Clinical trial NCT02942264
Conditions: Brain Tumor Astrocytoma Astroglioma Glioblastoma Gliosarcoma
Keywords: Brain Tumor Glioblastoma Relapse Randomized Temodar
Sponsor: National Cancer Institute (NCI)
Start date: 2016-12-14; Completion date: 2020-08-26
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

Zotiraciclib (TG02) is an investigational drug that penetrates the blood-brain barrier and might treat brain tumors. Temozolomide (TMZ) is a drug used to treat brain tumors.

Objective:

To find out if Zotiraciclib (TG02) is safe, and to find out if it in combination with TMZ is as effective as TMZ alone in people with brain tumors.

Eligibility:

People ages 18 and older with a brain tumor that has progressed after standard treatment

Design:

In phase I part, the Bayesian optimal interval (BOIN) design will be used to find the maximum tolerated dose (MTD) of Zotiraciclib (TG02) for Arm 1 (dose dense TMZ) and Arm 2 (metronomic TMZ) independently. Then a randomized cohort expansion compared progression free survival at 4 months (PFS4) of the two arms for an efficient determination of a TMZ schedule to combine with Zotiraciclib at MTD.

In Phase II part, a Bayesian design based on posterior probability will be used to monitor efficacy.

Participants will be screened with:

* Medical history
* Physical exam
* Blood and urine tests
* Magnetic resonance imaging (MRI) of the brain if they have not had one in 14 days
* Heart test
* Tissue sample from prior surgeries

Participants will take Zotiraciclib (TG02) plus TMZ by mouth in 28-day cycles.

* Some will take TMZ for 7 days on and 7 days off. Others will take it every day.
* They will all take Zotiraciclib (TG02) three days before Cycle 1, and then on four days during every cycle.
* They will all get treatment to prevent vomiting and diarrhea before and for 24 hours after each Zotiraciclib (TG02) dose.
* They will all keep a diary of when they take the drugs and their symptoms.

Participants will have study visits. These include:

* Physical exam, heart test, quality of life questionnaire, brain MRI, and urine tests every 4 weeks
* Blood tests every 2 weeks

Participants will continue treatment until their disease gets worse or they have intolerable side effects.

Participants will also be enrolled in another protocol to test molecular markers for their brain tumor.

Detailed description:
Background:

* Zotiraciclib (TG02) is a pyrimidine-based multi-kinase inhibitor that has been shown to have inhibitory effects on cyclin-dependent kinases (CDKs), Janus Kinase 2 (JAK2) and Fm-like tyrosine kinase 3 (Flt3). It is orally administered and penetrates blood brain barrier (BBB). There is clinical experience in using Zotiraciclib (TG02) as both a single agent and in combination with other chemotherapy agents for cancer treatment.
* Temozolomide (TMZ) is an oral alkylating agent that has proven efficacy in anaplastic glioma and glioblastoma. It was approved by the United States (U.S.) Food and Drug Administration (FDA) to treat anaplastic astrocytoma and glioblastoma in adults. Both a dose-dense (dd) schedule, 7 days on and 7 days off and a metronomic (mn) daily dosing schedule have been used to treat recurrent high-grade gliomas.
* Our preclinical data have demonstrated that Zotiraciclib (TG02) down-regulates cyclin-dependent kinase 9 (CDK9) activity and its target proteins, such as anti-apoptotic protein myeloid-cell leukemia (Mcl-1), X-linked inhibitor of apoptosis (XIAP) and survivin. A treatment with Zotiraciclib (TG02) and TMZ has synergistic anti-glioma effects in a variety of glioma models with different genetic background. This serves as the basis for this proposed clinical trial.

Objectives:

Phase I:

-To determine the maximum tolerated dose (MTD) of Zotiraciclib (TG02) plus TMZ using both the dd and mn TMZ schedules in adult patients with recurrent anaplastic astrocytoma or glioblastoma/gliosarcoma.

To select the treatment regimen with better progression free survival (PFS)4 between Zotiraciclib (TG02) plus dd TMZ or mn TMZ at each of the MTDs following cohort expansion.

Phase II:

-To determine the efficacy of Zotiraciclib (TG02) plus TMZ versus TMZ alone in patients with recurrent World Health Organization (WHO) grade III or IV astrocytoma as determined by progression free survival.

Eligibility:

* Documented pathology diagnosis of anaplastic astrocytoma \[WHO grade III\], or glioblastoma/gliosarcoma (WHO grade IV) with recurrent disease. If the pathology diagnosis is anaplastic glioma or anaplastic oligoastrocytoma, evidence of either intact 1p/19q chromosomes or molecular features suggesting astrocytic tumor must be present. (including, but not limited to α-thalassemia mental retardation X-linked (ATRX) and/or tumor protein P53 (TP53) mutation)
* No prior use of bevacizumab as a treatment for brain tumor.
* No more than two prior relapses for Phase I and no more than one prior relapse for Phase II.
* Patients must have recurrent disease, either histologically proven or with imaging suggestive of recurrent disease
* Tumor tissues available for review to confirm the histologic diagnosis.
* Tumor tissue blocks available for molecular profiling analysis.

Design:

* Phase I:

  * This portion of the study is conducted in two stages: The MTD finding and cohort extension. Two treatment arms and several dose levels are planned.
  * In the MTD finding part, TMZ with two alternate schedules (dd and mn) in combination with Zotiraciclib (TG02) will be administered.
  * A cohort extension of both arms will be performed at each MTD and the treatment arm with a better progression free survival at 4 months (PFS4) will be selected for the combination treatment arm for Phase II.
  * Pharmacokinetic, pharmacogenetic studies and neutrophil analysis will be performed during the cohort extension of both arms.
  * A maximum of 72 patients will be enrolled to this component for the trial.
* Phase II:

  --Patients will be randomized between two competing treatment arms: ("winner" of dd vs mn) TMZ + Zotiraciclib (TG02) versus dd/mn TMZ alone using a Bayesian clinical trial design. The dosage for the combination arm will be derived from the MTD determined in the Phase I component of the study.
* The treatment schedule will be identical to that described above in the phase I component, with each cycle comprising 28 days.
* Patients will continue treatment until tumor progression or unacceptable toxicity occurs.
* At progression, patients randomized to the control arm (Temozolomide \[TMZ\] alone) will be offered the opportunity to continue TMZ and additional treatment with Zotiraciclib (TG02).

Arms: arm 1: dose dense (dd) Temozolomide (TMZ) 125 mg/m\^2 x 7 days on / 7 days off plus Zotiraciclib (TG02) dose escalation arm 2: metronomic Temozolomide (TMZ) 50 mg/ m\^2 daily plus Zotiraciclib (TG02) dose escalation arm 3: Maximum tolerated dose (MTD) of Zotiraciclib (TG02) from phase I plus and "winner" of dose dense (dd) vs metronomic Temozolomide (TMZ) from phase I arm 4: "winner" of dose dense (dd) vs metronomic Temozolomide (TMZ) from phase I alone
Interventions: intervention 1: Zotiraciclib (TG02) intervention 2: Temozolomide (TMZ)
Intervention descriptions: intervention 1: Phase I: Two treatment arms and several dose levels are planned; In the maximum tolerated dose (MTD) finding part, Temozolomide (TMZ) with two alternate schedules (dose dense (dd) and metronomic (mn) in combination with Zotiraciclib (TG02) will be administered;

--A cohort extension of both arms will be performed at each MTD and the treatment arm with a better progression free survival at 4 months (PFS4) will be selected for the combination treatment arm for Phase II; Patients will be randomized between two competing treatment arms: (winner of dd vs mn) TMZ + Zotiraciclib (TG02) versus dd/mn TMZ alone using a Bayesian clinical trial design. The dosage for the combination arm will be derived from the MTD determined in the Phase I component of the study. intervention 2: Phase I: In the maximum tolerated dose (MTD) finding part, Temozolomide (TMZ) with two alternate schedules (dose dense (dd) and metronomic (mn) in combination with Zotiraciclib (TG02) will be administered; A cohort extension of both arms will be performed at each MTD and the treatment arm with a better progression free survival at 4 months (PFS4) will be selected for the combination treatment arm for Phase II; Patients will be randomized between two competing treatment arms: ("winner" of dd vs mn) TMZ + Zotiraciclib (TG02) versus dd/mn TMZ alone using a Bayesian clinical trial design.

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
Version Date: 06/01/2020
 Abbreviated Title: Ph I/II TMZ+TG02 astrocytoma 
CC Protocol #: 17C0009 F
NCT Number: NCT02942264
Version Date: 06/19/2020
Title: Phase I Trial of Zotiraciclib (TG02) Plus Dose-Dense or Metronomic Temozolomide 
Followed by Randomized Phase II Trial of Zotiraciclib (TG02) plus Temozolomide versus 
Temozolomide alone in Adults with Recurrent Anaplastic Astrocytoma and Glioblastoma
NCI Principal Investigator: 
Jing Wu, M.D., PhD 
NOB, CCR, NCI
37 Convent Dr. Rm 1142A
Bethesda, MD 20892
Tel:  240-760-6036
Email: jing.wu3@nih.gov
Investigational Agents:    
Drug Name:
Zotiraciclib (TG02)
IND Number:
132001
Sponsor:
CCR
Manufacturer:
Adastra Pharmaceuticals, Inc.
Commercial Agents: Temozolomide
Coordinating Center
Institution: 
                              
National Cancer Institute, Bethesda, MD
Overall Study PI:                    
Jing Wu, MD, PhD
                                         
NOB, CCR, NCI
                              
37 Convent Dr. Rm 1142A
                              
Bethesda, MD 20892
                             
Phone: 240-760-6036
                                                     
E-mail: jing.wu3@nih.gov 
                                          
 


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
Version Date: 06/01/2020
2
PRECIS 
Background: 

Zotiraciclib (TG02) is a pyrimidine-based multi-kinase inhibitor that has been shown to 
have inhibitory effects on CDKs, Janus Kinase 2 (JAK2) and Fm-like tyrosine kinase 3 
(Flt3). It is orally administered and penetrates blood brain barrier (BBB). There is clinical 
experience in using Zotiraciclib (TG02) as both a single agent and in combination with 
other chemotherapy agents for cancer treatment. 

Temozolomide (TMZ) is an oral alkylating agent that has proven efficacy in anaplastic 
glioma and glioblastoma. It was approved by the U.S. Food and Drug Administration 
(FDA) to treat anaplastic astrocytoma and glioblastoma in adults. Both a dose-dense (dd) 
schedule, 7 days on and 7 days off and a metronomic (mn) daily dosing schedule have 
been used to treat recurrent high-grade gliomas.

Our preclinical data have demonstrated that Zotiraciclib (TG02) down-regulates CDK9 
activity and its target proteins, such as anti-apoptotic protein Mcl-1, XIAP and survivin. 
A treatment with Zotiraciclib (TG02) and TMZ has synergistic anti-glioma effects in a 
variety of glioma models with different genetic background. This serves as the basis for 
this proposed clinical trial. 
Objectives:
Phase I:

To determine the maximum tolerated dose (MTD) of Zotiraciclib (TG02) plus TMZ 
using both the dd and mn TMZ schedules in adult patients with recurrent anaplastic 
astrocytoma or glioblastoma/gliosarcoma.
Phase II:

To determine the efficacy of Zotiraciclib (TG02) plus TMZ versus TMZ alone in patients 
with recurrent WHO grade III or IV astrocytoma as determined by progression free 
survival.
Eligibility:

Documented pathology diagnosis of anaplastic astrocytoma [WHO grade III], or 
glioblastoma/gliosarcoma [WHO grade IV] with recurrent disease. If the pathology 
diagnosis is anaplastic glioma or anaplastic oligoastrocytoma, evidence of either intact 
1p/19q chromosomes or molecular features suggesting astrocytic tumor must be present. 
(including, but not limited to ATRX and/or TP53 mutation)

No prior use of bevacizumab as a treatment for brain tumor. 

No more than two prior relapses for Phase I and no more than one prior relapse for Phase 
II.

Patients must have recurrent disease, either histologically proven or with imaging 
suggestive of recurrent disease 

Tumor tissues available for review to confirm the histologic diagnosis.

Tumor tissue blocks available for molecular profiling analysis. 


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
Version Date: 06/01/2020
3
Design:
Phase I: 

This portion of the study is conducted in two stages: The MTD finding and cohort 
extension.  Two treatment arms and several dose levels are planned. 

In the MTD finding part, TMZ with two alternate schedules (dd and mn) in combination 
with Zotiraciclib (TG02) will be administered. 

A cohort extension of both arms will be performed at each MTD and the treatment arm 
with a better progression free survival at 4 months (PFS4) will be selected for the 
combination treatment arm for Phase II.

Pharmacokinetic, pharmacogenetic studies and neutrophil analysis will be performed 
during the cohort extension of both arms. 

A maximum of 72 patients will be enrolled to this component for the trial.
Phase II:

Patients will be randomized between two competing treatment arms: (“winner” of dd vs 
mn) TMZ + Zotiraciclib (TG02) versus dd/mn TMZ alone using a Bayesian clinical trial 
design. The dosage for the combination arm will be derived from the MTD determined in 
the Phase I component of the study. 

The treatment schedule will be identical to that described above in the phase I 
component, with each cycle comprising 28 days. 

Patients will continue treatment until tumor progression or unacceptable toxicity occurs.

At progression, patients randomized to the control arm (Temozolomide [TMZ] alone) 
will be offered the opportunity to continue TMZ and additional treatment with 
Zotiraciclib (TG02).


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................4
1
INTRODUCTION ..................................................................................................................7
1.1
Study Objectives..................................................................................................................7
1.2
Background and Rationale...................................................................................................7
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT ......................................................30
2.1
Eligibility Criteria..............................................................................................................30
2.2
Screening Evaluation.........................................................................................................33
2.3
Participant Registration and Study Status Update Procedures ..........................................34
2.4
Baseline Evaluation ...........................................................................................................35
3
STUDY IMPLEMENTATION ............................................................................................36
3.1
Study Design:.....................................................................................................................36
3.2
Drug administration...........................................................................................................39
3.3
Dose Modification/Delays:................................................................................................40
3.4
Questionnaires ...................................................................................................................46
3.5
Assessments while On Study Therapy ..............................................................................47
3.6
Assessments after completion of study therapy.................................................................48
3.7
CCR Self-Administered Study Drugs Policy ....................................................................48
3.8
Study Calendar...................................................................................................................49
3.9
Surgical Guidelines............................................................................................................50
3.10
Criteria for Removal from Protocol Therapy and Off Study Criteria ...............................51
4
CONCOMITANT MEDICATIONS/MEASURES..............................................................52
4.1
Medications to Avoid or Use with Precaution (Zotiraciclib [TG02]) ...............................52
4.2
Medications to Avoid or Use with Precaution (TMZ).......................................................53
4.3
G-CSF and erythropoietin administration: ........................................................................53
4.4
Platelet support: .................................................................................................................53
4.5
Corticosteroids...................................................................................................................53
4.6
Febrile neutropenia ............................................................................................................53
4.7
Anti-emetics.......................................................................................................................53
4.8
Other Anticancer or Experimental Therapies....................................................................53
5
BIOSPECIMEN COLLECTION..........................................................................................54


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5.1
Correlative Studies for Research .......................................................................................54
5.2
Sample Storage, Tracking and Disposition .......................................................................58
6
DATA COLLECTION AND EVALUATION ....................................................................60
6.1
Data Collection ..................................................................................................................60
6.2
Data Sharing Plans.............................................................................................................62
6.3
Response Criteria...............................................................................................................62
6.4
Toxicity Criteria.................................................................................................................65
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN....65
7.1
Definitions .........................................................................................................................65
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING/IRB Reporting........................65
7.3
NCI Clinical Director Reporting .......................................................................................66
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN...................................66
8
SPONSOR SAFETY REPORTING.....................................................................................66
8.1
Definitions .........................................................................................................................66
8.2
Assessment of Safety Events.............................................................................................68
8.3
Reporting of Serious Adverse Events................................................................................68
8.4
Safety Reporting Criteria to the Pharmaceutical Collaborators ........................................68
8.5
Reporting Pregnancy .........................................................................................................69
8.6
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .....................69
9
Clinical monitoring plan.......................................................................................................69
10
STATISTICAL CONSIDERATIONS .................................................................................70
10.1
Phase I component:............................................................................................................70
10.2
Phase II component: ..........................................................................................................74
11
COLLABORATIVE AGREEMENTS.................................................................................76
11.1
Agreement Type ................................................................................................................76
12
HUMAN SUBJECTS PROTECTIONS...............................................................................76
12.1
Rationale For Subject Selection.........................................................................................76
12.2
Participation of Children....................................................................................................76
12.3
Participation Of Subjects Unable To Give Consent ..........................................................76
12.4
Evaluation of Benefits and Risks/Discomforts..................................................................77
12.5
Risks/Benefits Analysis.....................................................................................................77


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12.6
Consent and Assent Process and Documentation..............................................................78
13
PHARMACEUTICAL INFORMATION ............................................................................79
13.1
Temozolomide (Temodar®; Methazolastone)...................................................................79
13.2
Zotiraciclib (TG02)............................................................................................................81
14
REFERENCES .....................................................................................................................87
15
APPENDICES ......................................................................................................................90
15.1
Appendix: Performance Status Criteria.............................................................................90
15.2
Appendix: Pregnancy & contraception..............................................................................91
15.3
Appendix: CYP1A2 and CYP3A4 ....................................................................................92
15.4
Appendix: Study Flow Chart.............................................................................................93
15.5
Appendix: Rano.................................................................................................................95
15.6
Appendix: Dosing schedule for both treatments arms for Phase I study...........................96
15.7
Appendix: Pill diary...........................................................................................................97


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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objectives
1.1.1.1
Phase I
To determine the maximum tolerated dose (MTD) of Zotiraciclib (TG02) plus TMZ using both 
the dd and mn TMZ schedules in adult patients with recurrent anaplastic astrocytoma or 
glioblastoma/gliosarcoma.
1.1.1.2
Phase II
To determine the efficacy of Zotiraciclib (TG02) plus TMZ versus TMZ alone in patients with 
recurrent WHO grade III or IV astrocytoma as determined by progression free survival (PFS).
1.1.2
Secondary Objectives
1.1.2.1
To select the treatment regimen with better PFS4 between Zotiraciclib (TG02) plus dd 
TMZ or mn TMZ at each of the MTDs following cohort expansion.
1.1.2.2
To determine the objective response rate, PFS at 6 months (PFS6) and overall survival 
(OS) in the treatment arms. 
1.1.2.3
 To longitudinally evaluate patient reported outcome measures using self-reported 
symptom severity and interference with daily activities using the MDASI-BT 
1.1.3
Exploratory Objectives
1.1.3.1
To obtain tumor tissues from initial occurrence and /or recurrence to detect TP53, 
PTEN, IDH mutation, MYC amplification status.  The level of anti-apoptotic protein, 
such as Mcl-1 and XIAP, and caspase 3, cleaved PARP, c-Myc, CDK9 expression will 
be tested, if tissues are available at the time of recurrence.
1.1.3.2
To evaluate the imaging features by magnetic resonance imaging, including perfusion, 
before and during the treatment every two months.
1.1.3.3
To obtain blood samples after Zotiraciclib (TG02) dose on cycle 1, day -3 along with 
PK sample collection to analyze the effect of Zotiraciclib (TG02) on neutrophil count 
and functions. 
1.1.3.4
To perform pharmacokinetic and pharmacogenomic studies of Zotiraciclib (TG02) once 
the MTD is determined in each cohort.
1.1.3.5
To explore the feasibility of Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) in brain tumor patients 
receiving investigational cancer treatments.
1.2
BACKGROUND AND RATIONALE
1.2.1
Disease background
High grade astrocytomas include glioblastoma (GBM) [WHO grade IV] and anaplastic 
astrocytoma (AA), [WHO grade III]. Both are highly malignant and belong to gliomas. Gliomas 


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
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represent 80% of malignant CNS tumors. GBM accounts for 54% of gliomas and AA accounts 
for 7%.[1] 
Histologically, GBM displays a high mitotic index, cellular pleomorphism, and extensive 
vascular proliferation or necrosis. They are characterized by their intrinsic heterogeneity, high 
morbidity and mortality. Despite aggressive multimodality treatment approach in surgery, 
radiation therapy and cytotoxic chemotherapies, the prognosis of patients with GBM remains 
poor with a median survival rate of less than 18 months.[2] Recurrent GBM has an even more 
dismal prognosis with a median overall survival of approximately 25 weeks. [3]  
Anaplastic astrocytoma (AA) is classified by WHO as a grade III glioma, demonstrating a less 
aggressive behavior when comparing to GBM. AA frequently transforms to GBM. The treatment 
of recurrent AA is unsatisfying.  Chemotherapy and re-operation for recurrent AA is of modest 
benefit and only bring short responses. Wong et al reported that a progression free survival rate 
at 6 months is 31% and the median progression free survival is only 13 weeks based on eight 
phase II clinical trials that included 150 patients with recurrent AA.[3] In the pivotal clinical trial 
that led to the accelerated FDA approval in 1999 for TMZ as the treatment of recurrent AA, the 
PFS6 and median overall survival were reported as 46% and 13.6 months respectively.[4]
Most normal cells can activate the apoptotic pathways in response to DNA damage or abnormal 
proliferation. In contrast, tumor cells in AA developed mechanisms to increase cell proliferation 
and decreasing apoptosis. TP53 is one of the notably known genes that are implicated in 
apoptotic pathways of high grade astrocytoma.  The TP53 gene that maps to chromosome 17p is 
frequently inactivated in astrocytoma  and is found in one third of AAs.[5] P53 protein plays 
multiple important roles in a number of cellular processes including cell cycle arrest, response to 
DNA damage and apoptosis. As expected, the signaling pathways in gliomas including TP53 
inactivation are most commonly noted in secondary GBM, which evolves from AA, in contrast 
to the primary glioblastoma, which are featured by genetic alteration, including EGFR 
amplification and chromosome 10 loss with PTEN mutation.[6, 7] 
1.2.2
Zotiraciclib (TG02) in human cancers
1.2.2.1
Mechanisms of action of Zotiraciclib (TG02)
Zotiraciclib (TG02) is a pyrimidine-based multi-kinase inhibitor that has been shown to have 
inhibitory effects on cyclin-dependent kinases (CDKs), Janus kinase 2 (JAK2) and Fm-like 
tyrosine kinase 3 (Flt3).[8] It most potently inhibits CDK1, 2, 3, 5 and 9 with an IC50 of 3-9 nM 
and IC50 of 37nM for CDK 7. The IC50 for JAK2 is 19 nM. It is also effective against Flt3 and its 
drug resistant mutant with an IC50 of 19-21 nM.


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Figure 1:  Target kinase inhibition by Zotiraciclib (TG02) following oral dosing at 60mg/kg in 
nude mice bearing MCV-11 AML xenografts.
Among all mechanism of action, CDK9 inhibition is a one of the most appealing features of 
Zotiraciclib (TG02). CDK9 is a serine/threonine kinase that forms the catalytic core of the 
positive transcription elongation factor [9-11] and it is critical for stimulating transcription 
elongation through RNA polymerase II.[12]  To assess target engagement by Zotiraciclib (TG02) 
in tumor tissues, tumor lysate were analyzed after dosing MV4-11 AML xenograft-bearing mice 
with a single dose of 60mg/kg Zotiraciclib (TG02). Level of RNA-polymerase II 
phosphorylation at serine 2 was used as a readout for CDK9 inhibition. The inhibition was 
observed starting from 0.5 hours and reached to a maximum at 6 hours as demonstrated in Figure 
1 (Investigator’s Brochure, Version 6).  As a consequence of inhibiting CDK9 function, the 
short-lived proteins will be depleted due to their heightened requirement to be regularly 
refreshed.[13] Two such short-lived proteins that play an important role in cancer cell survival 
mechanisms are Myeloid Leukemia 1 (Mcl-1), a B-cell Lymphoma 2 (Bcl-2) family member and 
x-linked inhibitor of apoptosis (XIAP), an anti-apoptotic protein.[14] Both Mcl-1 and XIAP were 
found to be depleted following a treatment with TG02 in hematologic malignancy cell lines, 
including myeloma cell line, as demonstrated in Figure 2 (Investigator’s Brochure, Version 6). 
Figure 2:  Zotiraciclib (TG02) depletes anti-apoptotic proteins of the Bcl-2 and AP families in 
myeloma cell line.


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Since it was discovered in 1992, Mcl-1 has been shown to play an integral role in anti-apoptotic 
signaling pathways. Mcl-1 is highly expressed in a variety of human cancer cells, including CNS 
cancers. [15] Its overexpression is one of the survival mechanisms that allow cancer cells to 
survive and to further develop resistance to various apoptotic-inducing therapies. To underscore 
this point, in high grade gliomas, Mcl-1 was found to be the dominant anti-apoptotic Bcl-2-
related protein.[16]
XIAP expression has been noted in human glioma cell lines and apoptosis was blocked after 
XIAP gene transfer,[17] suggesting that XIAP is involved in apoptosis signaling in human 
gliomas.
CDK9 activity is regulated though activators, such as c-Myc [18] and NFkB [19], both are 
heavily involved in pathogenesis of malignant glioma.[20, 21]  In addition to their roles in 
transcription, CDKs can regulate other cellular process that were considered as the core function 
of cell cycle control mechanisms.[22] While not involved in cell cycle progression, CDK9 and 
its cyclin partner T1 have a role in cell differentiation.[23] CDK9 was also found to be crucial in 
MYC-driven tumors. Pharmacological or shRNA-mediated CDK9 inhibition led to anti-tumor 
effects that correlated with MYC expression level, suggesting CDK9 inhibition likely is a 
therapeutic approach for treating MYC-overexpression tumors.[24]
In vitro studies have demonstrated that Zotiraciclib (TG02) depletes survival proteins, including 
Mcl-1 and XIAP, leading to apoptosis in human tumor cells.[25] An oral dosing at 30-60mg/kg 
of Zotiraciclib (TG02) in mice AML xenografts demonstrated an inhibition of several target 
kinases, suggesting that the agent inhibited CDK9, CDK2, JAK2 and FLT3.[8]
1.2.2.2 Preclinical and clinical experience of Zotiraciclib (TG02)
Preclinical experiences
Extensive preclinical experiments have been performed to demonstrate the characteristics of 
Zotiraciclib (TG02). A Good Laboratory Practice (GLP) safety pharmacology study was 
conducted in 12 beagle dogs (6 females and 6 male) to evaluate the cardiovascular and 
respiratory effects of Zotiraciclib (TG02) after a single oral administration at 30mg/kg and 60 
mg/kg. A dose-related duration of emesis was observed. One female dog received Zotiraciclib 
(TG02) at 30mg/kg died due to circulatory failure secondary to diarrhea and dehydration caused 
by severe intestinal damage. Postmortem pathology exam demonstrated marked atrophy and 
hemorrhage of thymus in this individual dog. The surface of both small and large intestines was 
found to be covered by white mucosa layer. The histologic exam showed epithelial necrosis on 
the mucosa surface and in the lumen of crypts accompanied with marked hyperemia. All the 
other 11 dogs survived, and no changes were noted in skin and fur, eyes and mucous membranes, 
respiratory system, circulatory system, autonomic system and CNS. There were no Zotiraciclib 
(TG02) effects on cardiac function in dogs. The individual values for blood pressure, respiratory 
rate, body temperature and glucose levels were within physiological limits during the study in all 
groups.   Neither dose- nor sex-dependent variations were observed. Serum chemistry 
examination performed during the study showed dose dependent escalation in LDH, AST, ALT 
and CK in interval 2 hours and 6 hours after the administration of Zotiraciclib (TG02) with a 
trend to recovery of LDH and AST at 24 and 48 hours after Zotiraciclib (TG02) treatment.  


