Clinical trial NCT03522298
Conditions: Glioblastoma, Adult
Keywords: newly diagnosed unmethylated O6 methylguanine-methyltransferase (MGMT) promoter status
Sponsor: Kazia Therapeutics Limited
Start date: 2018-05-15; Completion date: 2023-03-30
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This protocol has a 2-part design:

This phase 2 study is an open-label, multicenter, dose-escalation and expansion study to assess the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK) and clinical activity of paxalisib in patients with newly-diagnosed glioblastoma (GBM) with unmethylated MGMT promoter status as adjuvant therapy following surgical resection and initial chemoradiation with temozolomide (TMZ).

Detailed description:
Stage 1 Dose-Escalation and Maximum Tolerated Dose The dose-escalation portion of the study (Stage 1) will use a standard "3 + 3" design to determine the MTD for QD dosing.

Approximately 6 - 12 patients with newly diagnosed GBM will be enrolled in Stage 1.

The MTD for QD dosing will be determined. The initial dose level for QD dosing will be 60 mg (Dose Level 0). This dose is based on the phase 1 findings outlined in the rationale in the protocol, adding 1 dose level to test for a potential MTD increase.

Dose-escalation will occur in Stage 1:

* The initial dose (Dose Level 0) for QD MTD determination in Step 1 will be 60 mg. Dose levels will increase in 15 mg steps;
* The dose-escalation portion of the study (Stage 1) will use a standard "3 + 3" design to assess the safety, tolerability, and PK of paxalisib administered orally in 28-day cycles;

Decisions regarding dose-escalation and selection will be made by a Cohort Review Committee (CRC).

All AEs, including DLTs, will be reported, with severity assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

After determination of the MTD, patients continue to receive their protocol-assigned dose levels of paxalisib until progression of their disease or an unacceptable toxicity, whichever occurs first.

Stage 2 Expansion stage (2) of the study will be a two-arm, randomized, open-label expansion study to further characterize the safety, tolerability and PK of paxalisib as well as to provide a preliminary assessment of single-agent activity of paxalisib in patients with GBM. Approximately 20 patients will be enrolled in the expansion cohort in 2 treatment arms (10 per am) to examine the PK of paxalisib in fed and fasted-conditions, according to the defined study eligibility criteria.

Stage 2 of the study will be initiated with recruitment of new patients as soon as the MTD has been determined.

Patients enrolled in Stage 2 may continue the study at the dose allocated until disease progression or unacceptable toxicity.

Arms: arm 1: This is an open-label study.

Patients in Stage 1 will be enrolled and sequentially assigned to a dose cohort.

The initial cohort will receive an oral dose of 60 mg paxalisib QD (4 x 15 mg capsules). Patients of future dose cohorts will receive paxalisib at increasing levels with 15 mg steps until a dose-limiting toxicity occurs (DLT) occurs. The dose level where \<1/3 of the patients exhibit a DLT will be determined the Maximum Tolerated Dose (MTD).

In stage 1, dose escalation will occur for QD dosing.

In stage 2, the expansion phase, patients will receive doses of oral paxalisib at the MTD in stage 1, until disease progression or an unacceptable toxicity, whichever occurs first.

Patients will be randomized in a 1:1 ratio to fed or fasted schedules.
Interventions: intervention 1: Paxalisib (GDC-0084)
Intervention descriptions: intervention 1: Patients will be dosed orally with paxalisib (GDC-0084) capsules (15-mg each) at the dose and schedule to which they are assigned.

Protocol documents:
Prot_SAP_000.pdf: 
NCT03522298
Study Protocol
A phase 2a study to evaluate the safety, pharmacokinetics and clinical 
activity of the PI3K/mTOR inhibitor GDC-0084 administered to 
patients with glioblastoma multiforme characterized by unmethylated 
O6-methylguanine-methyltransferase promoter status 
[NVGN-0084-201]
Date: 31 Mar 2020


Sponsor: Kazia Therapeutics Limited 
Version: Amendment 4 
Date: 31 Mar 2020
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
CONFIDENTIAL 
1 
A phase 2a study to evaluate the safety, pharmacokinetics and clinical activity 
of the PI3K/mTOR inhibitor GDC-0084 administered to patients with 
glioblastoma multiforme characterized by unmethylated O6-methylguanine-
methyltransferase promoter status 
Protocol Number: 
NVGN-0084-201 
IND Number: 
112,608 
Product: 
GDC-0084 
Indication: 
Newly diagnosed glioblastoma multiforme with 
unmethylated O6-methylguanine-methyltransferase 
promoter status  
Clinical Phase: 
2a 
Sponsor: 
Kazia Therapeutics Limited 
ACN 063 259 754 
Level 24, 300 Barangaroo Avenue 
Sydney, NSW 2000 
Australia 
Version: 
Amendment 4 
Date: 
31 Mar 2020 
CONFIDENTIALITY STATEMENT: 
This document contains information that is the property of Kazia Therapeutics Limited, Australia and 
therefore is provided to you in confidence for review by you, your staff, an applicable Institutional 
Review Board, and regulatory authorities. It is understood that this information will not be disclosed 
to others without written approval from Kazia Therapeutics Limited except to the extent necessary 
to obtain informed consent from patients (or their legal guardian) to whom the investigational product 
may be administered. 


Sponsor: Kazia Therapeutics Limited 
Version: Amendment 4 
Date: 31 Mar 2020
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
2 
DOCUMENT HISTORY 
Version 
Date 
Summary of changes 
Rationale for changes 
Final 
28 Sep 2017 
N/A 
Original final protocol 
Amendment 1 
29 Aug 2018 
See changes log document. 
See changes log document. 
Amendment 2 
26 April 2019 
See changes log document 
See changes log document 
Amendment 3 
26 Aug 2019 
See changes log document 
See changes log document 
Amendment 4 
31 Mar 2020 
See changes log document 
See changes log document 
PROTOCOL APPROVAL 
Protocol Title: 
A phase 2a study to evaluate the safety, pharmacokinetics and clinical activity of the 
PI3K/mTOR inhibitor GDC-0084 administered to patients with glioblastoma multiforme 
characterized by unmethylated O6-methylguanine-methyltransferase promoter status 
Protocol Number:      NVGN-0084-201 
 _________________________ 
  Date 
Sponsor Signatory: 
___________________________________ 
Signature     
 
Chief Executive Officer 
Kazia Therapeutics Limited 
ACN 063 259 754 
Level 24, 300 Barangaroo Avenue 
Sydney, NSW 2000 
Australia 
CONFIDENTIAL 


Sponsor: Kazia Therapeutics Limited  
Version: Amendment 4 
Date: 31 Mar 2020 
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
 
 
CONFIDENTIAL 
3 
1 
Glossary of Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time  
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0–last 
area under the curve from Time 0 to the time of the last measured 
AUC0-inf 
area under the curve from Time 0 to infinity 
CL 
clearance 
CL/F 
apparent clearance 
Cmax  
maximum concentration (drug in plasma) 
Cmin 
minimum concentration (drug in plasma) 
CR 
complete response 
CRC 
Cohort Review Committee 
CRF 
Case Report Form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
(National Cancer Institute’s) Common Toxicity Criteria for Adverse Events 
CYP3A4 
cytochrome P450 subtype 3A4 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
ECG 
electrocardiogram 
ECHO 
echocardiography 
EORTC  
European Organization for Research and Treatment of Cancer 
EoT 
end of treatment 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GBM 
glioblastoma multiforme 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GGT 
gamma-glutamyl transferase 
HR 
hazard ratio 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
INR 
international normalized ratio 
IRB  
Institutional Review Board 
KPS 
Karnofsky Performance Status  
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LVEF 
left ventricular ejection fraction 
MGMT  
O6-methylguanine-methyltransferase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent to treat 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MUGA 
multi-gated scan 


Sponsor: Kazia Therapeutics Limited  
Version: Amendment 4 
Date: 31 Mar 2020 
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
 
 
CONFIDENTIAL 
4 
NCI 
National Cancer Institute 
NCIC CTG  
National Cancer Institute of Canada Clinical Trials Group  
OS  
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PI3K 
phosphoinositide 3-kinase 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PP 
per-protocol 
PR 
partial response 
PT 
prothrombin time 
PTEN  
phosphatase and tensin homolog 
QD 
every day 
RANO 
Response Assessment in Neuro Oncology 
RBC 
red blood cell (count) 
RP2D 
recommended phase 2 dose 
RTK  
receptor tyrosine kinases 
SAE 
serious adverse event 
SAF 
safety (population) 
SAP 
statistical analysis plan 
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
time to maximum concentration 
T1/2 
plasma half-life 
TEAE 
treatment-emergent adverse event 
TGI 
tumor-growth inhibition 
TMF 
Trial Master File  
TMZ 
temozolomide 
TTF 
tumor treating fields 
TTP 
time to progression 
ULN 
upper limit of normal 
WBC 
white blood cell (count) 
WHO 
World Health Organization 
XRT/TMZ  
chemoradiation therapy with temozolomide 
 
 
 
 


Sponsor: Kazia Therapeutics Limited  
Version: Amendment 4 
Date: 31 Mar 2020 
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
 
 
CONFIDENTIAL 
5 
 
2 
Synopsis 
This phase 2a study comprises an open-label, multicenter dose-escalation and expansion study to 
assess the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK) and 
clinical activity of GDC-0084 in patients with newly-diagnosed GBM with unmethylated O6-
methylguanine-methyltransferase (MGMT) promoter status as adjuvant therapy following surgical 
resection and initial chemoradiation with TMZ.  
2.1 
Phase 2a study  
Study Number 
and Title 
NVGN-0084-201 
A phase 2a study to evaluate the safety, pharmacokinetics and clinical activity 
of the PI3K/mTOR inhibitor GDC-0084 administered to patients with 
glioblastoma multiforme characterized by unmethylated O6-methylguanine-
methyltransferase promoter status. 
 
Sponsor 
Kazia Therapeutics Limited 
ACN 063 259 754 
Level 24, 300 Barangaroo Avenue 
Sydney, NSW, 2000 
Australia 
Tel: +61 2 9472 4101 
 
Study Sites 
Approximately 5-7 sites in the US 
 
Indication 
Newly 
diagnosed 
glioblastoma 
multiforme 
(GBM) 
with 
unmethylated 
O6-methylguanine-methyltransferase (MGMT) promoter status after surgical 
resection and standard concomitant chemoradiation therapy with temozolomide 
(XRT/TMZ). 
 
Study 
Population 
Male and female patients ≥ 18 years with histologically confirmed diagnosis of 
GBM (World Health Organization [WHO] Grade IV astrocytoma) with 
unmethylated MGMT promoter status as confirmed by validated polymerase 
chain reaction (PCR) or validated alternate genomic analysis who have 
undergone surgical resection of the tumor(s) and initial treatment with XRT/TMZ 
(Stupp regimen) or XRT only if clinically indicated. 
 
Clinical Phase 
Phase 2a 
 
Objectives 
Primary Objective: 
• 
To evaluate the safety and tolerability of GDC-0084 in patients with 
newly diagnosed GBM. 
 
Secondary Objectives: 
• 
To determine the maximum tolerated dose (MTD) of GDC-0084 
administered once daily (QD) in patients with newly diagnosed GBM; 
• 
To evaluate the pharmacokinetics (PK) of GDC-0084 administered QD 
to patients with newly diagnosed GBM under fasted and fed conditions; 
 
Secondary Objectives: preliminary evaluation of Clinical Benefit: 
• 
To evaluate and document clinical response assessed as progression-
free survival (PFS) using RANO criteria for QD dosing schedule; 
• 
To document other measures of clinical activity, including overall 
survival (OS) and time to progression (TTP) for QD dosing schedule. 
 
Exploratory Objectives: 


Sponsor: Kazia Therapeutics Limited  
Version: Amendment 4 
Date: 31 Mar 2020 
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
 
 
CONFIDENTIAL 
6 
• 
To evaluate and document clinical response assessed as PFS using 
modified RANO criteria for QD dosing schedule; 
• 
To further characterize the PK parameters of GDC-0084 administered 
at the MTD; 
• 
To characterize the PK parameters of GDC-0084 when administered to 
both fasted and fed subjects; 
• 
To assess the distribution of GDC-0084 within the brain by 
fluorodeoxyglucose-positron emission tomography (FDG-PET) analysis 
of tumor and normal brain tissue (expansion cohort and patients with 
measurable disease only). 
 
Endpoints  
Primary Safety Endpoint: 
• 
Dose limiting toxicities (DLTs).  
 
Secondary Safety Endpoints:  
• 
Treatment-emergent adverse events (TEAEs), Grade 3-5 TEAEs, 
serious adverse events (SAEs), fatal AEs, and TEAEs leading to 
GDC-0084 discontinuation or study withdrawal; 
• 
Treatment-emergent Grade 3/4 clinical laboratory abnormalities; 
• 
Changes and shifts from baseline in clinical laboratory, vital signs, and 
electrocardiogram (ECG) parameters; 
• 
Change from baseline in corticosteroid use; 
• 
Change from baseline in left ventricular ejection fraction (LVEF);  
• 
Change from baseline in Karnofsky Performance Status (KPS); 
• 
Concomitant medication use; 
• 
Adherence to the dosing regimen. 
 
Secondary Endpoints of Clinical Benefit: 
• 
PFS measured from first dose in the dose-escalation portion (Stage 1) 
or from randomization in the cohort expansion portion of the study 
(Stage 2) to disease progression (RANO criteria) or death due to any 
cause; 
• 
OS measured from first dose in the dose-escalation portion (Stage 1) or 
from randomization in the cohort expansion portion of the study (Stage 
2) to death due to any cause; 
• 
TTP measured from first dose in the dose-escalation portion (Stage 1) 
or from randomization in the cohort expansion portion of the study 
(Stage 2) to date of earliest disease progression according to RANO 
criteria. 
 
Exploratory Endpoints: 
• 
PFS measured from first dose in the dose-escalation portion (Stage 1) 
or from randomization in the cohort expansion portion of the study 
(Stage 2) to disease progression (modified RANO criteria) or death due 
to any cause; 
• 
PK parameters including area under the curve from time 0 to last 
measurable time point (AUC0–last) and/or area under the curve from time 
0 to infinity (AUC0-inf), maximum concentration (Cmax), minimum 
concentration (Cmin), time to reach Cmax (Tmax), t1/2, apparent total 
clearance of the drug from plasma after oral administration (CL/F), and 
accumulation ratio for Cmax and AUC (fed and fasting); 
• 
Change in FDG-PET uptake in tumor and normal brain tissue (defined 
as normal brain tissue with similar cell type to tissue surrounding tumor) 
in response to GDC-0084 in patients with measurable disease; 
• 
Disease control rate (DCR) measured as the proportion of patients 
achieving a confirmed best overall response (BOR) of complete 
response (CR), partial response (PR), or stable disease (SD) according 
to a) RANO criteria and b) modified RANO criteria.  
 


Sponsor: Kazia Therapeutics Limited  
Version: Amendment 4 
Date: 31 Mar 2020 
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
 
 
CONFIDENTIAL 
7 
Assessment of 
Safety 
Safety assessments will consist of monitoring and recording of AEs and SAEs; 
measurement of protocol-specific hematology, clinical chemistry, and urinalysis 
variables; cardiac assessments; measurement of protocol specified vital signs; 
performance status and physical evaluations; concomitant medication use; and 
other protocol-specified tests that are deemed critical to the safety evaluation of 
the study drug. All assessments will be scheduled as indicated in the Schedule 
of Assessments. Additional assessments may be performed as clinically 
indicated.  
 
Study Design 
Phase 2a study - Stage 1 
 
Dose-Escalation and Maximum Tolerated Dose 
The dose-escalation portion of the study (Stage 1) will use a standard "3 + 3" 
design to determine the MTD for the QD dosing schedule.  
 
The initial dose level for QD dosing will be 60 mg (Dose Level 0), and the dose 
level will be increased in 15 mg increments in successive cohorts until an MTD 
is reached. It is expected that approximately 12 patients with newly-diagnosed 
GBM will be enrolled. 
 
Dose-Escalation Rules 
Dose-escalation will occur in Stage 1: 
• 
The initial dose (Dose Level 0) for QD MTD determination will be 60 mg. 
Dose levels will increase in 15 mg steps; 
• 
The dose-escalation portion of the study (Stage 1) will use a standard 
"3 + 3" design to assess the safety, tolerability, and PK of GDC-0084 
administered orally in 28-day cycles; 
• 
A minimum of 3 patients will be enrolled in each cohort. If none of these 
patients experiences a DLT within the DLT assessment period (Day 1 - 
28), escalation will proceed to the next higher dose level by opening the 
next higher dose cohort with newly recruited patients.  
• 
If 1 patient experiences a DLT, the cohort will be expanded until a 
second patient experiences a DLT or to a maximum of 6 patients. When 
a second patient has a DLT, the MTD is determined as 1 dose level 
below the current dose level; i.e. the highest dose level at which less 
than 1/3 of patients (e.g. 1 of 6) experiences a DLT will be declared the 
MTD.  
If 2 or more patients experience a DLT at Dose Level 0, the MTD will 
be declared at 45 mg, which was the MTD established in the previous 
phase I study in patients with advanced glioma with a QD dosing 
schedule.  On the basis of the review of real-time safety data and 
available preliminary PK data from this study with GDC-0084, dose-
escalation may be halted or modified by the sponsor as deemed 
appropriate. 
 
Decisions regarding dose-escalation and selection will be made by a CRC 
including the medical monitor, recruiting Investigators, sponsor representative 
and any other relevant and necessary expert on as needs basis, according to 
the CRC charter.  
 
Definition of Dose Limiting Toxicity  
All AEs, including DLTs, will be reported, with severity assessed according to 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.03. For dose-escalation purposes, DLT 
assessments will be performed by the sponsor in consultation with the 
Investigators during the CRC meetings. 
 
A DLT is defined as any one of the following toxicities occurring within the DLT 
assessment window (Cycle 1, Days 1−28) and assessed by the Investigator to 


Sponsor: Kazia Therapeutics Limited  
Version: Amendment 4 
Date: 31 Mar 2020 
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
 
 
CONFIDENTIAL 
8 
be probably or possibly related to GDC-0084: 
 
• 
Grade ≥ 3 non-hematologic or non-hepatic toxicity that is not related to 
hyperglycemia or hyperlipidemia or mucositis/stomatitis and is not due 
to disease progression or another clearly identifiable cause, excluding 
the following: 
o 
Alopecia of any grade; 
o 
Grade 3 fever or Grade 4 fever < 5 days duration; 
o 
Grade 3 infection < 5 days duration or that responds to 
treatment; 
o 
Grade 3 weight gain or loss; 
o 
Grade 3 diarrhea lasting less than 5 days or that responds to 
standard-of-care therapy including hospitalization  
o 
Grade 3 nausea or vomiting, in the absence of premedication, 
that lasts for less than 48 hours or responds to standard-of-
care therapy; 
o 
Grade 3 or asymptomatic Grade 4 electrolyte imbalance that 
resolves or improves within 7 days with or without medical 
intervention, including hospitalization;  
o 
Grade 3 or 4 serum amylase or lipase or creatine 
phosphokinase laboratory abnormality that is asymptomatic 
(without other laboratory evidence suggestive of pancreatitis, 
rhabdomyolysis, or other major organ dysfunction) and returns 
to baseline within 7 days of interrupting study drug; 
o 
Grade ≥ 3 total bilirubin or hepatic transaminase (aspartate 
aminotransferase [AST] and alanine aminotransferase [ALT]) 
elevations that return to ≤ Grade 1 (if normal at study entry) or 
≤ baseline values within 7 days of interrupting study drug; 
o 
Note: Allergic reactions that necessitate discontinuation of 
study drug will not be considered a DLT; 
• 
Grade ≥ 3 symptomatic fasting hyperglycemia (e.g., dehydration or 
acidosis requiring hospitalization); 
• 
Grade ≥ 4 fasting hypercholesterolemia or triglyceridemia for ≥ 14 days 
despite intervention with a lipid-lowering agent; 
• 
Grade ≥ 4 thrombocytopenia; 
• 
Grade 3 thrombocytopenia that lasts ≥ 7 days or is associated with 
clinically significant bleeding; 
• 
Grade ≥ 4 neutropenia (absolute neutrophil count < 500/μL) lasting ≥ 7 
days or accompanied by fever (oral or tympanic temperature ≥ 38.0°C 
[100°F]); 
• 
Grade ≥ 3 total bilirubin or hepatic transaminase (ALT or AST) 
elevations that do not return to ≤ Grade 1 (if normal at study entry) or 
≤ baseline values within 7 days of interrupting study drug; 
• 
For patients with Gilbert’s disease and with Grade 2 bilirubin at 
baseline, total bilirubin ≥ 10 x the upper limit of normal (ULN) will be 
considered a DLT; 
• 
Bradycardia Grade ≥ 2; 
• 
Myocardial ischemia Grade ≥ 2; 
• 
Mucositis/stomatitis Grade 3 not responding to standard-of-care 
therapy or Grade 4; 
• 
Decrease in left ventricular ejection fraction (LVEF) to ≤ 45%; 
• 
Increase of QTc to ≥ 500 msec or by 60 msec; 
• 
Pneumonitis Grade ≥ 2. 
 
