al. Validation of a prognostic model and the impact of mutations in patients with lower-
risk myelodysplastic syndromes. Journal of clinical oncology : official journal of the 
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American Society of Clinical Oncology. 2012 Sep 20;30(27):3376-82. PubMed PMID: 
22869879. Pubmed Central PMCID: 3438234. 
13. 
Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, et al. 
Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. 
Cancer research. 2010 Nov 15;70(22):8981-7. PubMed PMID: 21045145. Pubmed 
Central PMCID: 3058858. 
14. 
Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, et al. 
Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer 
cell. 2010 Sep 14;18(3):207-19. PubMed PMID: 20832749. Pubmed Central PMCID: 
3078749. 
15. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical 
trials. 1989 Mar;10(1):1-10. PubMed PMID: 2702835. Epub 1989/03/01. eng. 
16. 
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Statistics in medicine. 1995 Feb 
28;14(4):357-79. PubMed PMID: 7746977. Epub 1995/02/28. eng. 
 
 
 
 
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APPENDIX A: CYP2C9 Substrates with a narrow therapeutic index* 
 
S-Warfarin (anticoagulant) 
 
Phenytoin (antiepileptic) 
*Narrow therapeutic index is defined as “CYP substrates with narrow therapeutic range 
refers to drugs whose exposure-response relationship indicates that small increases in 
their exposure levels by the concomitant use of CYP inhibitors may lead to serious 
safety concerns (e.g., Torsades de Pointes).” 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginter
actionslabeling/ucm093664.htm 
Other CYP2C9 Substrates 
 
NSAIDs (analgesic, antipyretic, anti-inflammatory)  
o celecoxib 
o lornoxicam 
o diclofenac 
o ibuprofen  
o naproxen 
o ketoprofen 
o piroxicam 
o meloxicam 
o suprofen 
 
fluvastatin (statin) 
 
sulfonylureas (antidiabetic)  
o glipizide 
o glibenclamide 
o glimepiride 
o tolbutamide 
o glyburide 
 
irbesartanlosartan 
 
sildenafil (in erectile dysfunction) 
 
terbinafine (antifungal) 
 
amitriptyline (tricyclic antidepressant) 
 
fluoxetine (SSRI antidepressant) 
 
nateglinide (antidiabetic) 
 
rosiglitazone (antidiabetic) 
 
tamoxifen (SERM) 
 
torasemide (loop diuretic)ketamine 
 
 
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APPENDIX B: PK 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 
telaglenastat (CB-839) of each pharmacokinetic blood collection. The 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: 
Pharmacokinetic analysis will be carried out by central lab 
Intertek Pharmaceutical Services 
Attn:   
Sample Accessioning 
Address: 
10420 Wateridge Circle 
San Diego, CA 92121 
Phone: 
(858) 558-2599
Fax: 
(858) 558-2600
Email: 
sd.accessioning@intertek.com
All plasma samples will be analyzed for telaglenastat (CB-839) by using a validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) method of appropriate 
specificity and sensitivity according to Good Laboratory Practices (GLPs). 
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