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Table 1: Pharmacokinetic parameters of Zotiraciclib (TG02) in mice, rats and dogs
Pharmacokinetics (PK) analyses were conducted in female nude mice, male Wistar rats and male 
beagle dogs. Comparison of single intravenous (I.V.) and oral doses showed variable 
bioavailability following oral dosing. All three species showed a rapid absorption following oral 
dosing with Tmax ranging from 10 minutes to 60 minutes. The PK parameters of Zotiraciclib 
(TG02) in these 3 species are summarized in Table 1 (Investigator’s Brochure, Version 6). The 
plasma concentration versus time profile of Zotiraciclib (TG02) in female nude mice following a 
single dose of 5mg/kg intravenously and a single oral dose of 75mg/kg is demonstrated in Figure 
3 (Investigator’s Brochure, Version 6).  


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Figure 3: Plasma concentrations vs. time profile of Zotiraciclib (TG02) in female nude mice 
following a single IV dose of 5mg/kg and a single oral dose of 75 mg/kg (n=3)
The PK assessment following a single oral administration under fed and in unfed conditions in 
mice suggested no significant food-drug interaction. The percentage of plasma protein biding of 
Zotiraciclib (TG02) was measured by an equilibrium dialysis of Zotiraciclib (TG02) (1000ng/ml) 
spiked into human, dog, and mouse plasma against phosphate-buffered saline (PBS) at 37oC for 
4 hours. Results suggested that the percentage of plasma-bound Zotiraciclib (TG02) was 99.97% 
±  in human and similar in all species studied. Limited tissue distribution of Zotiraciclib 
(TG02) was assessed in female nude mice following a single oral dosing at 75mg/kg. The mean 
concentration of Zotiraciclib (TG02) in plasma and tissues were demonstrated in Figure 4 
(Investigator’s Brochure, Version 6). 


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Figure 4: Mean Plasma and tissue concentrations of Zotiraciclib (TG02) determined at different 
time points following a single oral administration of 75mg/kg to nude mice (n=3)
Table 2: Mean Pharmaceutical Parameters of Zotiraciclib (TG02) Following Oral Dosing at 30 
mg/kg and 60mg/kg in Nude Mice Bearing MV4-11 AML Xenografts
Zotiraciclib (TG02) preferentially distributed to liver, lungs and kidney followed by heart and 
brain.  The PK of Zotiraciclib (TG02) in plasma and tumor tissues in mice was also determined 
following a signal dosing of nude mice bearing subcutaneous xenografts of FLT-mutant AML 
MV4-11 at 30mg/kg and 60mg/kg. The PK parameters that are summarized in Table 2 
(Investigator’s Brochure, Version 6) suggested that the greater peak and aggregate drug exposure 
in the tumor than in the blood in this animal model. The tissue distribution after single dose of 
Zotiraciclib (TG02) in mice demonstrate that the AUC ratio of brain/plasma is 2.4, suggesting 
good blood brain barrier penetration, which is highly relevant to the potential use of Zotiraciclib 
(TG02) in brain tumor treatment (Table 3, data from Adastra Pharmaceutical). Figure 5 
(Investigator’s Brochure, Version 6) shows the mean plasma and tissue concentration profiles 
over time. The levels of Zotiraciclib (TG02) in plasma and tissue exceeded the biochemical IC50 
on the kinases CDK1, 2, and 9 (<10 nM) and FLT3 and JAK2 (20 nM to 40 nM); and exceeded 
the cellular IC50 on primary AML blasts (40nM to 50nM) for at least 24 hours at both doses. In 


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animals receiving an oral dose of 60mg/kg Zotiraciclib (TG02), intratumoral Zotiraciclib (TG02) 
concentrations peaked at 200-fold above these levels (~8 μM) and remained 10-fold over (~0.4 
μM) after 24 hours. By contrast, Zotiraciclib (TG02) was cleared relatively rapidly from plasma, 
with blood levels dropping below the threshold for cellular activity within 3 to 4 hours after a 
30mg/kg dose and 13 to 14 hours after a 60 mg/kg dose. 
Table 3: Limited Tissue distribution of Zotiraciclib (TG02) after a single PO administration at 
75mg/kg
Figure 5: Mean Plasma and Tumor Concentrations of Zotiraciclib (TG02) Following Oral Dosing 
at 30mg/kg and 60mg/kg in Nude Mice Bearing MV4-11 AML Xenografts
The in vitro metabolic T1/2 of Zotiraciclib (TG02) in human liver microsomes (LM; T1/2 = 48 
minutes), indicates involvement of Phase 1 metabolism. Species differences for in vitro 
metabolic T1/2 were noted as demonstrated in Figure 6 (Investigator’s Brochure, Version 6). The 
compound appears to be more stable in human and dog than in mouse and rat LMs. The major 
metabolites observed in all species were M1, N-de-methylation, and M2, resulting from 
oxidation of Zotiraciclib (TG02). 


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Figure 6: In-vitro Microsomal Stability of Zotiraciclib (TG02) In Liver Microsomes
To investigate the role of CYP450 isozymes in the metabolism of Zotiraciclib (TG02), CYP3A4, 
2D6, 1A2, 2C9, and 2C19 Bactosomes (recombinant isoform expression systems) were 
incubated with 5 μM Zotiraciclib (TG02) at 37°C for 45 minutes in the presence of nicotinamide 
adenine dinucleotide phosphate-oxidase. In this assay system, the t1/2 of Zotiraciclib (TG02) 
was approximately 30 minutes for CYP1A2 and CYP3A4 Bactosomes but >45 minutes for the 
other isoforms. These results indicate that Zotiraciclib (TG02) is primarily metabolized by 
CYP1A2 and CYP3A4. The potential for Zotiraciclib (TG02) to inhibit CYP450 isozymes was 
assessed using pooled human LM. The capacity of Zotiraciclib (TG02) (0.05, 0.25, 0.5, 2.5, 5, 
and 25 μM) to inhibit various CYP450 isozymes was investigated by measuring the inhibition 
potential (IC50 and inhibition constant [Ki]) on prototype reactions using specific substrates. 
Zotiraciclib (TG02) inhibited the catalytic activity of CYP2D6 (IC50 = 0.95 μM ± 0.16 μM), but 
not the other isozymes tested. The potential of Zotiraciclib (TG02) to induce human CYP3A4 
and CYP1A2 isozymes was investigated in cultured human hepatocytes from a single male 
human donor. Results suggested that Zotiraciclib (TG02) is a weak inducer of CYP1A2 in 
human hepatocytes when compared with positive control omeprazole. For CYP3A4, Zotiraciclib 
(TG02) caused no significant induction at the concentration range tested.  Trans-epithelial 
transport of Zotiraciclib (TG02) through Caco-2 monolayers in comparison with 2 control 
compounds indicates that Zotiraciclib (TG02) has high intestinal absorption. The efflux ratio 
value (~1) for Zotiraciclib (TG02) suggests no involvement of an active P-glycoprotein mediated 
transport mechanism. 
The toxicological profile of Zotiraciclib (TG02) was evaluated in mice and dogs following single 
and multiple oral doses for up to 28 days followed by a 28-day non-treatment recovery period. 
Genotoxicity (Ames test, in vitro chromosomal aberration assay, and in vivo mouse micronucleus 
test) was also conducted to provide an overall assessment of Zotiraciclib (TG02). The mean 
toxicokinetic parameters for Zotiraciclib (TG02) following a single oral administration to mice is 
summarized in Table 4 (Investigator’s Brochure, Version 6) and those following 28 days of daily 
oral administration is summarized in Table 5 (Investigator’s Brochure, version 6).


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Table 4: Mean Toxicokinetic Parameters for Zotiraciclib (TG02) Following a Single Oral 
Administration to Mice
Table 5: Mean Toxicokinetic Parameters for Zotiraciclib (TG02) Following 28 Days of Oral 
Administration to Mice.
In the GLP acute oral toxicity study in mice, groups of 10 mice/sex were administered 0 
(vehicle), 25 mg/kg, 50 m/kg, or 100 mg/kg Zotiraciclib (TG02). Cohorts of mice were 
humanely terminated on Days 3 and 15 and given a full postmortem evaluation. In addition, a 
subgroup of mice was designated for neurobehavioral assessment through the use of a functional 
observational battery (FOB), and another subgroup of mice was designated for a full TK profile 
on Day 1. All animals survived until scheduled termination. Rough coat was observed on Day 3 
in two males received 100 mg/kg and one male received 50 mg/kg. Body weight decreases were 
observed in the males and females in 100 mg/kg group on Days 2 and 3 and were considered the 
result of the test article administration. There were no changes in food consumption considered 
the result of the test article administration. The FOB suggests that a single oral dose of 50 mg/kg 
or 100 mg/kg Zotiraciclib (TG02) may induce acute increases in aggression and/or emotionality, 
consistent with minor increases in specific measures of spontaneous locomotor activity (e.g., 
rearing). Test article-related hematology changes included decreased reticulocytes on Day 3 in 
the 25 mg/kg males, and in both sexes of the 50 mg/kg and 100 mg/kg groups, which correlated 
with bone marrow atrophy/necrosis. Total WBC and differential WBC counts decreased in the 
50 mg/kg males only and in both sexes of the 100 mg/kg groups. These were the result of test 


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article administration and were consistent with thymic atrophy observed in the 100 mg/kg 
animals. Test article-related increases in platelet counts were noted in the 100 mg/kg females. 
There were no obvious changes in the serum chemistry parameters for any of the groups 
attributed to Zotiraciclib (TG02) citrate. Histopathologic changes due to Zotiraciclib (TG02) 
citrate were observed in the thymus, spleen, and bone marrow of mice examined on Day 3, and 
in the spleen of mice examined on Day 15. Zotiraciclib (TG02)-related atrophy was present in 
the thymus of all 100mg/kg mice examined at Day 3. Due to the thymic atrophy on Day 3, 
thymic weight parameters were reduced in both sexes of the 100 mg/kg group and in the 50 
mg/kg males. Thymic atrophy was not evident in recovery mice examined on Day 15. Bone 
marrow atrophy and/or necrosis were present on Day 3 in most 100 mg/kg mice and in some 25 
mg/kg and 50 mg/kg females and one (1) 50 mg/kg male. Bone marrow atrophy was not evident 
in recovery mice examined on Day 15. Hematopoiesis was reduced in the spleen of 100 mg/kg 
and 50 mg/kg mice and occasional 25 mg/kg females examined on Day 3 and was responsible 
for reduced splenic weight parameters in the 100 mg/kg males. Splenic hematopoiesis was not 
apparent in recovery group mice examined on Day 15. Based on the results of the single-dose 
study of Zotiraciclib (TG02) citrate in mice, a no observed adverse effect level was not 
determined. Test article-related findings on Day 3 included rough coat (50 mg/kg and 100 
mg/kg); body weight decreases (100 mg/kg); decreased reticulocytes (25 mg/kg [males only], 50 
mg/kg, and 100 mg/kg); decreased WBC counts (50 mg/kg [males only] and 100 mg/kg); 
increased platelet counts (100 mg/kg [females only]); and thymic, spleen, and bone marrow 
changes in organ weights and histopathology (25, 50, and 100 mg/kg). By Day 15, recovery was 
evident or complete for each of the parameters affected. 
Multiple dose toxicity was evaluated by a GLP oral 28-day toxicity study was conducted in CD-
1 mice to determine potential toxicity and TK of Zotiraciclib (TG02) citrate when administered 
by a daily oral gavage for up to 28 consecutive days and to monitor the persistence or 
reversibility of any adverse effects after a 28-day recovery period. Ten mice/sex/group were 
assigned to 1 of 4 dose groups at target dosage levels of 0 (control article), 10 mg/kg, 20 mg/kg, 
and 40 mg/kg Zotiraciclib (TG02). Endpoints used to evaluate the potential toxicity of 
Zotiraciclib (TG02) citrate were survival, clinical observations, body weights, food consumption, 
clinical pathology, necropsy, organ weights, and selected histopathology. Mice administered 10 
mg/kg/day Zotiraciclib (TG02) did not display any adverse clinical signs or statistically 
significant differences in mean body weight, food consumption, clinical pathology or organ 
weight values when compared to respective control values. Preliminary data revealed significant 
decreases in mean body weight and food consumption values in the 40 mg/kg males and females 
with a noted decrease in survival in this group. Based on the inability to field recovery animals at 
40 mg/kg (exceeded the MTD), animals within the core and recovery groups were reassigned so 
that recovery could also be assessed at the mid-dose level, 20 mg/kg. Mice administered 40 
mg/kg displayed adverse clinical observations suggestive of a general debilitation in their health 
status; whereas only rough hair coat was noted in some mice administered 20 mg/kg. 
Administration of 40 mg/kg Zotiraciclib (TG02) was related to decreases in reticulocyte counts, 
red blood cell (RBC) counts, hemoglobin, and hematocrit in males and females, and decreases in 
total WBC, lymphocyte, neutrophil, and monocyte counts in the males on Day 29. Mice 
administered 20 mg/kg Zotiraciclib (TG02) displayed decreases in total WBC, lymphocyte, 


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neutrophil, and monocyte counts on Day 29. On Day 57, the hematology results of the 20 mg/kg 
mice of both sexes and the 40 mg/kg females were similar to controls. 
Test article-related clinical chemistry changes on Day 29 in the 40 mg/kg group included 
increases in ALT, AST, CK, and LDH (males and females); increases in alkaline phosphate, 
BUN, sodium and chloride (males), and decreases in total bilirubin, total protein and ALB 
(males and females); decreases in serum cholesterol and blood glucose (males); and decreases in 
serum globulin and increases in the mean ALB/globulin ratio in the 40 mg/kg females. 
Zotiraciclib (TG02) related clinical chemistry changes on Day 29 in the 20 mg/kg males included 
increases in AST, LDH, BUN, and triglycerides and decreases in bilirubin; and in the females 
there were decreases in globulin and increases in the ALB/globulin ratio and BUN value. 
Zotiraciclib (TG02)-related changes were present in the thymus, spleen, bone marrow, stomach, 
liver, testes, uterus, and/or small intestines of 10 mg/kg, 20 mg/kg, and 40 mg/kg scheduled 
termination mice, and consisted of atrophy and or necrosis of lymphoid tissues, reduced or 
increased hematopoiesis in the spleen, atrophy of bone marrow elements, testicular degeneration, 
small uterus, and atrophy and necrosis and/or regeneration (increased mitoses) of enterocytes in 
the small intestines. Zotiraciclib (TG02)-related lesions were reversed at recovery (Day 57) 
except in the GI tract, where minimal residual lesions were present in the small intestine and 
lesions were mildly increased in the forestomach. Additionally, testicular degeneration was still 
present in the 20 mg/kg mice at recovery. 
In the confirmatory mutagenicity assay, no positive mutagenic response was observed. 
Zotiraciclib (TG02) citrate was evaluated for its genotoxic potential (clastogenicity/aneugenicity) 
as measured by its ability to increase the incidence of micronucleated polychromatic erythrocytes 
(MPCEs) in bone marrow of male and female mice. A significant increase in the incidence of 
MPCEs in bone marrow of male and female ICR mice received 100mg/kg Zotiraciclib (TG02), 
indicating the positivity in mouse micronucleus assay.
Clinical experiences
Two Phase 1 clinical studies with single agent Zotiraciclib (TG02) in hematological malignancy 
have been conducted (NCT01204164 and NCT01699152).  The primary objective of these 
studies was to determine the MTD and DLT. Phase 1 study in combination with carfilzomib in 
multiple myeloma is ongoing. Additional study with Zotiraciclib (TG02) in combination with a 
hypomethylating agent is under development. 


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Figure 7: Zotiraciclib (TG02) 24-hour exposure in patients
The interim analysis of pharmacokinetic (PK) data from clinical studies has been evaluated for 
55 acute leukemia patients, 18 multiple myeloma patients and 8 CLL patients. Mean exposures 
for Zotiraciclib (TG02) over twenty-four hours from Cycle 1 Day 1 (Figure 7) reveal dose-
dependent increases in exposure (AUC0-t), Cmax at approximately 2 hours and an estimated t1/2 
of 10 to 15 hours. Drug-related nausea and vomiting occur most frequently around Cmax on 
dosing days. 


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Table 6: Summary of Zotiraciclib (TG02) Clinical Studies
Multiple consecutive daily doses resulted in Zotiraciclib (TG02) drug accumulation that was not 
predicted based on the nonclinical toxicokinetic studies. Drug accumulation was associated with 
higher incidence and frequency of exposure-related TEAEs, such as fatigue. Zotiraciclib (TG02) 
was administered three times per week (TIW) to multiple myeloma patients; TIW dosing 
reduced but did not alleviate drug accumulation. BIW dosing, twice per week, alleviated drug 
accumulation in all populations and reduced the incidence and severity of drug-related fatigue. 
Schedules of Zotiraciclib (TG02) clinical studies are summarized in Table 6 (Investigator’s 
Brochure, Version 6). The preclinical pharmacodynamics data demonstrate that daily 
administration is not required to achieve anticipated therapeutic drug levels. Base on PK profiles, 
Zotiraciclib (TG02) will be administered no more than twice weekly (BIW). 
In a Phase 1 study of Zotiraciclib (TG02) in multiple myeloma patients, a single agent Zotiraciclib 
(TG02) was administered to 18 multiple myeloma patients on three different schedules of a 28-day 
cycle: 6 patients administered Zotiraciclib (TG02) daily (3 patients at 50 mg and 70 mg each); 9 
patients received Zotiraciclib (TG02) TIW on days 1, 3, 5, 8, 10, 12, 15, 17, 19 followed by a 9-day 


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rest (3 patients at 100 mg and 6 at 150 mg); 3 patients administered Zotiraciclib (TG02) BIW on 
days 1, 4, 8, 11, 15, 18 followed by a 10-day rest (all 3 patients at 200 mg). For the BIW schedule, 
all 3 patients successfully completed Cycle 1.  No patient experienced a dose-limiting toxicity 
(DLT).  At this time, it was decided to amend the protocol and pursue Zotiraciclib (TG02) in 
combination with carfilzomib.  No further dose escalation was evaluated for Zotiraciclib (TG02) as 
a single agent and no MTD was identified.
An open label phase Ib study was developed with the primary objectives to determine the MTD of 
Zotiraciclib (TG02) in combination with carfilzomib (American Society for Hematology 2015 
Abstract #3052). Zotiraciclib (TG02) was administered once daily on days 1, 4, 8, 11, 15, 18 of a 
28-day schedule. The starting dose of Zotiraciclib (TG02) was 150 mg with dose escalation in 50 
mg increments up to 300 mg. Carfilzomib was administered per the Full Prescribing Information or 
in accordance with institutional guidelines at the time of the study (i.e., dosing days 1, 2, 8, 9, 15 
and 16 at 20 mg/m2 for Cycle 1 and 27 mg/m2 for Cycle 2 and subsequent cycles). Fourteen patients 
were enrolled for dose escalation and 10 patients were enrolled for the MTD cohort expansion. The 
MTD for Zotiraciclib (TG02) in combination with carfilzomib was established at 250 mg 
Zotiraciclib (TG02) administered twice a week for 3 weeks (Days 1, 4, 8, 11, 15, and 18) on a 28-
days cycle. Two DLTs were observed, grade (Gr) 4 sepsis and neutropenia, both in 300 mg cohort. 
The most common drug-related adverse events were diarrhea (Gr 1-2: 4% and Gr3: 17%), nausea 
(Gr1-2: 79%), vomiting (Gr1-2: 50%), fatigue (Gr1-2: 38%, Gr3: 4%), anorexia (Gr: 21%), anemia 
(Gr1-2: 4%; Gr3:17%) and thrombocytopenia (Gr3: 8%, Gr4:13%). 
Zotiraciclib (TG02) inhibited the hERG channel, suggesting a risk factor for torsade de pointes 
(QTc prolongation) in human.  In the clinic, electrocardiographic QTc interval results for 73 patients 
enrolled in Parts 1 and 2 demonstrated that there were no clinically meaningful changes from 
baseline in resting 12-lead QTc intervals observed following administration of Zotiraciclib (TG02) 
on Cycle 1 Day 1 at 10 to 200 mg doses.  Additionally, no clinically meaningful changes from 
baseline in resting 12-lead QTc intervals were observed following multiple doses of Zotiraciclib 
(TG02) at 10 to 200 mg doses through Cycle 1, regardless of schedule.
Patients with prolonged QTc intervals (males: >450 ms; females: >470 ms as calculated by 
Fridericia’s correction formula) at screening/ baseline (based on the average QTc of triplicate 
ECGs), should be assessed for the following: normal electrolyte balance and concomitant 
medications known to prolong QTc. A patient can be reassessed for QTc interval after electrolytes 
are balanced and/or concomitant medications are stopped or replaced with an alternate medication.  
Patients, who continue to have prolonged QTc despite normal electrolyte balance and 
discontinuation of medications known to prolong QTc, will be excluded from the study.  Use of 
concomitant medications that prolong QTc interval should be avoided if possible, during this study.
Zotiraciclib (TG02) may carry a risk of damage to chromosomes and should not be given to 
pregnant women or WOCBP not using an effective form of birth control.  Men receiving 
Zotiraciclib (TG02) with female sexual partners of childbearing potential should use an effective 
form of birth control.
Zotiraciclib (TG02) may suppress bone marrow and the lymphoid system.  Based on the 


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preliminary observation from the first 16 patients on the phase I portion of this study, moderate to 
severe neutropenia has been observed.
1.2.3
Rationale for using Zotiraciclib (TG02) in glioma treatment
High grade glioma is a common primary CNS tumor with a poor prognosis. Despite aggressive 
treatment, the disease eventually progresses, and the treatment options are often limited at the 
time of recurrence. There is a great unmet need to develop novel therapies in patients with 
recurrent high-grade glioma.  
TMZ is an oral alkylating agent that has proven efficacy in AA and GBM. It has been proposed 
that the cytotoxic effect of TMZ is associated with induction of cell death or cell cycle arrest.[26] 
Mcl-1 was found to be essential for TMZ induced cell death.[27] Importantly, apoptosis was not 
found to be enhanced by ABT-737, an inhibitor of Bcl-2, but not Mcl-1. However, reducing 
expression of Mcl-1 increased TMZ-induced apoptosis, suggesting that targeting Mcl-1 enhances 
TMZ-induced cell death and therefore may improve response to TMZ treatment, even in patients 
with TMZ–refractory disease. 
p53 is a transcription factor and has an important role in regulating cell cycle and apoptosis in 
response to a variety of cellular stress events. TP53 mutation is a common genetic alteration in 
glioma. The incidence of TP53 mutations is high in malignant gliomas and is reported to be 
higher in AA than GBM.[28] The mutant TP53 has complex effects.  There is not only the lack 
of normal p53 protein function, but there is also other mutation related gain-of-functions,[29] 
such as the ability to disrupt mechanisms that maintain cellular genome integrity and anti-
apoptosis.  This confers a selective survival advantage on cells within a competitive 
microenvironment. The ability to modulate Mcl-1 makes the rational to test Zotiraciclib (TG02) 
in an effort to enhance the apoptosis in glioma cells. 
Furthermore, MYC gene amplification and MYC over-expression have been found in human 
glioblastoma.[30]  MYC expression has an important role in cell growth and apoptosis. 
However, attempts to inhibit MYC haven’t been successful. Therefore, there may be indirect 
mechanisms, through inhibition of CDK9 dependent transcription, to intervene in MYC 
oncogenic signaling pathway.  
PTEN is a tumor suppressor that is frequently inactivated in brain tumors and inactivating PTEN 
mutations were found in 36% of glioblastoma based on a TCGA study.[31]  Importantly, this 
was only found in primary but not secondary glioblastoma.[32] PTEN mutation is known to 
convey resistance to apoptosis-inducing treatments such as radiation and TMZ treatment, by 
upregulating anti-apoptotic proteins, including Mcl-1.[33]  It was also shown that lack of PTEN 
can fuel the cell cycle by increasing the nuclear availability of cyclin D and thus promotes the 
transition from G1-phase to S phase of the cell cycle.[34] 


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Figure 8: The cell viability of patient-derived glioma cell lines is determined using Beckman 
Coulter Vi-CELL TM XR cell viability analyzer with ViCELL Quad Pak Kit. U251, U87, LN229, 
LN18 were obtained from ATCC and the sphere-forming GSC 923, GSC827 were developed 
from NOB laboratory.  All cells were treated with different concentrations of Zotiraciclib (TG02) 
at 24-hour after the cell seeding and cell viability is detected following 72 hours culture.
The preliminary results of in vitro studies from our NOB laboratory and other laboratories have 
demonstrated that a subset of patient-derived glioblastoma cells is highly sensitive to Zotiraciclib 
(TG02). The IC50 of Zotiraciclib (TG02) are in the scale of nanomolar in the glioma cell lines 
that were studied (Figure 8). 
Figure 9: Western blot of several key molecular signals, reflecting the different genetic 
background of the cell lines that were used to study the effects of Zotiraciclib (TG02) treatments.


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Figure 10: Western blot of cleaved Caspase 3, PARP and phospo-H2AX in GSC923 following 
treatment with Zotiraciclib (TG02) at 8, 16, 24, and 48 hours.
The cells that were tested have a wide range of genetic alterations as demonstrated in Figure 9. 
The high sensitivity to a variety of glioblastoma cell lines suggested that the board spectrum of 
effects of Zotiraciclib (TG02) in treating high grade glioma, which is known for inter-tumoral 
heterogeneity. This provides the opportunity to allow enrichment of molecular markers through 
carefully designed clinical trials. GSC923, a patient derived stem-like cell line developed in 
NOB laboratory was selected as a cell model to investigate the apoptotic effect of Zotiraciclib 
(TG02) in glioma. GSC923 has MGMT expression, which makes it insensitive to TMZ. It is also 
featured by TP53 mutation and PTEN mutation. High c-Myc expression was also detected in this 
cell line. The genetic makeup makes GSC923 an appropriate in vitro model to study the biology 
of high grade astrocytoma. Caspase 3 activation was detected by both flow cytometry and 
Western blot in GSC923 following Zotiraciclib (TG02) treatment. Along with the presence of 
cleaved Poly (ADP-ribose) polymerase (PARP) and phosphorylated histone H2AX, the data 
suggested that Zotiraciclib (TG02) can induce apoptosis in glioma cells (Figure 10). As early as 
8 hours after treatment with Zotiraciclib (TG02) at 50 nM, CDK9 expression was shown to be 
decreased and further decreased expression was detected at 48 hours following Zotiraciclib 
(TG02) treatment (Figure 11).  The expression of anti-apoptotic proteins including survivin, 
XIAP, Mcl-1decreased along with the CDK9 inhibition following Zotiraciclib (TG02) treatment. 
The cell cycle analysis in GSC923 demonstrated the G2 arrest.
In summary, the potential to inhibit CDK9 activity leading to a subsequent apoptotic effect and 
modulation of cell cycle and other tyrosine kinases in cancer signaling pathways makes 
Zotiraciclib (TG02) a logical therapeutic agent to be tested in treatment of high grade 
astrocytoma. As described above, high-grade gliomas are known to harbor multiple genetic 
alterations, such as TP53 mutation, MYC amplification and PTEN that can lead to resistance to 
apoptosis and treatment failure. Zotiraciclib (TG02) is orally administered and penetrates BBB 
with good concentration in the brain. The pharmacological inhibition of CDKs with optimized 
pharmacokinetic features of Zotiraciclib (TG02) may provide a new therapeutic option for high 
grade gliomas.