After determination of the MTD, patients continue to receive their protocol-
assigned dose level of GDC-0084 until progression of their disease or an 
unacceptable toxicity, whichever occurs first. 
 


Sponsor: Kazia Therapeutics Limited  
Version: Amendment 4 
Date: 31 Mar 2020 
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
 
 
CONFIDENTIAL 
9 
Patients who experience disease progression or an unacceptable toxicity at any 
time during the study, or, in their opinion or the opinion of the Investigator, are 
not benefiting from GDC-0084, will be discontinued from study treatment. Under 
certain circumstances in which an AE (or DLT) is reversible and the risk/benefit 
assessment suggests a reasonable rationale for continued administration of 
study drug, patients may continue with agreement from the Investigator and the 
medical monitor. This may include dose reduction and change of treatment 
schedule. An End of Treatment (EoT) visit will be performed approximately 28 
days after the last dose of GDC-0084.  
 
Phase 2a study - Stage 2 
 
Expansion  
Stage 2 of the study will be a two-arm, open-label, expansion cohort to further 
characterize the safety, tolerability and PK of GDC-0084 as well as to provide a 
preliminary assessment of single-agent activity of GDC-0084 in patients with 
GBM, and to explore the effect of a fed versus fasting state on the PK of GDC-
0084. Approximately 20 patients will be enrolled in the expansion cohort, in two 
parallel groups of 10 patients each. Patients will be allocated to either a fed or a 
fasted arm via a central randomization process and will remain in their assigned 
arm for the duration of treatment. 
 
The expansion will be conducted according to the Schedule of Assessments, 
using GDC-0084 administered at the RP2D established in Stage 1 and on a QD 
schedule. As in Stage 1, GDC-0084 will be administered in 28-day cycles. 
 
Stage 2 of the study will be initiated with recruitment of new patients as soon as 
the RP2D for the QD dosing schedule has been determined. Patients enrolled 
in Stage 2 may continue the study at the dose allocated until disease progression 
or unacceptable toxicity.  
 
The image acquisition system must remain consistent throughout all scans for 
the same patient. MRI imaging will be performed according to standardized 
procedures. The blinded central review disease response assessments will be 
used as the primary measure for analysis, and the Investigator disease response 
assessments will be used as supportive measures for analysis. 
 
Pharmacokinetic 
Assessments 
For the quantification of GDC-0084 concentrations, PK blood samples will be 
obtained at the following time points on Days 1 (Cycle 1) and C2D1: pre-dose 
of GDC-0084 administration and at 30 (+/- 3) minutes, and at 1 (+/- 10 
minutes), 2 (+/- 15 minutes), 3 (+/- 15 minutes), 4 (+/- 15 minutes), 6 (+/- 15 
minutes), 8 (+/- 15 minutes) and 24 (+/- 1) hours post-dose.  
Exact times for dosing and blood sampling will be recorded.  
Length of Study 
The duration of the phase 2a study is estimated to be 2 years.  
 
Sample size and 
sample size 
determination 
In Stage 1, approximately 12 patients (range: 6 - 24 patients) will be recruited.  
 
Stage 2 is descriptive in nature. The sample size in Stage 2 (cohort expansion) 
is guided by practical rather than statistical considerations, and will enroll 
approximately 20 patients.  
 
The total sample size for phase 2a is approximately 32 patients (range: 26 - 44 
patients). 
 
Treatment 
Assignment and 
Blinding 
This is an open-label study.  
 
Patients in Stage 1 will be enrolled to their allocated dose at a QD dosing 
frequency. They will continue to receive study drug based on the cohort to which 
they are assigned, and intra-patient dose escalation is not permitted. Dose 


Sponsor: Kazia Therapeutics Limited  
Version: Amendment 4 
Date: 31 Mar 2020 
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
 
 
CONFIDENTIAL 
10 
reduction is permitted if clinically indicated. 
 
In the expansion portion (Stage 2), 20 patients will be randomized in a 1:1 ratio 
to receive GDC-0084 either under fasted or fed conditions. 
 
Statistical 
Analysis 
Analysis Populations: 
 
• 
The Intent -to-Treat (ITT) population includes all randomized patients; 
ITT analyses will be conducted on the basis of the arm assigned at 
randomization 
• 
The Modified Intent-to-Treat (mITT) population includes all eligible 
patients who received at least 1 dose of GDC-0084 and have evaluable 
post-baseline tumor response data;  
• 
Safety population (SAF): All eligible patients who received at least 1 
dose of GDC-0084 will be included in the safety population. Safety 
analyses will be conducted on the basis of initial received treatment;  
• 
PK population: All eligible patients in the safety population who have an 
adequate concentration vs. time profile to determine PK parameters; 
• 
A Per-Protocol (PP) subset will also be used to analyze endpoints of 
clinical benefit and will be based on study drug exposure (compliance 
and/or time on study drug) and major protocol deviations. The criteria 
for inclusion in the PP subset will be finalized and documented prior to 
database lock. 
 
Timing of Analyses: 
Regular cohort safety reviews will be performed as described above during 
Stage 1 to support dose-escalation and if necessary, de-escalation decisions. 
 
After all patients in Stage 2 have completed one cycle of treatment or 
discontinued treatment, an interim analysis of safety, PK, FDG-PET and select 
clinical benefit endpoints will be evaluated. 
 
A final analysis will be performed when all patients discontinue treatment and 
complete their End of Treatment visit. Supplemental analyses may be performed 
at the completion of the study but will be considered exploratory. 
 
General Considerations: 
Data from Stage 1 and Stage 2 may be summarized separately. For Stage 1 
assessment, summaries will be presented by dose level and overall. For Stage 
2, summaries will be presented by treatment arm (fed versus fasting) and overall. 
Selected safety parameters may be summarized using pooled data from the 
selected dose level in Stage 1 and fasted patients in Stage 2. 
 
There may be a statistical comparison of Cmax/AUC between fasted and fed 
patient data in stage 2. 
 
Descriptive statistics (N, mean, standard deviation, median, minimum, and 
maximum) will be presented for continuous variables. Geometric means and 
coefficient of variation will also be presented for PK data. Frequency distributions 
(counts and associated percentages) will be presented for categorical variables. 
Median, 25th and 75th percentiles and confidence intervals (CIs) will be presented 
for time-to-event data. Unless specified otherwise, CIs will be presented as 95% 
CIs. 
 
The study is descriptive in nature and is not powered for a confirmatory statistical 
goal or objective. Formal hypothesis testing will not be done, and no adjustment 
for multiple comparisons will be used. 
 
Individual patient data listings will be provided to support summary tables.  


Sponsor: Kazia Therapeutics Limited  
Version: Amendment 4 
Date: 31 Mar 2020 
Protocol Number: NVGN-0084-201 
IND Number: 112,608 
 
 
CONFIDENTIAL 
11 
The effects of noncompliance, treatment discontinuations, premature study 
withdrawals, subsequent therapies, and covariates will be assessed to 
determine the impact on the general applicability of results from this study. 
 
Analysis of Clinical Benefit: 
The Kaplan-Meier method will be used to describe and present PFS and any 
other time-to-event endpoints (OS, TTP, etc). Median PFS will be presented with 
95% CI, 25th and 75th percentiles and minimum and maximum values. Kaplan-
Meier estimates of PFS at 6, 9, and 12 months will also be presented with 95% 
CIs. 
The primary analysis of time to event endpoints (OS, TTP, and PFS) from Stage 
2 will be based on the mITT and/or PP as appropriate. 
For exploratory analyses, DCR will be compared between treatment arms using 
Fisher’s exact test. The difference in the proportion of responders and 
corresponding 95% CI (based on the Hauck-Anderson approach) will also be 
displayed. The blinded central review disease response assessments will be 
used as the primary measure for analysis, and the Investigator disease response 
assessments will be used as supportive measures for analysis. 
 
Safety Analysis: 
All safety analyses will be conducted in the safety population.  
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). The severity of AEs will be graded according to the United States 
NCI CTCAE, version 4.03. 
TEAEs are defined as any AE occurring or worsening on/after the first study drug 
dose and within 28 days after the last dose date. TEAEs leading to study drug 
discontinuation, TEAEs leading to dose reduction/interruption, TEAEs related to 
study drug, SAEs, TEAEs leading to study drug discontinuation, and TEAEs with 
an outcome of death will be summarized by system organ class, and preferred 
term. Disease progression and death will be reported as part of the study 
endpoints and not as AEs or SAEs. A summary of TEAEs of NCI CTCAE Grade 
3 or higher, as well as the most frequent TEAEs (preferred terms) by grade, and 
TEAEs by relationship to study treatment, will be provided. Additionally, a 
summary will be done for AEs using the worst grade of the event.  
Values and changes from baseline in clinical laboratory results will be 
summarized by visit. Clinical laboratory values will be graded according to the 
NCI CTCAE 4.03, for applicable tests. Shifts in CTC grades from baseline grade 
will be summarized. 
Vital signs, ECG, LVEF, corticosteroid use, KPS, and concomitant medication 
data will be summarized. 
In Stage 2 comparisons between treatment arms will be descriptive, no formal 
statistical analysis of safety will be performed. 
 
Pharmacokinetic Analysis: 
All PK analyses will be conducted on the PK and mITT populations.  
Serum concentrations before and after GDC-0084 administration and PK 
parameters (AUC0–last, AUC0-inf, Cmax, Cmin, Tmax, t1/2, CL/F, and accumulation 
ratio) will be summarized by dose level (Stage 1) and treatment arm (Stage 2). 
Individual and mean concentrations vs. time will be displayed graphically. 
 
Inclusion 
Criteria  
Patients must meet all the following inclusion criteria to be eligible for enrollment 
into the study: 
1. Signed informed consent approved by the Institutional Review Board. 
Patients must sign an authorization for the release of their protected 
health information; 
2. Age ≥ 18 years; 
3. Life expectancy > 12 weeks; 
4. Present with histologically confirmed intracranial (supratentorial) 
unmethylated MGMT promotor status GBM (WHO Grade lV 
astrocytoma) with an MGMT status that has been confirmed by validated 


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PCR or validated alternative genomic analysis; 
5. Have undergone maximal or subtotal surgical resection of their tumor 
and within 6 weeks of surgery commenced radiation and then received 
at least 75% of planned treatment with XRT/TMZ or XRT only (if clinically 
indicated), which consists of XRT by external beam to a partial brain 
field in daily fractions of 2.0 Gray (Gy), to a planned total dose to the 
tumor of 60.0 Gy, in conjunction with TMZ oral QD 75 mg/m2 in 
accordance with the Stupp regimen; Must have measurable disease, 
according to RANO criteria for inclusion in the expansion cohort. 
Patients with non-measurable disease can be included in the dose-
escalation cohorts;  
6. KPS ≥ 70; 
7. Cranial magnetic resonance imaging (MRI) must have been performed 
within 14 days prior to or on the day of the Enrollment/Week 1 Visit; 
8. Stable or decreasing corticosteroid dose within 7 days prior to the first 
dose; 
9. Adequate bone marrow/hematological function within 14 days prior to 
Day 1: 
a. White blood cell count (WBC) > 3,000/µL, absolute neutrophil 
count > 1,500/mm3; 
b. Platelet count of > 100,000/mm3;  
c. Hemoglobin > 10 mg/dL; 
d. Eligibility level for hemoglobin may be reached by transfusion; 
10. Adequate liver function within 14 days prior to Day 1:  
a. Total bilirubin ≤ 1.5 x ULN; 
b. AST and ALT ≤ 2.5 x ULN; 
11.  Adequate renal function within 14 days prior to Enrollment/Week 1 Visit:  
a. Creatinine ≤ 1.5 mg/dL; 
b. Urine dipstick for proteinuria < 2+. Patients discovered to have 
≥ 2+ proteinuria on dipstick urinalysis should undergo a 24-hour 
urine collection and must demonstrate ≤ 1.0 g of protein in 24 
hours; OR 
c. Urine protein/creatinine ratio ≤ 1.0; 
12. International normalized ratio (INR) or prothrombin time (PT) (secs) and 
activated partial thromboplastin time (aPTT) within 7 days prior to 
Enrollment:  
a. <1.5 x ULN (except for patients receiving anticoagulation 
therapy) in the absence of therapeutic intent to anti-coagulate 
the patient;  
b. Within therapeutic limits (according to the medical standard in 
the institution) in the presence of therapeutic intent to anti-
coagulate the patient;  
c. NOTE: Use of full-dose anti-coagulants is permitted as long as 
the INR or aPTT is within therapeutic limits (according to the 
medical standard in the institution) and the patient has been on 
a stable dose of anti-coagulants for at least 2 weeks before the 
Enrollment/Week 1 Visit. As per American Society of Oncology 
guidelines, low-molecular-weight heparin should be the 
preferred approach; 
13. Willing and able to comply with the protocol as judged by the 
Investigator;  
14. Patients must be willing to forego other drug therapy against the tumor 
while enrolled in the study. 
 
Exclusion 
Criteria 
Patients presenting with any of the following will not be included in the study: 
1. Previous radiotherapy to the brain or cytotoxic drug therapy (including 
Gliadel® wafers) in addition to the required postoperative radiation plus 
TMZ, non-cytotoxic drug therapy, or experimental drug therapy directed 
against the brain tumor prior to this regimen, will be excluded. Patients 
may have received or be receiving corticosteroids, analgesics, and other 


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CONFIDENTIAL 
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drugs to treat symptoms or prevent complications, but the dose must be 
stable at treatment start. NOTE: 5-aminolevulinic acid-mediated 
photodynamic therapy administered prior to surgery to aid in optimal 
surgical resection is not considered a chemotherapy agent; 
2. Any prior, or anticipated, concomitant treatment involving a medical 
device (such as Optune®) applying tumor treating fields (TTF).  Prior 
short-course Optune® monotherapy (i.e. without concurrent TMZ or 
other chemoRx) may be allowed with approval from the Medical Monitor; 
3. QTc  interval time of ≥ 470 msec; 
4. Undetermined/indeterminate MGMT status; 
5. Diabetic patients and/or ongoing insulin therapy; clinically confirmed 
prediabetic patients;  
6. Use of any strong CYP3A4 inducing or inhibiting agents within 14 days 
of first dose of GDC-0084; 
7. Significant medical illnesses that in the Investigator's opinion cannot be 
adequately controlled or would compromise the patient's ability to 
tolerate this therapy; 
8. Women who are pregnant (determined by serum beta chorion-
gonadotropin) or who are lactating. NOTE: Serum pregnancy test to be 
assessed within 7 days prior to first dose; 
9. Any disease likely to obscure toxicity; 
10. Diagnosed with infratentorial GBM; 
11. Diagnosed with tumor outside of brain; 
12. Diagnosed with gliomatosis cerebri; 
13. Evidence of recent hemorrhage on postoperative MRI of the brain. 
However, 
patients 
with 
clinically 
asymptomatic 
presence 
of 
hemosiderin, resolving hemorrhagic changes related to surgery, and 
presence of punctate hemorrhage in the tumor are permitted entry into 
the study; 
14. Male and female patients of childbearing potential unwilling or unable to 
use effective means of contraception (oral contraceptives, intrauterine 
contraceptive device, barrier method of contraception in conjunction with 
spermicidal jelly) throughout the study and for at least 28 days after the 
last dose of assigned treatment; 
15. Any previous malignancy; except for adequately controlled limited basal 
cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma 
in situ of the cervix, or any previous malignancy which has been absent 
of evidence of disease and has not required treatment for ≥3 years;  
16. Patients who have any other disease that would in the judgement of the 
investigator, exclude enrollment in this study.  Disease could be either 
metabolic or psychological, and based upon any evidence on clinical 
examination or special investigations (including a laboratory finding); 
17. Any other investigational drug or participation in another investigational 
study within 30 days prior to Enrollment/Week 1; 
18. Known hypersensitivity to any excipients of GDC-0084 formulation or of 
other PI3K/mTOR inhibitors; 
19. Unable to comply with the administration of the study treatment. 
 
Investigational 
Medicinal 
Product 
GDC-0084 15 mg capsules packaged in a white high-density polyethylene bottle 
with plastic child-resistant cap. Each bottle contains 35 capsules labeled for 
clinical use. 
 
Dose and 
Schedule 
Prior to Screening:  
All patients receive concomitant XRT/TMZ or XRT only delivered as fractionated 
focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for 
a total of 60 Gy, with concomitant administration of daily oral TMZ 75 mg/m2/day 
from the first day to the last day of radiotherapy. 
Patients must have recovered from side effects of this therapy to at least 
baseline or Grade 1 before entering the study. 
 


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After Screening/Enrollment: 
After screening, in Stage 1, the initial cohort will receive an oral dose of 60 mg 
GDC-0084 QD (4 x 15 mg capsules). Patients of future cohorts are planned to 
receive GDC-0084 at increasing levels with 15 mg steps according to the dose-
escalation rules until disease progression or an unacceptable toxicity, whichever 
occurs first.  
For the Stage 2 expansion, patients will receive doses of oral GDC-0084 at the 
MTD established for QD dosing during Stage 1, in 28-day cycles until disease 
progression or an unacceptable toxicity, whichever occurs first. 
 
Follow-up post 
End of 
Treatment 
There is a short-term follow-up visit 28 days after end of study treatment.  There 
is long-term follow-up performed by telephone conversation or site visit 
(depending on practical considerations) where all patients in Stage 1 and Stage 
2 who discontinue study treatment will be followed every 8 weeks until 
determination of progressive disease (PD) and then until death unless the 
patient requests to be withdrawn from survival follow-up or termination of the 
study by the Sponsor. This request must be documented in the source 
documents and signed by the Investigator.  


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Table of Contents 
1 
Glossary of Abbreviations ................................................................................................................3 
2 
Synopsis ...........................................................................................................................................5 
2.1 
Phase 2a study ........................................................................................................................5 
3 
Introduction ....................................................................................................................................18 
3.1 
Indication ................................................................................................................................18 
3.2 
Background ............................................................................................................................18 
3.3 
GDC-0084 ..............................................................................................................................19 
3.4 
Risk/Benefit Analysis .............................................................................................................19 
3.5 
Rationale for Conducting this Study ......................................................................................20 
3.6 
Study Objectives ....................................................................................................................21 
3.6.1 
Primary Objective ...........................................................................................................21 
3.6.2 
Secondary Objectives ....................................................................................................21 
3.6.3 
Exploratory Objectives ...................................................................................................21 
3.7 
Study Design ..........................................................................................................................21 
3.7.1 
Stage 1 ...........................................................................................................................22 
3.7.2 
Stage 2 ...........................................................................................................................25 
3.7.3 
Determination of Recommended Phase 2 Dose ...........................................................26 
4 
Methods: Patients, Interventions, and Outcomes ..........................................................................26 
4.1 
Study Setting ..........................................................................................................................26 
4.2 
Eligibility Criteria ....................................................................................................................26 
4.2.1 
Inclusion Criteria ............................................................................................................26 
4.2.2 
Exclusion Criteria ...........................................................................................................27 
4.2.3 
Contraception Guidelines...............................................................................................28 
4.3 
Enrollment Procedure ............................................................................................................28 
4.3.1 
Allocation to Treatment ..................................................................................................28 
4.4 
Study Interventions ................................................................................................................28 
4.4.1 
Treatment Schedule .......................................................................................................28 
4.4.2 
Schedule of Assessments..............................................................................................29 
4.5 
Endpoints ...............................................................................................................................33 
4.5.1 
Primary Endpoint ...........................................................................................................33 
4.5.2 
Secondary Endpoints .....................................................................................................33 
4.5.3 
Exploratory Endpoints ....................................................................................................33 
4.6 
Assessments ..........................................................................................................................33 
4.6.1 
Physical and Ophthalmologic Examination ...................................................................33 
4.6.2 
Height, Weight and Vital Signs ......................................................................................34 
4.6.3 
Radiographic Assessments ...........................................................................................34 
4.6.4 
Cardiac Assessment ......................................................................................................34 
4.6.5 
Karnofsky Performance Status ......................................................................................35 
4.6.6 
O6 Methylguanine-Methyltransferase Promoter Status .................................................35 
4.6.7 
Pharmacokinetic Assessments ......................................................................................35 
4.6.8 
Safety Laboratory Assessments ....................................................................................35 
4.6.9 
Pregnancy Test ..............................................................................................................36 
4.6.10 
Adverse Events ..............................................................................................................36 
4.6.11 
Unscheduled Visits ........................................................................................................36 
4.6.12 
Follow-up Visits ..............................................................................................................36 
4.7 
Duration of Therapy ...............................................................................................................36 
4.8 
Duration of Follow-up .............................................................................................................37 
4.8.1 
Schedule of Assessments in Follow-up .........................................................................37 
4.9 
Dose Delays and Dose Modifications ....................................................................................37 
4.9.1 
Retreatment Criteria .......................................................................................................37 
4.9.2 
Dose Modification Guidelines ........................................................................................37 
4.10 
Supportive Care Guidelines ...................................................................................................37 
4.10.1 
Hyperglycemia and Metabolic Effects............................................................................38 
4.10.2 
Potential Lung Inflammation/Pneumonitis .....................................................................38 
4.10.3 
Gastrointestinal Tract Toxicities .....................................................................................38 
4.10.4 
Potential Skin Disorder ..................................................................................................39 
4.10.5 
Potential Hematological or Immunosuppressant Effects ...............................................39 
4.10.6 
Potential Cardiac Effects................................................................................................39 
4.11 
Criteria for Removal from Study ............................................................................................39 


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4.11.1 
Removal of Patients .......................................................................................................39 
4.11.2 
Definition of Dose-Limiting Toxicity................................................................................40 
4.11.3 
Premature Discontinuation of Study in a Study Site ......................................................40 
4.11.4 
Sponsor Premature Discontinuation Criteria .................................................................41 
4.11.5 
Definition of End of Study ..............................................................................................41 
5 
Adverse Event Reporting ...............................................................................................................41 
5.1 
Adverse Events ......................................................................................................................41 
5.2 
Reporting Period ....................................................................................................................41 
5.3 
Definition of an Adverse Event ..............................................................................................42 
5.4 
Abnormal Test Findings .........................................................................................................42 
5.5 
Serious Adverse Events.........................................................................................................42 
5.5.1 
Drug Induced Liver Injury ...............................................................................................43 
5.6 
Hospitalization ........................................................................................................................44 
5.7 
Adverse Event Severity Assessment .....................................................................................44 
5.8 
Causality Assessment ............................................................................................................45 
5.9 
Exposure During Pregnancy ..................................................................................................45 
5.10 
Withdrawal Due to Adverse Events .......................................................................................46 
5.11 
Eliciting Adverse Event Information .......................................................................................46 
5.12 
Reporting Requirements ........................................................................................................46 
5.12.1 
Serious Adverse Event Reporting Requirements ..........................................................46 
5.12.2 
Non-Serious Adverse Event Reporting Requirements ..................................................47 
5.12.3 
Sponsor Reporting Requirements to Regulatory Authorities.........................................47 
6 
Data Collection, Management and Analysis ..................................................................................47 
6.1 
Source Data ...........................................................................................................................47 
6.2 
Data Collection, Management and Reporting ........................................................................47 
6.2.1 
Case Report Forms/Electronic Data Record .................................................................47 
6.2.2 
Record Retention ...........................................................................................................47 
6.3 
Statistical Methods .................................................................................................................48 
6.3.1 
Analysis Populations ......................................................................................................48 
6.3.2 
Timing of Analyses .........................................................................................................48 
6.3.3 
General Considerations .................................................................................................48 
6.3.4 
Analysis of Clinical Benefit .............................................................................................49 
6.3.5 
Safety Analysis...............................................................................................................50 
6.3.6 
Pharmacokinetic Analysis ..............................................................................................51 
6.3.7 
FDG-PET Analysis .........................................................................................................51 
6.4 
Sample Size ...........................................................................................................................51 
6.5 
Recruitment ............................................................................................................................51 
7 
Monitoring ......................................................................................................................................51 
7.1 
Cohort Review Committee .....................................................................................................51 
7.2 
Interim Analysis and/or Stopping Guidelines .........................................................................51 
7.3 
Clinical Monitoring ..................................................................................................................52 
7.4 
Auditing ..................................................................................................................................52 
8 
Pharmaceutical Information ...........................................................................................................52 
8.1 
Investigational Product...........................................................................................................52 
8.2 
Supply, Packaging and Labeling ...........................................................................................52 
8.3 
Storage and Handling ............................................................................................................53 
8.4 
Accountability .........................................................................................................................53 
8.5 
Preparation and Administration .............................................................................................53 
8.6 
Warnings and Precautions .....................................................................................................54 
8.7 
Prior and Concomitant Medication.........................................................................................54 
8.7.1 
Prior Medication .............................................................................................................54 
8.7.2 
Concomitant Medication ................................................................................................54 
9 
Correlative Studies .........................................................................................................................54 
9.1 
Pharmacokinetic Studies .......................................................................................................54 
10 
Ethical Conduct of the Study and Dissemination of Data ..........................................................54 
10.1 
Ethical Conduct of the Study .................................................................................................54 
10.2 
Research Ethics Approval......................................................................................................54 
10.3 
Protocol and Investigator’s Brochure .....................................................................................55 
10.4 
Protocol Amendments............................................................................................................55 
10.5 
Documentation and Materials Supplies .................................................................................55 


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10.6 
Informed Consent ..................................................................................................................55 
10.7 
Confidentiality.........................................................................................................................56 
10.8 
Declaration of Interests ..........................................................................................................56 
10.9 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ...................56 
10.10 Compensation for Medicine-induced Injury ...........................................................................56 
10.11 Direct Access to Data ............................................................................................................57 
10.12 Dissemination Policy ..............................................................................................................57 
11 
References .................................................................................................................................59 
12 
Appendix ....................................................................................................................................61 
 
 
 
 
 


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3 
Introduction 
3.1 
Indication 
GDC-0084 is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and 
mammalian target of rapamycin (PI3K/mTOR) and was efficacious in nonclinical models of tumors 
driven by activation of the PI3K pathway. GDC-0084 was designed to efficiently cross the blood-brain 
barrier to achieve high drug exposure in the brain, to maximize its impact on brain cancers such as 
gliomas, including glioblastoma multiforme (GBM), the most serious and aggressive form of primary 
brain cancer.  
GDC-0084 is being developed for the treatment of patients with newly diagnosed GBM with 
unmethylated O6-methylguanine-methyltransferase (MGMT) promoter status in the adjuvant setting 
following surgical resection and standard concomitant chemoradiation therapy with temozolomide 
(XRT/TMZ). 
3.2 
Background 
Gliomas comprise a heterogeneous group of neoplasms that differ in morphology, location within the 
central nervous system, extent of invasiveness, tendency to progression, and response to treatments. 
Gliomas are categorized by histological cell types into ependymomas, astrocytomas (GBM being the 
most common astrocytoma), oligodendrogliomas, and mixed gliomas. Gliomas are further categorized 
according to grade, which is determined by pathologic evaluation of the tumor. High-grade gliomas, 
categorized as World Health Organization (WHO) Grade III–IV, are highly malignant with poor 
prognosis. GBM is synonymous with WHO Grade IV astrocytoma and is the most aggressive form of 
the glial tumors, characterized by rapid proliferation of undifferentiated cells, angiogenesis, and 
extensive infiltration. GBM is the most common primary brain tumor, accounting for 16.7% of all brain 
and central nervous system tumors and approximately 50% of all gliomas (Ostrom, Gittleman et al. 
2014). Standard therapy of GBM includes surgical resection/debulking followed by concomitant 
radiotherapy and temozolomide (XRT/TMZ) or other chemotherapy. Evidence of common genetic 
abnormalities in signal transduction pathways that control angiogenesis and cell growth and survival 
have led to the development of new treatments that target molecules in these signaling pathways. 
However, there is no cure for GBM, the majority of patients relapse with a poor prognosis, and new 
treatment options are still needed. 
PI3K and mTOR are lipid and protein kinases, respectively, that are involved in tumor cell 
proliferation, survival, and migration upon activation by growth factor receptors and integrins. PI3K 
catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to generate 
phosphatidylinositol-3,4,5-trisphosphate (PIP3) (Cantley 2002), a second messenger involved in the 
phosphorylation of Akt and associated proteins in the Akt/mTOR pathway (Guertin and Sabatini 
2007). Activating and transforming mutations, as well as amplification, in the p110 subunit of PI3K 
are commonly found in solid and hematologic tumors. In addition, the PI3K/Akt pathway is activated in 
numerous types of cancer by receptor tyrosine kinase signaling or the loss of the phosphatase and 
tensin homolog (PTEN) (Shayesteh, Lu et al. 1999, Cantley 2002, Massion, Taflan et al. 2004, Wu, 
Mambo et al. 2005). 
Activation of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) 
pathway has been implicated in several types of cancer (Ward, Sotsios et al. 2003, Cantley 2004, 
Guertin and Sabatini 2007), including primary brain cancers such as GBM (McLendon, Friedman et 
al. 2008, Parsons, Jones et al. 2008, Fan and Weiss 2010). Loss of PTEN expression or function, and 
dysregulation of receptor tyrosine kinases (RTKs) that exert downstream effects on PI3K are common 
in GBM. Activating mutations in PIK3CA (the gene encoding the p110 catalytic subunit PI3Kα) and 
mutations in PIK3R1 (the gene encoding the regulatory subunit p85) are also evident in GBM. With 
the current standard of care, few patients survive beyond a few years, highlighting the need for new 
therapeutic strategies. The PI3K pathway is activated in ≥ 70% of GBM tumors, making it a 
compelling target for the treatment of GBM (McLendon, Friedman et al. 2008). GDC-0084 is a potent, 
oral, selective small molecule inhibitor of class I PI3K and mTOR kinase that is being developed as an 
anti-cancer therapeutic agent specifically aimed at treating GBM. 
Epigenetic silencing of the MGMT gene by promoter methylation has been associated with longer 
overall survival (OS) in patients with GBM who received XRT and TMZ. The MGMT gene encodes a 


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DNA-repair protein that removes alkyl groups from the O6- position of guanine, an important site of 
DNA alkylation. The restoration of the DNA consumes the MGMT protein, which the cell must 
replenish. Left unrepaired, chemotherapy-induced lesions, especially O6-methylguanine, trigger 
cytotoxicity and apoptosis. Epigenetic silencing of the MGMT gene by promoter methylation is 
associated with loss of MGMT expression and diminished DNA-repair activity. GBM patients with 
unmethylated MGMT have intact DNA repair mechanisms resulting in poorer prognosis, reduced 
progression-free survival (PFS), and shorter OS compared to those with methylated MGMT when 
treated with TMZ (Hegi, Diserens et al. 2005, Stupp, Hegi et al. 2009).  
The randomized clinical trial EORTC (European Organization for Research and Treatment of Cancer) 
26981-22981/NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) CE.3 established 
TMZ as part of the standard of care for GBM. It has long been established, however, that GBM 
patients with a methylated MGMT promoter (epigenetically silenced) are most likely to benefit from 
the addition of TMZ as an adjuvant therapy following combined XRT/TMZ (Hegi, Diserens et al. 2005, 
Stupp, Hegi et al. 2009). Patients with unmethylated MGMT promoter tumors derived only a 1-month 
improvement in median survival, and absolute increases in 2- and 5-year survival of approximately 
13% and 8%, respectively (Hegi, Diserens et al. 2005, Stupp, Hegi et al. 2009). The marginal benefit 
of combination therapy for the unmethylated population has brought into question the use of 
combination therapy as an absolute standard, particularly in the clinical trial setting (Alexander and 
Cloughesy 2017). While the Stupp regimen (Stupp, Mason et al. 2005) has been the standard of care 
in adjuvant and newly diagnosed GBM for over a decade, data have shown that OS in the two-thirds 
of patients who have unmethylated MGMT is only 12.7 months, and PFS is only 5.3 months (Hegi, 
Diserens et al. 2005).  
Patients with unmethylated MGMT, therefore, represent the patient group with the highest unmet 
need requiring new treatment options; a role that GDC-0084 may fulfil given that its action is 
independent of the MGMT promoter status of GBM tumors. 
3.3 
GDC-0084 
GDC-0084 is a potent, oral, selective, brain-penetrant small molecule inhibitor of PI3K/mTOR 
specifically designed to achieve blood brain barrier penetration with substantial free brain penetration 
for treatment of GBM. The PI3K pathway is activated in ≥ 70% of GBM tumors, making it a compelling 
target for the treatment of GBM. mTOR is a key mediator of PI3K signaling.  
GDC-0084 was designed to efficiently cross the blood-brain barrier to achieve high drug exposure in 
the brain, thus maximizing its ability to target brain cancers such as GBM. GDC-0084 as proven to be 
efficacious in nonclinical models of brain tumors driven by activation of the PI3K pathway, including 
growth inhibition of human glioma cell lines grown either in vitro or as subcutaneous or intracranial 
grafts in nude mice. Mouse xenograft models demonstrate dose-dependent tumor-growth inhibition 
(TGI) for GDC-0084 with 60% - 90% TGI observed at exposures equivalent to those achieved in the 
clinic. Mechanism-of-action studies indicate that phosphorylation of downstream PI3K pathway 
markers such as Akt and S6 are decreased in glioma lines treated with GDC-0084 and that drug 
treatment leads to G1 arrest. A correlation is seen between tissue concentrations of drug and status 
of pharmacodynamic markers in tumor xenografts. These in vitro and in vivo efficacy studies support 
the investigation of GDC-0084 as a single agent for the treatment of patients with GBM. In addition, 
GBM has been shown to be highly vascularized, and PI3K inhibitors demonstrate anti-angiogenic 
activity in nonclinical studies (Graupera, Guillermet-Guibert et al. 2008). 
3.4 
Risk/Benefit Analysis 
GDC-0084 is a potent, oral, selective, brain-penetrant small molecule inhibitor of PI3K/mTOR being 
developed as an anti-cancer therapeutic agent. It has proven to be efficacious in nonclinical models of 
brain tumors driven by activation of the PI3K pathway. Nonclinical studies have demonstrated that 
GDC-0084 inhibits proliferation of a large number of glioma cell lines in vitro and inhibits tumor growth 
in intracranial and subcutaneous mouse xenograft models of human GBM. GDC-0084 has favorable 
pharmacokinetic (PK) properties characteristic of an orally administered compound that can achieve 
clinical exposure consistent with that obtained in nonclinical efficacy studies. The results of the 
nonclinical toxicology program for GDC-0084 supported the evaluation of GDC-0084 as a potential 
therapeutic agent for GBM. 


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A phase 1 open-label, dose-escalation study (Wen et al, J Clin Oncol 34, 2016; NCT01547546), has 
been completed in 47 patients with progressive or recurrent high-grade gliomas. GDC-0084 was 
given once daily in cycles of 28 days. This first-in-human, phase 1 dose-escalation study of GDC-
0084 at doses between 2 and 65 mg once daily demonstrated a safety profile consistent with classic 
PI3K/mTOR-inhibitor related adverse events (AEs) with the most frequent AEs attributed to GDC-
0084 being fatigue, hyperglycemia, nausea, rash, hypertriglyceridemia, mucositis, hypophosphatemia, 
decreased appetite, and diarrhea with the most common Grade 3 AEs related to GDC-0084 being 
hyperglycemia (8.5%) and mucositis (6.4%). Dose limiting toxicities (DLTs) included 1 case of Grade 
2 bradycardia and Grade 3 myocardial ischemia (15 mg), Grade 3 stomatitis (45 mg), and 2 cases of 
Grade 3 mucosal inflammation (65 mg).  
 
The dose proposed for the current study is based on the results of the previous phase 1 study (Wen 
et al, J Clin Oncol 34, 2016; NCT01547546), which defined the maximum tolerated daily dose (MTD) 
of GDC-0084 in patients with high grade gliomas (WHO Grade III–IV), who had progressed during or 
after treatment with at least 1 prior XRT-containing regimen for gliomas and/or were not candidates 
for regimens known to provide clinical benefit. The MTD was determined to be 45 mg when GDC-
0084 was administered orally once daily (QD) in cycles of 28 days in these patients.  
However, for newly diagnosed GBM patients a dose of 60 mg may be more suitable. A higher clinical 
exposure is expected to be more effective, but still tolerable, in this healthier patient group,  
Thus, the starting dose in this Phase 2a study is 60 mg given orally QD in 28-day cycles. 
PK analysis in the phase 1 study confirmed GDC-0084 was rapidly absorbed and demonstrated linear 
and dose-proportional increases in exposure, with an elimination half-life supportive of both once daily 
and intermittent dosing. In this population of patients, the AEs and other safety findings were 
generally consistent with the established PI3K/mTOR inhibitor class effects and/or with the disease 
under study. The MTD was determined to be 45 mg in this patient population. The data therefore 
warrant further development of GDC-0084 in phase 2 studies in patients with newly diagnosed GBM 
with unmethylated O6-MGMT promoter status.  
3.5 
Rationale for Conducting this Study 
GBM is highly aggressive and patients have limited treatment options. Genetic alterations activating 
the PI3K pathway are common in patients with GBM (Parsons, Jones et al. 2008). GDC-0084 was 
designed to efficiently cross the blood-brain barrier with little efflux, providing greater drug exposure in 
the brain, thus maximizing its ability to target brain cancers such as GBM. A PI3K/mTOR inhibitor with 
significant brain penetration such as GDC-0084 may provide increased clinical benefit to GBM 
patients over currently available therapies (which either are not brain penetrant or do not target a key 
signaling pathway). GDC-0084 has proven to be efficacious in nonclinical models of brain tumors 
driven by activation of the PI3K pathway. Suppression of downstream factors in this pathway, such as 
phospho-Akt and phospho-S6, results in arrest of cell division and apoptosis in vitro and in vivo. 
Taken together with nonclinical toxicology findings that were generally reversible and consistent with 
inhibition of the PI3K/mTOR pathway, these in vitro and in vivo data support the daily and intermittent 
use of GDC-0084 as a single agent for the treatment of patients with GBM.  
GDC-0084 has been studied in a phase 1 clinical trial study (Wen et al, J Clin Oncol 34, 2016; 
NCT01547546) an open-label, multicenter, dose-escalation study evaluating the safety, tolerability, 
and PK of GDC-0084, administered orally, once daily, to 47 patients with progressive or recurrent 
high-grade gliomas. In this population of patients, the AEs and other safety findings were generally 
consistent with the established Class I phosphoinositide 3-kinase (PI3K) and mammalian target of 
rapamycin (mTOR) kinase inhibitor class-effects and/or with the disease under study. GDC-0084 is 
rapidly absorbed and demonstrates linear- and dose-proportional increases in exposure with 7/8 
patients dosed at the dose of 45 mg having drug exposures consistent with anti-tumor activity in pre-
clinical models. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans of tumor brain 
tissue and normal brain tissue suggest that GDC-0084 crosses the blood brain barrier, with a uniform 
distribution throughout the brain. The MTD was determined to be 45 mg when dosed once daily.  
The current phase 2 clinical development program will investigate the efficacy and safety of 
GDC-0084 in the treatment of patients with newly diagnosed GBM, with unmethylated MGMT 


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21 
promoter status, in the adjuvant setting following surgical resection and initial treatment with 
radiotherapy and temozolomide (XRT/TMZ).  
3.6 
Study Objectives 
3.6.1 
Primary Objective 
The primary objective of this study is: 
• 
To evaluate the safety and tolerability of GDC-0084 in patients with newly diagnosed GBM. 
 