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Figure 11: Western blot of surviving, XIAP Mcl-1 and c-MyC in GSC923 following treatment 
with Zotiraciclib (TG02) at 8, 16, 24, 48 hours.
1.2.4
Rationale for Zotiraciclib (TG02) starting dose
The starting dose of Zotiraciclib (TG02) was decided based on the results of an open label phase 
Ib study that was developed with the primary objectives to determine the MTD of Zotiraciclib 
(TG02) in combination with carfilzomib (American Society for Hematology 2015 Abstract 
#3052). In that study, Zotiraciclib (TG02) was administered once daily on days 1, 4, 8, 11, 15, 18 
of a 28-day schedule. The starting dose of Zotiraciclib (TG02) was 150mg with dose escalation 
in 50 m increments up to 300mg. Carfilzomib was administered according to the Full 
Prescribing Information or in accordance with institutional guidelines at the time of the study 
(i.e., dosing days 1, 2, 8, 9, 15 and 16 at 20mg/m2 for Cycle 1 and 27mg/m2 for Cycle 2 and 
subsequent cycles). Fourteen patients were enrolled for dose escalation and 10 patients were 
enrolled for the MTD cohort expansion. The MTD for Zotiraciclib (TG02) in combination with 
carfilzomib was established at 250mg Zotiraciclib (TG02) administered twice a week for 3 
weeks (Days 1, 4, 8, 11, 15, and 18) on a 28-days cycle. Carfilzomib is a selective proteasome 
inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In an 
open-label, single-arm phase 2 study (PX-171-003- A1 #NCT00511238), patients received 
single-agent carfilzomib 20 mg/m2 intravenously twice weekly for 3 of 4 weeks in cycle 1, then 
27 mg/m2 for ≤ 12 cycles.  Adverse events (AEs) were found to be manageable without 
cumulative toxicities.[35] Common AEs were fatigue (49%), anemia (46%), nausea (45%), and 
thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, 
primarily grades 1 or 2. Based on the Full Prescribing Information of temozolomide, more 
severe and frequent hematologic toxicities were described. In anticipation of more toxicities in 
patients receiving combination treatment with Zotiraciclib (TG02) and TMZ comparing to those 
receive Zotiraciclib (TG02) and carfilzomib, we decided to set the starting dose of Zotiraciclib 
(TG02) relatively lower and dosing less frequently followed by careful dose escalation, if the 
treatment is proved to be well tolerated. The starting dose of Zotiraciclib (TG02) is at 200 
mg/day orally on days 1, 12, 15, and 26 on a 28-days cycle in both treatment arms, except for 
that the first dose of Zotiraciclib (TG02) will be given 3 days prior to Day1 in cycle 1. TMZ is 


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administered at 125mg/m2 daily on days 1-7 and 15-21 orally in dd TMZ schedule and 50mg/m2 
daily in mn TMZ schedule. The dosing schedule was also designed with the intention to avoid 
potential overlapping toxicity from both drugs. The proposed dosing schedule will allow patients 
have less chance to have to take both medications on the same day. Based on our preclinical data 
that Zotiraciclib (TG02) reduces expression of anti-apoptotic protein and better anti-glioma 
effects with pretreatment of Zotiraciclib (TG02) and followed by combination treatment, one 
dose of Zotiraciclib (TG02) will be administered 3 days prior to first dose of TMZ in the first 
cycle. In the subsequent cycles, the doses that patients receive on day 26 would be the exactly 3 
days prior to TMZ administration on day 1 of the following cycles.
1.2.5
Rationale for combination treatment with TMZ
TMZ is an alkylating agent that has been used in malignant gliomas of all grades. It produces 
O6-methylguanine in DNA, which mispairs with thymine during the next cycle of DNA 
replication. Subsequent futile cycles of DNA mismatch repair lead to a p53-associated apoptotic 
cell death. 
A seminal study from 2005 provided level 1 evidence that the addition of TMZ to radiotherapy 
for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant 
survival benefit.[2] Since then, TMZ has become part of standard treatment for glioblastoma. 
Not only used in newly diagnosed glioblastoma, TMZ has been also frequently used in grade II 
and III gliomas, in both upfront and recurrent settings.  Clinical studies in recurrent high grade 
gliomas also demonstrated objective response to TMZ.[4, 36] However, the treatment effects are 
always limited by the resistance mechanisms, including not only MGMT expression, but also 
p53 and p21 status when the mismatch repair mechanism is intact.[37]  In gliomas with intact 
p53 function, TMZ can cause prolonged cell cycle arrest and apoptosis. However, in gliomas 
with TP53 mutation, TMZ induced cell cycle arrest is not sustained.[38] Zotiraciclib (TG02) not 
only promotes apoptosis by decreasing expression of survival proteins, such as Mcl-1, but also 
by regulating the cell cycle by inhibiting CDKs. This broad spectrum of mechanisms of action 
makes Zotiraciclib (TG02) a strong candidate to overcome resistance to TMZ treatment and 
subsequently lead to a prolonged response to treatment.


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Figure 12: Cell viability analysis of A. GDC923; and B. U251 by using cell counting following 
treatment with Zotiraciclib (TG02) and TMZ alone or in combination with different sequence: 
Zotiraciclib (TG02) treatment for 6 hours followed by TMZ; TMZ treatment for 6 hours 
followed by Zotiraciclib (TG02).
The preclinical study of cell proliferation assay from Neuro-Oncology Branch (NOB) laboratory 
using human-derived glioblastoma cell lines have demonstrated a significant additive effect of 
inhibiting tumor cell growth with combination treatment of Zotiraciclib (TG02) and TMZ. This 
additive effect was observed in both GSC and non-GSC cell lines (Figure 12). In in vitro study, 
GSC923 was served as a model of high grade glioma with MGMT promotor unmethylation and 
U251 was served as a model of glioma with methylated MGMT promotor. Cell lines with 
different MGMT promotor methylation status respond to combination treatment differently, 
suggesting the role of MGMT methylation as a stratification factor in the randomization of the 
clinical trials that is designed to test clinical efficacy of combination treatment of Zotiraciclib 
(TG02) and TMZ in high grade gliomas. Our cell-based assay also suggests that the pretreatment 
with Zotiraciclib (TG02) followed by a combination treatment with TMZ cause better anti-
glioma effects comparing to the opposite treatment sequence. This is consistent with the 
hypothesis that Zotiraciclib (TG02) enhances the apoptotic effects of TMZ by suppressing the 
expression of anti-apoptotic proteins, which is supported by the data demonstrated in Figure 13. 
In Figure 13, more decreased expression of survivin, XIAP and Mcl-1 is demonstrated after 
combination treatment with Zotiraciclib (TG02) and TMZ, comparing to the single treatment 
with either Zotiraciclib (TG02) or TMZ. These anti-apoptotic proteins seem to slightly induce by 
TMZ treatment, which potentially contributes to the treatment resistance.    


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Figure 13: Western blot Western blot of survivin, XIAP and Mcl-1 in GSC923 following 
treatment with Zotiraciclib (TG02), TMZ alone and in combination at 8, 16, 24, and 48 hours.
1.2.6
Rationale to test Zotiraciclib (TG02) in combination with TMZ with two different dosing 
schedules
Once patients with glioblastoma have recurrent disease after standard treatment defined as 
concurrent radiation plus daily TMZ followed by 6-12 cycles of adjuvant TMZ (150-200 mg/m2 
days 1-5 of a 28-day cycle), the disease is typically less responsive to TMZ. This resistance has 
been attributed to an increase in the tumor intracellular concentration of the enzyme O6-
methlyguanine DNA methyltransferase (MGMT).  It has been demonstrated that if the MGMT 
can be depleted, sensitivity to alkylating agents such as TMZ can be restored.  A study by 
Tolcher and his colleagues demonstrated that there was a more pronounced depletion of MGMT 
in peripheral blood mononuclear cells (PBMCs) after dose-intense dosing schedule of TMZ.[39] 
Building on this data, many studies explored the use of alternative schedules.  The most notable 
evaluated the 7-day on – 7-day off and a metronomic schedule that used daily continuous dosing 
of 50 mg/m2 of TMZ. 
Dose-dense schedule: In a prospective study, ninety adult patients with recurrent glioma were 
treated with TMZ at 150mg/m2/day on days 1-7 and 15-21.[40] PFS6 was reported to be 43.8% 
and one-year survival rate was 23%. In contrast, another study in a similar patient population 
reported a PFS6 of 10% and median overall survival was 21.6 weeks.[41] Both studies 
demonstrated good tolerance of the treatment.  
Metronomic dosing: A study of recurrent glioma patients who received metronomic TMZ at 
50mg/m2 yielded a PFS6 of 23.9% and a 1-year survival rate of 27.3% in recurrent glioblastoma 
and a PFS6 of 35.7% and a 1-year survival of 60.7% in recurrent anaplastic astrocytoma 
patients.[42] TMZ with both the dose-dense (dd) and metronomic (mn) schedules showed 
promising responses in recurrent high grade glioma patients. However, the superiority of either 
dosing schedule hasn’t been established and comparison within the same clinical trial setting is 
therefore warranted. 


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1.2.7
Rationale for pharmacokinetic, pharmacogenetic and neutrophil function assay
Since the clinical trial 17C0009 was open to accrual, an unexpected phenomenon has been 
observed on multiple occasions- neutropenia with quick onset and quick recovery. Per current 
protocol, the hematologic toxicities have been mainly attributed to TMZ which is known for the 
bone marrow toxicities, including thrombocytopenia, leukopenia, neutropenia and lymphopenia. 
The complete blood count (CBC) of more than one patient happened to be tested based on 
clinical needs at several occasions. In those tests, absolute neutrophil count (ANC) in some 
patients was found to be decreased significantly. Interestingly, the low ANC can be found to be 
recovered within 24-48 hours in most cases. In one case, patient was found to have grade 4 
neutropenia within 24 hours after one dose Zotiraciclib (TG02) but recovered to grade 1 
neutropenia 24 hours later. The quick onset and quick recovery suggested that the bone marrow 
dysfunction is unlikely to be the etiology for the neutropenia that was observed in these cases. In 
addition, in most cases where this transient neutropenia occurred, there were no decreases in 
lymphocytes, platelets and hemoglobin. Although there were no serious consequences, such as 
infection in these cases, study drug had to be discontinued. Without knowing the 
pathophysiology of this type of neutropenia, the study drug can be discontinued prematurely. On 
the other hand, patients will be at risk if the follow up lab tests are not scheduled appropriately. It 
would be important to understand the effect of Zotiraciclib (TG02) on neutrophil biology. 
To analyze the neutrophil function after Zotiraciclib (TG02) administration, information from 
pharmacokinetic study is crucial. To further understand why this neutropenia only happened in a 
subgroup of patients but not all patients receiving Zotiraciclib (TG02), we will add 
pharmacogenetic study by analyzing the genomic DNA and assess genotype of the most relevant 
drug metabolizing enzymes and transporters (DMET).  
1.2.8
Rationale for the patient-reported outcome
Precedence for measuring “non-therapeutic” endpoints exists in oncology research.  For 
example, Gemcitabine was approved by the FDA partially as a consequence of the decrease in 
pain reported in pancreatic patients who were treated, not on the basis of survival improvement, 
which was modest, at best. There have been efforts in neuro-oncology to evaluate secondary 
endpoints using validated instruments as an additional indicator of benefit.  
The M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) allow the self-
reporting of symptom severity and interference with daily activities.  The MDASI-BT have 
demonstrated reliability and validity in the adult primary brain tumor patient population[43, 44]
 This tool represents a modification of the widely used and validated M.D. Anderson Symptom 
Inventory, with particular attention to symptoms common in patients with brain tumors.   The 
availability of validated instruments provides an opportunity to prospectively assess the impact 
of treatment, both positive and negative, on patients.  The evaluation of symptom burden in this 
study will assist in finding the best possible treatment with the least toxicity.


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1.2.9
Rationale for utilizing PRO-CTCAE
PRO-CTCAE is a patient-reported outcome measurement system developed by the NIH to 
capture the symptomatic adverse events in patients on cancer clinical trials. It was designed as a 
companion to the Common Terminology Criteria for Adverse Event (CTCAE), which is often 
used per medical professionals’ evaluation. This instrument will allow us to select, but not be 
limited to the symptoms that are anticipated based on the previous experiences. It can be a 
flexible tool for descriptive reporting system, which patients can complete it at their own 
convenience. Since the timing for assessments are within 7 days, it certainly avoids the recall 
biases. It also can be used in conjunction with the CTCAE to provide a better understanding of 
the toxicities of the clinical trial treatments.  
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
Inclusion criteria are same in both Phase I and Phase II parts, except for the number of prior 
disease relapses in 2.1.1.5.
2.1.1.1
Patients must have pathologic diagnosis of anaplastic astrocytoma (defined as WHO 
grade III, or glioblastoma/gliosarcoma, WHO grade IV, which are confirmed by NCI 
Laboratory of Pathology. If the pathology diagnosis is anaplastic glioma or anaplastic 
oligoastrocytoma, evidence of either intact 1p/19q chromosomes or molecular features 
suggesting astrocytic tumor must be present. (including, but not limited to ATRX, 
TP53).
2.1.1.2
Patients must have recurrent disease, histologically proven or imaging suggestive of 
recurrent disease as determined by PI.   Prior implantation of Gliadel wafers is 
acceptable, if tumor recurrence is confirmed by histologic examination of the recurrent 
tumor.
2.1.1.3
Patients must have the ability to understand and the willingness to sign a written 
informed consent document.
2.1.1.4
Patients must be >18 years old.
2.1.1.5
No more than two prior disease relapses to be eligible for the phase I portion of the 
study and no more than one prior relapse to be eligible for phase II.
2.1.1.6
Patients must have undergone prior standard therapy for their primary disease.  For 
patients with glioblastoma, this would include surgical resection or biopsy, if safe 
resection was not permitted due to the tumor location, radiation and adjuvant 
temozolomide. For patients with anaplastic astrocytoma, this would include surgical 
resection, radiation and adjuvant chemotherapy (PCV or temozolomide).
2.1.1.7
Tumor tissue must be available for review to confirm histological diagnosis.
2.1.1.8
Tumor block or unstained slides must be available for molecular profiling. 
2.1.1.9
Karnofsky > 60%, (see 15.1.)


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2.1.1.10 Patients must have adequate bone marrow function (ANC > 1,500/mm3, platelet count 
of > 100,000/mm3), adequate liver function (ALT and AST< 3 times upper limit normal 
and alkaline phosphatase < 2 times upper limit normal, total bilirubin < 1.5mg/dl), and 
adequate renal function (BUN < 1.5 times institutional normal and serum creatinine < 
1.5 mg/dl) prior to registration.  These tests must be performed within 14 days prior to 
registration.  Total bilirubin:  patients with Gilbert’s Syndrome are eligible for the 
study. (Total bilirubin level can be exempted from the eligibility criterion.)
2.1.1.11 Patients must have recovered from the toxic effects of prior therapy to < grade 2 
toxicity per CTC version 4 (except deep vein thrombosis) 
2.1.1.12 At the time of registration, subject must be removed from prior therapy as follows:  

≥ 28 days from any investigational agent,

≥ 4 weeks (28 days) from prior cytotoxic therapy,

≥ 2 weeks (14 days) from vincristine, 

≥ 6 weeks (42 days) from nitrosoureas, 

≥ 3 weeks (21 days) from procarbazine administration, 

≥ 1 week (7 days) for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, 
cis-retinoic acid, etc. (radiosensitizer does not count).  
2.1.1.13 Patients having undergone recent resection of recurrent or progressive tumor will be 
eligible given all of the following conditions apply:
A. At least 2 weeks (14 days) have elapsed from the date of surgery and the patients have 
recovered from the effects of surgery. 
B. Evaluable or measurable disease following resection of recurrent malignant glioma is not 
mandated for eligibility into the study. 
C. To best assess the extent of residual disease post-operatively, an MRI should be done no 
later than 96 hours in the immediate post-operative period or at least within 4 weeks post-
operatively, within 14 days prior to registration.  If the 96-hour scan is more than 14 days 
before registration, the scan needs to be repeated.  The patient must have been on a stable 
steroid dose for at least 5 days prior to the baseline MRI. Steroids may be initiated as clinically 
indicated once baseline imaging has been completed with a goal of titrating steroids as soon as 
clinically warranted. 
2.1.1.14 Patients must have received prior radiation therapy and must have an interval of greater 
than or equal to 12 weeks (84 days) from the completion of radiation therapy to study 
entry except if there is unequivocal evidence for tumor recurrence (such as histological 
confirmation or advanced imaging data such as PET scan) in which case the principal 
investigator’s discretion may determine appropriate timepoint at which study therapy 
may begin.
2.1.1.15 Women of childbearing potential must have a negative -HCG pregnancy test 
documented within 14 days prior to registration. The effects of Zotiraciclib (TG02) on 
the developing human fetus are unknown. For this reason, women of childbearing 
potential must not be pregnant, must not be breast-feeding, and must practice adequate 
contraception (see 15.2 for details and definitions) for the duration of the study, and for 


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30 days after the last dose of study medication. 
2.1.1.16 Male patients on treatment with Zotiraciclib (TG02) must agree to use an adequate 
method of contraception for the duration of the study, and for 30 days after the last dose 
of study medication as the effects of Zotiraciclib (TG02) on the developing human fetus 
are unknown (see 15.2 for definition of adequate methods of contraception.
2.1.1.17 Patients must agree to enroll on the NOB Natural History protocol to allow the 
assessment of molecular tumor markers.
2.1.2
Exclusion Criteria
2.1.2.1
Patients who are receiving any other investigational agents.  However, prior enrollment 
on a study using investigational agents is acceptable as per section 2.1.1.12.
2.1.2.2
Patients with prior bevacizumab use for tumor treatment. Patients who received 
bevacizumab for symptom management, including but not limited to cerebral edema, 
pseudo progression can be included in the study. (To date, there have been no effective 
regimens developed for recurrent malignant gliomas that are refractory to bevacizumab.  
Inclusion of this patient population may impact the ability to determine the efficacy of 
Zotiraciclib [TG02] with TMZ.)
2.1.2.3
Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from providing informed consent. 
2.1.2.4
Any condition, including the presence of clinically significant laboratory abnormalities, 
which places the patient at unacceptable risk if he/she were to participate in the study or 
confounds the ability to interpret data from the study. These would include:
2.1.2.4.1
Active infection (including persistent fever) including known history of HIV or 
Hepatitis C infection, because these patients are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.
2.1.2.4.2 Diseases or conditions that obscure toxicity or dangerously alter drug metabolism.  
2.1.2.4.3 Serious concurrent medical illness (e.g. symptomatic congestive heart failure).


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2.1.2.5
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to temozolomide and/or Zotiraciclib (TG02).
2.1.2.6
Patients with a history of any other cancer (except non-melanoma skin cancer; or 
melanoma in-situ following curative surgical resection; or carcinoma in-situ of the 
cervix or bladder), unless in complete remission and off all therapy for that disease for a 
minimum of 3 years, are ineligible.
2.1.2.7
Zotiraciclib (TG02) is primarily metabolized by CYP1A2 and CYP3A4. Patients 
receiving any medications or substances that are strong inhibitors or inducers of 
CYP1A2 and/or CYP3A4 are ineligible.  Lists including medications and substances 
known or with the potential to interact with the CYP1A2 and CYP3A4 isoenzymes are 
provided in 15.3. 
2.1.2.8
Patients, who continue to have prolonged QTc (males: >450ms; females: >470ms as 
calculated by Fridericia’s correction formula) despite normal electrolyte balance and 
discontinuation of medications known to prolong QTc, will be excluded from the study.  
2.1.3
Recruitment Strategies
This protocol may be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media platforms.  
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc.  

Review of existing  MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
A waiver of consent for these activities has been requested in section 12.6.1.
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study 01-C-0129  (provided the procedure is permitted on that study) on which 
screening activities may also be performed. Assessments performed at outside facilities or on 
another NIH protocol within the timeframes below may also be used to determine eligibility once 
a patient has signed the consent.
To be completed within 14 days of study registration, unless otherwise indicated


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2.2.3
Unstained paraffin tissue from surgical samples will be obtained. A representative 
paraffin tissue block (at least 5 mm x 5 mm) or unstained slides will be obtained from 
previous surgery to confirm the histological diagnosis and molecular markers before 
entry into the clinical trial. 
2.2.4
All patients with recurrent anaplastic astrocytoma or glioblastoma/gliosarcoma will need 
to have confirmation of pathology diagnosis on initial disease or recurrent disease, by a 
Neuropathologist at the NIH. The recurrent status of the disease must be confirmed by 
either by pathology diagnosis on tissue from recurrent disease or by imaging review by 
the PI. Confirmation of pathology diagnosis may occur any time prior to study entry.
2.2.5
A Gd-DPTA enhanced MRI, with DWI, ADC, SWI, FLAIR, perfusion, dynamic contrast 
enhanced, and dynamic susceptibility contrast sequences is needed within 14 days of 
entry into the study in all patients without surgical resection to establish the diagnosis of 
recurrent disease.  The treating physician will review the Gd-DPTA MRI scan done prior 
to study entry documenting progression, if no tumor tissue available for pathology 
diagnosis.
2.2.6
Complete history and physical exam completed by principal or associate investigator, 
including thorough documentation of signs and symptoms caused by the tumor, 
determination of KPS, neurological function and mental status. 
2.2.7
Screening laboratory tests will include CBC, differential, platelets, PT, PTT, INR, total 
protein, albumin, calcium, phosphorus, magnesium, glucose, BUN, creatinine, sodium, 
potassium, total bilirubin, alkaline phosphatase, LDH, SGPT (ALT), SGOT (AST), 12-
lead EKG and a pregnancy test for women of child bearing potential.
2.3
PARTICIPANT REGISTRATION AND STUDY STATUS UPDATE PROCEDURES
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here.
Patients must initiate study treatment within 7 calendar days after registration.
2.3.1
Treatment Assignment and/or Randomization/ Stratification Procedures*
Cohorts
Number
Name
Description
1
Cohort 1
Patients with recurrent anaplastic astrocytoma or 
glioblastoma/gliosarcoma assigned to Phase 1 


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2
Cohort 2
Patients with recurrent anaplastic astrocytoma or 
glioblastoma/gliosarcoma assigned to Phase 2 
Arms
Number
Name
Description
1
Phase I Arm I
dose dense TMZ+ Zotiraciclib (TG02)
2
Phase I Arm 2
metronomic TMZ+ Zotiraciclib (TG02)
3
Phase II Arm 1
TMZ + Zotiraciclib (TG02)
4
Phase II Arm 2
TMZ (Control Arm)
Stratifications
Name
Distinct Options
KPS
Yes
No
MGMT promoter methylation status of the 
tumor
Yes
No
Presence of Measurable Disease
Yes
No
In Phase I, study patients will be assigned to one of two arms to receive Zotiraciclib (TG02) plus 
dd TMZ or Zotiraciclib (TG02) plus mn TMZ in 1:1 ratio*.  Once a phase II dose/schedule is 
determined, patients will be randomized to the following arms in 1:1 ratio - Zotiraciclib (TG02) 
plus TMZ (dose and schedule selected from phase 1 component) or Control Arm – TMZ (dosing 
schedule will match combination arm). Patients’ KPS, MGMT promoter methylation status of 
the tumors and the presence of measurable disease at study entry will be used as stratification 
factors. 
*In Phase I, Post-interim analysis patients will be registered to cohort 1 and assigned to ARM 1, 
at a TG02 dose level of 200mg. Patients will be enrolled consecutively to cohort 1. Details are 
described in Section 3.2.1.3.


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2.4
BASELINE EVALUATION
Baseline tests do not need to be repeated if the same tests were done within 14 days of treatment 
initiation. 
2.4.1
A complete history and physical (including baseline blood pressure measurement) and 
neurological examination (include documentation of the patients’ height, weight and 
Karnofsky Performance Status), as well as documentation of measurable and/or evaluable 
disease shall be performed on all patients.  
2.4.2
A baseline Gd-DPTA enhanced MRI, with DWI, ADC, SWI, FLAIR, perfusion, dynamic 
contrast enhanced and dynamic susceptibility contrast sequences should be performed. 
The baseline on-study MRI should be performed on a steroid dosage that has been stable 
or decreasing for at least 5 days. If the steroid dose was increased between the date of 
imaging and the initiation of therapy (or at that time), a new baseline MRI is required. 
MRI study needs to be done within 14 days of the initiation of the study treatment. 
2.4.3
Pre-treatment laboratory tests will include CBC, differential, platelets, PT, PTT, INR, 
total protein, albumin, calcium, phosphorus, magnesium, glucose, BUN, creatinine, 
sodium, potassium, total bilirubin, alkaline phosphatase, LDH, SGPT (ALT), SGOT 
(AST), 12-lead EKG and a pregnancy test for women of child bearing potential. Blood 
tests must be performed within 14 days (+ 3 working days) of registration, with day 0 = 
registration date. Pregnancy test must be obtained 14 days (+ 3 working days) before 
treatment starts. 
2.4.4
Patients will complete a baseline MD Anderson Symptom Inventory-Brain Tumor 
Module (MDASI-BT) (Error! Reference source not found.). The MDASI-BT will only 
be completed by the patient, unless changes in vision or weakness make this difficult. If 
this occurs, then the caregiver or research assistant may read the questions to the patient 
or assist with marking the severity number or score as described by the patient. A patient 
caregiver may complete the questionnaires as a patient-preference proxy if the patient’s 
deficits preclude self-report. If the MDASI-BT is completed by the patient for Natural 
History study, 16C0151 within (+/-) 14 days from the initiation of the treatment, then it 
can be used as the baseline.
2.4.5
Rapid clinical deterioration from the time of study entry to initiation of treatment will 
mandate a full re-evaluation including physical examination, KPS, MRI, and laboratory 
studies including CBC and blood chemistries and MDASI as outlined in Sections 2.5.1 - 
2.4.4.


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3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN:
3.1.1
Phase I:  
The phase I component is designed to find the MTD of Zotiraciclib (TG02) in combination with 
2 schedules of TMZ – dose dense and metronomic. Patients will be enrolled and equally assigned 
into the two dosing schedule arms for MTD finding. In each arm, the MTD will be determined 
independently using the Bayesian Optimal Interval (BOIN) design, fully described in Section 8 
and recently published [45]. Once the MTDs of the two regimens (dd TMZ + Zotiraciclib 
(TG02) and mn TMZ + Zotiraciclib [TG02]) have been established, cohort expansion will be 
carried out at the each of the MTDs. Patients will be equally randomized into to the two cohort 
expansions. A post interim analysis cohort will be carried out in cohort 1 arm 1 to confirm MTD. 
The MTD that has higher progression-free survival rate at 4 months (PFS4) will be selected and 
used in phase II. 
3.1.2
Phase II:  
The two-arm randomized phase II will determine if the addition of Zotiraciclib (TG02) to the dd 
or mn TMZ schedule (determined by the expanded phase I) improves outcome in patients with 
recurrent malignant glioma using PFS as the primary outcomes measure.  Patients will be equally 
randomized into the combination Arm (Zotiraciclib [TG02] plus TMZ selected from phase I) and 
control arm (TMZ). The randomization will stratify by the presence of measurable disease at the 
study entry, KPS and MGMT promoter methylation status.  Additional outcomes such as PFS6, 
overall survival from study entry and symptom burden (using the MDASI-BT instrument in 
Appendix Error! Reference source not found.) will also be collected.
The study schema is illustrated in Study Flow Chart in Appendix 15.4.
3.1.3
Definition of dose limiting toxicities (DLT)
All patients in the MTD finding phase of the phase I part will be evaluable for assessment of 
toxicity to define DLTs. The DLT-defining period is the first 4 weeks’ treatment in the Phase I 
study.
Toxicities will be graded per the Common Terminology Criteria for Adverse events (CTCAE) 
Version 4.0.  If multiple toxicities are seen, the presence of DLT should be based on the most 
severe toxicity experienced. DLT is defined as any of the following events occurring in the first 
cycle of treatment (4 weeks) and attributable to the study drugs:
Any of the following hematological toxicities: 

Grade 4 neutropenia lasting 5 days or more.