3.6.2 
Secondary Objectives 
The secondary safety objectives of this study, including the expansion cohort, are:  
• 
To determine the MTD of GDC-0084 administered QD; in patients with newly diagnosed 
GBM; 
• 
To evaluate the PK of GDC 0084 administered QD to patients with newly-diagnosed GBM 
under fasted and fed conditions; 
The secondary objectives of the preliminary evaluation of clinical benefit in this study, including the 
expansion cohort, are:  
• 
To evaluate and document clinical response assessed as PFS using RANO criteria for QD 
dosing schedule; 
• 
To document other measures of clinical activity, including OS and time to progression (TTP) 
for QD dosing schedule.  
 
3.6.3 
Exploratory Objectives 
Exploratory objectives in this study are: 
• 
To evaluate and document clinical response assessed as PFS using modified RANO criteria 
for QD dosing schedule; 
• 
To further characterize the PK parameters of GDC-0084 administered at the MTD; 
• 
To characterize the PK parameters of GDC-0084 when administered to both fasted and fed 
subjects; 
• 
To assess the distribution of GDC-0084 within the brain by FDG-PET analysis of tumor and 
normal brain tissue (expansion cohort only); 
 
3.7 
Study Design 
This phase 2a study consists of an open-label, multicenter dose-escalation study with expansion, 
designed to assess the safety, tolerability, MTD, PK and clinical activity of GDC-0084 in patients with 
newly-diagnosed GBM (WHO Grade IV astrocytoma) with unmethylated MGMT promoter status.  
The MGMT promoter status must be confirmed by validated polymerase chain reaction (PCR) or 
validated alternative genomic analysis. Eligible patients must have undergone surgical resection of 
the tumor(s) and initial treatment with XRT/TMZ (Stupp regimen). 
The maximum overall duration of the study is estimated to be 2 years. This study will comprise 2 
stages, Stage 1 (dose-escalation) and Stage 2 (dose expansion and fed/fasted investigation)..  
Stage 1 (dose-escalation) will enroll approximately 12 patients (range: 6 - 24 patients; i.e. up to 6 
patients at 60 mg, at 75 mg, at 90 mg, at 105 mg….) for determination of the QD MTD.  
Stage 2 (dose expansion) will enroll 20 patients, who will receive GDC-0084 QD at the MTD 
established for QD dosing in Stage 1. Patients in Stage 2 will be randomized in a 1:1 ratio to either 
receive the drug under fasted conditions or under fed conditions.  


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CONFIDENTIAL 
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The total sample size for the study is approximately 32 patients (range: 26 - 44 patients). 
3.7.1 
Stage 1 
Dose-Escalation and Maximum Tolerated Dose 
GDC-0084 administration will occur in 28-day cycles to investigate whether it is possible to increase 
the previously established MTD of 45 mg QD relating to Phase 1 patients with progressive or recurrent 
high-grade gliomas. Starting dose will be 60 mg QD, subsequently escalating in 15 mg increments until 
the MTD is reached. PK will be evaluated from the initial 60 mg dose level (Dose Level 0) onwards. If 
the QD MTD cannot be escalated above 45 mg, then it will revert to 45 mg QD, which is the MTD 
established in an earlier phase 1 study. A standard “3 + 3” design will be adopted. A minimum of 3 
patients will be enrolled, even if the MTD is confirmed as 45 mg.  During Cycle 1 (Days 2 to Day 28) all 
doses are to be administered at least 1 hour before or 2 hours after food to ensure the study medication 
is taken on an empty stomach. 
 
Figure 1 provides a study diagram.  
 
 


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Figure 1: Study Diagram
Phase 2a study: Determination of RP2D for GDC-0084
Stage 1 Dose-escalation portion
Begin at 60mg and escalate in a 3+3 
approach
Stage 2 Expansion portion
1:1 randomization to receive GDC-
0084 QD at the MTD established 
for QD dosing under either fed or 
fasted conditions
pans


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Dose-Escalation Rules 
Dose-escalation will occur in Stage 1: 
• 
The initial dose (Dose Level 0) for QD MTD determination in will be 60 mg. Dose levels will 
increase in 15 mg steps; 
• 
The dose-escalation portion of the study (Stage 1) will use a "3 + 3" design to assess the 
safety, tolerability, and PK of GDC 0084 administered orally in 28-day cycles; 
• 
Each dose cohort will initially enroll 3 patients. If none of these patients experiences a DLT 
within the DLT assessment period (Day 1 - 28), escalation will proceed to the next higher 
dose level by opening the next higher dose cohort with newly recruited patients; 
• 
If 1 patient experiences a DLT, the cohort will be expanded until a second patient experiences 
a DLT or to a maximum of 6 patients. When a second patient has a DLT, the MTD is 
determined as 1 dose level below the current dose level; i.e. the highest dose level at which 
less than 1/3 of patients (e.g. 1 of 6) experiences a DLT will be declared the MTD.  
• 
If 2 or more patients experience a DLT at Dose Level 0, the MTD will be declared at 45 mg, 
which was the MTD established in the previous phase I study in patients with advanced 
glioma with a QD dosing schedule. 
On the basis of the review of real-time safety data and available preliminary PK data from this study 
with GDC-0084, dose-escalation may be halted or modified by the sponsor as deemed appropriate. 
Decisions regarding dose-escalation and selection will be made by a CRC including the medical 
monitor, recruiting Investigators, sponsor representative and any other relevant and necessary expert 
on as needs basis, according to the CRC charter.  
Definition of Dose Limiting Toxicity  
All AEs, including DLTs, will be reported, with severity assessed according to National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. In case a 
patient experiences one of the below, study participation will be terminated for this patient and the 
EoT visit should be performed.  
For dose-escalation purposes, DLT assessments will be performed by the sponsor in consultation 
with the Investigators during the CRC meetings. 
A DLT is defined as any one of the following toxicities occurring within the DLT assessment window 
(Cycle 1, Days 1 - 28) and assessed by the Investigator to be probably or possibly related to 
GDC-0084: 
• 
Grade ≥ 3 non-hematologic or non-hepatic toxicity that is not related to hyperglycemia or 
hyperlipidemia or mucositis/stomatitis and is not due to disease progression or another clearly 
identifiable cause, excluding the following: 
o 
Alopecia of any grade; 
o 
Grade 3 fever or Grade 4 fever < 5 days duration; 
o 
Grade 3 infection < 5 days duration or that responds to treatment; 
o 
Grade 3 weight gain or loss; 
o 
Grade 3 diarrhea lasting less than 5 days or that responds to standard-of-care 
therapy including hospitalization; 
o 
Grade 3 nausea or vomiting, in the absence of premedication, that lasts for less than 
48 hours or responds to standard-of-care therapy; 
o 
Grade 3 or asymptomatic Grade 4 electrolyte imbalance that resolves or improves 
within 7 days with or without medical intervention, including hospitalization;  
o 
Grade 3 or 4 serum amylase or lipase or creatine phosphokinase laboratory 
abnormality that is asymptomatic (without other laboratory evidence suggestive of 
pancreatitis, rhabdomyolysis, or other major organ dysfunction) and returns to 
baseline within 7 days of interrupting study drug; 


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o 
Grade ≥ 3 total bilirubin or hepatic transaminase (aspartate aminotransferase [AST] 
and alanine aminotransferase [ALT]) elevations that return to ≤ Grade 1 (if normal at 
study entry) or ≤ baseline values within 7 days of interrupting study drug; 
o 
Note: Allergic reactions that necessitate discontinuation of study drug will not be 
considered a DLT; 
• 
Grade ≥ 3 symptomatic fasting hyperglycemia (e.g., dehydration or acidosis requiring 
hospitalization); 
• 
Grade ≥ 4 fasting hypercholesterolemia or triglyceridemia for ≥ 14 days despite intervention 
with a lipid-lowering agent; 
• 
Grade ≥ 4 thrombocytopenia; 
• 
Grade 3 thrombocytopenia that lasts ≥ 7 days or is associated with clinically significant 
bleeding; 
• 
Grade ≥ 4 neutropenia (absolute neutrophil count < 500/μL) lasting ≥ 7 days or accompanied 
by fever (oral or tympanic temperature ≥ 38.0°C [100°F]); 
• 
Grade ≥ 3 total bilirubin or hepatic transaminase (ALT or AST) elevations that do not return to 
≤ Grade 1 (if normal at study entry) or ≤ baseline values within 7 days of interrupting study 
drug; 
• 
For patients with Gilbert’s disease and with Grade 2 bilirubin at baseline, total bilirubin ≥ 10 x 
upper limit of normal (ULN) will be considered a DLT; 
• 
Bradycardia Grade ≥ 2; 
• 
Myocardial ischemia Grade ≥ 2; 
• 
Mucositis/stomatitis Grade 3 not responding to standard-of-care therapy or Grade 4.   Sites 
should consider using an alcohol-free dexamethasone 0.5 mg per 5mL oral solution (elixir) if 
such symptoms eventuate.  Patients may be instructed to use 10ml oral solution swished for 
up to two minutes and then spit, up to four times daily (Rugo et al. 2017). 
• 
Decrease in left ventricular ejection fraction (LVEF) to ≤ 45%; 
• 
Increase of QTc to ≥ 500 msec or by 60 msec; 
• 
Pneumonitis Grade ≥ 2. 
After determination of the MTD, patients continue to receive their protocol assigned dose levels of 
GDC-0084 until progression of their disease or an unacceptable toxicity, whichever occurs first. 
Patients who experience disease progression or an unacceptable toxicity at any time during the study, 
or, in their opinion or the opinion of the Investigator, are not benefiting from GDC-0084, will be 
discontinued from study treatment. Under certain circumstances in which an AE (or DLT) is reversible 
and the risk/benefit assessment suggests a reasonable rationale for continued administration of study 
drug, patients may continue with agreement from the Investigator and the medical monitor. This may 
include dose reduction and change of treatment schedule. An End of Treatment visit will be performed 
approximately 28 days after the last dose of GDC-0084. 
3.7.2 
Stage 2 
Stage 2 of the study will be a two-arm, randomized, open-label expansion cohort to further 
characterize safety, tolerability and PK of GDC-0084 when administered QD in 28-day cycles, and to 
explore the effect of food on the PK of GDC-0084, as well as to provide a preliminary assessment of 
single-agent activity of GDC-0084 in patients with GBM.  
The expansion will start with a screening period, followed by treatment and follow-up periods. It will be 
initiated with recruitment of new patients as soon as the MTD for QD dosing has been determined.  
Approximately 20 patients will be enrolled in the expansion cohort according to the defined study 
eligibility criteria, to perform the comparison of safety and clinical activity. On Days 1 and C2D1, 10 
patients will receive GDC-0084 in a fed state, while the remaining 10 patients will receive GDC-0084 
in a fasted state.  Patients will be allocated to either fed or fasted arms via a central randomization 
mechanism. 
Patients enrolled in Stage 2 may continue the study at the dose allocated until disease progression or 
unacceptable toxicity.  


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3.7.3 
Determination of Recommended Phase 2 Dose 
The RP2D expected to be established during this study is planned to be a dose of GDC-0084 that is 
both safe and tolerated, and that yields a higher exposure which would include Cmax and AUC 
compared to the results of the previous phase 1 study on a QD regimen.  
The RP2D will be confirmed by the CRC after completion of dose escalation. 
4 
Methods: Patients, Interventions, and Outcomes 
4.1 
Study Setting 
The study will be conducted at approximately 5-7 clinical sites in the US. A list of sites will be 
maintained in the Trial Master File (TMF).  
4.2 
Eligibility Criteria 
4.2.1 
Inclusion Criteria 
Patients must meet all the following inclusion criteria to be eligible for enrollment into the study: 
1) Signed informed consent approved by the Institutional Review Board (IRB). Patients must 
sign an authorization for the release of their protected health information; 
2) Age ≥ 18 years; 
3) Life expectancy > 12 weeks; 
4) Present with histologically confirmed intracranial (supratentorial) unmethylated MGMT 
promotor status GBM (WHO Grade lV astrocytoma) with an MGMT status that has been 
confirmed by validated PCR or validated alternative genomic analysis; 
5) Have undergone maximal or subtotal surgical resection of their tumor and within 6 weeks of 
surgery commenced radiation and then received at least 75% of planned treatment with 
XRT/TMZ or XRT only (if clinically indicated), which consists of XRT by external beam to a 
partial brain field in daily fractions of 2.0 Gray (Gy), to a planned total dose to the tumor of 
60.0 Gy, in conjunction with TMZ oral QD 75 mg/m2 in accordance with the Stupp regimen; 
6) Karnofsky Performance Status (KPS) ≥ 70; 
7) Cranial magnetic resonance imaging (MRI) must have been performed within 14 days prior to 
or on the day of the Enrollment/Week 1 Visit; 
8) Stable or decreasing corticosteroid dose within 7 days prior to the first dose; 
9) Adequate bone marrow/hematological function within 14 days prior to Day 1: 
- 
White blood cell count (WBC) > 3,000/µL, absolute neutrophil count > 1,500/mm3; 
- 
Platelet count of > 100,000/mm3;  
- 
Hemoglobin > 10 mg/dL; 
- 
Eligibility level for hemoglobin may be reached by transfusion; 
10) Adequate liver function within 14 days prior to Day 1:  
- 
Total bilirubin ≤ 1.5 x ULN; 
- 
AST and ALT ≤ 2.5 x ULN; 
11) Adequate renal function within 14 days prior to Enrollment/Week 1 Visit:  
- 
Creatinine ≤ 1.5 mg/dL; 
- 
Urine dipstick for proteinuria < 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick 
urinalysis should undergo a 24-hour urine collection and must demonstrate ≤ 1.0 g of 
protein in 24 hours; OR 
- 
Urine protein/creatinine ratio ≤ 1.0; 
12) International normalized ratio (INR) or prothrombin time (PT) (secs) and activated partial 
thromboplastin time (aPTT) within 7 days prior to Enrollment:  
- 
<1.5 x ULN (except for patients receiving anticoagulation therapy) in the absence of 
therapeutic intent to anti-coagulate the patient;  


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CONFIDENTIAL 
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- 
Within therapeutic limits (according to the medical standard in the institution) in the 
presence of therapeutic intent to anti-coagulate the patient;  
- 
NOTE: Use of full-dose anti-coagulants is permitted as long as the INR or aPTT is within 
therapeutic limits (according to the medical standard in the institution) and the patient has 
been on a stable dose of anti-coagulants for at least 2 weeks before the Enrollment/Week 
1 Visit. As per American Society of Oncology guidelines, low-molecular-weight heparin 
should be the preferred approach; 
13) Willing and able to comply with the protocol as judged by the Investigator;  
14) Patients must be willing to forego other drug therapy against the tumor while enrolled in the 
study. 
4.2.2 
Exclusion Criteria 
Patients presenting with any of the following will not be included in the study: 
1) Previous radiotherapy to the brain or cytotoxic drug therapy (including Gliadel® wafers) in 
addition to the required postoperative radiation plus TMZ, non-cytotoxic drug therapy, or 
experimental drug therapy directed against the brain tumor prior to this regimen, will be 
excluded. Patients may have received or be receiving corticosteroids, analgesics, and other 
drugs to treat symptoms or prevent complications but the dose must be stable at treatment 
start. NOTE: 5 aminolevulinic acid-mediated photodynamic therapy administered prior to 
surgery to aid in optimal surgical resection is not considered a chemotherapy agent; 
2) Any prior, or anticipated, concomitant treatment involving a medical device (such as Optune®) 
applying tumor treating fields (TTF).  Prior short-course Optune® monotherapy (i.e. without 
concurrent TMZ or other chemoRx) may be allowed with approval from the Medical Monitor 
3) QT interval time of ≥ 470 msec; 
4) Undetermined/indeterminate MGMT status; 
5) Diabetic patients and/or ongoing use of insulin therapy; clinically confirmed prediabetic 
patients;  
6) Use of any strong CYP3A4 inducing or inhibiting agents within 14 days of first dose of GDC-
0084; 
7) Significant medical illnesses that in the Investigator's opinion cannot be adequately controlled 
or would compromise the patient's ability to tolerate this therapy; 
8) Women who are pregnant (determined by serum beta chorion-gonadotropin) or who are 
lactating. NOTE: Serum pregnancy test to be assessed within 7 days prior to first dose; 
9) Any disease likely to obscure toxicity; 
10) Diagnosed with infratentorial GBM; 
11) Diagnosed with tumor outside of brain; 
12) Diagnosed with gliomatosis cerebri; 
13) Evidence of recent hemorrhage on postoperative MRI of the brain. However, patients with 
clinically asymptomatic presence of hemosiderin, resolving hemorrhagic changes related to 
surgery, and presence of punctate hemorrhage in the tumor are permitted entry into the 
study; 
14) Male and female patients of childbearing potential unwilling or unable to use effective means 
of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of 
contraception in conjunction with spermicidal jelly) throughout the study and for at least 28 
days after the last dose of assigned treatment; 
15) Any previous malignancy; except for adequately controlled limited basal cell carcinoma of the 
skin, squamous carcinoma of the skin or carcinoma in situ of the cervix, or any previous 
malignancy which has been absent of evidence of disease and has not required treatment for 
≥ 3 years;  


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CONFIDENTIAL 
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16) Patients who have any other disease that would in the judgement of the investigator, exclude 
enrollment in this study.  Disease could be either metabolic or psychological, and based upon 
any evidence on clinical examination or special investigations (including a laboratory finding); 
 
17) Any other investigational drug or participation in another investigational study within 30 days 
prior to Enrollment/Week 1; 
18) Known hypersensitivity to any excipients of GDC-0084 formulation or of other PI3K/mTOR 
inhibitors; 
19) Unable to comply with the administration of the study treatment. 
4.2.3 
Contraception Guidelines 
All male and female patients who, in the opinion of the Investigator, are biologically capable of having 
children and are sexually active, must agree to use a highly effective method of contraception 
consistently and correctly for the duration of the active treatment period and for at least 30days after 
the last dose of investigational product. The Investigator, in consultation with the patient, will select 
the most appropriate method of contraception for the individual patient from the permitted list of 
contraception methods, and instruct the patient in its consistent and correct use. The Investigator, at 
each study visit, will confirm and document consistent and correct use. In addition, the Investigator 
will instruct the patient to call immediately if the selected birth control method is discontinued or if 
pregnancy is known or suspected.  
Highly effective methods of contraception are those that, alone or in combination, result in a failure 
rate of less than 1% per year when used consistently and correctly and include: 
• 
Established use of oral, injected or implanted hormonal methods of contraception; 
• 
Correctly placed intrauterine device or intrauterine system; 
• 
Male condom or female condom used TOGETHER WITH a spermicide (i.e., foam, gel, film, 
cream, suppository); 
• 
Male sterilization with appropriately confirmed absence of sperm in the post-vasectomy 
ejaculate; 
• 
Bilateral tubal ligation or bilateral salpingectomy. 
4.3 
Enrollment Procedure 
The Investigator will enroll the individual patients into the study. It is the Investigators responsibility 
that enrollment will only occur after all inclusion and exclusion criteria have been checked and 
eligibility of the patient is verified using a patient eligibility worksheet.  This includes the collection of 
all necessary assessment results per the Schedule of Assessments (see Section 0).  
4.3.1 
Allocation to Treatment 
This is an open-label study; therefore, blinding is not applicable. 
In the dose-escalation portion (Stage 1), withdrawals occurring prior to completion of the DLT period 
will be replaced so as to ensure that a full cohort is available at the time of CRC review. Replacement 
patients can only be made for those who discontinue for reasons other than safety. 
In the expansion portion (Stage 2), 20 patients will be randomized in a 1:1 ratio to receive GDC-0084 
at the RP2D for QD dosing, under either fed or fasted conditions on Days 1 and C2D1.  Details of the 
fed/fasted instructions are provided in section 4.4.1. of this protocol.   
 
4.4 
Study Interventions 
4.4.1 
Treatment Schedule 
Prior to Screening 


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All patients will receive concomitant XRT/TMZ or XRT delivered as fractionated focal irradiation in 
daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy, with concomitant 
administration of daily oral TMZ 75 mg/m2/day from the first day to the last day of radiotherapy. 
Patients must have recovered from side effects of this therapy to at least baseline or Grade 1 before 
entering the study.  Lymphopenia and/or alopecia may be Grade 2 if clinically indicated in the 
judgement of the investigator.  
After Screening/Enrollment 
After screening, in Stage 1, the initial cohort will receive an oral dose of 60 mg GDC-0084 QD 
(4 x 15 mg capsules). Patients of future cohorts are planned to receive GDC-0084 at increasing levels 
with 15 mg steps according to the dose-escalation rules until disease progression or an unacceptable 
toxicity, whichever occurs first.  
For the Stage 2 expansion, patients will receive doses of oral GDC-0084 at the RP2D established from 
Stage 1 for QD dosing in 28-day cycle until disease progression or an unacceptable toxicity, whichever 
occurs first. 
 
Fed and Fasted Instructions 
Days 
 
C1D1 and C2D1 only  
(i.e. just 2 days in total) 
All other days 
 
Fed 
Arm 
 
 
 
 
On days C1D1 and C2D1 ONLY, patients allocated to the fed arm should 
consume a high-fat, high-calorie meal approximately 30 minutes prior to 
dosing, and should then refrain from eating for at least 4 hours post-dose.  
The high-fat (approximately 50 percent of total caloric content of the meal) 
and high-calorie (approximately 800 to 1000 calories) meal should derive 
approximately 150, 250, and 500-600 calories from protein, carbohydrate, 
and fat, respectively.  
Example of the meal is two eggs fried in butter, two strips of bacon, two 
slices of toast with butter, four ounces of hash brown potatoes and eight 
ounces of whole milk.  Alternatively, for vegetarians, beans, peas, tofu and 
cheese are good sources of protein and fat that satisfy protocol criteria.  
Patient can follow their 
own normal diet, which 
ideally should remain as 
consistent as possible,  
 
and;  
 
Capsules must be taken 
1 hour before food or 2 
hours after food, as 
stated in Diary. 
Fasted 
Arm 
 
 
 
 
On Days C1D1 and C2D1, those patients allocated to the fasted arm 
should have fasted overnight for at least 10 hours, and should continue to 
fast for at least 4 hours post-dose. Water may be consumed as required, 
except for the period one hour before dosing to one hour post-dosing.   
 
As above. 
4.4.2 
Schedule of Assessments  
Screening evaluations are to be conducted within 28 days prior to start of protocol-directed therapy. 
Scans must be done within 14 days prior to the start of therapy. If the patient's condition is 
deteriorating during the 28-day screening period, laboratory evaluations should be repeated within 24 
hours prior to initiation of the first cycle of therapy. Timing of assessments is given in Table 1 below. 
Details of assessments are outlined in Section 4.6. 
 


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Table 1: Schedule of Assessments – Stage 1 and Stage 2 
 
 
Cycle 1 
Cycle 2 
Repeat Cycle 2 
Assessments for Cycle 
3 and onwards  
 
 
Screening
Day -28 to 
-1 
Enrollment / 
Week 1 
Day 1 
Day 1 
Every  
4 Weeks 
Every  
8 Weeks 
End of 
Treatment Visit  
 
Short-Term 
Follow-up Visit 
Long term 
Follow-up 
Visitsk 
Visit Window 
 
 
+/- 3 days 
+/- 3 days 
+/- 3 days 
Within 7 days 
28 days from 
last dose +/- 3 
days 
+/- 14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
MGMT Promoter Statusa 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical/Cancer History 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
 
X 
X 
 
Ophthalmologic Examinationb 
X 
 
 
 
X 
 
 
 
Urine Test for proteinc 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
X 
X 
 
Weight  
X 
X 
X 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
KPS 
X 
X 
X 
X 
 
X 
X 
 
MRId 
 
X 
 
 
X 
X 
 
 
FDG-PET scane 
 
X 
 
 
 
 
 
 
ECGf 
X 
X 
X 
X 
 
X 
X 
 
LVEF (ECHO or MUGA) 
X 
 
 
 
X 
 
 
 


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Cycle 1 
Cycle 2 
Repeat Cycle 2 
Assessments for Cycle 
3 and onwards  
 
 
Screening
Day -28 to 
-1 
Enrollment / 
Week 1 
Day 1 
Day 1 
Every  
4 Weeks 
Every  
8 Weeks 
End of 
Treatment Visit  
 
Short-Term 
Follow-up Visit 
Long term 
Follow-up 
Visitsk 
Visit Window 
 
 
+/- 3 days 
+/- 3 days 
+/- 3 days 
Within 7 days 
28 days from 
last dose +/- 3 
days 
+/- 14 days 
aPTT/PT/INR 
X 
X 
X 
X 
 
X 
 
 
bHCG Pregnancy Testg 
X 
X 
X 
X 
 
X 
 
 
PK Samplingh 
 
X 
X 
 
 
 
 
 
Hematology, Chemistryi 
X 
X 
X 
X 
 
X 
X 
 
GDC-0084 Administrationj 
 
X 
X 
X 
 
 
 
 
Study Drug Compliance 
 
 
X 
X 
 
X 
 
 
Concomitant Medications/Procedures 
X 
X 
X 
X 
 
X 
X 
 
AEs 
X 
X 
X 
X 
 
X 
X 
 
Disease status (including PFS and OS) 
 
 
 
 
 
 
 
X 
Disease related therapies 
 
 
 
 
 
 
 
X 
EoT = End of Treatment, FU = Follow-up, ECG = electrocardiogram, LVEF = left ventricular ejection fraction, ECHO = echocardiography, MUGA = multi-gated scan 
a 
Samples should be obtained during surgery prior to XRT+TMZ to confirm MGMT promoter status. Your tissue sample may be sent to Covance lab for further analysis.  
b 
Standard slit-lamp examination looking primarily for corneal opacity. 
c 
By dipstick and within 14 days of enrollment 
d 
Cranial MRI scan must have been performed within 14 days prior to or on the day of the Enrollment/Week 1 visit. 
e 
FDG-PET will occur at Randomization/Week 1, Days 3, 7, of Cycle 1 (only for expansion cohort patients with measurable disease, subject to research site capability).  
f 
Except at screening, ECGs should be performed approximately two hours post-dose, which is expected to be approximately the tmax for GDC-0084 
g 
For visits after enrollment, urine testing is used and may be confirmed by central testing if required. 
h 
At Cycle 1 Day 1, and at Cycle 2 Day 1 samples will be collected at least 15 minutes prior to the visit dose.  At Cycle 1 Day 1 only, samples will be collected at 30 
minutes, and at 1, 2, 3, 4, 6 8 and 24hours post dose (Cycle 1 Day 2). The 24 hour sample should be obtained at least 15 minutes prior to administration of the following 
day’s dose, if applicable. 
i 
Option for central and local testing.  


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j 
GDC-0084 administration (QD), depending on dose-escalation step (Stage 1) and treatment arm (Stage 2). 
 
days 
k 
The long-term FU frequency is q8 wks.  These assessments are made by telephone conversation or site visit (depending on practical considerations) 
 


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4.5 
Endpoints 
4.5.1 
Primary Endpoint 
The primary endpoint of this study is safety-related and is the occurrence of DLTs during the study.  
4.5.2 
Secondary Endpoints 
Secondary endpoints are related to both, safety and clinical benefit as listed below.  
Secondary Safety Endpoints:  
• 
Treatment-emergent AEs (TEAEs), Grade 3-5 TEAEs, serious adverse events (SAEs), fatal 
AEs, and TEAEs leading to GDC 0084 discontinuation or study withdrawal; 
• 
Treatment-emergent Grade 3/4 clinical laboratory abnormalities; 
• 
Changes and shifts from baseline in clinical laboratory, vital signs, and ECG parameters; 
• 
Change from baseline in corticosteroid use; 
• 
Change from baseline in LVEF;  
• 
Change from baseline in KPS; 
• 
Concomitant medication use; 
• 
Adherence to the dosing regimen. 
Secondary Endpoints of Clinical Benefit: 
• 
PFS measured from first dose in the dose-escalation portion (Stage 1) or from randomization 
in the cohort expansion portion of the study (Stage 2) to disease progression (RANO criteria) 
or death due to any cause; 
• 
OS measured from first dose in the dose-escalation portion (Stage 1) or from randomization 
in the cohort expansion portion of the study (Stage 2) to death due to any cause; 
• 
TTP measured from first dose in the dose-escalation portion (Stage 1) or from randomization 
in the cohort expansion portion of the study (Stage 2) to date of earliest disease progression 
according to RANO criteria. 
4.5.3 
Exploratory Endpoints 
Exploratory endpoints in this study are:  
• 
PFS measured from first dose in the dose-escalation portion (Stage 1) or from randomization 
in the cohort expansion portion of the study (Stage 2) to disease progression (modified RANO 
criteria) or death due to any cause; 
• 
PK parameters including area under the curve from time 0 to last measurable time point 
(AUC0–last) and/or area under the curve from time 0 to infinity (AUC0-inf), maximum 
concentration (Cmax), minimum concentration (Cmin), time to reach Cmax (Tmax), t1/2, apparent 
total clearance of the drug from plasma after oral administration (CL/F), and accumulation 
ratio for Cmax and AUC (fed and fasted); 
• 
Change in FDG-PET uptake in tumor and normal brain tissue (defined as normal brain tissue 
with similar cell type to tissue surrounding tumor) in response to GDC-0084 in patients with 
measurable disease; 
• 
DCR measured as the proportion of patients achieving a confirmed best overall response 
(BOR) of complete response (CR), partial response (PR), or stable disease (SD) according to 
a) RANO criteria and b) modified RANO criteria. 
4.6 
Assessments 
All assessments outlined in this section will be performed in accordance with the Schedule of 
Assessments (see Table 1).  
4.6.1 
Physical and Ophthalmologic Examination 
The physical examination will include an evaluation of body systems (e.g. cardiovascular, 
gastrointestinal, neurological, head and neck, respiratory, dermatology). Evaluation for pre-existing 


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conditions that might exclude the patient from eligibility or could interfere with the patient’s 
participation and compliance with the protocol should be performed at Screening. 
The ophthalmologic examination should include use of a slit-lamp or similar equipment to assess 
corneal opacity.   
4.6.2 
Height, Weight and Vital Signs  
Body height (at screening only), weight, and vital signs (blood pressure, pulse and temperature) will 
be measured. 
4.6.3 
Radiographic Assessments  
For all patients, an MRI of the brain will be performed; cranial MRI scan must have been performed 
within 14 days prior to or on the day of the Enrollment/Week 1 visit and then every 8 weeks starting at 
Week 8. The international standardized brain tumor imaging protocol will be followed for MRI imaging. 
Minimum sequences required are: 3D pre-contrast T1, T2/FLAIR, and 3D post-contrast T1. Slice 
thickness for 3D pre- and post-contrast T1 images should be ≤ 1.5 mm with no gap and slice 
thickness for 2D T2 and FLAIR should be ≤ 4 mm with no interslice gap.  
For the expansion cohort, the assessment of disease progression will be done by MRI analysis 
according to RANO criteria. Evaluation will be conducted by a central radiography vendor using 
2 central readers who are blind to treatment assignment (fed or fasted), with an adjudication process 
when there is disagreement between the 2 central readers. 
Patients in Stage 2 with measurable disease, and subject to research site having capability, will be 
required to undergo FDG-PET imaging and analyses will be performed by accredited specialist 
facilities.  
FDG-PET imaging will occur at Randomization/Week 1, Days 3 and 7 of Cycle 1. Timing and days of 
FDG-PET imaging may change on the basis of PK e.g. Tmax and other data analyzed during the study. 
FDG-PET imaging may be obtained using a stand-alone PET or combined PET/computed 
tomography (CT) scanner, or hybrid PET/MRI systems.  
The image acquisition system must remain consistent throughout all scans for the same patient. MRI 
imaging will be performed according to standardized procedures. The central review disease 
response assessments will be used as the primary measure for analysis, and the Investigator disease 
response assessments will be used as supportive measures for analysis. 
At the Randomization/Week 1 visit, the baseline pre-treatment FDG-PET imaging must be performed 
prior to the pre-dose PK sample and the first intake of GDC-0084. Imaging should be completed at 
least 1 hour prior to pre-dose PK sampling. For logistical reasons, the pre-treatment FDG-PET may 
be performed up to 1 day prior to the Randomization/Week 1 visit.  
Prior to the scheduled FDG injection, patients should fast for at least 4 hours (preferably 6 
hours). The blood glucose level should be determined at the time of the FDG-PET scan. Use of 
anti-hyperglycemic medications, including insulin, immediately prior to the FDG-PET scan is not 
permitted, as these agents will impact FDG uptake and compromise the interpretability of the 
FDG-PET scan. Specifically, no short-acting insulin should be administered within 4 hours prior to 
FDG administration. 
Median and mean FDG-PET standard uptake value within the contrast enhancing, measurable target 
lesion(s), contralateral normal-appearing cortical tissue, and contralateral normal-appearing white 
matter will be quantified. 
4.6.4 
Cardiac Assessment  
Cardiac assessment will be performed by the Investigator and be based on assessment of medical 
history, physical examination, 12-lead ECG results (including QTc) and evaluation of LVEF by 
echocardiography (ECHO) or multi-gated scan (MUGA) as well as, as clinically indicated, 
measurement of troponin T and B-type natriuretic peptide as potential biomarkers of early 


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cardiotoxicity. Cardiology consult may be sought by the Investigator if required to confirm suitability for 
inclusion in the study. 
Except for baseline ECGs at screening, ECGs should be conducted approximately 2 hours post-dose, 
to coincide with the approximate timing of Tmax determined in a prior clinical study. 
4.6.5 
Karnofsky Performance Status  
The KPS will be determined using the criteria defined in the Appendix. 
4.6.6 
O6 Methylguanine-Methyltransferase Promoter Status  
The unmethylated MGMT promoter status will be confirmed by validated PCR or alternate validated 
technique, according to standard practice at each site.   
4.6.7 
Pharmacokinetic Assessments  
Pre- and post-dose plasma samples will be collected for PK analysis. All doses of GDC-0084 used for 
PK evaluations are to be administered in the clinic and are to be given with 240 mL of water.  In Stage 
1, patients should fast for 10 hours pre-dose and for 4 hour post-dose on days when they undergo PK 
assessments. In Stage 2, those subjects allocated to the fasted arm should fast for 10 hours pre-dose 
and for 4 hours post-dose on days when they undergo PK assessments. Those subjects allocated to 
the fed arm should consume a high-fat, high-calorie meal approximately 30 minutes prior to dosing, 
and should fast thereafter for at least 4 hours.  All patients should be consistently seated or standing 
for the first 4 hours post dose on PK days, except when ECG recordings are made. 
Stage 1 
On Day 1 of Cycle 1, plasma samples for PK analysis will be collected at least 15 minutes prior to the 
visit dose, and then at 30 (+/- 3) minutes, and at 1 (+/- 10 minutes), 2 (+/- 15 minutes), 3 (+/- 15 
minutes), 4 (+/- 15 minutes), 6 (+/- 15 minutes), 8 (+/- 15 minutes) and 24 (+/- 1) hours post dose. The 
24- hour sample should be obtained at least 15 minutes prior to administration of the following day’s 
dose.  On Day 1 of Cycle 2, plasma samples for PK analysis will be collected at least 15 minutes prior 
to administration of GDC-0084.  The site should also record the time that the Day 28 dose was taken 
based on patient information and/or diary card. 
Stage 2 
On Day 1 of Cycle 1, an appropriate plasma sample for PK analysis will be collected at least 15 
minutes prior to the visit dose, and then at 30 (+/- 3) minutes, and at 1 (+/- 10 minutes), 2 (+/- 15 
minutes), 3 (+/- 15 minutes), 4 (+/- 15 minutes), 6 (+/- 15 minutes), 8 (+/- 15 minutes) and 24 (+/- 1 
hour). The 24-hour sample should be obtained at least 15 minutes prior to administration of the 
following day’s dose.  On Day 1 of Cycle 2, an appropriate plasma sample for PK analysis will be 
collected at least 15 minutes prior to the visit dose. The site should also record the time that the Day 
28 dose was taken based on patient information and/or diary card. 
All samples for concentrations of GDC-0084 will be analyzed by a central laboratory. Samples should 
be collected in accordance with the procedures specified by the central laboratory and detailed in the 
Laboratory Manual.  
4.6.8 
Safety Laboratory Assessments  
Blood samples of approximately 10 mL per assessment of hematological and serum chemistry 
parameters will be collected and processed in accordance with the laboratory procedures. 
All hematology and serum chemistry samples will be submitted by the Investigator to the certified 
laboratory for analysis. Blood samples for hematology and serum chemistry will be prepared using 
standard procedures. Laboratory results should be reviewed by the Principal Investigator or another 
qualified study staff member as soon as received.  
Safety laboratory panels are defined as follows: 


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• 
Hematology and Coagulation: red blood cell count (RBC), hemoglobin, hematocrit, 
reticulocyte count, WBC with differential (neutrophils, bands, eosinophils, basophils, 
lymphocytes, monocytes, and other cells), platelet count aPTT, PT, and INR; 
• 
Serum chemistry: blood urea nitrogen (BUN) or urea, creatinine, sodium, chloride, potassium, 
magnesium, bicarbonate, calcium, phosphorus, total protein, albumin, alkaline phosphatase, 
fasting glucose, total bilirubin, direct and indirect bilirubin, lactate dehydrogenase (LDH), 
cholesterol, uric acid, triglyceride levels, gamma glutamyl transferase (GGT), AST, and ALT. 
Abnormalities in clinical laboratory tests that are considered clinically significant by the Investigator 
will be recorded on the laboratory Case Report Form (CRF) page. If abnormal laboratory results are 
also considered an AE, then a corresponding AE CRF will also be completed. If values after the first 
dose meet criteria defining them as serious, they must be reported as SAEs. 
Unscheduled and repeat laboratory tests may be performed by the laboratory to allow a short as 
possible turnaround time for rapid clinical management of the patient, if necessary. A Laboratory 
Manual with instructions on specimen collection, processing, storing, and shipping will be in place for 
all participating sites. 
4.6.9 
Pregnancy Test  
For female patients of childbearing potential, a serum pregnancy test, will be performed immediately 
before administration of first dose of the investigational product. At subsequent visits, a negative 
pregnancy urine test result is required before the patient may receive the investigational product. If 
the urine pregnancy test is positive, then confirmation of pregnancy will be by bHCG blood test. If 
bHCG blood test is negative, then administration schedule may resume. Pregnancy tests may also be 
repeated as per request of the IRB or if required by local regulations. 
4.6.10 
Adverse Events  
The assessment of AEs will be performed throughout the study, according to the criteria and 
procedures outlined in Section 5.  
4.6.11 
Unscheduled Visits  
Unscheduled visits may be conducted at any time during the study by the Investigator if clinically 
indicated for the care of the patient. An unscheduled visit may include any of the protocol required 
assessments listed in Section 4.6. The exact assessments conducted at the unscheduled visit will be 
specified by the Investigator and recorded in the CRF. Additional tests and procedures may be 
performed at the unscheduled visit for the clinical care of the patient after discussion with, and 
agreement of, the medical monitor. 
4.6.12 
Follow-up Visits  
There is a short-term follow-up visit 28 days after end of study treatment (last dose).  There is long-
term follow-up performed by telephone conversation or site visit (depending on practical 
considerations) where all patients in Stage 1 and Stage 2 who discontinue study treatment will be 
followed every 8 weeks until determination of progressive disease (PD) and then until death unless 
the patient requests to be withdrawn from survival follow-up or termination of the study by the 
Sponsor. This request must be documented in the source documents and signed by the Investigator.  
4.7 
Duration of Therapy 
After the screening period of up to 28 days, patients start to take GDC-0084 in 28-day cycles (every 
day continuous dosing is intent). Dose and regimen depend on the study stage and findings during 
the study (see Section 3.7 and Section 4.4.1).  
In the absence of treatment delays due to AEs, treatment may continue until 1 of the following criteria 
applies: 
• 
DLTs (Stage 1, Cycle 1); 
• 
Disease progression; 
• 
Intercurrent illness that prevents further administration of treatment; 


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• 
Patient decides to withdraw from the study;  
• 
General or specific changes in the patient's condition that render the patient unacceptable for 
further treatment in the judgment of the Investigator. 
4.8 
Duration of Follow-up 
There is a short-term follow-up visit 28 days after end of study treatment.  There is long-term follow-up 
performed by telephone conversation or site visit (depending on practical considerations) where all 
patients in Stage 1 and Stage 2 who discontinue study treatment will be followed every 8 weeks until 
determination of progressive disease (PD) and then until death unless the patient requests to be 
withdrawn from survival follow-up or termination of the study by the Sponsor. This request must be 
documented in the source documents and signed by the Investigator.  PD and death will be reported 
as part of the study endpoints and not as AEs or SAEs. 
4.8.1 
Schedule of Assessments in Follow-up 
Procedures during follow-up will be performed according to the Schedule of Assessments (Table 1).  
4.9 
Dose Delays and Dose Modifications 
4.9.1 
Retreatment Criteria 
Prior to proceeding to the next cycle, patients must have recovered the following organ function: 
• 
Absolute neutrophil count  1.5 x 109/L; 
• 
Platelets  100 x 109/L; 
• 
Total bilirubin within normal institutional limits; 
• 
AST/ALT ≤ 2.5 X institutional ULN. 
Laboratory evaluations must be performed within 48 hours prior to initiation of each cycle of 
therapy. Patients not fulfilling these criteria should have treatment delayed until the recovery of organ 
function. Patients who cannot be retreated within 2 weeks of the end of the previous cycle should be 
removed from study.  
4.9.2 
Dose Modification Guidelines 
In general, dose modifications are not foreseen during the study. However, under certain 
circumstances in which the risk/benefit assessment suggests a reasonable rationale for continued 
treatment with GDC-0084, e.g., after an AE (or DLT), patients may continue with a reduced dose or a 
change of treatment schedule if the Investigator and medical monitor agree.  
Patients in Stage 1 will be enrolled to their allocated dose at a QD dosing frequency. They will continue 
to receive study drug based on the cohort to which they are assigned, and intra-patient dose escalation 
is not permitted. Dose reduction is permitted if clinically indicated. 
 