 Febrile neutropenia defined as grade 3-4 neutropenia with fever ≥38.5ºC and/or 
infection requiring antibiotic or antifungal treatment.

Grade 4 thrombocytopenia lasting more than 2 days.

Grade 3 thrombocytopenia with bleeding of any duration


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
Grade 3 or 4 anemia lasting more than 2 days.
Any non-hematologic grade 3 or 4 toxicity, except the following  

nausea or vomiting that responds to symptomatic therapy and lasts ≤7 days.

Diarrhea that responds to symptomatic therapy within 2 days. 

fatigue that responds to symptomatic therapy and lasts ≤7 days.

weight gain (in patients on steroids)

venous thromboembolic disease (rationale for not including this event as a DLT 
described below)

If there is a dose reduction of either or both study medications or if a dose is held or 
discontinued in cycle 1, this constitutes a DLT, per PI discretion.

Grade 4 lymphopenia is not considered as a DLT for this study. All patients for this study 
have treated with alkylating agents and radiation treatment. Lymphopenia can be highly 
associated with the previous treatment or have a low threshold to have severe 
lymphopenia because of the previous treatments. In case of isolated laboratory 
abnormalities that may not reach clinical significance, a determination will be made by PI 
or in consultation with the IRB on a case-by-case basis to determine if DLT needs to be 
declared. 

Failure to recover from treatment related toxicities to be eligible for re-treatment within 4 
weeks of the last dose of the drugs.  
3.1.4
Dose escalation 
We will employ the Bayesian optimal interval (BOIN) design [46] to guide dose escalation and 
find the MTD. The details of the design are provided in Section 8. There are two treatment arms 
in the Phase I study: the combination treatment with Zotiraciclib (TG02) and dd TMZ; and the 
combination treatment of Zotiraciclib (TG02) with mn TMZ. Dose escalation will be conducted 
independently in these two arms. Several dose levels of Zotiraciclib (TG02) are planned as 
outlined in the Dose Escalation Table below.
Table 7: Dose Escalation Table
Arm 1: Dose-dense temozolomide
Level
TMZ (mg/m2 x 7 days on/7 days off)**
TG 02 (mg/day on  1, 12,15,26 
per 28 day cycle)*
-1
125
150
0 (starting dose)
125
200
I
125
250
II
125
300***


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
Version Date: 06/01/2020
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Arm 2: Metronomic temozolomide
Level
TMZ (mg/m2 daily)**
TG 02 (mg/day on 1, 12,15,26
per 28 day cycle)*
-1
50
150
0 (starting dose)
50
200
I
50
250
II
50
300***
* The first dose of Zotiraciclib (TG02) will be given 3 days prior to Day1 of cycle 1. The 
subsequent doses for cycle 1 will be given on days 1, 12, 15, and 26. Zotiraciclib (TG02) will be 
given on days 1, 12, 15, and 26 every 28-days cycle in all the cycles starting cycle 2. 
**BSA (body surface area) for Temozolomide dosing calculation will be capped at 2.2m2 to avoid 
excessive risk of myelosuppression.
*** One patient in MN arm developed severe toxicities which lead to ICU admission after one 
dose of Zotiraciclib (TG02) at 300mg. The etiology was not completely clear. However, due to the 
patient’s safety concern, does level II of Zotiraciclib (TG02) was determined to be eliminated in 
both study arms by the investigator and pharmaceutical manufacturer.
3.2
DRUG ADMINISTRATION
3.2.1
Phase I treatment
3.2.1.1
Drug dosage
There are two treatment arms in this component: the combination treatment of Zotiraciclib 
(TG02) and dd TMZ; and the combination treatment of Zotiraciclib (TG02) with mn TMZ. In 
both treatment arms, several dose levels are planned as outlined in section 3.1.4. The starting 
dose of Zotiraciclib (TG02) is 200 mg/day orally on days 1, 12, 15, and 26 on a 28-days cycle in 
both treatment arms, except for that the first dose of Zotiraciclib (TG02) will be given 3 days 
prior to Day1 in cycle 1. The dosing schedule for both treatment arms are illustrated in the 
Appendix 15.6. TMZ is administered at 125mg/m2 daily on days 1-7 and 15-21 orally in dd 
TMZ schedule and 50mg/m2 daily in mn TMZ schedule. The dosing schedule was designed 
with the intention to avoid potential overlapping toxicity from both drugs. The proposed dosing 
schedule will allow patients have less chance to have to take both medications on the same day. 
Based on our preclinical data that Zotiraciclib (TG02) reduces expression of anti-apoptotic 
protein and better anti-glioma effects with pretreatment of Zotiraciclib (TG02) and followed by 
combination treatment, one dose of Zotiraciclib (TG02) will be administered 3 days prior to 
first dose of TMZ in the first cycle. In the subsequent cycles, the doses that patients receive on 
day 26 would be the exactly 3 days prior to TMZ administration on day 1 of the following 
cycles. We will employ the Bayesian optimal interval (BOIN) design [46] to guide dose 
escalation and find the MTD. The details of the design are provided in Section 8.


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
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3.2.1.2
Cohort expansion:
After identifying the MTD for each of the TMZ dosing schedules in combination with 
Zotiraciclib (TG02) (i.e., 125mg/m2 TMZ on days 1-7 and 15-21 per cycle, and 50 mg/m2 
TMZ daily), cohort expansion will be conducted independently at each of the MTDs until the 
total number of patients treated at each of the MTDs reaches 18 patients (including the patients 
who have been treated in the dose-finding part). The dosing schedule with a higher PFS4 will be 
selected and used in phase II.
3.2.1.3
Post interim analysis cohort: 
Patients will be enrolled to Arm 1 only to receive Zotiraciclib (at Dose level 0 and in 
combination of dd TMZ).  TG02 dose is 200 mg/day orally on days 1, 12, 15, and 26 on a 28-
days cycle, except for that the first dose of Zotiraciclib (TG02) will be given 3 days prior to 
Day1 in cycle 1. TMZ is administered at 125mg/m2 daily on days 1-7 and 15-21 orally on a 28-
days cycle.
3.2.2
Phase II treatment:
The combination treatment selected from phase I (with better PFS4) will be tested against the 
TMZ alone with the same dosing schedule as it is in the combination arm. Patients will be 
randomized on a 1:1 basis between two competing treatment arms: TMZ + Zotiraciclib (TG02) 
versus TMZ alone using a Bayesian phase II trial design. The details of the design are provided 
in Section 8.
The dosage for the combination arm is derived from the MTD of the combination determined in 
the phase I component of the study. The treatment schedule will be identical to that described 
above in the phase I component, with each cycle comprising 28 days. 
Patients will continue treatment until tumor progression or unacceptable toxicity occurs or 
completion of 12 cycles of treatment.  At progression, patients randomized to the control arm 
(TMZ alone) will be offered the opportunity to continue TMZ and the additional treatment with 
Zotiraciclib (TG02). After administration of 12 cycles of treatment, patients may stay on the 
study treatment, if there is evidence of clinical benefit based on treating physician’s discretion.
If patient vomits Zotiraciclib (TG02), do not re-administer.
3.3
DOSE MODIFICATION/DELAYS:
If an adverse event occurs wherein both TMZ and Zotiraciclib (TG02) would require dose de-
escalation, the Principal Investigator shall have the discretion of first dose reducing one of the 2 
study drugs with the consideration of previously known drug toxicities/side effects in an effort to 
further define attribution.


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
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41
Table 8: Start of Each Cycle for both TMZ and Zotiraciclib (TG02)
Temozolomide and Zotiraciclib (TG02)
Hematologic*
ANC ≥ 1.5 x 109/L 
and PLT ≥ 100 x 
109/L
No dose modification
ANC< 1.5 x 109/L 
and/or Platelet count < 
100 x 109/L
Delay up to 4 weeks until ANC ≥ 1.5 x 
109/L and PLT ≥ 100 x 109/L. If 
unresolved after 4 weeks, then stop. If 
resolved, dose delay/reductions based on  
Table 9. 
Non-
Hematologic
Grade 1 or less
No dose modification
Grade 2 
Zotiraciclib (TG02):  Delay up to 4 
weeks until ≤ Grade 1. If unresolved after 
4 weeks, then dose reduce by 1 dose level.
Temozolomide:  dose delay/reductions 
based on Table 9, if adverse event 
attributed to Temozolomide.
Grade 3
Zotiraciclib (TG02):  Delay up to 4 weeks 
until ≤ Grade 1. If unresolved after 4 
weeks, then stop.  If resolved to </= 
Grade 1, then dose reduce by 1 dose level.
Temozolomide:  dose delay/reductions 
based on Table 9, if adverse event 
attributed to Temozolomide.
Grade 4
Discontinue treatment
*With the exception of lymphopenia, grade 1-4. Patient may start a cycle with G2 WBC, as long 
as the ANC ≥ 1.5 x 109/L.
3.3.1
Temozolomide (TMZ) Dose Modifications
Dose modification(s) are based on adverse event occurrence and may be implemented during any 
treatment cycle (Table 11) or prior to initiation of each new cycle per Table 8.  If multiple AEs 
are seen, the dose administered should be based on the dose reduction required for the most 
severe grade of any single AE. If TMZ is delayed or discontinued in combination therapy, the 
Zotiraciclib (TG02) component of treatment may continue, unless there is clear reason to 
discontinue Zotiraciclib (TG02) simultaneously. 


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
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Table 9: TMZ Dose Levels for Modification Table
Dose Level
DD TMZ Dose, 
mg/m2/day
MN TMZ Dose, 
mg/m2/day
-2 
80
32
-1
100
40
 0 
125 
50
3.3.1.1
Delay 
For treatment on day 1 of each cycle (within the prior 72 hours), ANC ≥ 1.5 x 109/L, platelet 
count ≥ 100 x 109/L and all grade 2 -3 non-hematologic AEs (except nausea and vomiting) must 
have resolved (to grade ≤ 1). For grade 4, discontinue treatment. For the purposes of this study, 
any clinically insignificant Grade 2 or 3 electrolyte abnormalities with attribution of unlikely 
related to or unrelated to study medications, will not require holding or dose-reducing study 
medications.  
If AEs persist, treatment may be delayed by 1 week for up to 4 consecutive weeks. If, after 4 
weeks of delay, all AEs have still not resolved to grade 1 or less: then any further treatment with 
temozolomide should be stopped, as summarized in Table 8 and Table 11.
3.3.1.2
Dose reductions (Summarized in Table 11)
If any non-hematologic AE observed was grade 3 (except nausea and vomiting) and/or if 
platelets < 50 x 109/L and/or ANC < 1 x 109/L, then the dose should be reduced by one dose 
level. For patients who would require dose reductions to a dose level < -2 as defined in table 10, 
temozolomide will be stopped. Also, if any of the same non-hematologic grade 3 AE recurs 
(except, nausea and vomiting,) after reduction for that AE, then temozolomide will be stopped. 
If any treatment-related non-hematologic AE observed was grade 4 (except nausea and vomiting) 
then adjuvant temozolomide treatment should be stopped. 
Any dose reductions of temozolomide will be determined according to (1) non-hematologic AE, 
as well as (2) the lowest/worst ANC and platelet counts observed. No dose escalation should be 
attempted. If the dose reduction occurs in the middle of the cycle, the reduced dose should be 
applied as soon as the treatment resumes (i.e. next dose).
3.3.2
Zotiraciclib (TG02) Dose Modifications
If multiple AEs are seen, the dose administered should be based on the dose reduction required 
for the most severe grade of any single AE.  Prior studies of Zotiraciclib (TG02) indicate that 
non-hematologic toxicities have been the dose-limiting toxicities.  Therefore, in the combination 
regimens, attribution of treatment-related toxicities will be made based on best available 
information.  As Zotiraciclib (TG02) has not been reported with high rates of prolonged 
myelotoxicity, these toxicities will likely be attributed to temozolomide and dose modifications 


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
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43
made as outlined in Section 3.3.1 above.  Conversely, non-hematologic adverse events such as 
nausea and vomiting, intractable diarrhea, fatigue and prolongation of the QTc interval on ECG 
will be attributed to Zotiraciclib (TG02).  Liver toxicities are a known toxicity of TMZ, which 
has been tested extensively in patients with high grade glioma. Zotiraciclib (TG02) has also been 
reported to cause elevated liver enzymes. To better understand the attribution of this toxicity, in 
the event of elevated ALT/ AST of grade 2 or above when a patient has received the combined 
treatment, dose modification will be made on one drug at a time. Should the need for dose 
modification arise again due to the same toxicity, dose of the second drug will be reduced.  If a 
dose reduction occurs in the middle of the cycle, the reduced dose should be applied as soon as 
the treatment resumes.
Details for dose modification, delay at beginning of each cycle and during the cycle are 
summarized in Table 8 and Table 11 respectively.   
The dose of Zotiraciclib (TG02) will be initiated at the phase I dose for patients enrolled on the 
dose-finding component or at the MTD for both the cohort expansion of the phase I and the 
phase II component of the trial. The same dose will be continued unless > or = grade 3 drug 
related toxicity occurs; treatment will be held until toxicity resolves to grade 1 or less. At that 
time, the dose will be reduced to one level below the dose that caused the grade 3 toxicity. Only 
two dose reductions will be allowed for Zotiraciclib (TG02).   Patients enrolled prior to 
determination of the MTD will have stepwise reductions as necessary based on the Table 10 
below.  Please note, if the MTD is 150 mg/day, then no dose reduction will be allowed.  
Additionally, if the patient is treated at dose Level 0, only one dose reduction (to 150 mg/day) 
will be allowed.
Table 10: Zotiraciclib (TG 02) Dose Modification Table
Dose Level
TG 02 (mg/day on days 1, 12, 15, 26 
per 28 day cycle)*
-1
150
0
200
1
250
2
300
Summary of Dose Modification or Discontinuation 
Table 11: Dose Modifications and Delay*  
                Zotiraciclib (TG02) 
                           TMZ
Grade
Hematologic**
Non-hematologic 
Hematologic**
Non-hematologic 
0-1
No dose 
modification
No dose 
modification
No dose 
modification
No dose 
modification


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
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Table 11: Dose Modifications and Delay*  
                Zotiraciclib (TG02) 
                           TMZ
2
Hold until resolved 
to ≤ G1; if persists 
beyond 4 weeks, 
dose reduce one 
level.
Hold until 
resolved to ≤ 
grade 1; if > 4 
weeks then dose 
reduce 1 level.
Hold until resolved 
to ≤ grade 1; if > 4 
weeks then dose 
reduce 1 level.
No dose 
modifications for 
non-hematologic 
AEs (G 0-2), 
unless the 
adverse event 
attributed to 
Temozolomide.
3
If not recovered to 
≤ G2 within 3 
days, STOP. 
If recovered to ≤ 
G2 within 3 days, 
re-start @ one dose 
level lower once 
recovered to G1 or 
less.***
Delay up to 4 
weeks until ≤ 
Grade 1.  If 
unresolved after 4 
weeks, then stop.  
If resolved to ≤ 
grade 1; then dose 
reduce by 1 level.
Hold until resolved 
to ≤ grade 1; if > 4 
weeks, then stop.
             
Hold until 
resolved to ≤ 
grade 2; if 
greater than 4 
weeks then stop.  
If less than 4 
weeks, reduce by 
one dose level. If 
the same non-
hematologic 
grade 3 AE 
recurs after 
reduction for that 
AE, then stop. 
4
If not recovered to 
≤ G2 within 3 
days, STOP. 
If recovered to ≤ 
G2 within 3 days, 
re-start @ one dose 
level lower once 
recovered to G1 or 
less
Stop treatment.
Stop treatment.
Stop treatment.
 
* If the patient develops a lower extremity deep venous thrombosis and requires anticoagulation or 
intervention (grade 2 or 3 toxicity), treatment may be restarted after a 2-week rest period if the patient is 
stably anticoagulated and is judged medically stable to begin chemotherapy. (Please note: DVT is graded 
in the CTC version 4.0 as grade 1= superficial thrombosis, grade 2= DVT, medical intervention indicated, 
grade 3= uncomplicated pulmonary embolism, medical intervention indicated, grade 4=life-threatening 
pulmonary embolism, cerebrovascular event, arterial insufficiency, urgent intervention indicated).
** With the exception of lymphopenia, grade 1-4.
***If G3 neutropenia recovers within 72 hours, the Principal Investigator may consider no dose reduction 
of Zotiraciclib (TG02). 


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If leukopenia is grade 2 or above while ANC is grade 1 or less, the principal investigator may not 
consider it for dose modification and delay.
3.3.3
Pre-medications
3.3.3.1
 Zotiraciclib (TG02)
Patients must receive vigorous prophylactic treatment for nausea and vomiting.  Prophylactic use of 
moderately anti-emetogenic treatments (e.g., 5-HT3 antagonist) has been more effective at 
controlling nausea and vomiting than lightly anti-emetogenic treatments or treatment after onset. 
3.3.3.1.1 Prophylaxis for Nausea/Vomiting
Zotiraciclib (TG02) is potentially highly emetogenic. Vigorous anti-emetic prophylaxis is 
required prior to administration of Zotiraciclib (TG02) and should continue at least 24 hours after 
Zotiraciclib (TG02) administration or until nausea/vomiting returns to Grade 0 or 1. Anti-emetic 
prophylaxis is also highly recommended to be started on the day prior to Zotiraciclib (TG02) 
administration. 
Some recommended prophylaxis regimens include but is not limited to the following:

5-HT3 antagonist (e.g., ondansetron, granisetron, palonosetron, etc.) 

2.5 mg olanzapine or 

other moderate anti-emetic regimens tailored to the individual patient at the Investigator’s 
discretion
3.3.3.1.2 Prophylaxis for Diarrhea
Due to frequent reports of diarrhea with Zotiraciclib (TG02) administration, vigorous anti-
diarrheal prophylaxis (e.g., loperamide or equivalent) is required prior to administration of 
Zotiraciclib (TG02) and should continue at least 24 hours after Zotiraciclib (TG02) 
administration or until diarrhea returns to Grade 0 or 1.  
The recommended prophylaxis includes but is not limited to the following:  
a.
Loperamide the day prior to and the day of Zotiraciclib (TG02). Suggest that if patient 
had diarrhea on day of Zotiraciclib (TG02) that Loperamide 2-4mg is administered 
following first loose stool on day after Zotiraciclib (TG02) and after each stool if an hour 
as elapsed since last dose, as needed thereafter.
b. Once diarrhea has occurred, Loperamide 4mg after first loose stool, and Loperamide 4mg 
after the second and third stool respectively, with patient to call the study team 
practitioner after third loose stool.  
c.
Consider Lomotil and Tincture of Opium, if diarrhea continues. A nutrition consult may 
also be beneficial for potential diet modifications. 


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
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3.4
QUESTIONNAIRES
3.4.1
MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT):
The MDASI-BT will be administered at baseline and at the time of imaging analysis as outlined 
in the protocol. Of note, every attempt should be made to administer the MDASI-BT prior to 
informing the patients about the results of the imaging study. The MDASI-BT will be completed 
only by the patient, unless changes in vision or weakness make this difficult. If this occurs, then 
the caregiver or research assistant may read the questions to the patient or assist with marking the 
severity number or score as described by the patient. A caregiver may complete the 
questionnaires as a patient proxy if the patient’s deficits preclude self-report; however, this must 
be done at every assessment from baseline to end of treatment.  In addition, information 
regarding demographics and treatment history will be collected as part of the larger study and 
used in this analysis.   
The MDASI-BT consist of symptoms rated on an 11-point scale (0 to 10) to indicate the 
presence and severity of the symptom, with 0 being “not present” and 10 being “as bad as you 
can imagine.” Each symptom is rated at its worst in the last 24 hours. Symptoms included on the 
instrument include those commonly associated with cancer therapies, and those associated with 
the underlying disease.  The questionnaire also includes ratings of how much symptoms 
interfered with different aspects of a patient’s life in the last 24 hours. These interference items 
include: general activity, mood, work (includes both work outside the home and housework), 
relations with other people, walking, and enjoyment of life. The interference items are also 
measured on 0 - 10 scales. The average time to complete this instrument is 5 minutes. The 
MDASI-BT has been translated into multiple languages, but the English language version will be 
used for this study[44].
3.4.2
PRO-CTCAE*:
Patients will complete a baseline PRO-CTCAE any time after enrollment but before starting 
treatment, and again on days 2, 8, 14, 21, and 28 in each treatment cycle, if the patient is able. 
There are 13 questions in total. The questions are focused on 12 symptoms that are commonly 
reported by the patients taking Zotiraciclib (TG02). It takes 5-10 minutes to complete the 
questionnaire. It will only be completed by the patient, unless changes in vision or weakness 
make this difficult. If this occurs, then the caregiver may read the questions to the patient or 
assist with marking the answers as described by the patient. A patient caregiver may complete 
the questionnaires as a patient-preference proxy if the patient’s deficits preclude self-report. The 
questionnaires are allowed to be completed within +/-2 days form the scheduled dates. The PRO-
CTCAE is only going to be conducted in the cohort expansion part of the study.
Patients will complete at least 2 questionnaires per cycle.  
*The PRO-CTCAE will not be performed in the Post Interim Analysis cohort.


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
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3.5
ASSESSMENTS WHILE ON STUDY THERAPY
3.5.1
Cycle 1 Assessments
During the 2nd week of treatment (i.e. 28-day cycle), the patient will have a complete blood 
count (CBC) with differential and platelet count. In phase I study, if grade 3 neutropenia is 
identified, repeat CBC with differential every 3 days until it improves to ≤ grade 2. Patient may 
have CBC drawn at NIH lab or outside community lab.
During the 4th week of treatment (i.e. 28-day cycle), the patient will have the following 
assessments:

Physical exam with vital signs, neurological exam, neurological function score and 
neurological examination (including documentation of the patient’s Karnofsky 
Performance Status), mental status score.  Weight is also included. Toxicity monitoring.

A complete blood count (CBC) with differential and platelet count. In phase I study, if 
grade 3 neutropenia is identified, repeat CBC with differential every 3 days until it 
improves to ≤ grade 2.

PT, PTT, INR, total protein, albumin, calcium, phosphorus, magnesium, glucose, BUN, 
creatinine, sodium, potassium, total bilirubin, alkaline phosphatase, LDH, SGPT (ALT), 
SGOT (AST) and a pregnancy test for women of childbearing potential

12-lead EKG. 
On days 2, 8, 14, 21, and 28, patients will complete PRO-CTCAE form. (+/- 2 days). 
The PRO-CTCAE will not be performed in the Post Interim Analysis cohort.
3.5.2
Cycle 2 Assessments
During the 2nd week of treatment, the patient will have a complete blood count (CBC) with 
differential and platelet count. In phase I study, if grade 3 neutropenia is identified, repeat CBC 
with differential every 3 days until it improves to ≤ grade 2.   Patient may have CBC drawn at 
NIH lab or outside community lab.                                                                                                                             
During the 4th week of treatment (i.e. 28-day cycle), the patient will have the following 
assessments:

Physical exam with vital signs, neurological exam, neurological function score and 
neurological examination (including documentation of the patient’s Karnofsky 
Performance Status), mental status score. Weight is also included.

A Gd-DPTA enhanced MRI, with DWI, ADC, SWI, FLAIR, perfusion, dynamic contrast 
enhanced and dynamic susceptibility contrast sequences should be performed. 

MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT). If the MDASI-
BT is completed by the patient for Natural History study within 14 days from the MRI 
assessment, it can be used but only if it was administered prior to informing patient of 
tumor imaging results.

Toxicity monitoring


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
A complete blood count (CBC) with differential and platelet count every two weeks. In 
phase I study, if grade 3 neutropenia is identified, repeat CBC with differential every 3 
days until it improves to ≤ grade 2.

PT, PTT, INR, total protein, albumin, calcium, phosphorus, magnesium, glucose, BUN, 
creatinine, sodium, potassium, total bilirubin, alkaline phosphatase, LDH, SGPT (ALT), 
SGOT (AST) and a pregnancy test for women of childbearing potential

12-lead EKG. 

Response evaluation.
3.5.3
Subsequent cycles
For all subsequent odd-numbered cycles (i.e. cycle 3, 5, 7, 9, 11), patients will repeat 
assessments outlined in section  3.5.1
For all subsequent even-numbered cycles (i.e. cycle 4, 6, 8, 10, 12), patients will repeat 
assessments outlined section 3.5.2. 
3.6
ASSESSMENTS AFTER COMPLETION OF STUDY THERAPY
Follow-Up Phase – Survival/Post-Disease Progression
Once a subject completes Phase II of study therapy or starts a new anti-cancer therapy, the 
subject moves into the survival follow up phase and should be contacted approximately within 
every 6 months to assess for survival status until death, withdrawal of consent, or the end of the 
study, whichever occurs first.
3.7
CCR SELF-ADMINISTERED STUDY DRUGS POLICY 
All oral self-administered investigational agents will be properly accounted for, handled, and 
disposed in accordance with existing federal regulations and principles of Good Clinical 
Practice. All oral study drugs will be recorded in the patient diaries found in Appendix 15.7.  
This will be used as a memory aide for subjects. A clinical research team maintains the primary 
source record.