4.10 Supportive Care Guidelines 
Participants will follow their oncology care plan. All medications required as part of a participant’s 
normal clinical care for support of their medical conditions are permitted during the study, except for 
prohibited medications listed below. All concomitant medications must be recorded in the source 
documentation and in the CRFs for the duration of patient participation. 
The following medications/treatments are prohibited during the study:  
• 
Another investigational drug;  
• 
Strong Cytochrome P450 subtype 3A4 (CYP3A4) inhibitors (such as but not limited to, 
atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, 
ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit juice) 
or strong CYP3A4 inducers (such as but not limited to, rifampin, carbamazepine, 
rifapentine, phenytoin, phenobarbital, and St. John’s wort or hyperforin). 


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Enzyme-inducing anti-epileptic drugs should also be avoided. If use of such drugs is necessary, the 
risks and benefits should be discussed with the medical monitor prior to its concomitant use with 
GDC-0084. 
Based on nonclinical toxicology findings for GDC-0084, known toxicities associated with PI3K and 
mTOR inhibitors (including rapamycin analogues) in the clinic, and clinical safety data from study 
G028070, the guidelines for monitoring and management of specific toxicities detailed below should 
be considered. 
4.10.1 
Hyperglycemia and Metabolic Effects  
It is known that PI3K-mTOR pathway inhibitors can affect glucose and/or insulin metabolism, leading 
to hyperglycemia. Cases of hyperglycemia, including Grade 3 in severity, have been observed in the 
GDC-0084 single-agent study GO28070. Glucose levels at baseline and during study should be 
carefully monitored, and appropriate dose delays/dose modifications for managing hyperglycemia 
should be implemented per protocol guidelines. Patients should be instructed to report symptoms 
associated with hyperglycemia such as thirst, frequent urination, and blurred vision. Use of oral 
anti-hyperglycemic agents, such as metformin, for patients experiencing Grade  2 hyperglycemia 
may be implemented. Anti-hyperglycemic agents should be used to control severe hyperglycemia per 
institutional standard of care.  
Other metabolic effects known to be associated with mTOR inhibitors include hyperlipidemia. Cases 
of low-grade hypercholesterolemia and hypertriglyceridemia have been observed in the GDC-0084 
single-agent study GO28070. Cholesterol and triglyceride levels should be monitored per protocol 
guidelines. Use of lipid-lowering therapy for patients experiencing Grade  2 elevations may be 
initiated per institutional standard of care and protocol guidelines.  
4.10.2 
Potential Lung Inflammation/Pneumonitis  
Lung inflammation was not observed in any of the rat studies and was not observed in the 29-day dog 
study. Evidence of lung inflammation was observed in the 8-day dog pilot study. However, this finding 
was observed only at doses exceeding the MTD in this species. Interstitial lung inflammation/non-
infectious pneumonitis has been observed in cancer patients receiving other PI3K and mTOR 
inhibitors. Patients should be monitored carefully for changes in pulmonary status (including physical 
examinations, pulse oximetry, and periodic CT scans) during treatment with GDC-0084. Patients 
experiencing symptomatic or asymptomatic pneumonitis should be treated per standard of care and 
protocol guidelines adapted from recommendations by (White, Camus et al. 2010) for the 
management of pneumonitis in cancer patients receiving everolimus. Use of corticosteroids should be 
considered for symptomatic cases of non-infectious pneumonitis. Appropriate dosing adjustment 
should be performed per protocol guidelines. 
4.10.3 
Gastrointestinal Tract Toxicities  
In the IND-enabling toxicology studies of GDC-0084, dose-limiting gastrointestinal inflammation and 
degeneration were observed. As a class effect, PI3K and mTOR inhibitors have been associated with 
GI effects including stomatitis/oral mucositis, nausea, vomiting, diarrhea, and colitis. Although rare, 
cases of fatal bowel perforation have been reported in patients who received temsirolimus. Nausea, 
vomiting, and diarrhea have been reported in patients receiving single-agent GDC-0084 in Study 
GO28070. Grade 3 mucosal inflammation was also reported for a patient dosed with 45 mg 
GDC-0084 and two patients dosed with 65 mg GDC-0084 in Study GO28070. GI effects should be 
closely monitored by physical examination and symptom and laboratory evaluations. Development of 
stomatitis/oral mucositis, abdominal pain, nausea, vomiting, and clinically significant changes in stool 
(e.g., diarrhea, bloody stools) may necessitate more frequent monitoring, and study drug may be held 
if symptoms are prohibitive for normal function. 
Gastrointestinal toxicities will be managed according to institutional standard-of-care and protocol 
guidelines. During the study, patients are to receive maximum supportive care as clinically indicated. 
Maximum supportive care for nausea and vomiting may include standard-of-care symptom 
management. Maximum supportive care for diarrhea should include standard-of-care treatment with 
anti-motility therapy and dietary adjustments. Additionally, supplemental intravenous fluids are 


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permitted. Patients experiencing mucositis/stomatitis should also treated as per standard of care.  In 
addition, sites should consider using an alcohol-free dexamethasone 0.5 mg per 5mL oral solution 
(elixir) if such symptoms eventuate.  Patients may be instructed to use 10ml oral solution swished for 
up to two minutes and then spit, up to four times daily (Rugo et al. 2017).  
 
4.10.4 
Potential Skin Disorder  
Treatment-related rash has been commonly reported in cancer patients receiving other PI3K and 
mTOR inhibitors in clinical studies. This rash is commonly manifested as maculo-papular with or 
without pruritus. Rash and other dermatologic events should be closely monitored, and patients 
should apply Sun Protection Factor 50+ sunscreen if exposed to direct sunlight for longer than 15 
minutes after the appearance of any rash. For severe rash, dosing of GDC-0084 should be 
interrupted and patients should be treated with supportive therapy per standard of care. Use of topical 
antihistamine, as well as topical or systemic corticosteroids, may be considered. 
4.10.5 
Potential Hematological or Immunosuppressant Effects  
As a result of observed changes in WBC count and absolute lymphocyte count in nonclinical 
toxicology studies with GDC-0084, patients will be required to have adequate hematologic function to 
enter the study and bone-marrow toxicities from prior therapies must be resolved before initiation of 
GDC-0084. Patients will be monitored routinely for changes in circulating blood cell counts, including 
a WBC count with differential. Because of the known immunosuppressive activity of mTOR inhibitors, 
patients who are immunocompromised as the result of human immunodeficiency virus will be 
excluded from the study. Many patients with high-grade gliomas will have received prior TMZ, a 
therapy that frequently causes lymphopenia. Such patients will be able to enroll in the trial and will be 
monitored closely for opportunistic infections. Prophylactic antibiotics such as 
sulfamethoxazole/trimethoprim are encouraged when the absolute lymphocyte count is  500/μL. The 
decision to initiate prophylactic antibiotics should be discussed with the medical monitor.  
4.10.6 
Potential Cardiac Effects  
One patient receiving 15 mg GDC-0084 QD in Cohort 4 of study GO28070 experienced an AE of 
Grade 2 bradycardia and Grade 3 myocardial ischemia, and 1 patient receiving 30 mg GDC 0084 QD 
in Cohort 6 experienced an event of Grade 2 myocardial infarction. Both patients developed 
asymptomatic cardiac ischemia accompanied by troponin elevations and ECG T-wave inversions. 
One subject dosed at 30 mg GDC-0084 had a QTcF value marginally greater than 450 msec at 24 h 
after dosing, and five subjects had QTcF increases of > 30 msec above baseline on at least one 
occasion, but no QTcF increases > 60 msec were recorded.  
Analysis of the relationship between GDC-0084 plasma concentrations and QTcF showed a slight 
positive trend for absolute QTcF and QTcF change from baseline. Based on this limited sample size, 
GDC-0084 has the potential to prolong the QTc interval. Patients with QTc interval > 470 msec will be 
excluded from this study and a specific, detailed QT and overall cardiac risk mitigation plan will be 
observed for phase 2. 
Patients with significant cardiac history (e.g., myocardial infarction or symptomatic bradycardia, active 
congestive heart failure, and angina pectoris) should be excluded from study participation. During the 
study, patients should be instructed to contact their treating physician if they experience dizziness, 
light-headedness, fainting, sensations of heart palpitations, or slow or irregular pulse. 
Electrocardiograms should be closely monitored. Cardiac enzymes may be measured if deemed 
necessary. 
4.11 Criteria for Removal from Study  
4.11.1 
Removal of Patients  
Patients will be advised in the Informed Consent Form (ICF) that they have the right to withdraw from 
the study at any time without prejudice, and may be withdrawn at the Investigator’s, the contract 
research organization’s (CRO’s) or Kazia Therapeutics Limited’s discretion at any time. If a patient 


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drops out of the study or is withdrawn from the study, the withdrawal form in the patient’s CRF should 
be completed and all study drug supplies should be retrieved. On the withdrawal page the Investigator 
should record the date of the withdrawal, the person who initiated withdrawal and the reason for 
withdrawal. 
Reasonable effort should be made to contact any patient lost to follow up during the course of the 
study in order to complete assessments and retrieve any outstanding data and study 
medication/supplies.  
The following are reasons for patient withdrawal: 
Withdrawn by the Investigator due to: 
• 
AE; 
• 
Protocol deviation (e.g. dosing regimen, failure to comply with clinic visit schedule); 
• 
Administration of an excluded medication; 
• 
Co-existing disease; 
• 
Worsening of condition; 
• 
Pregnancy; 
• 
Clinically significant abnormal laboratory value(s). 
The patient requested withdrawal due to: 
• 
An AE for which the Investigator did not consider removal from the study necessary; 
• 
Perceived insufficient therapeutic effect; 
• 
Co-existing disease; 
• 
Withdrawal of consent. 
Other reasons for withdrawal may include: 
• 
Patient died; 
• 
Kazia Therapeutics Limited/CRO request the patient to be withdrawn; 
• 
Lost to follow-up; 
• 
Administrative problems. 
Withdrawals will only be replaced in the dose finding/MTD portion (Stage 1) of the phase 2a study to 
ensure that a full cohort is available at the time of CRC review. 
4.11.2 
Definition of Dose-Limiting Toxicity 
Toxicities will be graded according to the NCI CTCAE v4.03. If a patient experiences one of the 
below, study participation will be terminated for this patient and the EoT visit should be performed.  
For dose-escalation purposes, DLT assessments will be performed by the Kazia Therapeutics Limited 
in consultation with the Investigators during CRC meetings. A DLT is defined as any one of the 
following toxicities occurring within the DLT assessment window (Cycle 1, Days 1 − 28) and assessed 
by the Investigator to be related to GDC-0084.  
Details on DLTs are given in Section 3.7.1. 
4.11.3 
Premature Discontinuation of Study in a Study Site 
Kazia Therapeutics Limited reserves the right to discontinue the study at any time. The reasons will 
be discussed with the Investigator. A study site may also be discontinued by Kazia Therapeutics 
Limited for significant deviations from the protocol or due to difficulties experienced in running the 
study at that site. 
Kazia Therapeutics Limited may terminate this study at 1 particular or several study sites for 1 of the 
following reasons: 
• 
Non-compliance with Good Clinical Practice (GCP) and/or regulatory requirements; 
• 
Site cannot recruit an adequate number of patients; 
• 
False documentation in the CRF due to carelessness or deliberately; 


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• 
Inadequate co-operation with Kazia Therapeutics Limited or its representatives; 
• 
The Investigator requests closure of his/her study site.  
If the study is prematurely terminated at 1 or more sites, all Investigators have to inform their patients 
and take care of appropriate follow-up and further treatment. IRBs and regulatory authorities will be 
informed about the reason and time of termination according to the applicable laws and regulations. 
4.11.4 
Sponsor Premature Discontinuation Criteria 
Premature termination of this study may occur because of a regulatory authority decision, change in 
opinion of the IRB, drug safety problems, or at the discretion of Kazia Therapeutics Limited. In 
addition, Kazia Therapeutics Limited retains the right to discontinue development of GDC-0084 at any 
time. 
A decision to prematurely discontinue the study is binding to all Investigators of all study sites. IRBs 
and regulatory authorities will be informed about the reason and time of termination according to the 
applicable laws and regulations. If the study is terminated prematurely, all Investigators have to inform 
their patients and arrange for appropriate follow-up and further treatment. 
4.11.5 
Definition of End of Study 
End of the study in all participating sites and countries is defined as the date the last patient 
completes the follow-up post End of Treatment visit. Kazia Therapeutics Limited will notify IRBs and 
regulatory authorities about the regular termination of the study as required according to national laws 
and regulations. 
5 
Adverse Event Reporting 
5.1 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship to the 
investigational medicinal product will be reported as described in the following sections. All AEs will 
be collected in response to a general question about the patient’s well-being and any possible 
changes from the baseline or previous visit, but shall not be specifically solicited with respect to 
particular AEs. 
For all AEs, the Investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE requiring 
immediate notification to Kazia Therapeutics Limited or its designated representative. For all AEs, 
sufficient information should be obtained by the Investigator to determine the causality of the AE. The 
Investigator is required to assess causality. AEs will be followed until resolved, stable, or until the 
patient’s last study visit or is lost to follow-up. If an AE is not resolved or stabilized at the patient’s last 
visit, it is up to the discretion of the Investigator and Kazia Therapeutics Limited’s medical monitor to 
determine if further monitoring of the event is warranted. 
As part of ongoing safety reviews conducted by Kazia Therapeutics Limited, any non-serious AE that 
is determined by the sponsor to be serious will be reported by Kazia Therapeutics Limited as an SAE. 
To assist in the determination of case seriousness, further information may be requested from the 
Investigator to provide clarity and understanding of the event in the context of the clinical study.  
5.2 
Reporting Period 
For AEs, the active reporting period to Kazia Therapeutics Limited or its designated representative 
begins from the time that the patient provides informed consent, which is obtained prior to the 
patient’s participation in the study, i.e., prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration 
of the investigational product, including administration during long term treatment.  
Additionally, all SAEs brought to the attention of the Investigator during the period starting from the 
time the patient signed the ICF and ending not earlier than 28 days following administration of the last 


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dose of study drug for that patient must be reported. Disease progression and death will be reported 
as part of the study endpoints and not as AEs or SAEs unless there is unambiguous evidence that 
death was due to a cause other than disease under study. 
5.3 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment or 
usage. Examples of AEs include but are not limited to:  
• 
Abnormal test findings (see section 5.4); 
• 
Clinically significant symptoms and signs; 
• 
Changes in physical examination findings; 
• 
Hypersensitivity; 
• 
Drug abuse; 
• 
Drug dependency; 
• 
Additionally, they may include the signs or symptoms resulting from: 
o 
Drug overdose; 
o 
Drug withdrawal; 
o 
Drug misuse;  
o 
Drug interactions; 
o 
Extravasation; 
o 
Exposure during pregnancy; 
o 
Exposure via breastfeeding; 
o 
Medication error. 
Worsening of signs and symptoms of the malignancy under study should be reported as AEs in the 
appropriate section of the CRF. Disease progression and death will be reported as part of the study 
endpoints and not as AEs or SAEs unless there is unambiguous evidence that death was due to a 
cause other than disease under study. 
5.4 
Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as an AE 
are as follows:  
• 
Test result is associated with accompanying symptoms; and/or 
• 
Test result requires additional diagnostic testing or medical/surgical intervention; and/or 
• 
Test result leads discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy; and/or 
• 
Test result considered to be an AE by the Investigator or sponsor; 
• 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
5.5 
Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose that: 
• 
Results in death (when there is unmistakable evidence that death was due to a cause other 
than disease under study, otherwise death is report as a study endpoint); 
• 
Is life-threatening (immediate risk of death); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity (substantial disruption of the ability to 
conduct normal life functions); 
• 
Results in congenital anomaly/birth defect; 
• 
Is determined to be an important medical event by the Investigator. 
Progression of the malignancy under study (including signs and symptoms of progression) should not 
be reported as an SAE unless the outcome is fatal within the safety reporting period. Hospitalization 


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due to signs and symptoms of disease progression should not be reported as an SAE. Disease 
progression and death will be reported as part of the study endpoints and not as AEs or SAEs. 
Events that are clearly consistent with the expected pattern of progression of GBM should not be 
recorded as AEs. These data will be captured as efficacy assessment data only. In most cases, the 
expected pattern of progression will be based on the RANO criteria. In rare cases, the determination 
of clinical progression will be based on symptomatic deterioration. However, every effort should be 
made to document progression using objective criteria. If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an AE. 
Medical and scientific judgment is exercised in determining whether an event is an important medical 
event. An important medical event may not be immediately life-threatening and/or result in death or 
hospitalization. However, if it is determined that the event may jeopardize the patient or may require 
intervention to prevent one of the other AE outcomes, the important medical event should be reported 
as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse. 
5.5.1 
Drug Induced Liver Injury  
Abnormal values in AST and/or ALT concurrent with abnormal elevations in total bilirubin that meet 
the criteria outlined below in the absence of other causes of liver injury are considered potential cases 
of drug-induced liver injury (potential Hy’s Law cases) and should always be considered important 
medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury depends on 
the patient’s individual baseline values and underlying conditions. Patients who present with the 
following laboratory abnormalities should be evaluated further to definitively determine the etiology of 
the abnormal laboratory values: 
• 
Patients with AST or ALT and total bilirubin baseline values within the normal range who 
subsequently present with AST or ALT  3 x ULN concurrent with a total bilirubin  2 x ULN 
with no evidence of hemolysis and an alkaline phosphatase  2 x ULN or not available; 
• 
For patients with preexisting ALT OR AST OR total bilirubin values above the upper limit of 
normal, the following threshold values should be used in the definition mentioned above: 
• 
For patients with pre-existing AST or ALT baseline values above the normal range: AST or 
ALT  2 x the baseline values and  3 x ULN, or  8 x ULN (whichever is smaller); 
• 
For patients with pre-existing values of total bilirubin above the normal range: Total bilirubin 
increased by one time the ULN or ≥ 3 x the lower limit of normal (whichever is smaller). 
If able to do so, the patient should return to the investigational site and be evaluated as soon as 
possible, preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history and physical assessment. For oncology studies, the 
possibility of hepatic neoplasia (primary or secondary) should be considered. In addition to repeating 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, GGT, PT/INR, and alkaline phosphatase. A detailed history, including relevant 
information, such as review of ethanol, acetaminophen, recreational drug and supplement 
consumption, family history, occupational exposure, sexual history, travel history, history of contact 
with a jaundiced patient, surgery, blood transfusion, history of liver or allergic disease, and work 
exposure, should be collected. Further testing for acute hepatitis A, B, or C infection and liver imaging 
(e.g., biliary tract) may be warranted. All cases confirmed on repeat testing as meeting the laboratory 
criteria defined above, with no other cause for liver function test (LFT) abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs. Such potential Hy’s Law cases 
should be reported as SAEs. 


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5.6 
Hospitalization 
AEs reported from studies associated with hospitalization or prolongations of hospitalization are 
considered serious. Any initial admission (even if less than 24 hours) to a healthcare facility meets 
these criteria. Admission also includes transfer within the hospital to an acute/intensive care unit (e.g., 
from the psychiatric wing to a medical floor, medical floor to a coronary care unit, neurological floor to 
a tuberculosis unit). 
Hospitalization does not include the following: 
• 
Rehabilitation facilities; 
• 
Hospice facilities; 
• 
Respite care (e.g., caregiver relief); 
• 
Skilled nursing facilities; 
• 
Nursing homes; 
• 
Routine emergency room admissions; 
• 
Same day surgeries (as outpatient/same day/ambulatory procedures), 
• 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE 
is not in itself an SAE. Examples include:  
o 
Admission for treatment of a preexisting condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (e.g., for work-up of 
persistent pre-treatment lab abnormality); 
o 
Social admission (e.g., patient has no place to sleep); 
o 
Administrative admission (e.g., for yearly physical exam); 
o 
Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol); 
o 
Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery); 
o 
Hospitalization for observation without a medical AE; 
o 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient, 
o 
Admission exclusively for the administration of blood products, 
o 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs. However, the medical condition for which the procedure 
was performed should be reported if it meets the definition of an AE. For example, an 
acute appendicitis that begins during the AE reporting period should be reported as the 
AE, and the resulting appendectomy should be recorded as treatment of the AE. 
5.7 
Adverse Event Severity Assessment 
Patients will be evaluated for safety if they have received any treatment. Adverse events and other 
symptoms will be graded according to National Cancer Institute’s Common Toxicity Criteria for 
Adverse Events version 4.03 (CTCAE v4.03). 
 
Table 2: CTCAE v4.03 Grading 
Grade 
Clinical Description of Severity 
0  
No change from normal or reference range  
(This grade is not included in the Version 4.03 document but may be used in certain 
circumstances.) 
1 
Mild  
2 
Moderate  
3 
Severe  
4 
Life-threatening or disabling  
5 
Death related to AE 


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5.8 
Causality Assessment 
The Investigator’s assessment of causality must be provided for all AEs (serious and non-serious); 
the Investigator must record the causal relationship in the CRF, as appropriate, and report such an 
assessment in accordance with the serious adverse reporting requirements if applicable.  
The causality assessment categorization will be:  
• 
Unrelated: If there is no relationship and/or other factors (medicinal products or underlying 
disease) prove an explanation. Clearly due to extraneous causes; 
• 
Unlikely related: If the event occurs within an improbable temporal relationship, and/or in 
which other factors provide a more plausible explanation; 
• 
Possibly related: If the event occurs within a reasonable time sequence, but can also be 
explained by concurrent disease, medicinal products, or chemicals and investigational 
product causality is one of other causes for the described clinical event; 
• 
Probably related: If the event occurs within a reasonable time sequence, was unlikely to be 
attributed to other factors (concurrent disease, medicinal products); 
• 
Related: If the event occurs within a reasonable time sequence and could cannot be 
attributed to other factors (e.g., concurrent disease, chemicals, confounding drug 
administration must be absent. 
An Investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally, the facts 
(evidence) or arguments to suggest a causal relationship should be provided. If the Investigator does 
not know whether the investigational product caused the event, then the event will be handled as 
“related to investigational product” for reporting purposes, as defined by the sponsor (see 
Section 5.12). 
If the Investigator's causality assessment is "unknown but unrelated to investigational product", this 
should be clearly documented on study records. In addition, if the Investigator determines an SAE is 
associated with study procedures, the Investigator must record this causal relationship in the source 
documents and CRF, as appropriate, and report such an assessment in accordance with the SAE 
reporting requirements, if applicable. 
5.9 
Exposure During Pregnancy 
Patients who become pregnant during the study period (up to 28 days after receiving the last 
investigational product dose) must not receive additional doses of investigational product and should 
be withdrawn from the study.  
Patients should be instructed to notify the Investigator if it is determined after completion of the study 
that they became pregnant either during the study or within one month (minimum 28 days) after 
receiving the last investigational product dose.  
If a pregnancy occurs within 28 days of dosing, the pregnancy should be followed to term, any 
premature terminations reported, and the health status of the mother and child including date of 
delivery and the child’s gender and weight should be reported to Kazia Therapeutics Limited after 
delivery. The mother may freely choose to terminate the pregnancy as her own decision. Neither the 
sponsor nor Investigators should influence this decision in any way. Similarly, neither the Investigators 
nor sponsor have the right to intervene or influence this decision and any ensuing procedures. If this 
occurs, the termination of pregnancy should be considered an elective surgical procedure and any 
associated AEs attributed accordingly.  
If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic pregnancy, spontaneous 
abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live born, a terminated 
fetus, an intrauterine fetal demise, or a neonatal death]), the Investigator should follow the procedures 
for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows:  
• 
Spontaneous abortion includes miscarriage and missed abortion; 


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• 
Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs when 
the Investigator assesses the neonatal death as related or possibly related to exposure to 
investigational product. 
5.10 Withdrawal Due to Adverse Events  
Withdrawal due to AE should be distinguished from withdrawal due to other causes, according to the 
definition of AE noted earlier, and recorded on the appropriate AE CRF page.  
When a patient withdraws due to an SAE, the SAE must be reported in accordance with the reporting 
requirements defined in Section 5.12. 
5.11 Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study patient. In addition, each study patient will be questioned about AEs. 
5.12 Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for SAEs. If an SAE occurs, expedited 
reporting will follow local and international regulations, as appropriate. 
5.12.1 
Serious Adverse Event Reporting Requirements 
If an SAE occurs, Kazia Therapeutics Limited, or its delegated representative, is to be notified within 
24 hours of Investigator awareness of the event.  
In particular, if the SAE is fatal or life-threatening, notification must be made immediately to Kazia 
Therapeutics Limited, or its delegated representative, irrespective of the extent of available AE 
information. This timeframe also applies to additional new information (follow-up) on previously 
forwarded SAE reports as well as to the initial and follow-up reporting of exposure during pregnancy 
and exposure via breastfeeding cases.  
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (e.g., if an outpatient study patient initially seeks treatment elsewhere), the Investigator is 
to report the event within 24 hours after learning of it and document the time of his/her first awareness 
of the AE. 
For all SAEs, the Investigator is obligated to pursue and provide information to Kazia Therapeutics 
Limited in accordance with the timeframes for reporting specified above. In addition, an Investigator 
may be requested by Kazia Therapeutics Limited to obtain specific additional follow-up information in 
an expedited fashion. This information collected for SAEs is more detailed than that captured on the 
AE CRF and must be provided on an additional CRF for collection of detailed SAE information. Where 
the same data are collected, the forms must be completed in a consistent manner. For example, the 
same AE term should be used in all occasions this AE is referenced. AEs should be reported using 
concise medical terminology. In general, information to be provided will include a description of the 
AE in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality. Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided. In the case of a patient’s death, a summary 
of available autopsy findings must be submitted as soon as possible to Kazia Therapeutics Limited or 
its designated representative.  
Information should be forwarded to the CRO’s Pharmacovigilance group via the following e-mail 
address: 
GlobalSAEinbox@chiltern.com 
The IRB must be informed if the SAE, in the opinion of Kazia Therapeutics Limited or the Investigator, 
is likely to affect the safety of the patients or the conduct of the study.  


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5.12.2 
Non-Serious Adverse Event Reporting Requirements 
All AEs and SAEs will be reported on the AE page(s) of the CRF.  
5.12.3 
Sponsor Reporting Requirements to Regulatory Authorities 
AE reporting, including suspected serious unexpected adverse reactions (SUSARs), will be carried 
out in accordance with applicable local regulations. 
6 
Data Collection, Management and Analysis 
6.1 
Source Data 
Source documents (including all demographic and medical information, CRFs, and a copy of the 
signed ICF indicating the study number and title) for each patient in the study will be maintained by 
the Investigator (generally in the patient’s files), and all information in the CRFs must be traceable to 
the source documents.  
All data should be recorded directly into the patient’s medical record as source data. It will be 
confirmed at the study initiation monitoring visit which documents will be considered as source data 
for each site. These will be documented and reviewed by the monitor at each monitoring visit. 
Source documents must be available to document the existence of the patient and substantiate the 
integrity of study data collected. 
6.2 
Data Collection, Management and Reporting 
Procedures for data management (i.e., entry, storage, etc.) are outlined in the study’s Data 
Management Plan.  
6.2.1 
Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included patient. The completed original CRFs 
are the sole property of Kazia Therapeutics Limited and should not be made available in any form to 
third parties, except for authorized representatives of Kazia Therapeutics Limited or appropriate 
regulatory authorities, without written permission from Kazia Therapeutics Limited. 
The Investigator has ultimate responsibility for the collection and reporting of all clinical, safety and 
laboratory data entered on the CRFs and any other data collection forms (source documents) and 
ensuring that they are accurate, authentic / original, attributable, complete, consistent, legible, timely 
(contemporaneous), enduring and available when required. The CRFs must be signed by the 
Investigator or by an authorized staff member to attest that the data contained on the CRFs is true. 
Any corrections to entries made in the CRFs, source documents must be dated, initialed and 
explained (if necessary) and should not obscure the original entry. Data transcribed on the CRF, 
which are derived from source documents, should be consistent with the source documents or the 
discrepancies should be explained. 
In most cases, the source documents are the hospital's or the physician's patient chart. In these 
cases, data collected on the CRFs must match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents. In these cases, a 
document should be available at the Investigator’s site as well as at Kazia Therapeutics Limited and 
clearly identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document. 
6.2.2 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or Kazia Therapeutics Limited, the 
Investigator agrees to keep records, including the identity of all participating patients (sufficient 


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information to link records, e.g., CRFs and hospital records), all original signed informed consent 
documents, copies of all CRFs, safety reporting forms, source documents, and detailed records of 
treatment disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, telephone calls reports). The records should be retained by the Investigator according to 
International Council on Harmonization (ICH), local regulations, or as specified in the Clinical Study 
Agreement, whichever is longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the required 
period (e.g., retirement, relocation), Kazia Therapeutics Limited should be prospectively notified. The 
study records must be transferred to a designee acceptable to Kazia Therapeutics Limited, such as 
another Investigator, another institution, or to an independent third party arranged by Kazia 
Therapeutics Limited. Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  
The Investigator must obtain Kazia Therapeutics Limited's written permission before disposing of any 
records, even if retention requirements have been met. 
6.3 
Statistical Methods 
A Statistical Analysis Plan (SAP) will be prepared as a separate document and will include a more 
technical and detailed description (including the handling of missing data, transformations and other 
data handling procedures as well as templates for Tables, Listings, and Figures) of the planned 
statistical summaries. The SAP is a higher level document that the relevant statistical-related text 
following.  The SAP will be finalized before initiating any statistical analysis. Tabulation of summary 
statistics and data analysis will be performed using SAS®. 
6.3.1 
Analysis Populations 
The following analysis populations are defined:  
• 
The Intent -to-Treat (ITT) population includes all randomized patients; ITT analyses will be 
conducted on the basis of the arm assigned at randomization 
• 
The Modified Intent-to-Treat (mITT) population includes alll eligible patients who received at 
least 1 dose of GDC-0084  and have evaluable post-baseline tumor response data; mITT 
analyses will be conducted on the basis of the treatment assigned at randomization; 
• 
Safety population (SAF): All eligible patients who received at least 1 dose of GDC 0084 will be 
included in the safety population. Safety analyses will be conducted on the basis of initial 
received treatment;  
• 
PK population: All eligible patients in the safety population who have an adequate concentration 
vs. time profile to determine PK parameters 
• 
A Per-Protocol (PP) subset will also be used to analyze endpoints of clinical benefit and will be 
based on study drug exposure (compliance and/or time on study drug) and major protocol 
deviations. The criteria for inclusion in the PP subset will be finalized and documented prior to 
database lock. 
 
6.3.2 
Timing of Analyses 
Regular cohort safety reviews will be performed as described above during Stage 1 to support 
dose-escalation and if necessary, de-escalation decisions. 
 
A final analysis will be performed when all patients discontinue treatment and complete their EoT visit. 
Supplemental analyses may be performed at the completion of the study but will be considered 
exploratory. 
6.3.3 
General Considerations 
Data from Stage 1 and Stage 2 may be summarized separately. For Stage 1 assessment, summaries 
will be presented by dose level and overall. For Stage 2, summaries will be presented by treatment 
arm (fed versus fasting) and overall. Selected safety parameters may be summarized using pooled 
data from the selected dose level in Stage 1 and fasted patients in Stage 2. 


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There may be a statistical comparison of Cmax/AUC between fasted and fed patient data in Stage 2. 
Descriptive statistics (N, mean, standard deviation, median, minimum, and maximum) will be 
presented for continuous variables. Geometric means and geometric coefficient of variation will also 
be presented for PK data. Frequency distributions (counts and associated percentages) will be 
presented for categorical variables. Median, 25th and 75th percentiles and confidence intervals (CIs) 
will be presented for time-to-event data. Unless specified otherwise, CIs will be presented as 95% 
CIs. 
The study is descriptive in nature and is not powered for a confirmatory statistical goal or objective. 
However, comparisons of treatment arms may be performed in Stage 2. Formal hypothesis testing will 
not be done, and no adjustment for multiple comparisons will be used. 
Individual patient data listings will be provided to support summary tables.  
The effects of noncompliance, treatment discontinuations, premature study withdrawals, subsequent 
therapies, and covariates will be assessed to determine the impact on the general applicability of 
results from this study. 
6.3.4 
Analysis of Clinical Benefit 
Analyses of tumor-related endpoints will include all evaluable data collected until initiation of 
subsequent anti-cancer therapy. Sensitivity analyses may be performed excluding data collected after 
the End of Treatment Visit.  
Requirements for PD confirmation and any impact on the calculations for analysis (i.e., PFS, TTP, 
duration or stable disease, etc.) and associated sensitivity analyses will be described in the SAP.  
For Stage 2 tumor-related endpoints, the responses assigned by the blinded central review will be 
used as the primary measure for analysis, and the responses assigned by the Investigator will be 
used as supportive measures for analysis.  
PFS is defined as the time in months from start date and/or date of disease diagnosis until disease 
progression or death due to any cause. Patients without disease progression or death will be 
censored at the last evaluable radiographic assessment. Patients with no post-dose radiographic 
assessment will be censored at their start date (Day 1). The primary analysis of PFS will be 
conducted in the SAF for Stage 1 and the mITT for Stage 2. Analyses of PFS may be repeated in the 
PP. 
The Kaplan-Meier method will be used to describe and present PFS. Median PFS will be presented 
with 95% CI, 25th and 75th percentiles and minimum and maximum values. Kaplan-Meier estimates of 
PFS at 6, 9, and 12 months will also be presented with 95% CIs. PFS will also be displayed 
graphically using Kaplan-Meier estimates. 
For Stage 2, differences between treatment arms will be tested using a two-sided log rank test. 
Stratified hazard ratio (HR) estimates of the treatment comparisons with associated 95% CIs will be 
estimated from a Cox regression model.   
OS is defined as the time in months from start date and/or disease diagnosis until death due to any 
cause. Patients who are alive at the time of analysis will be censored at the date last known to be 
alive. The primary analysis of PFS will be conducted in the SAF for Stage 1 and the ITT for Stage 2. 
Analyses of OS may be repeated in the mITT and/or PP. 
TTP is defined as the time in months from start date and/or until disease progression . Patients 
without disease progression will be censored at the last evaluable radiographic assessment. Patients 
with no post-dose radiographic assessment will be censored at their start date (Day 1). 
Analyses of OS and TTP will be performed using the same methods as described for PFS.  
Post-hoc stratification/analysis factors may include disease progression (post-surgery at time of 
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The exploratory endpoint DCR is defined as the proportion of patients achieving a confirmed BOR of 
CR, PR or SD according to a) RANO criteria and b) modified RANO criteria. BOR is defined as the 
best response recorded from first dose (Stage 1) or randomization (Stage 2) until progressive disease 
, death, withdrawal of consent or end of study, whichever occurs first. To be assigned a status of CR, 
PR or SD, the response must be confirmed by repeat assessments that should be performed no less 
than 28 days after the criteria for response are first met, i.e., patients need to have two consecutive 
assessments of CR, PR or SD. To be assigned a BOR of SD patients must have a minimum duration 
of SD of at least 6 weeks. 
The number and proportion of responders and non-responders based on objective response rate and 
DCR will be presented with 95% Clopper-Pearson CIs. Further, objective response rate and DCR will 
be compared between treatment arms using Fisher’s exact test. The difference in the proportion of 
responders and corresponding 95% CI (based on the Hauck-Anderson approach) will also be 
displayed. 
Analyses of PFS will be repeated using modified RANO criteria. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
6.3.5 
Safety Analysis 
All safety analyses will be conducted in the safety population.  
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). The 
severity of AEs will be graded according to the United States NCI CTCAE, version 4.03. 
TEAEs are defined as any AE occurring or worsening on/after the first study drug dose and within 28 
days after the last dose date. TEAEs leading to study drug discontinuation, TEAEs leading to dose 
reduction/interruption, TEAEs related to study drug, SAEs, TEAEs leading to study drug 
discontinuation, and TEAEs with an outcome of death will be summarized by system organ class, and 
preferred term. Disease progression and death will be reported as part of the study endpoints and not 
as AEs or SAEs. A summary of TEAEs of NCI CTCAE Grade 3 or higher, as well as the most 
frequent TEAEs (preferred terms) by grade, and TEAEs by relationship to study treatment, will be 
provided. Additionally, a summary will be done for AEs using the worst grade of the event.  
Values and changes from baseline (last value obtained prior to first dose) in clinical laboratory results 
will be summarized by visit. Clinical laboratory values will be graded according to the NCI CTCAE 
4.03, for applicable tests. Shifts in CTC grades from baseline grade will be summarized. The number 
and percentage of patients with treatment-emergent Grade 3/4 clinical laboratory abnormalities will 
also be presented. The number and percentage of patients with abnormally high glucose values 
(hyperglycemia) or abnormally low platelet values (thrombocytopenia) will be summarized overall and 
by CTC grade (since these are DLT criteria). 
KPS data will be summarized categorically (number and percentage of patients with each score at 
each visit).  
Values and changes from baseline in vital signs will be summarized by visit. 
Values and changes from baseline in ECG, parameters will be summarized by visit. The number and 
percentage of patients with an increase of QTc to ≥ 500 msec or a change from baseline of at least 60 
msec will be presented overall and by visit. The number and percentage of patients with ECG 
abnormalities at each visit will also be presented.  
Values and changes from baseline in LVEF will be summarized by visit. The number and percentage 
of patients with a drop in LVEF to ≤ 45% will be presented. Troponin T and B-type natriuretic peptide 
values will be listed. 
Changes in corticosteroid use will be summarized. Further details on corticosteroid use will be defined 
in the SAP.  
Concomitant medications are defined as any medications taken on/after the first study drug dose 
(including those started prior to first dose and ongoing at time of first dose) and within 28 days after 


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the last dose date. Concomitant medication use will be summarized. Any medications started and 
stopped prior to first dose or started after last dose + 28 days will be listed but not summarized. 
Treatment exposure will be summarized. Patient diaries will be used to assess compliance.  
6.3.6 
Pharmacokinetic Analysis 
All PK analyses will be conducted on the PK population.  
Serum concentrations before and after GDC-0084 administration and PK parameters (AUC0–last and/or 
AUC0-inf, Cmax, Cmin, Tmax, t1/2, CL/F, and accumulation ratio for Cmax and AUC) will be summarized by 
dose level (Stage 1) and treatment arm (Stage 2). Individual and mean concentrations vs. time will be 
displayed graphically. 
Non-compartmental analysis will be used to calculate the PK parameters. Further details will be 
provided in the SAP. 
6.3.7 
FDG-PET Analysis 
All FDG-PET analyses will be conducted on the ITT population in Stage 2.  
For Stage 2 only (and patients who have these tests ony), FDG-PET uptake in tumor and normal 
brain tissue before and following administration of GDC-0084 will be summarized by visit and across 
treatment arm. 
6.4 
Sample Size 
The sample size in Stage 1 is based on the 3 + 3 design. In Stage 2, no formal sample size 
calculation was performed. The number of patients planned to recruit is guided by practical rather 
than statistical considerations.  
Stage 1 (dose-escalation) will enroll approximately 12 patients (range: 6 - 24 patients). 
  