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3.8
STUDY CALENDAR
Screening/
Baseline
Cycle 1
Cycle 2
Subsequent 
Odd 
numbered 
cycles
Subsequent
Even 
numbered 
cycles
Off- 
study visit8  
Procedure
Wk
1
Wk 
2*
Wk
3
Wk
4*
Wk
1
Wk
2*
Wk
3
Wk
4*
Wk
2*
Wk
4*
Wk
2*
Wk
4*
30 days (+/- 
15) after 
last dose of 
treatment 8 
Informed Consent
X
Medical History
X
Physical Exam1
X
X1
X1
X1
X1
X1
MDASI-BT
X
X
X7
ProCTCAE***
X
X
X
X
X
X
X
X
X
X
X
X
X
GD-DPTA 
MRI of brain 
X
X
X6 
Hematology2
X
X
X
X
X
X
X
X
X
X
Chemistry3
X
X
X
X
X
X
PT/PTT/INR
X
X
X
X
X
12-lead EKG
X
X
X
X
Pregnancy Test 4 
X
X
X
X
X
X
Tumor Pathology
X
Paraffin Tissue block 5
X
Response evaluation
X
X
Research samples (PK, 
PG, neutrophil)9,10
X9,10


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1.
Physical examination includes vital signs, neurological exam, neurological function score, Karnofsky 
performance score, mental status score. Height and weight are also included. Height measured only 
at baseline.  
2.
Includes CBC with differential and platelets. In phase I study, once grade 3 neutropenia is identified, 
CBC with differential will be tested every 3 days until it improves to ≤ grade 2.
3.
Includes: Total protein, albumin, Ca, Mg, P, glucose, BUN, creatinine, Na, K, total bilirubin, alkaline 
phosphatase, LDH, SGPT (ALT), SGOT (AST).
4.
Only for women of childbearing potential as defined in section 15.2. To be performed before each 
new cycle of therapy.
5.
If a tissue block is unavailable, unstained slides are acceptable.
6.
Brain MRI w/wo contrast needs to be done every two cycles of treatment. 
7.
MDASI-BT questionnaire needs to be completed at imaging cycles within +/- 1week. (prior to 
imaging results having been discussed with the patient).  If the MDASI-BT is completed by the 
patient for Natural History study (CC 16C0151) within 14 days from the MRI assessment, it can be 
used but only if it was administered prior to informing patient of tumor imaging results.
8.
If patient does not return for 30-day safety visit, patient will be taken off study for reason listed in 
section 3.10.3 If patient does not return, physical exam and blood work is not mandatory. 
9.
On cycle 1 day -3, collect following samples from patients in the Phase 1 cohort expansion only: PK 
studies (1 6mL green sodium heparin tube at following timepoints-pre-dose, 1hr, 2hr, 4hr, 12hr, 24hr, 
48hr, and 72hr post-oral dose); PG studies (1 purple tube EDTA, 6mL, pre-dose) and neutrophil 
analysis (2 additional purple top EDTA, 6mL each for CBC/diff and neutrophil marker; and 1 
additional heparinized green top tube, 6 mL for plasma isolation for monitoring neutrophil activation 
markers) at following timepoints- pre-dose, 1hr, 2hr, 4hr, 12hr, 24hr, 48hr, and 72hr post-oral dose). 
All effort will be made to collect samples at prescribed time points; missed timepoints or collections 
outside the window will be documented but not constitute a deviation. 
10. Research sample will be collected for PK/PG study from patients enrolled to the Post-Interim 
Analysis cohort at the following timepoints: pre-dose, 1hr, 2hr, 4hr, 24hr, and 48hr post-oral dose. 
This will avoid the requirement for inpatient admission. The neutrophil sample will not be collected.
*+/- 3 business days
** Allowance for scheduling changes: Brief interruption and delay in the 28-day cycle may occasionally 
be required due to travel delays, airport closure, inclement weather, family responsibilities, security alerts 
and government holidays, etc. This can also extend to complications of disease not attributable to disease 
progression or protocol therapy. These delays will not be considered protocol deviation.  However, any 
interruption more than 14 calendar days will not be permitted. 
*** on days 2, 8, 14, 21, and 28 (+/- 2 days). The ProCTCAE data will not be collected from patients 
enrolled to the post-interim analysis cohort.
3.9
SURGICAL GUIDELINES
If neurosurgical management is required for reasons not due to tumor progression, these 
procedures must be documented, including the indications for surgery, the surgical operative 
note and pathology report. Study treatment may be resumed per discretion of the PI.
 


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3.10
 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
3.10.1 Criteria for Removal from Protocol Therapy

After administration of 12 cycles of treatment, unless there is clear evidence of clinical 
benefit to justify continuation of treatment based on treating physician’s opinion. 

Progressive disease if patient not eligible for or refuses crossover or progressive 
disease * after crossover to TMZ+ Zotiraciclib (TG02)

The patient may withdraw from the study at any time for any reason 

Unacceptable Toxicity as defined in section 3.3

Investigator discretion

Treatment related adverse events not resolved within a 4-weeks rest period or 
requiring more than two dose de-escalations of any drug whichever is earlier. 

Pregnancy
* Delayed imaging responses have been observed in some patients who received protocol 
treatment.  If a patient is clinically stable or clinically improved, even while MRI showed >25% 
increase in tumor size, the patient may continue on study treatment per P.I. discretion for one 
additional cycle, at which time a repeat scan will be done.  If tumor size continues to increase, 
disease progression will be dated back to the date of prior MRI.
3.10.2  Off-Study Visit
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
If patient does not return for off study follow up safety visit, patient will be taken off study per 
appropriate reason listed in section 3.10.3. 
During the follow up safety visit, the following study tasks will be performed:

A complete physical (including baseline blood pressure measurement) and neurological 
examination (include documentation of the patients’ Karnofsky Performance Status).  

MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) (Error! 
Reference source not found.)

Laboratory tests will include CBC, differential, platelets, total protein, albumin, calcium, 
phosphorus, magnesium, glucose, BUN, creatinine, sodium, potassium, total bilirubin, 
alkaline phosphatase, LDH, SGPT (ALT), SGOT (AST) and a pregnancy test for women 
of childbearing potential.

Take patient off study (section Error! Reference source not found.)
3.10.3 Off-Study Criteria

Participant requests to be withdrawn from study

Patients lost to or refuse to follow up


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
Death

Screen failure

PI discretion based on clinical indications

Patient to start alternative therapy

Patient completed follow up period 

Phase II patient completed follow up until death
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
MEDICATIONS TO AVOID OR USE WITH PRECAUTION (ZOTIRACICLIB [TG02])
4.1.1
Medications that Prolong QTc
Use of certain medications that prolong QTc interval should be avoided throughout the trial. These 
medications include but are not limited to: azithromycin, clarithromycin, erythromycin, 
roxithromycin, metronidazole (with alcohol), moxifloxacin, fluconazole (in cirrhosis), ketoconazole, 
nelfinavir, chloroquine, mefloquine, halothane, disopyramide, procainamide, quinidine, 
amiodarone, sotalol, amitriptyline, clomipramine, impipramine, dothiepin, doxepin, risperidone, 
fluphenazine, haloperidol, clozapine, thioridiazine, ziprasidone, pimozide, droperidol, terfenadine, 
astemizole, probucol, dolasetron mesylate, and cisapride. 
However, it is understood that patients with malignancy treated with potentially myelotoxic 
cytotoxic chemotherapy may require certain classes of medications such as azole antifungal agents 
and certain antibiotics that have been reported to prolong QTc. If patients require these medications 
every effort should be made to maintain a normal electrolyte balance with special attention to K+ 
and Mg++ levels. An ECG in triplicate should be obtained after beginning such a medication to 
determine any change to the QTc duration based on the average QTc of triplicate ECGs. 
In the event of QT/QTc prolongation, electrolytes will be corrected to keep the potassium and 
magnesium within normal limits and the ECG in triplicate will be repeated. Patients may be 
monitored on telemetry at the Investigator's discretion.
During the trial, patients who show a QTc interval prolongation as per CTCAE (based on the 
average QTc of triplicate ECGs) as calculated by Fridericia’s correction formula, should be tested 
for the electrolytes noted above. If the electrolytes are at normal levels but QTc interval remains 
prolonged, study drug should be held until QTc interval is no longer prolonged.
4.1.2
CYP450 Drug Interactions (Related to Drug Metabolism)
Strong inhibitors/inducers of CYP3A4 and CYP1A2 and drugs that are known substrates for 
CYP1A2 and CYP2D6 with a narrow therapeutic index should be used with caution in this study. 
Known inhibitors of CYP1A2 include acyclovir and fluvoxamine, and known inhibitors of 
CYP3A4 include atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, 


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nelfinavir, ritonavir, saquinavir, and telithromycin. 
Known inducers of CYP1A2 include omeprazole, insulin, and cigarette smoking, and known 
inducers of CYP3A4 include rifampin and carbamazepine. 
Sensitive CYP1A2 substrates with narrow therapeutic indices include theophylline and tizanidine, 
and sensitive CYP2D6 substrates with narrow therapeutic indices include thioridazine and 
tamoxifen. 
Exceptions are allowed per PI discretion, if clinically indicated.
4.2
MEDICATIONS TO AVOID OR USE WITH PRECAUTION (TMZ)
Administration of valproic acid decreases oral clearance of temozolomide by about 5%.
4.3
G-CSF AND ERYTHROPOIETIN ADMINISTRATION: 
Routine prophylactic use is not permitted. However, therapeutic use in patients with 
complications (severe neutropenia with fever or anemia), may be considered at the investigator’s 
discretion.
4.4
PLATELET SUPPORT:
Prophylactic use of platelet is only used when Platelet count < 20 x 109/L. Platelet transfusion is 
provided for active bleeding patients with thrombocytopenia to keep platelet count above 50 x 
109/L. 
4.5
CORTICOSTEROIDS 
Should be used in the smallest dose to control symptoms of cerebral edema and mass effect and 
discontinued if possible.
4.6
FEBRILE NEUTROPENIA 
It may be managed according to the local institution's Infectious Disease guidelines.  Measures 
may include appropriate laboratory testing, including blood and urine cultures and the institution 
of broad-spectrum antibiotics.  If a source for the fever is not identified or the fever resolves 
when the neutrophil count recovers, antibiotics may be discontinued, and the patient observed.
4.7
ANTI-EMETICS
Prophylactic and therapeutic use is allowed. Other concomitant medications and the therapies 
considered necessary for the well-being of the patient may be given at the discretion of the 
treating physician. All concomitant medications must be recorded.
4.8
OTHER ANTICANCER OR EXPERIMENTAL THERAPIES
No other anticancer therapy (including chemotherapy, radiation, hormonal treatment or 
immunotherapy) of any kind is permitted during the study period. No other antitumor drugs 
under investigation may be used concomitantly with the study drug.


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5
BIOSPECIMEN COLLECTION
5.1
CORRELATIVE STUDIES FOR RESEARCH
Test/assay
Volume 
blood 
(approx.)
Type 
of tube
Collection point (+/- 
48hrs)
Location of 
specimen analysis
Target 
DNA 
Sequencing
Tumor 
tissue block
-
Initial and/or Recurrence 
Laboratory of 
Pathology
Western 
Blot and 
PCR
Fresh 
Frozen 
Tumor 
-
Surgery at Disease 
recurrence
NOB Laboratory
6mL 
Sodium 
Heparin 
(green 
top)
Cycle 1 day -3 at the 
following time points: 
pre-dose, 1hr, 2hr (peak), 
4hr, 12hr-, 24hr, 48hr, and 
72hr post oral dose.  For 
patients in the cohort 
expansion only
Dr. Figg’s Lab
PK and 
PG*
Up to 6mL
EDTA 
(purple 
top)
Cycle 1 day – 3 For 
patients in the cohort 
expansion only
Dr Figg’s Lab
(1 tube) 
Processed by NOB 
Laboratory and sent 
to
Dept of Laboratory 
Medicine
Neutrophil 
analysis**
12mL
EDTA 
(purple 
top)
Cycle 1 day -3 at the 
following time points: 
pre-dose, 1hr, 2hr (peak), 
4hr, 12hr, 24hr, 48hr, and 
72hr post oral dose. For 
patients in the cohort 
expansion only
(1 tube)
Processed by NOB 
Laboratory and sent 
to
Neutrophil 
Monitoring Lab 
(NML)


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Test/assay
Volume 
blood 
(approx.)
Type 
of tube
Collection point (+/- 
48hrs)
Location of 
specimen analysis
6mL
(green 
top)
Cycle 1 day -3 at the 
following time points: 
pre-dose, 1hr, 2hr (peak), 
4hr, 12hr, 24hr, 48hr, and 
72hr post oral dose. For 
patients in the cohort 
expansion only
Processed by NOB 
Laboratory and sent 
to
Neutrophil 
Monitoring Lab 
(NML)
*PK/PG analysis: For patients in Post-Interim Analysis cohort, samples will be collected 
in Cycle 1 day -3 at the following time points only: pre-dose, 1hr, 2hr (peak), 4hr, 24hr, 
and 48hr post oral dose.  
**Neutrophil analysis will not be collected and performed in patients in Post-Interim 
Analysis cohort.
5.1.1
The brain tumor tissue block from initial and /or recurrence will be collected to detect 
MGMT methylation, TP53, PTEN, IDH mutation, MYC amplification status by 
performing targeted DNA sequencing at the laboratory of Pathology, CCR, NIH (if not 
included in the Natural History Study [CC 16C0151]).
5.1.1.1 Tissue blocks can be shipped to Department of Pathology at NCI at the following 
address:
Laboratory of Pathology
Center for Cancer Research
National Cancer Institute 
Building 10, Room 2S235
Bethesda, MD 20892-1500
Ph: 301-480-5010 
5.1.1.2
Procedures for storage of tissue specimens in the Laboratory of Pathology
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly, and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation.  Unutilized excess tissues are stored for up to 
three months, in accordance with College of American Pathologists/Joint Commission on 
Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then 
discarded.  Following completion of the diagnostic workup, the slides and tissue blocks are 
stored indefinitely in the LP’s clinical archives.  All specimens are catalogued and retrieved 
utilizing the clinical laboratory information systems, in accordance with CAP/JCAHO 
regulations.  The use of any stored specimens for research purposes is only allowed when the 
appropriate IRB approval has been obtained.  In some cases, this approval has been obtained via 
the original protocol on which the patient was enrolled. 


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5.1.2
Fresh frozen brain tumor tissue will be obtained if patient undergoes surgery at the time 
of disease progression. Pro-survival proteins, including Mcl-1, XIAP and survivin will be 
tested at protein by Western blot and at mRNA level by PCR in the NOB laboratory.
5.1.2.1 The samples should be shipped to the following address ON DRY ICE in appropriately 
labeled package in accordance with local and federal regulations for biological material:
Wei Zhang MD, PhD.
Neuro-Oncology Branch, NCI, NIH
Bldg. 37, Room 1142
Bethesda, MD  20892
Office: 240-760-6835 or 301-435-3136
Cell:  240-274-0469
Pager:  102-12209
5.1.2.2 If the surgery is performed at Neurosurgery Department at NINDS, NIH, the following 
personnel will be contacted for tissue pick up.
Wei Zhang MD, PhD.
Neuro-Oncology Branch, NCI, NIH
Bldg. 37, Room 1142
Bethesda, MD  20892
Office: 240-760-6835 or 301-435-3136
Cell:  240-274-0469
Pager:  102-12209
5.1.3
 Pharmacokinetic (PK) and Pharmacogenetic (PG)Studies
5.1.3.1
Pharmacokinetic Studies
PK studies will be done in all patients that are enrolled in the cohort expansion part and the Post-
Interim Analysis cohort. Blood samples for the determination of plasma levels of Zotiraciclib 
(TG02) will be obtained from each patient (see section 5.1.3.3  for schedule and tube types). 
Bioanalytical measurements for Zotiraciclib (TG02) will be conducted on an ultra HPLC-MSMS 
system using an assay developed and validated by the Clinical Pharmacology Program.  This 
data will be used to monitor plasma concentrations of Zotiraciclib (TG02) to correlate to 
pharmacodynamic endpoints, clinical response, toxicity, and pharmacogenetic analyses. 
5.1.3.2
Pharmacogenetic studies (PG)
PG studies will be done in all patients that are enrolled in the cohort expansion part and the Post-
Interim Analysis cohort.  One blood sample per patient (6mL) will be collected (see section 
5.1.3.3 for schedule) to analyze the genomic DNA and assess genotype of the most relevant drug 
metabolizing enzymes and transporters (DMET). DNA will be analyzed on a DMET Plus 
(Affymatrix) genotyping platform that has the capacity to test for 1,936 genetic variations in 225 
drug disposition genes, including 47 CYP (phase I metabolism) genes, 13 non-CYP (phase I 
metabolism) genes, 78 phase II metabolizing genes (including UGTs), 63 transporters, 4 genes 
involved in facilitation of drug transporters, 9 genes involved in global regulation of drug 
metabolizing/transporting proteins, 4 drug binding proteins.


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Of specific interest to Zotiraciclib (TG02) are polymorphisms in CYP3A4, CYP1A2, and 
ABCB1 (P-glycoprotein), all of which are included in the DMET analysis.
The samples will be placed at room temperature. The date and exact time of each blood draw 
should be recorded on the sample tube and the PK/PG sheet. Contact Dr. Figg’s Clinical 
Pharmacology Program (Blood Processing Core) in Bldg. 10/5A09 at 
NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is 
preferred).
5.1.3.3
Sample Collection 
PKs: Blood samples for the determination of plasma levels of Zotiraciclib (TG02) will be 
obtained from each patient via 6mL green sodium heparin tube collected on the first daily dose 
on cycle 1 day -3 at the following time points: pre-dose, 1hr, 2hr (peak), 4hr, 12hr, 24hr, 48hr, 
and 72hr post oral dose. For patients in the post-interim analysis cohort, blood will be collected, 
pre-dose, 1hr, 2hr, 4hr, 24hr, and 48hr post oral dose.  
PGs: 6 mL of blood will be collected in an EDTA (purple top) tube on day -3 of cycle 1.
5.1.3.4
Sample processing
The samples will be placed immediately on wet ice and refrigerated. The date and exact time of 
each blood draw should be recorded on the sample tube and the PK sheet. 
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
Upon arrival in the Clinical Pharmacology Program, samples will be centrifuged, and the plasma 
transferred into cryovials for storage at -80 C until the time of analysis. In addition, samples will 
be barcoded.
5.1.4
Neutrophil analysis
Neutrophil analysis studies will be done in all patients that are enrolled in the cohort expansion 
part.
Three tubes of blood will be collected at all PK time points for the following studies: WBC and 
differential analysis, neutrophil morphology studies (photographs), neutrophil function assays, 
surface marker analysis and for spinning out cells and saving plasma to send to Dr. Douglas 
Kuhns for monitoring activation markers released into the plasma such as specific granule 
marker.  (See section 5.1.4.1 for tube types and collection information.  Note: The pediatric size 
tubes can be used as alternatives for blood sample collection, if it is necessary.)


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WBC with differential and imaging analysis will be done at Department of Laboratory Medicine. 
Plasma and neutrophil isolation will be done by NOB laboratory and analysis will be done in 
Neutrophil Monitoring Laboratory (NML).
5.1.4.1
Collection
a.
CBC with differential (a tube of 6 cc blood collected in purple top tube) will be done on 
cycle 1 day -3 at the following time points*: pre-dose, 1hr, 2hr, 4hr, 12hr, 24hr, 48hr, and 
72hr post oral Zotiraciclib (TG02). Neutrophil morphology will be studies by using 
Cellavision program.
b. Collect blood sample (6 cc of blood in heparinized green top tube) at the time of PK sample 
collection for plasma isolation for monitoring neutrophil activation markers. 
c.
Collect (6 cc of blood in purple top tube with EDTA), fix and stain neutrophils at the same 
time points of the PK sample collection. Samples will be used for neutrophil cell surface 
markers including but not limited to CD11a, CD11b, CD11c, CD32, CD18, CD67, CD64, CD18, 
CD45, CD62L, CD63, 7D5.
* All effort will be made to collect samples at prescribed time points; missed timepoints or 
collections outside the window (+/- 30 minutes from the scheduled time) will be documented but 
not constitute a deviation.
5.1.4.2
Contact of NOB laboratory
Ying Pang, MD., PhD.
Neuro-Oncology Branch, NCI, CCR
Bldg. 37, Room 1142
Bethesda, MD  20892
Office:  240-760-6216
5.1.4.3
Contact of NML
Douglas Kuhns, PhD.
Building 310, Rm 204
Frederick, MD 21702
Office: 301-846-6378
5.1.5
Labeling of Samples
Labels on all samples will at least include the following information:

Patient initials, ID number

Protocol number

Collection date
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  


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Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. 
5.2.1
Clinical Pharmacology Program
All samples sent to the Clinical Pharmacology Program (CPP) will be barcoded, with data 
entered and stored in Labmatrix utilized by the CPP. This is a secure program, with access to 
Labmatrix limited to defined Figg lab personnel, who are issued individual user accounts. 
Installation of Labmatrix is limited to computers specified by Dr. Figg. These computers all have 
a password restricted login screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.).Barcoded 
samples are stored in barcoded boxes in a locked freezer at either -20 or -80C according to 
stability requirements.  These freezers are located onsite in the CPP and offsite at NCI Frederick 
Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be 
accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the CPP. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval.
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following OHSRP/IRB approval of an additional protocol, 
granting the rights to use the material or if the use is not considered to be human subjects 
research.
 
5.2.2
Neutrophil Monitoring Laboratory (NML) / Frederick Laboratory 
Plasma and neutrophil isolation will be done by NOB laboratory and analysis will be done in 
Neutrophil Monitoring Laboratory (NML) in Frederick.
Samples will be sent to the NOB laboratory and sent to Frederick laboratory will be barcoded 
with data entered and stored in the Labmatrix system utilized by the CCR, NCI. This is a secure 
system with access limited to defined personnel. All such personnel with access to patient 
information annually complete the NIH online Protection of Human Subjects course.
Labmatrix creates a unique barcode ID for every sample which cannot be traced back to patients 
without Labmatrix access. The data recorded for each sample includes the patient ID, name, trial 
name/protocol number, date/time drawn, as well as box and freezer location. Patient 
demographics associated with the Clinical Center patient number are provided in the system. For 


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each sample, there are notes associated with the processing method (delay in sample processing, 
storage conditions on the ward, etc.).
5.2.3
Department of Laboratory Medicine
Samples will be processed by the NOB laboratory and then sent to Department of Laboratory 
Medicine will be barcoded with data entered and stored in the Labmatrix system utilized by the 
CCR, NCI. This is a secure system with access limited to defined personnel. All such personnel 
with access to patient information annually complete the NIH online Protection of Human 
Subjects course.
5.2.4
Protocol Completion/Sample Destruction
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below. 
The study will remain open so long as sample or data analysis continues.  Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. 
If the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved.
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2. 
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The MDASI-
BT responses will be entered by study subjects directly into Scribe/Labmatrix. 
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts. All data obtained during the conduct of the 
protocol will be kept in secure network drives or in approved alternative sites that comply with 
NIH security standards. Primary and final analyzed data will have identifiers so that research 
data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention, Study Day 1, through 30 days after the last 
administration of investigational agent/intervention.  Adverse events that are serious need to be 
recorded through 30 days after the last administration of investigational agent/intervention. 
Beyond 30 days after the last intervention, only adverse events which are serious and related to 
the study intervention need to be recorded.


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An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.
6.1.1
Non-Relevant Toxicities for Brain Tumor Protocols
Lymphopenia is a common finding among patients with primary brain tumors and is directly 
attributable to concurrent use of corticosteroids.  To date, even Grade III lymphopenia has not 
been associated with a worsening of clinical outcome.  Therefore, we will not consider this 
parameter in the determination of optimal dosing of drugs.
Weight gain is a common finding among patients with primary brain tumors.  This too is directly 
attributed to the concurrent use of corticosteroids. Doses of steroids or study agents will not be 
modified as a consequence of weight gain.  Corticosteroid dosage will be based on maintenance 
of control of edema in the brain and the standard clinical practice to use the minimal effective 
dose of corticosteroids will be employed.
Alopecia is a common occurrence in patients with brain tumors as a consequence of cranial 
radiotherapy.  Alopecia will not be recorded or graded as toxicity.
Venous thromboembolic disease is a common complication occurring in up to 30% of patients 
with malignant gliomas.[47, 48] In this study, patients who develop deep vein thrombosis may 
receive anticoagulation and resume therapy once they are stable on anticoagulation. Grade III 
deep vein thrombosis will not be considered a DLT for the phase I portion.
The routine use of filgrastim or other white cell growth factors is not permitted during cycle 1 of 
the Phase I portion unless clinically indicated, but it may be used beyond this period or once the 
assessment of DLT has been completed. 


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6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows: 

Coded, linked data in an NIH-funded or approved public repository.  

Coded, linked data in BTRIS (automatic for activities in the Clinical Center)

Coded, linked or identified data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:

BTRIS (automatic for activities in the Clinical Center)

Approved outside collaborators under appropriate individual agreements.

Publication and/or public presentations.
When will the data be shared?

Before publication.

At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
6.3.1
General
The primary efficacy endpoint for this study is progression free survival (PFS) from patient 
registration.  However, objective response status should be measured and recorded. 
6.3.2
Definitions
Evaluable for maximum tolerated dose: All subjects enrolled in the Phase I dose escalation 
cohorts from the time of their first treatment with Zotiraciclib (TG02) +TMZ to the end of cycle 
1. Patients who develop a DLT during cycle 1 and thus do not complete treatment for the cycle 
should be considered evaluable for MTD.
Evaluable for toxicity:  All eligible patients who complete at least one cycle of protocol therapy 
or who have a DLT after the protocol therapy is started are evaluable for toxicity from the time 
of their first treatment. 


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*If the patients miss doses of Zotiraciclib (TG02) or TMZ in the first cycle of treatment due to 
reasons that are unrelated to toxicity, it will be the PI’s decision about whether they are evaluable 
for toxicity in the dose finding stage.  
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy at MTD 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.) 
Phase I patients removed from study treatment within 28 days for reasons other than toxicity 
may be replaced.
6.3.3
Disease Parameters
Measurable Disease: Bi-dimensionally measurable lesions with clearly defined margins by GD-
DPTA enhanced MRI scan.
Evaluable Disease: Uni-dimensionally measurable lesions, masses with margins not clearly 
defined. Patients with only this kind of imaging will not be allowed to enter this study unless 
they have recently undergone surgery and have histologically proven recurrent disease.
Non-Evaluable Disease: Not Applicable for response evaluation.
Objective-Status, To Be Recorded at Each Evaluation: If there are too many measurable lesions 
to measure at each evaluation, choose the largest two to be followed before a patient is entered 
on study.  The remaining lesions will be considered evaluable for the purpose of objective status 
determination.  Unless progression is observed, objective status can only be determined when 
ALL measurable and evaluable sites and lesions are assessed.
6.3.4
Response Criteria
Response and progression will be evaluated in this study using the new proposed criteria 
Response Assessment in Neuro-Oncology Criteria (RANO) (see Appendix 15.5 ).[49] 
Complete response: Requires all of the following:

Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks.

No new lesions and stable or improved non-enhancing lesions (T2/FLAIR)

Patient off steroids or on physiologic replacement only.

Stable or improved clinically.
Partial response: Requires all of following:

≥ 50 % decrease compared to baseline (prior to treatment) in the sum of the products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 
weeks;

No new lesions and stable or improved non-enhancing lesions (T2/FLAIR).

Patients off steroids or on physiologic replacement only.


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
Stable or improved clinically.
Stable disease: Requires all of the following:

Not complete response, partial response or progression. 

Stable non-enhancing lesions (T2/FLAIR). 

Patient on same or lower dose of steroids compared to baseline scan.
Progression: Requires any of the following:

≥ 25 % increase compared to baseline in the sum of the products of perpendicular 
diameters of enhancing lesions compared with the smallest measurement obtained either 
at baseline or best response with the patient on stable or increasing doses of steroids. 

Significant increase in T2/FLAIR non-enhancing lesions with the patient on stable or 
increasing doses of steroids (not caused by comorbid events e.g. Radiation therapy, 
demyelination, ischemic injury, infection, seizures, medication adverse events or changes 
in corticosteroid dose). 

Any new lesions.

Failure to return for evaluation as a result of death or deteriorating condition or clear 
progression of non-measurable disease.
6.3.5
Patients will undergo response evaluations every 2 months.  

RANO criteria will be used to determine response and progression (includes CR, PR, SD 
and PD) 15.5.

Neurological exam.

Performance status by Karnofsky Performance Status.
6.3.6
Evaluation of Best Overall Response
This will be calculated from the sequence of objective statuses. For patients with all disease sites 
assessed every evaluation period, the best response will be defined as the best objective status as 
measured according to Section 6.3.4.  If the response does not persist at the next regular 
scheduled MRI, the response will still be recorded based on the prior scan but will be designated 
as a non-sustained response.  If the response is sustained, e. g. still present on the subsequent 
MRI, it will be recorded as a sustained response, lasting until the time of tumor progression.  
Best response is unknown if the patient does not qualify for a best response or increasing disease 
and if all objective status determinations before progression are unknown.
6.3.7
Duration of Response
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.


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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. 
6.3.8
Progression-Free Survival
PFS is defined as the duration of time from start of registration to time of progression or death, 
whichever occurs first.
6.3.9
Time to Death: 
From date of registration to date of death due to any cause.
6.3.10 Neurological Exam: 
Although not used for determining response, it is useful to evaluate improvement in the 
neurologic exam, (as compared to the baseline assessment), that should coincide with objective 
measurement of tumor size. The criteria are as follows:
0= No neurologic symptoms, fully active at home/work without assistance
1= Minor neurologic symptoms, fully active at home/work without assistance
2= Moderate neurologic symptoms, fully active at home/work but requires assistance
3= Moderate neurologic symptoms, less than fully active at home/work and requires assistance
4= Severe neurologic symptoms, totally inactive requiring complete assistance at home or 
institution, unable to work
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING/IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Only IND Safety Reports that meet 
the definition of an unanticipated problem will need to be reported per these policies.


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7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
SPONSOR SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:


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
Death,

A life-threatening adverse event (see section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.

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.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.0.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  

Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.


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8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. 
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
All events listed below must be reported in the defined timelines to OSROSafety@mail.nih.gov.
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described 
below:  
Safety reports (subject to redaction, if required) sent to the FDA will be concurrently sent to the 
manufacturer:


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Jillian Chapas-Reed
Vice President, Clinical Operations
Adastra Pharmaceuticals, Inc.
Telephone: 410-920-2475
jchapas-reed@adastrarx.com
www.adastrarx.com 
8.5
 REPORTING PREGNANCY 
8.5.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as 
SAEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented.
8.5.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 30 
days after the last dose of Zotiraciclib (TG02)
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 30 days after the last dose 
should, if possible, be followed up and documented.
8.6
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
9
CLINICAL MONITORING PLAN
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 


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affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on:

Informed consent process

Eligibility confirmation

Drug administration and accountability

Adverse events monitoring

Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.
10 STATISTICAL CONSIDERATIONS  
10.1 PHASE I COMPONENT: 
We will employ the Bayesian Optimal Interval (BOIN) design [46] to find the MTD. The BOIN 
design is a novel Bayesian dose-finding method that optimizes patient ethics by minimizing the 
chance of exposing patients to sub-therapeutic and overly toxic doses. The BOIN design yields 
an average performance comparable to that of the continual reassessment method (CRM) in 
terms of selecting the MTD, but has a lower risk of assigning patients to sub-therapeutic or 
overly toxic doses (i.e., better patient ethics). 
There are two dosing schedule treatment arms in the Phase I study: the combination treatment 
with Zotiraciclib (TG02) and dd TMZ; and the combination treatment of Zotiraciclib (TG02) 
with mn TMZ. Dose finding will be conducted independently in these two arms. For each arm, 
the target toxicity rate is 0.35 and the maximum sample size for dose finding is 24 patients. We 
will enroll and treat patients in cohorts of size 3. We consider four dose levels and the starting 
dose is level 0 (i.e., TMZ 125mg/m2 + 200mg/day Zotiraciclib (TG02)).


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Table 12
Level
Arm 
TMZ (mg/m2 x 7 days on/7 days off)
TG 02 (mg/day on 1, 12,15,26 
per 28 days cycle)*
-1
125
150
0 (starting dose)
125
200
I
125
250
II
125
300**
Level
Arm 
TMZ (mg/m2 daily)
TG 02 (mg/day on 1, 12,15,26
per 28 days cycle)*
-1
50
150
0 (starting dose)
50
200
I
50
250
II
50
300**
* The first dose of Zotiraciclib (TG02) will be given 3 days prior to Day1 of cycle 1. The 
subsequent doses for cycle 1 will be given on days 1, 12, 15, and 26. Zotiraciclib (TG02) will be 
given on days 1, 12, 15, and 26 every 28-day cycle in all the cycles starting cycle 2. 
** One patient in MN arm developed severe toxicities which lead to ICU admission after one dose 
of Zotiraciclib (TG02) at 300mg. The etiology was not completely clear. However, due to the 
patient’s safety concern, does level II of Zotiraciclib (TG02) was determined to be eliminated in 
both study arms by the investigator and pharmaceutical manufacture.
The BOIN trial design is described as follows:
1. Patients in the first cohort are treated at dose level 0. 
2. To assign a dose to the next cohort of patients, we conduct dose escalation/de-escalation 
according to the rule displayed in Table 13.
Table 13: Dose escalation/de-escalation rule for the BOIN design.
The number of patients treated at the current dose
Action
3
6
9
12
15
18
Escalate if # of patients
who experienced DLT <=
0
1
2
3
4
4
De-escalate if # of patients 
who experienced DLT >=
2
3
4
6
7
8
Eliminate if # of patients 
who experienced DLTs >=
3
5
6
7
9
10
When using Table 13, please note the following:


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(a) “Eliminate” means that we eliminate the current and higher doses from the trial to 
prevent treating any future patients at these doses because they are overly toxic. 
(b) When we eliminate a dose, we automatically de-escalate the dose to the next lower level. 
When the lowest dose is eliminated, we stop the trial for safety. In this case, no dose should 
be selected as the MTD. 
(c) If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, we treat 
the new patients at the current dose.
(d) If the current dose is the lowest dose and the rule indicates dose de-escalation, we will 
treat the new patients at the lowest dose unless the number of DLTs reaches the elimination 
boundary, at which point we will terminate the trial for safety.  
(e) If the current dose is the highest dose and the rule indicates dose escalation, we will treat 
the new patients at the highest dose.
(f) If the number of patients treated at the current (or any) dose reaches 12, we will stop the 
trial early and select the MTD as described below.
3. Repeat step 2 until the maximum sample size of 24 is reached or the trial is stopped.
After the trial is completed, we select the MTD based on isotonic regression as specified 
previously. [46] Specifically, we select as the MTD the dose for which the isotonic estimate of 
the toxicity rate is closest to the target toxicity rate. If there are ties, we select the higher dose 
level when the isotonic estimate is lower than the target toxicity rate; and we select the lower 
dose level when the isotonic estimate is greater than the target toxicity rate.
After identifying the MTD for each of the TMZ dosing schedules in combination with 
Zotiraciclib (TG02) (i.e., 125mg/m2 TMZ on days 1-7 and 15-21 per cycle, and 50 mg/m2 TMZ 
daily), cohort expansion will be conducted independently at each of the MTDs until the total 
number of patients treated at each of the MTDs reaches 18 patients (including the patients who 
have been treated in the dose-finding part). The dosing schedule with a higher PFS at 4 months 
(PFS4) will be selected and used in phase II. If the difference between the PFS4 values from the 
two full cohorts treated at each of the MTDs is less than 10% of the average of the two PFS4 
values, then the dosing schedule with fewer AEs will be selected as the “winner.” During the 
cohort expansion phase, the elimination rule displayed in the last row of Table 13 will be used to 
monitor toxicity. Given the cohort expansion of 18 patients at the MTD, there is 72.6% chance to 
correctly pick the better schedule when the PFS4 for two schedules are 50% and 60% (i.e., 10% 
difference in PFS4), respectively; and there is 81.9% chance to correctly pick the better schedule 
when the PFS4 for two schedules are 50% and 65% (i.e., 15% difference in PFS4) 
Table 14 shows the operating characteristics of the BOIN design for this trial with 4 scenarios 
defined by different DLT rates for 4 doses.  These operating characteristics are based on 1,000 
simulations of the trial using R package “BOIN”, which is available from CRAN.  The operating 
characteristics show that the design selects the true MTD with high probabilities and allocates 
more patients to the dose levels with the DLT rate closest to the target of 0.35. 


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Table 14 Operating Characteristics of the BOIN design
Dose level
Number 
of pts
% early 
stopping 
-1
0
1
2
True DLT rate
0.05
0.15
0.35
0.47
Selection %
0.3
25.3
54.3
20.1
19.7
0.0
# pts treated
0.4
7.5
8.5
3.4
True DLT rate
0.12
0.35
0.44
0.55
Selection %
16.2
59.3
21.2
3.3
18.5
0.0
# pts treated
4.0
9.7
3.9
1.0
True DLT rate
0.35
0.50
0.55
0.62
Selection %
57.0
28.3
4.3
0.2
17.1
10.2
# pts treated
8.2
7.4
1.4
0.1
True DLT rate
0.05
0.10
0.16
0.35
Selection %
0.1
4.4
24.2
71.3
20.7
0.0
# pts treated
0.2
4.6
7.2
8.7
In phase I, for each arm, the maximum sample size of 24 patients will be used for dose finding. 
As there are 4 doses, on average at least 6 patients will be treated at the MTD. After the MTD is 
selected, cohort expansion will be conducted at the MTD until the total number of patients 
treated at the MTD reaches 18 patients (including the patients who have been treated in the dose-
finding part). Thus, no more than 12 additional patients will be enrolled during the cohort 
expansion phase. Therefore, the maximum number of patients for phase I, including dose finding 
and cohort expansion, is 24+12=36 patients per treatment arm, and 72 in total for two treatment 
arms.
During the interim analysis of the Phase I study, we identified TG02 of 250 mg as the MTD in 
both Arm 1 and Arm 2. Cohort expansion was conducted independently at each of the MTD into 
treatment arms, and the PSF4 was found to be 38% in Arm 1 and 25% in Arm 2. Therefore, 
based on the preplanned analysis, the DD TMZ dosing schedule is considered a “winner” to be 
used in Phase II study. However, a better PFS was found in patients who received TG02 at dose 
level 0, compared to those received TG02 at dose level 1, which is MTD, in Arm 1, the winner 
arm, suggesting the lower dose with the scheduled TMZ may be sufficient if not more beneficial 
for patients with recurrent high grade astrocytoma. However, we cannot make the conclusion 
based on the small sample number in Arm 1 at dose level 0. Therefore, we would like to continue 
enrolling to the maximum, allow the additional 12 patients enrolled to be treated with TG02 at 
dose level 0 combined with dd TMZ. 
We do not plan to change the study design. The primary endpoint is still toxicity. The objective 
is to add a small cohort expansion to better characterize the dose-toxicity relationship and obtain 
some preliminary efficacy readout to determine RP2D. If PFS4 month difference between MTD 
and (MTD-1) is less than 5%, select the lower dose, I.e., MTD-1, as the RP2D; otherwise select 
the MTD as RP2D.


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There should not be safety concerns because additional patients will be treated with TG02 at a 
dose that is lower than the MTD that was identified previously. 
The purpose for enrolling more patients is to further define a dosage not only safe but optimal for 
the patients before we move to Phase II study. Only AE and PFS4 will be recorded in these 
subjects. 
10.2 PHASE II COMPONENT:
A randomized phase II trial will be used to compare the combination of Zotiraciclib (TG02) plus 
TMZ (selected from phase I) with TMZ alone in patients with recurrent grade III or IV malignant 
glioma. The TMZ alone arm will use the same dosing schedule as it is in the combination arm.  
The primary endpoint is progression free survival. We will enroll at least 10 patients and at most 
40 patients for each arm at a rate of 4 patients per month. Patients will be equally randomized 
into two arms. Patients’ KPS, MGMT promoter methylation status of the tumors and the 
presence of measurable disease at study entry will be used as stratification factors. We will 
follow all patients for at least 12 months, and monitor futility and toxicity as described below. 
We will use the methods described by Thall et al., to monitor progression-free survival (PFS), 
and we will stop enrolling patients early if, based on the available data, we have reason to 
believe that the median PFS of  the Zotiraciclib (TG02) plus TMZ arm is less than that of the  
TMZ arm.[50] Formally, we will stop enrolling patients early if
Pr (median PFSTG02+TMZ ≥ median PFSTMZ | data from the trial) < 0.78,
The futility monitoring will be conducted after enrolling 20, 40 and 60 patients (for two arms 
combined). Below are the operating characteristics of the above futility monitoring rule, 
assuming that the median PFS of the TMZ alone arm is 3 months.
Table 15 Operating Characteristics of the Futility Monitoring rule
Median PFS for Zotiraciclib (TG02) +TMZ (months)
1
2
3
4
5
Early stop probability
0.999
0.812
0.374
0.170
0.097
Average sample size
23.7
42.1
62.6
70.9
74.7
Similar Bayesian methods will also be used to monitor the rate of DLT. We will monitor the two 
arms independently. Specifically, we will stop enrolling patients if the Pr(DLT > 35% | data) > 
0.9. That is, we will stop enrolling patients if the data indicate that there is more than 90% chance 
that the true DLT rate is higher than 35%. This decision rule gives the following stopping rule, 
assuming a Beta (0.1, 0.4) prior distribution for DLT rate, 
Stop enrolling pts if [# of pts with DLT] / [# of pts evaluated] ≥ 4/5, 6/10, 10/20, and 15/30.
Below are the operating characteristics of the toxicity monitoring rule.
Table 16: Operating Characteristics of the Toxicity Monitoring Rule
True toxicity rate
0.2
0.3
0.4
0.5
0.6


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Early stop probability
0.014
0.096
0.345
0.716
0.939
Average sample size
39.6
37.3
31.0
21.3
13.5
At progression, patients on the control arm will be offered treatment with Zotiraciclib (TG02) 
in combination with continued treatment with TMZ.  If an effective salvage regimen, this may 
impact the secondary OS endpoint, but will not affect the primary endpoint of the study. The 
maximum number is 80 patients.
Statistical Analysis Plan
We will use descriptive statistics to summarize the demographic and clinical characteristics of 
patients.  We will tabulate adverse events by grade by dose level and overall. For the cohort 
expansion and phase II component, we will estimate the proportion of patients with response 
with 95% exact binomial confidence intervals, and use descriptive statistics to summarize 
response duration.  We will estimate PFS/OS with the Kaplan-Meier product limit estimator. 
Log-rank test will be used to compare the PFS/OS between Zotiraciclib (TG02)+TMZ and 
TMZ.
Changes of symptom burden (i.e., MDASI-BT) through study time points will be assessed by 
paired t-tests and linear mixed model. In the mixed model, subject-specific random intercept 
will be used to account for within-subject correlation, and measurement time will be included 
as a covariate. A sample size of 40 patients has 80% power to detect an effect size of 0.454 
between time points using a two-tailed test with an alpha of 0.05. The two-sample t-test and 
linear mixed model will be used to evaluate differences in symptom burden using the 
MDASI-BT between Zotiraciclib (TG02) plus TMZ and TMZ. Cox proportional hazard 
model will be used to evaluate the relationship between MDASI-BT and disease progression. 
Logistic regression will be used to evaluate the relationship between MDASI-BT and 
tolerance to treatment.
Treatment effects will be evaluated by advanced MRI imaging study. Perfusion and diffusion –
based MRI parameters, including but not restricted to blood volume, blood flow mean and 
median Apparent Diffusion Coefficient (ADC) value will be analysed. Results will be 
summarized. The mean and median value at different time points will be tabulated. Changes in 
such parameters will be analysed for statistical significance and correlate with the disease status.  
10.2.1 Patient Reported Outcomes
Received MDASI-BT form will be checked versus the timing schedule and considered as valid if 
they fall within ten days of the scheduled assessment window.  Compliance rates will be 
calculated as the number of received valid forms over the number of expected forms. Differences 
between groups in compliance will be tested by use of Fisher’s exact test at every time point.
We will use descriptive statistics to describe how patients rate symptom severity and interference 
with function at each time point.  Error bar graphs for each of the symptoms will be constructed 
at each time point.  The proportion of patients rating their symptoms to be 5 or greater (on a 0-10 
scale) will also be reported.  We will construct individual patient profiles for each of the selected 
symptoms to describe the individual patients’ patterns of change over time. We will calculate the 
mean symptom severity, and mean symptom interference at the time of clinical evaluation. 
Estimates of differences in the mean symptom severity and mean symptom interference between 
responders and non-responders will be estimated in the intent to treat population.  All patients 


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with at least one valid questionnaire will be included in the analyses.  Questionnaires completed 
at study registration will be considered baseline.  All questionnaire data received after 
randomization will be used in the primary analyses.
Differences of at least 2 points will be classified as the minimum clinically meaningful change in 
the symptom severity and symptom interference measures. For example, an increase of 2 points 
or more would mean a moderate improvement, whereas a decrease of 2 points or more would be 
interpreted as moderate worsening. For individual symptoms, a rise in a symptom score means 
deterioration, whereas a reduced score means improvement of the specific symptom.
11 COLLABORATIVE AGREEMENTS 
11.1 AGREEMENT TYPE
The study agent, Zotiraciclib (TG02) is provided by Adastra Pharmaceuticals, Inc. under a 
Clinical Trials Agreement (CTA #01007-16). Results or study data may be communicated to 
CTA partner, Adastra Pharmaceuticals, Inc. according to the terms of the NIH- Advanced 
Accelerator Applications SA CTA. There is an executed Material Transfer Agreement 
(MTA#40216-15) with Adastra Pharmaceuticals.
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
This study was designed to include women and minorities but was not designed to measure 
differences of intervention effects.  Males and females will be recruited with no preference to 
gender.  No exclusion to this study will be based on race.  Minorities will actively be recruited to 
participate.
12.2 PARTICIPATION OF CHILDREN
Because no dosing or adverse event data are currently available on the use of TMZ in 
combination with Zotiraciclib (TG02) in subjects <18 years of age, children are excluded from 
this study.
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (a potential for reduction in their tumor volume, which may or may not 
have favorable impact on symptoms and/or survival), all subjects will be offered the opportunity 
to fill in their wishes for research and care, and assign a substitute decision maker on the NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 


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capacity to appoint a surrogate.  For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for 
appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed.
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
12.4.1 The primary risk to patients participating in this research study is from toxicity of the 
Zotiraciclib (TG02) and TMZ as described in the protocol. 
12.4.2 Alternative Approaches or Treatments
Patients will be consented verbally and in writing regarding the risks and benefits of this trial, the 
treatment requirements, and alternative approaches to entering on this trial.  
12.4.3 Procedure for Protecting Against or Minimizing any Potential Risks
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity. This study may involve risks to patients, which are currently unforeseeable. All patients 
will have blood tests, examinations and scans as described in the study calendar (Section 3.8).  
Patients will also be required to have a local physician to provide long-term care and to monitor 
for complications.  If patients suffer any physical injury as a result of the participation in this 
study, immediate medical treatment is available at the Clinical Center, National Cancer Institute, 
Bethesda, Maryland. Although no compensation is available, any injury will be evaluated and 
treated in keeping with the benefits or care to which patients are entitled under applicable 
regulations.
12.4.4 Provisions for Monitoring Data Collection to Ensure Safety of Subjects
As information is gathered from this trial, clinical results will be shared with patients as they 
become available. Laboratory and clinical data will be frequently gathered and any new 
significant finding(s) found during the course of the research, which may affect a patient’s 
willingness to participate further, will be explained. Confidentiality of information concerning 
participants will be maintained, including in all publications and presentations resulting from this 
study.  Names of participants and/or material identifying participants will not be released without 
permission, except as such release is required by law.  Records at the National Cancer Institute 
are maintained according to current legal requirements, and are made available for review, as 
required by the Food and Drug Administration or other authorized users, only under the 
guidelines established by the Federal Privacy Act.
12.5 RISKS/BENEFITS ANALYSIS
12.5.1 Benefits
The potential benefit to a patient on this study is a reduction in the bulk of their tumor and 
improvement in cancer lesions, which may or may not have favorable impact on symptoms 
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12.5.2 Risks
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or this protocol document.  Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents.
12.5.3 MR Imaging with gadolinium
The MRIs to be done in this study will involve contrast.  The risks associated with MRIs and 
contrast are discussed in the consent form.
Although MR imaging with gadolinium has been used as part of the standard care for patients 
with high grade gliomas, long term toxicities of gadolinium as a consequence of gadolinium 
accumulation in the body has been reported. All investigators will ascertain the MR imaging 
history of all prospective study participants to determine the extent of prior exposure to 
gadolinium contrast.  Radiology will be consulted if there is a history of repeated gadolinium 
exposure.
12.5.4 Risks/Benefits Analysis
Given the potential benefits and the efforts to minimize risk with the administration of this 
combination, this protocol involves greater than minimal risk, but presents the potential for direct 
benefit to individual subjects, including those able to consent as well as those that may lose the 
capacity to do so over the course of the trial.
12.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided to the participant for review prior to 
consenting.  A designated study investigator will carefully explain the procedures and tests 
involved in this study, and the associated risks, discomforts and benefits. In order to minimize 
potential coercion, as much time as is needed to review the document will be given, including an 
opportunity to discuss it with friends, family members and/or other advisors, and to ask questions 
of any designated study investigator. A signed informed consent document will be obtained prior 
to entry onto the study.
12.6.1 The initial consent process as well as re-consent, when required, may take place in person 
or remotely (e.g., via telephone or other NIH approved remote platforms)  per discretion 
of the designated study investigator and with the agreement of the participant/consent 
designee(s).  Whether in person or remote, the privacy of the subject will be maintained. 
Consenting investigators (and participant/consent designee, when in person) will be 
located in a private area (e.g., clinic consult room). When consent is conducted remotely, 
the participant/consent designee will be informed of the private nature of the discussion 
and will be encouraged to relocate to a more private setting if needed.  Request for 
Waiver of Consent for Screening Activities
Prior to the subject signing the consent for this study pre-screening activities listed in section 
2.2.1 may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects.  A waiver will not adversely affect the rights and welfare of the subjects given that the 


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activities are only intended to determine suitability for screening for participation in research 
protocols.  These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources.  The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening.
13 PHARMACEUTICAL INFORMATION 
13.1 TEMOZOLOMIDE (TEMODAR®; METHAZOLASTONE)
For more information, please refer to the Package Insert.
13.1.1 Source 
Temozolomide will be purchased from commercial sources to the NIH CC Pharmacy.
13.1.2 Formulation and preparation 
Temozolomide Capsules are available in 5-mg, 20-mg, 100-mg, 140-mg, 180-mg, and 250- mg 
strengths. The capsules contain a white capsule body with a color cap, and the colors vary based 
on the dosage strength. 
Each strength of TEMODAR must be dispensed in a separate vial or in its original package (one 
strength per one container). Follow the instructions below: Based on the dose prescribed, 
determine the number of each strength of TEMODAR capsules that are needed. Label each 
container with the appropriate number of capsules to be taken each day. Dispense to the patient, 
making sure each container lists the strength (mg) per capsule and that he or she understands to 
take the appropriate number of capsules of TEMODAR from each package or vial to equal the 
total daily dose prescribed by the physician. TEMODAR is store at 25°C, excursions permitted 
to 15-30°C.
13.1.3 Contraindications
There are no dietary restrictions for patients taking TEMODAR. TEMODAR may affect 
testicular function, so male patients should exercise adequate birth control measures. 
TEMODAR may cause birth defects. Female patients should avoid becoming pregnant while 
receiving this drug. Women who are nursing prior to receiving TEMODAR should discontinue 
nursing. It is not known whether TEMODAR is excreted into breast milk. Because many drugs 
are excreted in human milk, and because of the potential for serious adverse reactions in nursing 
infants and tumorigenicity shown for temozolomide in animal studies, a decision should be made 
whether to discontinue nursing or to discontinue the drug, taking into account the importance of 
TEMODAR to the mother.
13.1.4 Administration procedures
Patients should take each day’s dose with a full glass of water at the same time each day. Taking 
the medication on an empty stomach or at bedtime may help ease nausea. If patients are also 
taking anti-nausea or other medications to relieve the side effects associated with TEMODAR, 


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they should be advised to take these medications 30 minutes before they take TEMODAR. 
Temozolomide causes the rapid appearance of malignant tumors in rats. Patients SHOULD NOT 
open or split the capsules. If capsules are accidentally opened or damaged, rigorous precautions 
should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous 
membranes. The medication should be kept away from children and pets. The TEMODAR 
capsules should be swallowed whole and NEVER CHEWED.
13.1.5 Side Effects
The most common adverse reactions (≥10% incidence) are: alopecia, fatigue, nausea, vomiting, 
headache, constipation, anorexia, convulsions, rash, hemiparesis, diarrhea, asthenia, fever, 
dizziness, coordination abnormal, viral infection, amnesia, and insomnia. The most common 
Grade 3 to 4 hematologic laboratory abnormalities (≥10% incidence) that have developed 
during treatment with temozolomide are: lymphopenia, thrombocytopenia, neutropenia, and 
leukopenia. 
The adverse reaction from clinical trials that are conducted in different patient population are 
summarized as following:
Newly Diagnosed Glioblastoma: During the concomitant phase (TEMODAR+radiotherapy), 
adverse reactions including thrombocytopenia, nausea, vomiting, anorexia, and constipation 
were more frequent in the TEMODAR+RT arm. The incidence of other adverse reactions was 
comparable in the two arms. The most common adverse reactions across the cumulative
TEMODAR experience were alopecia, nausea, vomiting, anorexia, headache, and constipation. 
Forty-nine percent (49%) of patients treated with TEMODAR reported one or more severe or 
life-threatening reactions, most commonly fatigue (13%), convulsions (6%), headache (5%), and 
thrombocytopenia (5%). Overall, the pattern of reactions during the maintenance phase was
consistent with the known safety profile of TEMODAR. Myelosuppression (neutropenia and 
thrombocytopenia), which is a known dose-limiting toxicity for most cytotoxic agents, including 
TEMODAR, was observed. When laboratory abnormalities and adverse reactions were 
combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were 
observed in 8% of the patients, and Grade 3 or Grade 4 platelet abnormalities, including 
thrombocytopenic reactions, were observed in 14% of the patients treated with TEMODAR.
Refractory Anaplastic Astrocytoma: The incidence of adverse reactions in the 158 patients in 
the anaplastic astrocytoma study for whom data are available. In the absence of a control group, 
it is not clear in many cases whether these reactions should be attributed to temozolomide or the 
patients’ underlying conditions, but nausea, vomiting, fatigue, and hematologic effects appear to 
be clearly drug-related. The most frequently occurring adverse reactions were nausea, vomiting,
headache, and fatigue. The adverse reactions were usually NCI Common Toxicity Criteria (CTC) 
Grade 1 or 2 (mild to moderate in severity) and were self-limiting, with nausea and vomiting 
readily controlled with anti-emetics. The incidence of severe nausea and vomiting (CTC Grade 3 
or 4) was 10% and 6%, respectively. Myelosuppression (thrombocytopenia and neutropenia) was 
the dose-limiting adverse reaction. It usually occurred within the first few cycles of therapy and 
was not cumulative. Myelosuppression occurred late in the treatment cycle and returned to 