Stage 2 (dose expansion) will enroll 20 at the MTD established in Stage 1 for QD dosing.  
The total sample size for this study is approximately 32 patients (range: 26 - 44 patients). 
6.5 
Recruitment 
To achieve adequate patient enrollment to reach the targeted sample size, Kazia Therapeutics 
Limited and the CRO will adopt a close collaboration with the recruiting Investigators. This will ensure 
timely discovery and resolution of any recruitment related issues that may be encountered.  
7 
Monitoring 
7.1 
Cohort Review Committee 
On the basis of the review of real-time safety data and available preliminary PK data from this study 
with GDC-0084, dose-escalation may be halted or modified by Kazia Therapeutics Limited as deemed 
appropriate.  
Decisions regarding dose-escalation and selection will be made by a CRC including the medical 
monitor, recruiting Investigators, sponsor representative and any other relevant and necessary expert 
on as needs basis, according to the CRC charter. For dose-escalation purposes, and selection of 
appropriate dose levels and schedules DLT assessments and other safety/PK will be reviewed by 
Kazia Therapeutics Limited in consultation with the Investigators during CRC meetings. 
7.2 
Interim Analysis and/or Stopping Guidelines 
A description of planned analyses is shown in Section 6. There is no interim analysis planned for early 
efficacy or futility/early stopping. Guidelines for discontinuing the study are given in  
Section 4.11.  


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7.3 
Clinical Monitoring 
The study will be monitored by a CRO. Its representatives will be allowed access to all information 
resulting from this study and Kazia Therapeutics Limited will have an unrestricted right to use such 
information. The study monitor will have access to laboratory test reports and other patient records 
needed to verify the entries on the CRF. The patients’ confidentiality will be respected as required by 
local law. 
The sponsor and the CRO are responsible for ensuring the proper conduct of the study with regards 
to protocol adherence and validity of the data recorded on the CRFs. Therefore, a clinical monitor is 
assigned to the study. With duties to aid the Investigator and at the same time, the CRO, in the 
maintenance of complete, legible, organized and easily retrievable data. In addition, a clinical monitor 
will explain, interpret and ensure the Investigator’s understanding of all applicable regulations 
concerning the clinical evaluation of the investigational product and ensure an understanding of the 
protocol, reporting responsibilities and the validity of the data. 
Details on data collection and monitoring activities can be found in the study’s Monitoring Plan. 
7.4 
Auditing 
This study may be audited by Kazia Therapeutics Limited or its designee to verify the authenticity of 
recorded data, protocol adherence and compliance with ICH-E6. Patients participating in the study 
should be informed that their records might be reviewed for this purpose, and by government health 
authorities. The patients’ confidentiality will be respected as required by local law. 
Further, audits at a study site may take place at any time during or after the study. The independent 
audit can be carried out by the CRO’s or Kazia Therapeutics Limited’s quality assurance personnel 
(including a third-party auditor contracted by Kazia Therapeutics), or a regulatory authority. 
8 
Pharmaceutical Information 
8.1 
Investigational Product  
GDC-0084 is a potent, oral, selective, brain-penetrant small molecule inhibitor of class I PI3K and 
mTOR kinase which has been specifically developed for the treatment of brain cancer. 
Name:  
GDC-0084  
Active ingredient: 
(5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-
yl)pyrimidin-2-amine) 
Excipients: 
Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and 
colloidal silicon dioxide 
Presentation: 
White conforming opaque size 0 capsules for oral administration manufactured in 
accordance with Good Manufacturing Practice (GMP) 
Dosage: 
15 mg GDC-0084 per capsule 
Batch numbers and retest/expiry dates will be documented in the TMF and in the final clinical study 
report.  
8.2 
Supply, Packaging and Labeling 
The 15 mg GDC-0084 capsules will be produced and supplied by Kazia Therapeutics vendor(s) in 
accordance with GMP. 
Primary packaging of the product will be 60CC white high-density polyethylene round bottle, induction 
sealed with child resistant closure. Each bottle contains 35 capsules. 


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Clinical labeling, warehousing and distribution, including returns, will be organized centrally. The label 
will contain the information as required by the relevant regulatory authority and national requirements. 
Labelling will be performed according to GMP and ICH GCP guidelines and local law. 
8.3 
Storage and Handling 
The investigational product must be stored in securely locked areas not generally accessible until 
dispensed to the patients. The medication must be stored at between 15°C and 30°C (59°F–86°F). 
The key to the storage area is to be kept by the Investigator or other person responsible for the 
medication. The store will be accessible only to those persons authorized by the Investigator to 
dispense study medication. The Investigator is responsible for the dispensing of medication according 
to the dosage regimen outlined in this protocol. All investigational product (partly used, unused and 
empty packaging) is to be left in the original packaging and must be returned to Kazia Therapeutics 
Limited’s nominated vendor for destruction at the end of the study. 
8.4 
Accountability 
The investigational product supplied by Kazia Therapeutics Limited is to be used exclusively in this 
clinical study according to the instructions of this protocol. 
The Investigator must confirm the receipt of the investigational product with his/her signature. A copy 
of this receipt must be kept by the Investigator and another copy will be stored in the TMF. It is 
requested that any damaged or defective investigational product is promptly reported to the CRO and 
Kazia Therapeutics Limited. 
The Investigator, or an approved representative (e.g. pharmacist), should maintain records of the 
product’s delivery to the study site, the inventory at the site, the use by each patient, and will ensure 
that all investigational product is stored in a secured, limited access area. These records should 
include dates, quantities, batch/serial numbers, retest/expiration dates (if applicable), and the unique 
code numbers assigned to the investigational product(s) and study patients. Investigators should 
maintain records that document adequately that the patients were provided with the doses specified 
by the protocol and reconcile all investigational product received from Kazia Therapeutics Limited’s 
vendors. 
All used and unused supplies must be retained for verification and drug accountability and must be 
returned to Kazia Therapeutics Limited’s nominated vendor for destruction after completion of the 
study. 
To ensure adequate records, all investigational product will be accounted for on an ongoing basis 
throughout the study in accountability forms at the study site. Records will be kept in accordance with 
the applicable regulatory requirements and the Investigator will ensure that the investigational product 
is dispensed only by qualified site staff.  
8.5 
Preparation and Administration 
The capsules should never be opened and should be swallowed whole, not chewed. 
In Stage 1, patients will be instructed to take the capsules according to the current dose level 
investigated as a single dose. For Stage 2, doses depend on the findings of Stage 1. Timing of intake 
in relation to food or beverage consumption and other procedures is outlined in the respective 
sections on study design (Section 3.7) and assessments (Section 4.64.6).  
During the PK sampling period, i.e. from Enrollment/Week 1 until Day 1 of Cycle 2, patients will take 
GDC-0084 under supervision of qualified study site personnel, at least 15 min after the pre-dose PK 
blood sample. Thereafter, patients will take their GDC-0084 dose self dependently and compliance 
will be checked every 4 weeks by the Investigator.  


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8.6 
Warnings and Precautions 
Information on known AEs and potential risks associated with the investigational product as well as 
further guidance for the Investigator on safety monitoring and management for specific can be found 
in the Investigator’s Brochure (IB).  
8.7 
Prior and Concomitant Medication 
8.7.1 
Prior Medication 
Medications not permitted before the start of the study (i.e., before first intake of the study drug) are: 
• 
Previous radiotherapy to the brain or cytotoxic drug therapy (including Gliadel wafers) in 
addition to the required postoperative radiation plus TMZ, non-cytotoxic drug therapy. 
8.7.2 
Concomitant Medication 
Medications not permitted at any point during the course of this study are:  
• 
Insulin therapy; 
• 
Strong CYP3A4 inducing or inhibiting agents; 
• 
Other investigational drugs. 
9 
Correlative Studies  
9.1 
Pharmacokinetic Studies 
Detailed information, in addition to that provided in this protocol, on the PK sampling procedures, 
including sampling time plans, processing of the samples and shipping, can be found in the study’s 
Laboratory Manual.  
10 Ethical Conduct of the Study and Dissemination of Data 
10.1 Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as the 
general principles set forth in the International Ethical Guidelines for Biomedical Research Involving 
Human Subjects (Council for International Organizations of Medical Sciences 2002), Guidelines for 
GCP (ICH 1996), and the Declaration of Helsinki (World Medical Association, latest version).  
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on GCP, 
and applicable local regulatory requirements and laws. 
10.2 Research Ethics Approval 
It is the responsibility of the Investigator to have prospective approval of the study protocol, protocol 
amendments, informed consent documents, and other relevant documents, e.g., recruitment 
advertisements, if applicable, from the Institutional Review Board (IRB). All correspondence with the 
IRB should be retained in the Investigator File. Copies of IRB approvals should be forwarded to Kazia 
Therapeutics Limited, or its agent. This approval must refer to the study by exact protocol title and 
number, identify the documents reviewed and state the date of review and/or approval. 
The only circumstance in which an amendment may be initiated prior to IRB approval is where the 
change is necessary to eliminate apparent immediate hazards to the patients. In that event, the 
Investigator must notify the IRB and Kazia Therapeutics Limited in writing immediately after the 
implementation. 
During the study, the Investigator should provide to the IRB all documents that are subject to review. 
The IRB must be informed by the Investigator of all subsequent protocol amendments and of 
SUSARs occurring during the study which are likely to affect the safety of the patients or the conduct 


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of the study. Approval for such changes must be transmitted in writing to Kazia Therapeutics Limited 
by the Investigator. 
10.3 Protocol and Investigator’s Brochure 
All study personal must be familiar with the protocol to be able to conduct the study in the manner 
specified.  
Kazia Therapeutics Limited has supplied the Investigator with an Investigator’s Brochure (IB), which 
describes the investigational product being tested and its known adverse effects. The Investigator 
must be familiar with this document before the study commences. Kazia Therapeutics Limited will 
provide additional information requested by the Investigator before commencing the study or during 
its conduct.  
10.4 Protocol Amendments 
This protocol cannot be altered or changed except through a formal protocol amendment, which must 
be approved by the IRB before it may be implemented. Protocol amendments will be filed with the 
appropriate regulatory agencies having jurisdiction over the conduct of the study.  
Neither the Investigator nor the CRO should not implement any deviation from, or changes of, the 
protocol without agreement by Kazia Therapeutics Limited and prior review and documented approval 
from the IRB of an amendment. The only exceptions are where necessary to eliminate immediate 
hazards to study patients, or when the changes involve only logistical or administrative aspects of the 
study (e.g., change in monitor, change of telephone numbers). Such non-substantial protocol 
amendments may or may not be required to be submitted for approval to the IRB and regulatory 
agencies. The CRO will ensure that the Investigators submit necessary protocol amendments to the 
appropriate IRB. 
All agreed protocol amendments must be clearly documented using standard procedures and must be 
signed and dated by Kazia Therapeutics Limited and the Investigator. 
10.5 Documentation and Materials Supplies 
All supplies provided to the Investigators for the purpose of carrying out the study are supplied only 
for the purpose of the study and must not be used for any other purpose. The Principal Investigator or 
(a) person(s) delegated by the Principal Investigator is/are responsible for the security and 
accountability of all supplies. All such supplies, if not used during the course of the study and not 
forming a part of the documentation required to be retained by the Investigator, must be returned to 
Kazia Therapeutics Limited at the conclusion of the study. 
10.6 Informed Consent  
The ICF must be in compliance with ICH GCP, local regulatory requirements, and legal requirements. 
The Investigator, or a person designated by the Investigator, will obtain written informed consent from 
each patient or the patient's legal representative before any study-specific activity is performed. The 
Investigator will retain the original of each patient's signed consent document. 
Information should be given in both oral and written form whenever possible and deemed appropriate 
by the IRB. The Investigator must ensure that each study patient, or his/her legal representative, is 
fully informed about the nature and objectives of the study and possible risks associated with 
participation. The patient will be given sufficient time to consider the study’s implications before 
deciding whether to participate. 
The ICF used in this study, and any changes made during the course of the study, must be 
prospectively approved by both the IRB and Kazia Therapeutics Limited, or its agent, before use. 
Consent forms must be in a language fully comprehensible to the prospective patient. Informed 
consent will be documented by the use of a written consent form approved by the IRB and signed by 
the patient and the Investigator obtaining the consent. The ICF will also be annotated with the study 
patient number. 


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The written consent document will embody the elements of informed consent as described in the 
Declaration of Helsinki and will also comply with local regulations. Consent must be documented by 
the patient’s dated signature. The signature confirms the consent is based on information that has 
been understood. Each patient’s signed ICF must be kept on file by the Investigator for possible 
inspection by regulatory authorities and Kazia Therapeutics Limited. 
Should there be any amendments to the final protocol, such that would directly affect the patient’s 
participation in the study e.g. a change in any procedure, the ICF must be amended to incorporate 
this modification and the patient must agree to sign this amended form indicating that they re-
consenting to participate in the study. 
Patients will be instructed that they are free to obtain further information from the Investigator at any 
time and that they are free to withdraw their consent and discontinue participation in the project at any 
time without prejudice. The prospective patient will also be advised that access to medical records 
would be required. 
10.7 Confidentiality 
All parties will ensure protection of patient personal data and will not include patient names on any 
sponsor forms, reports, publications, or in any other disclosures, except where required by laws.  
Patient names, address, birth date and other data which may identify the patient will be replaced by a 
numerical code consisting of a numbering system provided by Kazia Therapeutics Limited, or its 
delegate, in order to de-identify the study patient. In case of data transfer, Kazia Therapeutics Limited 
and its agents will maintain high standards of confidentiality and protection of patient personal data. 
Additionally: 
Either prior to or during the course of the study, Kazia Therapeutics Limited or their representatives 
will provide the Principal Investigator and persons delegated by him/her with confidential information, 
for example, but not limited to, the protocol and the IB. The information may not be disclosed to 
anyone else without prior approval from Kazia Therapeutics Limited in writing. This obligation of 
confidentiality shall survive the completion or early termination of the study. 
10.8 Declaration of Interests 
By the time of the signature of this protocol by the relevant parties, i.e., Kazia Therapeutics Limited 
and principal Investigator(s), there are no competing interests proclaimed by the Principal 
Investigator(s). In case of changes during the execution of the study, Kazia Therapeutics Limited must 
be notified of evolving potential competing interests. Measures will then be taken to adjust the 
applicable legal framework according to law requirements.  
10.9 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable Competent 
Authority in any area of the world, or if the Investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, Kazia Therapeutics 
Limited should be informed immediately.  
In addition, the Investigator will inform Kazia Therapeutics Limited immediately of any urgent safety 
measures taken by the Investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of. 
10.10 Compensation for Medicine-induced Injury 
According to local regulations Kazia Therapeutics Limited will provide insurance coverage to all 
patients during study period. Kazia Therapeutics Limited assumes liability for and will indemnify all 
injuries that occur to patients whenever a causal relationship can be established between the event 
and the clinical study procedure or the study substance under study if the following can be 
demonstrated: 


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• 
The event resulted from a study substance, provided that the substance was administered 
according to the current protocol and manufacturer’s instructions; 
• 
The event occurred as a consequence of diagnostic procedures performed according to the 
study protocol; 
• 
The event resulted from therapeutic or diagnostic measures legitimately required as a 
consequence of unexpected events caused by the study substance, by comparative 
medication, or by diagnostic procedures called for by the study protocol. 
Kazia Therapeutics Limited is not liable for events that occur solely as a consequence of the 
underlying illness of the patient, or for events resulting from diagnostic or therapeutic measures not 
specifically required by the protocol, or for events resulting from negligence (including failure to act 
according to accepted medical practice, or to comply strictly with the protocol or the terms of this 
Agreement) of the Investigator or any other involved and/or related clinical staff and facilities. 
This indemnity provided by Kazia Therapeutics Limited shall further apply as follows: 
• 
Kazia Therapeutics Limited is to be informed as soon as possible of any complaint, action or 
suit of proceeding giving rise to the right of indemnification, and the Investigator agrees to co-
operate fully with Kazia Therapeutics Limited in the defense or disposition of all such cases; 
• 
Kazia Therapeutics Limited will be permitted, at its costs and discretion, to handle and control 
the defense or disposition of all such cases; 
• 
No case will be settled without the prior written consent of Kazia Therapeutics Limited. 
10.11 Direct Access to Data 
Direct access is defined as the permission to examine, analyze, verify and reproduce any records and 
reports that are important to evaluation of a clinical study. Any party (e.g. domestic and foreign 
regulatory authorities, Kazia Therapeutics Limited, CRO and their monitors and auditors) with direct 
access should take all reasonable precautions within the constraints of the applicable regulatory 
requirements to maintain the confidentiality of patient identities and Kazia Therapeutics Limited 
proprietary information. 
10.12 Dissemination Policy 
In accordance with standard editorial and ethical practice, Kazia Therapeutics Limited will support 
publication of multicenter studies only in their entirety and not as individual center data except for data 
from sub-studies. 
The following rules will apply for determining authorship: 
• 
Authorship credit will be based on the Vancouver statement by the International Committee of 
Medical Journal Editors, i.e. substantial contribution to the following criteria: 
o 
Conception and design or analysis and interpretation; 
o 
Drafting article or critically revising it for intellectual content; 
o 
Final approval of the version to be published; 
• 
Additional criteria for authorship include: 
o 
Contributors who register 20% or more of the evaluable cases on the study; 
o 
Significant contribution to the Cohort Review Committee. 
In an appropriate footnote, or at the end of the article, the following statement will be made: 
“Participating Investigators included: (a list of the individuals who have contributed patients and 
their institutions).” 
Investigator agrees to submit all manuscripts or abstracts to Kazia Therapeutics Limited prior to 
submission. This allows Kazia Therapeutics Limited to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the authors of the 
manuscript. Investigator will collaborate with the study statistician for preparation of study data 
analyses intended to be used in the publication(s) of the study. 


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Any formal publication of the study in which input of Kazia Therapeutics Limited personnel exceeded 
that of conventional monitoring will be considered as a joint publication by Investigator and Kazia 
Therapeutics Limited. 
Moreover, the following points need to be considered: 
• 
Without Investigator’s prior written consent, Kazia Therapeutics Limited may not make 
reference, either directly or indirectly, in a commercial publication, to Investigator’s name or 
institution, or any of its employees in which Investigator performed the present study, 
connected with the research and its results; 
• 
Kazia Therapeutics Limited may not use Investigator’s name or its employees connected to 
the research or to the institution in which Investigator performed the present study in its 
commercial publications as recommendation of quality and/or of the finished product and/or of 
the drug and the clinical benefit of its use; 
• 
Should Kazia Therapeutics Limited decide to publish the research results, it must publish 
them in their entirety and must not quote anything out of context; 
• 
Nothing in the aforementioned limitations in clauses will prevent Kazia Therapeutics Limited 
from quoting from articles, provided that the scientific source of data (scientific conventions, 
scientific newspapers) is mentioned.  
 
 


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11 References 
Alexander, B. M. and T. F. Cloughesy (2017). "Adult Glioblastoma." Journal of Clinical Oncology 
35(21): 2402-2409. 
Cantley, L. (2004). "The role of phosphoinositide 3-kinase in human disease." Harvey lectures 100: 
103. 
Cantley, L. C. (2002). "The phosphoinositide 3-kinase pathway." Science 296(5573): 1655-1657. 
Fan, Q.-W. and W. A. Weiss (2010). Targeting the RTK-PI3K-mTOR axis in malignant glioma: 
overcoming resistance. Phosphoinositide 3-kinase in Health and Disease, Springer: 279-296. 
Graupera, M., J. Guillermet-Guibert, L. Foukas, L. Phng, R. Cain, A. Salpekar, W. Pearce, S. Meek, J. 
Millan, P. Cutillas, A. Smith, A. Ridley, C. Ruhrberg, H. Gerhardt and B. Vanhaesebroeck (2008). 
"Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell 
migration." Nature: 453:662–456. 
Guertin, D. and D. Sabatini (2007). "Defining the role of mTOR in cancer." Cancer Cell: 12:19–22. 
Heg , M. E., A.-C. Diserens , T. Gorlia , M.-F. Hamou , N. de Tribolet , M. Weller , J. M. Kros , J. A. 
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Protocol Number: NVGN-0084-201 
IND Number: 112,608 
 
 
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12 Appendix 
Karnofsky Performance Status