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normal, on average, within 14 days of nadir counts. The median nadirs occurred at 26 days for 
platelets (range: 21-40 days) and 28 days for neutrophils (range: 1-44 days). Only 14%
(22/158) of patients had a neutrophil nadir and 20% (32/158) of patients had a platelet nadir, 
which may have delayed the start of the next cycle. Less than 10% of patients required 
hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression.
In clinical trial experience with 110 to 111 women and 169 to 174 men (depending on 
measurements), there were higher rates of Grade 4 neutropenia (ANC less than 500 cells/μL) and 
thrombocytopenia (less than 20,000 cells/μL) in women than men in the first cycle of therapy 
(12% vs. 5% and 9% vs. 3%, respectively). In the entire safety database for which hematologic 
data exist (N=932), 7% (4/61) and 9.5% (6/63) of patients over age 70 experienced Grade 4 
neutropenia or thrombocytopenia in the first cycle, respectively. For patients less than or equal to 
age 70, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia 
in the first cycle, respectively. Pancytopenia, leukopenia, and anemia have also been reported.
13.2 ZOTIRACICLIB (TG02) 
13.2.1 Description of Zotiraciclib (TG02) Citrate
The chemical name for Zotiraciclib (TG02) citrate is (16E)-14-Methyl-20-oxa-5,7,14,26-tetraaza-
tetracyclol[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene − citric 
acid. The molecular formula of Zotiraciclib (TG02) citrate is C23H24N4O  C6H8O7 and it has a 
molecular weight of 564.58 (TG02 citrate salt) and 372.46 (TG02 base). 
The structure is as follows:
 TG02 Citrate
Trade name
Zotiraciclib citrate 
Manufacturer
Adastra Pharmaceuticals, Inc.
Strength (mg)
50, 150
Dosing 
instructions
Take appropriate number of capsules with 8oz. water while fasting (i.e., at least 1 
hour before or 2 hours after a meal). Capsules should not be crushed or broken for 
administration.
Route
Oral
Dosage form
Capsule
Storage
Store at 25°C (77°F); excursions permitted 15°C to 30°C (59°F to 86°F)


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13.2.2 Source 
Zotiraciclib (TG02) is an investigational agent. The IND holder is the NCI Center for Cancer 
Research. Adastra Pharmaceutical, Inc. will provide Zotiraciclib (TG02) citrate capsules for this 
protocol.
13.2.3 Toxicity 
All toxicities observed in patients are from the data provided in the Investigators Brochure 
Version 6. All data are derived from clinical studies that are summarized in the table 6 in Section 
1. 
11.2.3.1 Single agent Zotiraciclib (TG02) in Acute Leukemia Patients
Fifty-five acute leukemia patients were evaluated for the safety and efficacy of single agent 
Zotiraciclib (TG02). 96% (53/55) patients experienced Treatment Emergent Adverse Events 
(TEAE). Most frequently reported TEAEs (43/55 patients 78%) occurred in the System Organ 
Class of Gastrointestinal Disorders. They were also frequently reported in the following System 
Oran Classes: General Disorders and Administration Site Conditions (23/55 patients, 42%), 
Metabolism and Nutrition Disorders (22/55 patients, 40%), Nervous system Disorders 
(17/55patients, 31%), Respiratory, Thoracic and Mediastinal Disorders (14/55 patients, 25%), 
and Skin and Subcutaneous Tissue Disorders (12/55 patients, 22%).
The most frequently reported TEAEs were as follows: nausea (32/55 patients, 58%), vomiting 
(21/55 patients 38%), fatigue (15/55 patients, 27%) and diarrhea, decreased appetite and 
abdominal pain (13/55 patients each, 24%).
Thirty-nine patients (39/55 patients, 71%) had ≥1 treatment-related TEAEs. Five patients (9%) 
experienced grade 5/fatal TEAE and all five were assed as unrelated to the study drug by the 
investigator. Three patients (5%) had grade 4/life threatening TEAE, including hyperglycemia, 
cardio-respiratory arrest and enterococcal sepsis. All events were assed as unrelated to the study 
drug. The most commonly reported grade 3TEAEs were fatigue (11%) and nausea (7%).
When TEAEs were analyzed by their maximum severity, regardless of causality, five acute 
leukemia patients (5/55 [9%]) who were administered single agent Zotiraciclib (TG02) 
experienced a Grade 5/fatal TEAE (Schedule A, 3/27 patients [11%]; Schedule B, 2/22 [9%]; 
Schedule D, 0/6 [0%]). The Preferred Terms for the Grade 5 TEAEs were pneumonia (2 
patients), sepsis, intracranial hemorrhage, and cardio-respiratory arrest. All five events were 
assessed as unrelated to study drug by the investigator. 
Three acute leukemia patients (3/55 [5%]) administered single agent Zotiraciclib (TG02) 
experienced a Grade 4/life-threatening TEAE (Schedule A, 1/27 patients [4%]; Schedule B, 2/22 
patients [9%]; Schedule D, 0/6 patients [0%]). The Preferred Terms for the Grade 4 TEAEs were 
hyperglycemia, cardio-respiratory arrest and enterococcal sepsis. All events were assessed as 
unrelated to study drug by the investigator. The most frequently reported Grade 3 TEAEs were 
fatigue (6/55 patients [11%]) and nausea (4/55 patients [7%]) occurring on Schedules A and B. 
No Grade 3 or higher fatigue, nausea, vomiting or diarrhea occurred on Schedule D.
Serious Adverse Events: Fifteen acute leukemia patients (15/55 [27%]) administered single agent 
Zotiraciclib (TG02) experienced ≥1 SAE (Schedule A, 5/27 patients [19%]; Schedule B, 8/22 
patients [36%]; Schedule D 2/6 patients [33%]). No individual body system had an incidence of 


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SAEs of ≥10%. No significant differences were noted between schedules. Four patients (4/55 
patients [7%]) experienced ≥ 1 serious suspected adverse reaction considered related to study 
drug by the investigator (Schedule A, 1/27 patients [4%]; Schedule B, 3/22 patients [14%]; 
Schedule D, (0/6 patients [0%]). 

Patient 03-002 (Schedule A, 10 mg) experienced two occurrences of related nausea 
resulting in hospitalization and three occurrences of related vomiting resulting in 
hospitalization (2 of the occurrences occurred concomitantly with the related nausea). 
Study drug was interrupted. The patient recovered without sequelae from all events. 

Patient 03-018 (Schedule B, 50 mg) experienced related vomiting that resulted in 
hospitalization. Study drug was interrupted due to this event.

Patient 01-053 (Schedule B, 150 mg) experienced two occurrences of related fatigue 
which required hospitalization. The first occurrence of fatigue occurred during Cycle 1 
and was considered a DLT. Study drug was withheld and resumed at the start of Cycle 2 
at 100 mg. The second occurrence of fatigue was in Cycle 2. Study drug was held and 
resumed at the start of Cycle 3 at 100 mg on Days 1-3 and 8-10, a reduced schedule. The 
patient came off study at the end of Cycle 4 for progressive disease. This patient also 
experienced the non-related SAE of respiratory syncytial virus infection. The patient 
recovered without sequelae from all events.

Patient 03-057 (Schedule B, 150 mg) experienced the related SAE of severe failure to 
thrive, which required hospitalization. Study drug was interrupted and subsequently 
discontinued the study due to this event. The patient recovered without sequelae from the 
SAE.
Study Drug Discontinuations Due to TEAEs: Seven acute leukemia patients (7/55 [13%]) 
administered single agent Zotiraciclib (TG02) discontinued study drug due to a TEAE (Schedule 
A, 3/27 [11%]; Schedule B, 3/22 patients [14%]; Schedule D 1/6 patients [17%]). No individual 
body system had an incidence of SAEs of ≥10%. No significant differences were noted between 
schedules. The Preferred Terms for these TEAEs were vomiting, pneumonia, maculopapular 
rash, dyspepsia, nausea, fatigue and balance disorder (in one patient) and stomatitis.
Deaths: Five patients (5/55 [9%]) experienced a Grade 5/ fatal TEAE (Schedule A, 3/27 patients 
[11.1%]; Schedule B, 2/22 patients [4.5%]; Schedule D, (0/6 patients [0%]).

Patient 01-026 (Schedule A, 50 mg Zotiraciclib (TG02)) died of pneumonia. The patient 
had discontinued study drug and the event occurred during the follow-up period. The 
event was assessed as not related to study drug by the investigator.

Patient 01-044 (Schedule A, 70 mg Zotiraciclib (TG02)) died of pneumonia. The event 
was assessed as not related to study drug by the investigator.

Patient 03-015 (Schedule A, 30 mg Zotiraciclib (TG02)) died due to sepsis and refractory 
AML. The patient had discontinued study drug and the event occurred during the follow-
up period. The event was assessed as not related to study drug.

Patient 01-059 (Schedule B, 150 mg Zotiraciclib (TG02)) died due to intracranial 
hemorrhage. The patient had discontinued study drug and the event occurred during the 
follow-up period. The event was assessed as not related to study drug by the investigator.


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
Patient 03-049 (Schedule B, 100 mg Zotiraciclib (TG02) died due to cardiopulmonary 
arrest. The event was assessed as not related to study drug by the investigator.
11.2.3.2 Single agent Zotiraciclib (TG02) in Multiple Myeloma (MM) Patients
Eighteen multiple myeloma patients administered single agent Zotiraciclib (TG02) were 
evaluated for safety. All patients had discontinued from the study as of the data cut-off date. The 
reasons for discontinuation were withdrawal of consent (7/18 patients [39%]), progressive 
disease (7/18 patients [39%]), other (2/18 patients [11%]), adverse event (1/18 patients [6%]) 
and investigator decision (1/18 patients [6%]).  Most frequently reported TEAEs (17/18 patients 
94%) occurred in the System Organ Class of Gastrointestinal Disorders. The most frequently 
reported TEAEs were as follows: diarrhea (10/18 patients, 56%), nausea and fatigue (9/18 
patients, 50%), vomiting and constipation (7/18 patients each, 39%), hypophosphatemia (6/18 
patients, 33%), decreased appetite and hypokalemia (5/18 patients each, 28%). The incidence of 
the TEAEs constipation, hypophosphatemia, decreased appetite and hypokalemia did not differ 
significantly between the dosing schedules. Diarrhea, fatigue, nausea and vomiting occurred 
more frequently on Schedule G than Schedule C. Higher doses were administered in Schedule G 
(100 and 150 mg) than in Schedule C (50 and 70 mg). Fatigue and vomiting occurred more 
frequently on Schedule G than Schedule H. A less dose-intense schedule was administered in 
Schedule H (BIW for 3 weeks) than in Schedule G (TIW for 3 weeks) although the number of 
patients in Schedule H is small. 
• Diarrhea: Schedule C, 2 pts [33%]; Schedule G, 6 pts [78%]; Schedule H, 2 pts [67%] 
• Fatigue: Schedule C, 1 pts [17%]; Schedule G, 7 pts [77%]; Schedule H, 1 pt [33%] 
• Nausea: Schedule C, 1 pts [17%]; Schedule G, 6 pts [67%]; Schedule H, 2 pts [67%] 
• Vomiting: Schedule C, 0 pts [0%]; Schedule G, 6 pts [67%]; Schedule H, 1 pt [33%]
Fifteen patients (15/18 patients, 83%) had ≥1 treatment-related TEAEs. One patients (17%) 
experienced grade 5/fatal TEAE and the event was assed as unrelated to the study drug by the 
investigator. Five patients (28%) had grade 4/life threatening TEAE, including GI hemorrhage, 
thrombocytopenia, neutrophil count decreased, platelet count reduced and hyperuricemia. All 
events were assed as unrelated to the study drug. The most commonly reported grade 3TEAEs 
were hypophosphatemia (28%).
Serious Adverse Events: Five multiple myeloma patients (5/18 patients [28%]) administered 
single agent Zotiraciclib (TG02) experienced ≥1 SAE (Schedule C, 4/6 patients [67%]; 
Schedule G, 0/9 patients [0%]; Schedule H, 1/3 patients [33%]). Each of the SAEs (GI 
hemorrhage and respiratory failure [in the same patient], fatigue, pneumonia, bone pain and 
pneumonia streptococcal) were experienced by 1 patient each. One patient (1/18 [6%]) 
experienced a serious suspected adverse reaction considered related to study drug by the 
investigator. Patient 02-058 (Schedule C, 70 mg) experienced Grade 3 related fatigue resulting in 
hospitalization. This event was considered a DLT. Study drug was interrupted and then 
discontinued due to this event. The patient recovered without sequelae from the event.
Study Drug Discontinuations Due to TEAEs: Two multiple myeloma patients (2/18 [11%]) 
administered single agent Zotiraciclib (TG02) discontinued study drug due to a TEAE (Schedule 
C, 2/6 patients [33%], Schedules G and H (0/12 patients [0%]). One patient discontinued study 
drug due to fatigue that was assessed by the investigator as related to study drug and a DLT. The 


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patient recovered without sequelae from the event. The second patient discontinued study drug 
due to musculoskeletal bone pain that was assessed by the investigator as not related to study 
drug. The patient recovered with sequela from the event.
Deaths: One multiple myeloma patient (1/18 [16.7%]) administered single agent Zotiraciclib 
(TG02) experienced Grade 5 fatal respiratory failure. Patient 05-045 (Schedule C, 50 mg) died of 
respiratory failure. The event was assessed as not related to study drug by the investigator and 
related to the patient’s underlying disease state (i.e., progressive disease).
11.2.3.3 Single Agent Zotiraciclib (TG02) in Chronic Lymphocytic Leukemia (CLL) patients
Only eight CLL patients administered single agent Zotiraciclib (TG02) were evaluated for the 
drug safety. Seven of them (88%) experienced ≥1 TEAEs.
Most frequently reported TEAEs (17/18 patients 94%) occurred in the System Organ Class of 
Gastrointestinal Disorders. The most frequently reported TEAEs were as follows: nausea (6/8 
patients, 75%), diarrhea (4/8 patients, 50%), vomiting, constipation, cough and dyspnea (3/8 
patients each, 38%). Four patients developed treatment –related TEAEs with nausea being the 
most frequently reported treatment –related TEAEs. No dose-related trends were noted due to the 
small number of patients. 
No CLL patients experienced a Grade 5/ fatal TEAE. Three CLL patients (3/8 patients [38%]) 
administered single agent Zotiraciclib (TG02) experienced Grade 4/ Life-Threatening TEAEs. 
Preferred Terms for the Grade 4 TEAEs were sepsis and thrombocytopenia (1 patient), sepsis, 
pneumonia staphylococcal and staphylococcal bacteremia (1 patient), thrombocytopenia, 
neutropenia and hypotension. The events of sepsis and thrombocytopenia occurring in the same 
patient were assessed as related to study drug by the investigator. The other Grade 4 TEAEs 
were assessed as unrelated to study drug by the investigator. No Grade 3 TEAE was experienced 
by more than one patient (1/8 [13%]). 
Serious Adverse Events: Three CLL patients (3/8 [38%]) administered single agent Zotiraciclib 
(TG02) experienced ≥ 1 SAE. The body systems in which the SAEs occurred were Infections 
and Infestations (2/8 patients [25%]), Blood and Lymphatic System Disorders (1/8 patients 
[13%]) and Psychiatric Disorders (1/8 patients [13%]). Only the SAE of sepsis was experienced 
by more than one patient (2/8 patients [25%]). Two CLL patients (2/8 [25%]) experienced a 
serious suspected adverse reaction considered by the investigator to be related to study drug. 

Patient 200-005 (Schedule A, 70 mg) experienced related confusion state resulting in 
hospitalization. This event was Grade 2 and did not meet the criteria for a DLT. Study 
drug was interrupted. The patient recovered without sequelae from the event. 

Patient 400-010 (Schedule A, 100 mg) experienced related sepsis, thrombocytopenia and 
febrile neutropenia. Sepsis was considered a DLT. Study drug was interrupted and 
restarted at 70 mg, a reduced dose. 
Study Drug Discontinuations Due to TEAEs: One CLL patient (1/8 [13%]) administered single 
agent Zotiraciclib (TG02) discontinued study drug due to a TEAE. Patient 100-003 discontinued 
study drug due to pneumonia staphylococcal, staphylococcal abscess and staphylococcal 
bacteremia. The patient recovered without sequelae from the events.
Deaths: No CLL subjects administered single agent Zotiraciclib (TG02) died on study. 


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13.2.4 Formulation and preparation 
Zotiraciclib (TG02) citrate capsules will be provided as formulated dry powder blend containing 
Zotiraciclib (TG02) citrate in hard gelatin capsules. Capsule strengths are expressed as Zotiraciclib 
(TG02). The formulation compositions and brief descriptions of the capsule products are shown in 
the following table. The capsule strengths (50 and 150mg) are distinguished by size and color, and 
the actual dose of Zotiraciclib (TG02) has been corrected for citrate salt (e.g., 50mg Zotiraciclib 
(TG02) is 76mg Zotiraciclib (TG02) citrate). 
Table 17:  Description of Zotiraciclib (TG02) Citrate Capsules
Strength (mg)
50mg
(TG02-50)
150mg
(TG02-150)
Capsule size
2
0
Capsule color
Swedish orange
Light blue
Ingredients (mg/capsule)
TG02 citrate
76.0
228.0
Silicified microcrystalline 
cellulose, NF
109.9
88.2
Hypromellose 2910, USP
10.5
18.0
Crospovidone, NF
10.5
18.0
Magnesium stearate, NF
1.1
1.8
13.2.5 Stability and Storage 
Zotiraciclib (TG02) citrate capsules should be stored at room temperature 25°C (77°F), with 
excursions permitted at 15°C to 30°C (59°F to 86°F).
13.2.6 Administration procedures
Patients are instructed to swallow the appropriate number of capsules whole with 8oz. of water 
while fasting (i.e., at least 1 hour before or 2 hours after a meal). Capsules should not be crushed or 
broken for administration. 
13.2.7 Incompatibilities  
Please refer to section 13.1. A copy of the drug brochure will be provided to the Pharmacy 
Department. 


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Yung, W.K., et al., Multicenter phase II trial of temozolomide in patients with anaplastic 
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Louis, D.N., Molecular pathology of malignant gliomas. Annu Rev Pathol, 2006. 1: p. 
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Li, J., et al., PTEN, a putative protein tyrosine phosphatase gene mutated in human 
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Fujisawa, H., et al., Acquisition of the glioblastoma phenotype during astrocytoma 
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Goh, K.C., et al., TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 
with potent anti-leukemic properties. Leukemia, 2012. 26(2): p. 236-43.
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Loyer, P., et al., Role of CDK/cyclin complexes in transcription and RNA splicing. Cell 
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Atkinson, J.M., et al., An integrated in vitro and in vivo high-throughput screen identifies 
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Nechaev, S. and K. Adelman, Pol II waiting in the starting gates: Regulating the 
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Lam, L.T., et al., Genomic-scale measurement of mRNA turnover and the mechanisms of 
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Carter, B.Z., et al., Small-molecule XIAP inhibitors derepress downstream effector 
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Quinn, B.A., et al., Targeting Mcl-1 for the therapy of cancer. Expert Opin Investig 
Drugs, 2011. 20(10): p. 1397-411.


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downregulation of the anti-apoptotic protein Mcl-1. Neuro Oncol, 2011. 13(11): p. 1202-
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apoptosis (XIAP) in human malignant glioma. Cell Death Differ, 1999. 6(4): p. 370-6.
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432-45.
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Barboric, M., et al., NF-kappaB binds P-TEFb to stimulate transcriptional elongation by 
RNA polymerase II. Mol Cell, 2001. 8(2): p. 327-37.
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Bhat, K.P., et al., Mesenchymal differentiation mediated by NF-kappaB promotes 
radiation resistance in glioblastoma. Cancer Cell, 2013. 24(3): p. 331-46.
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Herms, J.W., et al., c-myc oncogene family expression in glioblastoma and survival. Surg 
Neurol, 1999. 51(5): p. 536-42.
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Malumbres, M. and M. Barbacid, Cell cycle, CDKs and cancer: a changing paradigm. 
Nat Rev Cancer, 2009. 9(3): p. 153-66.
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Simone, C. and A. Giordano, New insight in cdk9 function: from Tat to MyoD. Front 
Biosci, 2001. 6: p. D1073-82.
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Huang, C.H., et al., CDK9-mediated transcription elongation is required for MYC 
addiction in hepatocellular carcinoma. Genes Dev, 2014. 28(16): p. 1800-14.
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Alvarez-Fernandez, S., et al., Potent antimyeloma activity of a novel ERK5/CDK 
inhibitor. Clin Cancer Res, 2013. 19(10): p. 2677-87.
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Gunther, W., et al., Temozolomide induces apoptosis and senescence in glioma cells 
cultured as multicellular spheroids. Br J Cancer, 2003. 88(3): p. 463-9.
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Gratas, C., et al., Bak and Mcl-1 are essential for Temozolomide induced cell death in 
human glioma. Oncotarget, 2014. 5(9): p. 2428-35.
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Shiraishi, S., et al., Influence of p53 mutations on prognosis of patients with 
glioblastoma. Cancer, 2002. 95(2): p. 249-57.
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Oren, M. and V. Rotter, Mutant p53 gain-of-function in cancer. Cold Spring Harb 
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Trent, J., et al., Evidence for rearrangement, amplification, and expression of c-myc in a 
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Cancer Genome Atlas Research, N., Comprehensive genomic characterization defines 
human glioblastoma genes and core pathways. Nature, 2008. 455(7216): p. 1061-8.
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Tohma, Y., et al., PTEN (MMAC1) mutations are frequent in primary glioblastomas (de 
novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol, 1998. 57(7): p. 
684-9.
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Austin, M. and S.J. Cook, Increased expression of Mcl-1 is required for protection 
against serum starvation in phosphatase and tensin homologue on chromosome 10 null 


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mouse embryonic fibroblasts, but repression of Bim is favored in human glioblastomas. J 
Biol Chem, 2005. 280(39): p. 33280-8.
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localization of cyclin D1. Mol Cell Biol, 2003. 23(17): p. 6139-49.
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Siegel, D.S., et al., A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in 
patients with relapsed and refractory multiple myeloma. Blood, 2012. 120(14): p. 2817-
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Bower, M., et al., Multicentre CRC phase II trial of temozolomide in recurrent or 
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Bocangel, D.B., et al., Multifaceted resistance of gliomas to temozolomide. Clin Cancer 
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Hirose, Y., M.S. Berger, and R.O. Pieper, p53 effects both the duration of G2/M arrest 
and the fate of temozolomide-treated human glioblastoma cells. Cancer Res, 2001. 61(5): 
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Tolcher, A.W., et al., Marked inactivation of O6-alkylguanine-DNA alkyltransferase 
activity with protracted temozolomide schedules. Br J Cancer, 2003. 88(7): p. 1004-11.
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Han, S.J., et al., Phase II trial of 7 days on/7 days off temozolmide for recurrent high-
grade glioma. Neuro Oncol, 2014. 16(9): p. 1255-62.
42.
Perry, J.R., et al., Phase II trial of continuous dose-intense temozolomide in recurrent 
malignant glioma: RESCUE study. J Clin Oncol, 2010. 28(12): p. 2051-7.
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Armstrong, T.S., et al., Reliability and validity of the M. D. Anderson Symptom 
Inventory-Spine Tumor Module. J Neurosurg Spine, 2010. 12(4): p. 421-30.
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Armstrong, T.S., et al., Validation of the M.D. Anderson Symptom Inventory Brain Tumor 
Module (MDASI-BT). J Neurooncol, 2006. 80(1): p. 27-35.
45.
Liu, S.a.Y., Ying, Bayesian optimal interval designs for phase I clinical trials. Journal of 
the Royal Statistical Society: Series C (Applied Statistics), 2015. 64(3).
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Liu, S. and Y. Yuan, Bayesian optimal interval designs for phase I clinical trials. Journal 
of the Royal Statistical Society: Series C (Applied Statistics), 2015. 64(3): p. 507-523.
47.
Wen, P.Y. and P.W. Marks, Medical management of patients with brain tumors. Curr 
Opin Oncol, 2002. 14(3): p. 299-307.
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Semrad, T.J., et al., Epidemiology of venous thromboembolism in 9489 patients with 
malignant glioma. J Neurosurg, 2007. 106(4): p. 601-8.
49.
Wen, P.Y., et al., Updated response assessment criteria for high-grade gliomas: response 
assessment in neuro-oncology working group. J Clin Oncol, 2010. 28(11): p. 1963-72.
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Thall, P.F., L.H. Wooten, and N.M. Tannir, Monitoring event times in early phase 
clinical trials: some practical issues. Clin Trials, 2005. 2(6): p. 467-78.


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15 APPENDICES
15.1 APPENDIX: PERFORMANCE STATUS CRITERIA
Karnofsky Performance Scale
Percent
Description
100
Normal, no complaints, no evidence of disease.
90
Able to carry on normal activity; minor signs or symptoms of 
disease.
80
Normal activity with effort; some signs or symptoms of disease.
70
Cares for self, unable to carry on normal activity or to do active 
work.
60
Requires occasional assistance, but is able to care for most of his/her 
needs.
50
Requires considerable assistance and frequent medical care.
40
Disabled, requires special care and assistance.
30
Severely disabled, hospitalization indicated.  Death not imminent.
20
Very sick, hospitalization indicated. Death not imminent.
10
Moribund, fatal processes progressing rapidly.
0
Dead.


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15.2 APPENDIX: PREGNANCY & CONTRACEPTION
Pregnancy tests for females of childbearing potential and adequate methods of 
contraception 
A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months).
Pregnancy tests must occur within 14 days prior to initiation of study.  FCBP must have a 
pregnancy test before each new cycle; at discontinuation of Zotiraciclib (TG02) and at Day 
28 post the last dose of Zotiraciclib (TG02).  
Required Pregnancy test: Serum -HCG 
Adequate method of contraception: one highly effective method or more than one of the 
additional methods.
Highly effective methods:

Intrauterine device (IUD)

Hormonal (birth control pills, injections, implants)

Tubal ligation

Partner’s vasectomy

Abstinence
Additional effective methods:

Latex condom

Diaphragm

Cervical Cap


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15.3 APPENDIX: CYP1A2 AND CYP3A4
 Lists including medications and substances known or with the potential to interact with 
the CYP1A2 and CYP3A4 isoenzymes

Known inhibitors of CYP1A2:   
o
Acyclovir
o
fluvoxamine

Known inhibitors of CYP3A4:
o
 Atazanavir
o
Clarithromycin
o
indinavir
o
itraconazole 
o
ketoconazole 
o
nefazodone 
o
nelfinavir 
o
ritonavir 
o
saquinavir
o
telithromycin 

Known inducers of CYP1A2:
o
omeprazole
o
insulin
o
cigarette smoking, 

Known inducers of CYP3A4:
o
rifampin and 
o
carbamazepine 

Sensitive CYP1A2 substrates with narrow therapeutic indices: 
o
theophylline and 
o
tizanidine, 

Sensitive CYP2D6 substrates with narrow therapeutic indices: 
o
thioridazine  
o
tamoxifen 


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15.4 APPENDIX: STUDY FLOW CHART


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15.5 APPENDIX: RANO
Criteria for Response Assessment Incorporating MRI and Clinical Factors


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15.6 APPENDIX: DOSING SCHEDULE FOR BOTH TREATMENTS ARMS FOR PHASE I STUDY


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15.7 APPENDIX: PILL DIARY
Dose-dense arm
Cycle 1
Patient Initials: __________________Patient ID#: __________________Phase___Cycle # 
1:____________
This diary is for you to record that you took the drugs as instructed by your doctor. Please put a 
check mark or your initials after each dose. Please sign this diary at the end of the cycle. Bring the 
diary and all study drug bottles back to your next clinic visit.
TG02
AM
Temozolomide
PM
Zotiraciclib 
 
 
Frequency:
 
Only on Day 1, Day 12, Day 15, Day 26
 
*Cycle 1 only:   extra dose on     D -3
Frequency:  7days ON,   7 days OFF
DAY #
DATE
TIME
DOSE
INITIALS
DAY 
#
DATE
TIME
DOSE
INITIALS
-3 *
 
 
 
 
 
 
 
 
 
 
off day
 
 
 
 
 
 
 
 
 
off day
 
 
 
 
 
 
 
 
1
 
 
 
 
1
 
 
 
 
 
off day
 
 
 
2
 
 
 
 
 
off day
 
 
 
3
 
 
 
 
 
off day
 
 
 
4
 
 
 
 
 
off day
 
 
 
5
 
 
 
 
 
off day
 
 
 
6
 
 
 
 
 
off day
 
 
 
7
 
 
 
 
 
off day
 
 
 
8
off day
 
 
 
 
off day
 
 
 
9
off day
 
 
 
 
off day
 
 
 
10
off day
 
 
 
 
off day
 
 
 
11
off day
 
 
 
12
 
 
 
 
12
off day
 
 
 
 
off day
 
 
 
13
off day
 
 
 
 
off day
 
 
 
14
off day
 
 
 
15
 
 
 
 
15
 
 
 
 
 
off day
 
 
 
16
 
 
 
 
 
off day
 
 
 
17
 
 
 
 
 
off day
 
 
 
18
 
 
 
 
 
off day
 
 
 
19
 
 
 
 
 
off day
 
 
 
20
 
 
 
 
 
off day
 
 
 
21
 
 
 
 


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off day
 
 
 
22
off day
 
 
 
 
off day
 
 
 
23
off day
 
 
 
 
off day
 
 
 
24
off day
 
 
 
 
off day
 
 
 
25
off day
 
 
 
26
 
 
 
 
26
off day
 
 
 
 
off day
 
 
 
27
off day
 
 
 
 
off day
 
 
 
28
off day
 
 
 
My signature signifies that the study drug(s) have been taken as indicated:                                                    
Patient's Signature _________________________________Date: ____________________________      


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Dose Dense Arm
Cycle 2 and beyond
Patient Initials: __________________Patient ID#: __________________Phase____/Cycle #_____ 
____________
This diary is for you to record that you took the drugs as instructed by your doctor. Please put a 
check mark or your initials after each dose. Please sign this diary at the end of the cycle. Bring the 
diary and all study drug bottles back to your next clinic visit.
TG02
AM
Temozolomide
PM
Zotiraciclib 
 
 
Frequency:
 
Only on Day 1, Day 12, Day 15, Day 26
 
*Cycle 1 only:   extra dose on     D -3
Frequency:  7days ON,    7 days OFF
DAY #
DATE
TIME
DOSE
INITIALS
DAY 
#
DATE
TIME
DOSE
INITIALS
1
 
 
 
 
1
 
 
 
 
 
off day
 
 
 
2
 
 
 
 
 
off day
 
 
 
3
 
 
 
 
 
off day
 
 
 
4
 
 
 
 
 
off day
 
 
 
5
 
 
 
 
 
off day
 
 
 
6
 
 
 
 
 
off day
 
 
 
7
 
 
 
 
 
off day
 
 
 
8
off day
 
 
 
 
off day
 
 
 
9
off day
 
 
 
 
off day
 
 
 
10
off day
 
 
 
 
off day
 
 
 
11
off day
 
 
 
12
 
 
 
 
12
off day
 
 
 
 
off day
 
 
 
13
off day
 
 
 
 
off day
 
 
 
14
off day
 
 
 
15
 
 
 
 
15
 
 
 
 
 
off day
 
 
 
16
 
 
 
 
 
off day
 
 
 
17
 
 
 
 
 
off day
 
 
 
18
 
 
 
 
 
off day
 
 
 
19
 
 
 
 
 
off day
 
 
 
20
 
 
 
 
 
off day
 
 
 
21
 
 
 
 
 
off day
 
 
 
22
off day
 
 
 
 
off day
 
 
 
23
off day
 
 
 
 
off day
 
 
 
24
off day
 
 
 
 
off day
 
 
 
25
off day
 
 
 
26
 
 
 
 
26
off day
 
 
 


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off day
 
 
 
27
off day
 
 
 
 
off day
 
 
 
28
off day
 
 
 
My signature signifies that the study drug(s) have been taken as indicated:                                                    
Patient's Signature _________________________________Date: _____________________________   


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Metronomic arm
Cycle 1
Patient Initials: __________________Patient ID#: __________________Phase___/Cycle # 1 
____________
This diary is for you to record that you took the drugs as instructed by your doctor. Please put a check 
mark or your initials after each dose. Please sign this diary at the end of the cycle. Bring the diary and all 
study drug bottles back to your next clinic visit.
TG02
AM
Temozolomide
PM
Zotiraciclib 
 
 
Frequency:
 
Only on Day 1, Day 12, Day 15, Day 26
 
*Cycle 1 only:   extra dose on     D -3
Frequency:  Daily
DAY #
DATE
TIME
DOSE
INITIALS
DAY #
DATE
TIME
DOSE
INITIALS
-3 *
 
 
 
 
 
 
 
 
 
 
off day
 
 
 
 
 
 
 
 
 
off day
 
 
 
 
 
 
 
 
1
 
 
 
 
1
 
 
 
 
 
off day
 
 
 
2
 
 
 
 
 
off day
 
 
 
3
 
 
 
 
 
off day
 
 
 
4
 
 
 
 
 
off day
 
 
 
5
 
 
 
 
 
off day
 
 
 
6
 
 
 
 
 
off day
 
 
 
7
 
 
 
 
 
off day
 
 
 
8
 
 
 
 
 
off day
 
 
 
9
 
 
 
 
 
off day
 
 
 
10
 
 
 
 
 
off day
 
 
 
11
 
 
 
 
12
 
 
 
 
12
 
 
 
 
 
off day
 
 
 
13
 
 
 
 
 
off day
 
 
 
14
 
 
 
 
15
 
 
 
 
15
 
 
 
 
 
off day
 
 
 
16
 
 
 
 
 
off day
 
 
 
17
 
 
 
 
 
off day
 
 
 
18
 
 
 
 
 
off day
 
 
 
19
 
 
 
 
 
off day
 
 
 
20
 
 
 
 
 
off day
 
 
 
21
 
 
 
 
 
off day
 
 
 
22
 
 
 
 
 
off day
 
 
 
23
 
 
 
 
 
off day
 
 
 
24
 
 
 
 
 
off day
 
 
 
25
 
 
 
 
26
 
 
 
 
26
 
 
 
 
 
off day
 
 
 
27
 
 
 
 


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off day
 
 
 
28
 
 
 
 
My signature signifies that the study drug(s) have been taken as indicated:                                                      
Patient's Signature _________________________________Date: _____________________________         


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Metronomic Arm
Cycle 2 and beyond
Patient Initials: __________________Patient ID#: __________________Phase___/Cycle 
#_____________________
This diary is for you to record that you took the drugs as instructed by your doctor. Please put a 
check mark or your initials after each dose. Please sign this diary at the end of the cycle. Bring the 
diary and all study drug bottles back to your next clinic visit.
TG02
AM
Temozolomide
PM
Zotiraciclib 
 
 
Frequency:
 
Only on Day 1, Day 12, Day 15, Day 26
 
*Cycle 1 only:   extra dose on     D -3
Frequency:  Daily
DAY #
DATE
TIME
DOSE
INITIALS
DAY 
#
DATE
TIME
DOSE
INITIALS
1
 
 
 
 
1
 
 
 
 
 
off day
 
 
 
2
 
 
 
 
 
off day
 
 
 
3
 
 
 
 
 
off day
 
 
 
4
 
 
 
 
 
off day
 
 
 
5
 
 
 
 
 
off day
 
 
 
6
 
 
 
 
 
off day
 
 
 
7
 
 
 
 
 
off day
 
 
 
8
 
 
 
 
 
off day
 
 
 
9
 
 
 
 
 
off day
 
 
 
10
 
 
 
 
 
off day
 
 
 
11
 
 
 
 
12
 
 
 
 
12
 
 
 
 
 
off day
 
 
 
13
 
 
 
 
 
off day
 
 
 
14
 
 
 
 
15
 
 
 
 
15
 
 
 
 
 
off day
 
 
 
16
 
 
 
 
 
off day
 
 
 
17
 
 
 
 
 
off day
 
 
 
18
 
 
 
 
 
off day
 
 
 
19
 
 
 
 
 
off day
 
 
 
20
 
 
 
 
 
off day
 
 
 
21
 
 
 
 
 
off day
 
 
 
22
 
 
 
 
 
off day
 
 
 
23
 
 
 
 
 
off day
 
 
 
24
 
 
 
 
 
off day
 
 
 
25
 
 
 
 
26
 
 
 
 
26
 
 
 
 


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
Version Date: 06/01/2020
104
 
off day
 
 
 
27
 
 
 
 
 
off day
 
 
 
28
 
 
 
 
My signature signifies that the study drug(s) have been taken as indicated:                                                    
Patient's Signature _________________________________Date: _____________________________   


Abbreviated Title: Ph I/II TMZ+ TG02 astrocytoma
Version Date: 06/01/2020
105

ICF_001.pdf: 
PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 1 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Jing Wu, MD
STUDY TITLE: 
Phase I Trial of Zotiraciclib (TG02) Plus Dose-Dense or 
Metronomic Temozolomide Followed by Randomized 
Phase II Trial of Zotiraciclib (TG02) plus Temozolomide 
versus Temozolomide alone in Adults with Recurrent 
Anaplastic Astrocytoma and Glioblastoma
STUDY SITE:
NIH Clinical Center
Cohort: Affected Patient
Consent Version:  06/01/2020
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Jing Wu, M.D., PhD   Tel:  240-760-6036 
Email: jing.wu3@nih.gov
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time 
needed to ask any questions and discuss this study with NIH staff, and with your family, friends, 
and personal health care providers. Taking part in research at the NIH is your choice. 
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may 
change your mind and stop participating in the study at any time and for any reason. In either 
case, you will not lose any benefits to which you are otherwise entitled. However, to be seen at 
the NIH, you must be taking part in a study or are being considered for a study. If you do choose 
to leave the study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
This study will test an investigational drug called Zotiraciclib (TG02) citrate. An 
“investigational drug” is a drug that is being tested and is not approved for sale in the 
United States by the Food and Drug Administration (FDA). The purpose of this 
research study is to find out what effects (good and bad) Zotiraciclib (TG02) citrate 
has on you and your cancer. You will also receive temozolomide which is FDA 
approved and commonly used for recurrent high-grade astrocytoma.
This study has two parts: a phase I part and a phase II part. In the phase I part, the main 
purpose is to learn about the safety of the study drug, Zotiraciclib (TG02). The study 
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 2 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
investigators have given Zotiraciclib (TG02) citrate to people in this study and found 
the highest dose of Zotiraciclib (TG02) citrate that people can tolerate when given in 
combination with temozolomide in two different treatment schedules. It was also found 
that one temozolomide treatment schedule was better than the other. However, we want 
to make sure that the highest dose that people tolerated is also the dose you need.  
Providing direct medical benefit to you is not the purpose of this part of the study.
In the phase II part, the  dose of Zotiraciclib (TG02) in combination temozolomide 
chosen in phase 1 will be compared to temozolomide alone. The dosing schedule of 
temozolomide used in this part of the study will depend on the response to each phase I 
part. The purpose of this part of the study is to find out if Zotiraciclib (TG02) citrate in 
combination temozolomide is as effective as temozolomide alone for people with the 
brain tumors.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
We are asking you to be in this study because you have a brain tumor that has 
progressed after your standard treatment.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Up to 152 participants will take part in this study. Up to 72 participants will be enrolled 
in the phase I part and up to 80 participants will be enrolled in the phase II part.
DESCRIPTION OF RESEARCH STUDY
You will also be enrolled in the Neuro Oncology Branch Natural History protocol to 
assess molecular markers of your brain tumor. If you agree to be in this study, we 
will ask you to do the following things:
BEFORE YOU BEGIN THE STUDY
Before you can start this protocol, we will do an evaluation to see if you are eligible to 
participate in this study. You may be enrolled in a screening study to determine your 
eligibility. This will include a physical examination and blood laboratory studies. You 
will also need to have an MRI of the brain if you have not had one in 14 days and an 
EKG will be done. We must also be certain we have complete information about your 
history any past treatments, including surgeries. You will need to provide surgical tissue 
samples from prior surgeries. Women who are capable of having children will have a 
pregnancy test. You cannot take part in this study if you are pregnant.
Any concerns you or your clinician may have can be further explored, and you may be 
referred to a specialist for further evaluation or treatment if necessary.
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 3 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
DURING THE STUDY
You will also complete a questionnaire about the severity of your symptoms and the interference 
these symptoms have in your daily life over the last 24 hours. You will complete this symptom 
burden questionnaire before you start study therapy and whenever you have a CT scan or MRI. 
You will also complete a questionnaire related to symptoms associated with treatment on day 2, 
8, 14, 21, and 28 of each cycle as described in the study visit table below.  These questionnaires 
related to symptoms associated with treatment will not be done for some patients.
PHASE I
If you are found to be eligible to take part in this study, you will receive Zotiraciclib 
(TG02) plus temozolomide by mouth. We need you to keep a diary of when you take the 
temozolomide and the Zotiraciclib (TG02) and any symptoms you may have. The nurse 
will give you a diary form for this purpose. Please bring it along with all of your study 
medication bottles with you to clinic when you come at the end of each cycle, even if 
they are empty.
As indicated above, two schedules of temozolomide in combination with Zotiraciclib 
(TG02) have been tested on this study. In order to clarify the dose of the favored 
schedule, we will test a small group of participants (up to 12). If you are in this group, 
you will receive the following doses:
Temozolomide dosing schedule
Temozolomide can be given in a schedule referred to as “dose dense”. In this study, dose 
dense temozolomide is given as 125 mg/m2 for 7 days on and 7 days off in each cycle. In 
the phase I part of this study, participants will be assigned to receive Zotiraciclib (TG02) 
plus dose dense temozolomide (Arm 1).
Zotiraciclib (TG02) Dosing
You will take the first 200 mg dose of Zotiraciclib (TG02) 3 days prior to Day1 of cycle 1. 
You will take a 200 mg dose of Zotiraciclib (TG02) on days 1, 12, 15, and 26 of every 28-
day cycle in all the cycles.
The 12 participants treated at the TG02 200 mg dose level will be followed to determine 
the progression free survival at 4 months.
PHASE II
The dose of Zotiraciclib (TG02) selected in phase I in combination with the fixed dose 
temozolomide will be compared to the same temozolomide dosing schedule alone in the 
phase II part of the study. The treatment schedule for both parts is the same. You will 
continue treatment until your disease gets worse, you have intolerable side effects or you 
have completed 12 cycles of treatment. At the time your disease worsens, if you have 
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 4 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
received temozolomide alone, you may be crossed over to receive Zotiraciclib (TG02) 
plus temozolomide.
Following 12 cycles of treatment, participants may continue if there is evidence of 
clinical benefit.
PRE-MEDICATIONS:
Due to the possibility of nausea, vomiting and diarrhea with Zotiraciclib (TG02) 
treatment, participants will receive treatment to prevent vomiting and diarrhea before 
and for 24 hours following Zotiraciclib (TG02) administration. These may be tailored to 
the individual participant.
STUDY VISITS:
Screen 
Base-
line
Cycle 1
Cycle 2
Subsequent 
Odd 
numbered
cycles
Subsequent 
Even 
numbered
cycles
Off- 
therapy
Procedure
Wk 
2
Wk 
4
Wk 
2
Wk 
4
Wk 
2
Wk 
4
Wk 
2
Wk 
4
Office visit
X
X
X
X
X
Brain MRI
X
X
X
X
Blood work
X
X
X
X
X
X
X
X
X
X
EKG
X
X
X
X
Questionnaires*
X
X
X
X
Pregnancy
Test
X
X
X
X
X
X
* Questionnaires:
Symptom Burden Questionnaire will be done at baseline and with MRI scans.
At cycle 1, 2 and every 4 weeks:

You will have a physical exam in NOB clinic

You will have a pregnancy test (if appropriate) and an EKG at cycle 1, 2 
and every 8 weeks
Every other week:

You will have blood collected for routine blood tests every other week
Every 8 weeks:
You will have an MRI of the brain. With each MRI:

You will also be asked to complete a symptom burden questionnaire to 
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 5 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
determine if you have symptoms of depression, anxiety, and general well-being 
or function. This will take only a few minutes to complete. 
ADDITIONAL RESEARCH BLOOD AND TISSUE SAMPLES:
Research blood will be collected in the final 12 patients enrolled in Phase I at the 
following times: pre-dose, 1 hour, 2 hours, 4 hours, 24 hours and 48 hours after the 
dose. This set of blood samples will only occur in the first cycle of the protocol. 
Tumor sample will be needed to confirm the diagnosis before you start the study. 
Should you need surgery for your cancer during the study, we may collect tissue for 
research purposes.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study 
because we don’t know how this medicine would affect your baby or your unborn child. If 
you are a woman who can become pregnant, or are the partner of a woman who can 
become pregnant, you will need to practice an effective form of birth control before 
starting study treatment, during study treatment and for 30 days after the last dose of study 
medication. If you think that you or your partner is pregnant, you should tell your study 
doctor or nurse at once.
Effective forms of birth control include:
•
abstinence
•
intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
Other forms of birth control require the use of more than 1 method:

Latex condom

Diaphragm

Cervical Cap
RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study?
While on the study, you are at risk for these side effects. You should discuss these with 
your doctor. There also may be other side effects that we cannot predict. Other drugs 
will be given to make side effects less serious and uncomfortable.
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 6 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
ZOTIRACICLIB (TG02) RISKS IN HUMANS
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Zotiraciclib (TG02), more than 20 and up to 100 may have:

Diarrhea

Nausea (urge to vomit)

Vomiting

Upset stomach

Constipation

Decreased appetite

Abdominal pain

Moderate to severe low white blood cell 
count

Low potassium and phosphorus in the blood

Shortness of breath and cough

Elevated blood sugar

Dizziness

Elevated blood pressure

Muscle aching

Low platelet count
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Zotiraciclib (TG02), from 4 to 20 may have:

Pneumonia

rash

Elevated liver enzyme

confusion

Severe infection

fever

Kidney failure
Please tell the study doctor or study staff right away if you have any side effects. Please 
tell them if you have any other problems with your health or the way you feel during the 
study, whether or not you think they are related to the study drug.
Zotiraciclib (TG02) citrate may affect the electrical activity of the heart that coordinates 
the heart's beating. Medications that affect this electrical activity of the heart, taken with 
Zotiraciclib (TG02) citrate should be avoided. Your study doctor will make decisions 
about your medications on a case by case basis and discuss this with you.
You should inform the study doctor before you start any new medications, including 
prescription, over-the-counter, or herbal products. If you are having stomach upset, 
consult with your physician for recommended medications.
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 7 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
TEMOZOLOMIDE RISKS
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Temozolomide, more than 20 and up to 100 may have:
Constipation, nausea, vomiting, diarrhea
Dizziness
Muscle weakness, paralysis, difficulty walking
Trouble with memory
Tiredness
Difficulty sleeping
Hair loss
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Temozolomide, from 4 to 20 may have:
Headache, seizure
Infection, especially when white blood cell count is low
Low platelet count
Moderate to severe low white blood cell count
Anemia which may cause tiredness
Bruising, bleeding
RARE, AND SERIOUS
In 100 people receiving Temozolomide, 3 or fewer may have:
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat
Cancer of bone marrow caused by chemotherapy
Damage to the bone marrow (irreversible) which may cause infection, bleeding, may 
require blood transfusions
Rash
Severe skin rash with blisters and can involve inside of mouth and other parts of the body
Other Risks
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or develop 
an infection with redness and irritation of the vein at the site where blood is drawn. 
Frequent blood collection may cause anemia (low red blood cell count), which may 
create a need for blood transfusions.
Questionnaires may contain questions that are sensitive in nature. You may refuse to 
answer any question that makes you feel uncomfortable. The primary use of the 
information you provide is to assess the severity of your symptoms. Submission of 
this information is voluntary. If you have concerns after completing the 
questionnaire, you are encouraged to contact your doctor or the study doctor.
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
MRI scans cannot be done on people who have a cardiac pacemaker, neural pacemaker, 
surgical metal clips in the brain or on blood vessels, cochlear implants, or foreign metal 
objects within the eye. At the time of your MRI, you will be asked about these things.  
When you are in the scanning machine, a feeling of claustrophobia may come over you, 
and there will be a repetitive thumping noise.  Cool air will surround you, and the room 
is lit so you will not feel like you are in a cave or underground. It is important to remain 
still during the MRI scan. If you are very claustrophobic in MRI scanners, you may ask 
your physician for a mild sedative for the procedure. If you do this, you must not drive a 
vehicle after the MRI. You can notify the MRI technologist of any discomfort you feel. 
The medicine that is used for the injection may rarely (1:2000) cause an allergic reaction 
such as hives, shortness of breath, or low blood pressure. The medical personnel in the 
MRI room are prepared to treat you for this kind of reaction. The MRI study will be 
stopped.
This study may involve unpredictable risks to the participants.
Risks for gadolinium enhanced MRI scans:
Procedure
During part of the MRI you will receive gadolinium, a contrast agent, through an intravenous 
(iv) catheter. It will be done for medical purposes.
Risks
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein 
with pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly. Mild symptoms that may occur include: coldness in the arm at 
injection, a metallic taste, headache, and nausea. In an extremely small number of patients, 
fewer than one in 300,000 people, more severe symptoms have been reported including: 
shortness of breath, wheezing, lowering of blood pressure. You should not receive gadolinium 
if you previously had an allergic reaction to it.  You will be asked about such allergic reactions 
before gadolinium is given.
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”.  This condition always involves the skin and can also 
involve the muscles, joints and internal organs.  NSF has resulted in a very small number of 
deaths.  A blood test of your kidney function may be done within the month before an MRI 
scan with gadolinium contrast. You will not receive gadolinium for a research MRI scan if 
your kidney function is below the safe level. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to 
years.  The effects of the retained gadolinium are not clear. At this time, retained gadolinium 
has not been linked to health risks in people whose kidneys work well.  Some types of 
gadolinium contrast drugs are less likely to remain in the body than others.  In this study, we 
will use the gadolinium contrast drugs that are less likely to remain in the body.
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 9 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
We use gadobutrol which is a form of gadolinium contrast that is less likely to accumulate in 
the body than older types of gadolinium. You will receive additional information called a 
medication guide about the contrast medication you will receive.
Please tell your research team if you have had any MRI scans in the past 12 months. We will 
also give you additional information called a “Medication Guide.”  Upon request, we will give 
you individual information about retained gadolinium we see on your studies.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study?
The aim of this study is to determine a safe dose and to see if this experimental treatment 
will cause your tumors to shrink. We do not know if you will receive personal medical 
benefit from taking part in this study. These potential benefits could include shrinking of 
your tumor or lessening of your symptoms, such as pain, that are caused by the cancer. 
Because there is not much information about the drug’s effect on your cancer, we do not 
know if you will benefit from taking part in this study, although the knowledge gained 
from this study may help others in the future who have cancer.
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study?
Instead of being in this study, you have these options:

You could have a different treatment for your relapsed brain tumor. Possible 
alternative treatments include Optune, procarbazine, Gliadel® wafer, 
lomustine, carmustine, carboplatin, irinotecan, bevacizumab, etoposide. 
Enrolling in this trial means you will be foregoing available treatments that are 
approved based on studies demonstrating some clinical benefit in patients with 
your disease.  You do not have to join this study.

Taking part in another study

Getting comfort care, also called palliative care. This type of care helps reduce 
pain, tiredness, appetite problems and other problems caused by the cancer. It 
does not treat the cancer directly. Instead, it tries to improve how you feel. 
Comfort care tries to keep you as active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY 
Your doctor may decide to stop your therapy for the following reasons:
if he/she believes that it is in your best interest
if your disease comes back during treatment and you cannot or choose not to cross over 
to TMZ+ Zotiraciclib (TG02)
if you have side effects from the treatment that your doctor thinks are too severe
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 10 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
if new information shows that another treatment would be better for you
if you become pregnant
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Adastra Pharmaceuticals 
or designated representatives. If you withdraw your consent and leave the trial, any samples of 
yours that have been obtained for the study and stored at the NCI can be destroyed upon 
request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed.
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for 
conflicts of interest.  This process is detailed in a Protocol Review Guide.  You may ask your 
research team for a copy of the Protocol Review Guide or for more information.  Members of 
the research team who do not work for NIH are expected to follow these guidelines, but they 
do not need to report their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not 
a conflict of interest. 
Adastra Pharmaceuticals is providing the Zotiraciclib (TG02) for this study to NIH without 
charge.  No NIH investigator involved in this study receives payments or other benefits from 
any company whose drug, product or device is being tested.  However, there are some non-
NIH collaborators on this study who may receive payments or benefits, limited by the rules of 
their workplace.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The 
amount of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may 
be paid directly by the NIH and some may be reimbursed after you have paid.  Someone will 
work with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or 
paid for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 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.
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
As part of this study, we are obtaining specimens and data from you. We plan to use these 
specimens and data for studies going on right now, as well as studies in the future. These 
studies may provide additional information that will be helpful in understanding brain tumors 
or other diseases or conditions. This could include studies to develop other research tests, 
treatments, drugs, or devices, that may lead to development of a commercial product by the 
NIH and/or its research or commercial partners. There are no plans to provide financial 
compensation to you if this happens. Also, it is unlikely that we will learn anything from these 
studies that may directly benefit you. By agreeing to let us use your specimens and data, you 
give the NIH any rights you may have in the specimens and data. 
We may share your specimens and data with other researchers. They may be doing research in 
areas similar to this research or in other unrelated areas. These researchers may be at NIH, 
other research centers and institutions, or industry sponsors of research.
We will not contact you to ask about each of these future uses.  These specimens and data will be 
stripped of identifiers such as name, address or account number, so that they may be used for 
future research on any topic and shared broadly for research purposes. It is also possible that the 
stored specimens and data may never be used.  Results of research done on your specimens and 
data will not be available to you or your doctor.  It might help people who have cancer and other 
diseases in the future.  
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 12 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad 
sharing with the research community. These databases are commonly called data repositories. 
The information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we 
cannot offer you a choice of whether your data will be shared.  If you do not wish to have your 
data placed in a repository, you should not enroll in this study.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens and data. You should be aware that there is a 
slight possibility that someone could figure out the information is about you. 
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration 
(FDA), which are involved in keeping research safe for people.

 National Institutes of Health Intramural Institutional Review Board

Qualified representatives from Adastra Pharmaceuticals, the pharmaceutical company 
who produces Zotiraciclib (TG02)
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release 
any information about your research involvement without your written permission.  However, if 
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 13 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
you sign a release of information form, for example, for an insurance company, the NIH will 
give the insurance company information from your medical record.  This information might 
affect (either favorably or unfavorably) the willingness of the insurance company to sell you 
insurance.
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self 
or others including, for example, child abuse and neglect, and by signing below you consent to 
those disclosures. Other permissions for release may be made by signing NIH forms, such as the 
Notice and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your medical record without your permission, for 
example, if it is requested by Congress. Information may also be released for certain research 
purposes with due consideration and protection, to those engaged by the agency for research 
purposes, to certain federal and state agencies, for HIV partner notification, for infectious disease 
or abuse or neglect reporting, to tumor registries, for quality assessment and medical audits, or 
when the NIH is involved in a lawsuit.  However, NIH will only release information from your 
medical record if it is permitted by both the Certificate of Confidentiality and the Privacy Act.
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 14 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Jing Wu, 
MD., jing.wu3@nih.gov, at 240-760-6036. You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 15 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally 
authorized to make research decisions on behalf of the adult participant unable to consent and have the 
authority to provide consent to this study. As applicable, the information in the above consent was described 
to the adult participant unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language 
facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020


PATIENT 
IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/01/2020
Page 16 of 16
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
An interpreter, or other individual, who speaks English and the participant’s preferred language 
facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 17C0009
IRB APPROVAL DATE: 07/07/2020