A Phase I/II, Open-Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics and Anti-tumor Efficacy of DZD9008 in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) With EGFR or HER2 Mutation
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer
Sponsor: Dizal Pharmaceuticals

Clinical Study Protocol
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
1
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to Dizal (Jiangsu) Pharmaceutical Co., Ltd and opportunity to 
object.
Dizal Research and Development Site 
Representative Signature
Study Physician
Signature
Date
Clinical Study Protocol 
Drug Substance
DZD9008
Protocol Number
DZ2019E0001
Edition Number
12.0
Edition Date
July 24, 2023
A Phase I/II, Open-Label, Multicenter Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Anti-tumor Efficacy of DZD9008 in 
Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) with 
EGFR or HER2 mutation
Sponsor: Dizal (Jiangsu) Pharmaceutical Co., Ltd
Regulatory Agency Identifier Number(s)
IND: NCT03974022
EudraCT: 2019-003126-25

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
2 
 
Version History 
Version 12.0, July 24, 2023 
Summary of major changes from the previous version: 
1) Section 2.3.5 Clinical information of DZD9008, Section 3.2.2 Rationale for Part B, 
Dose Extension of DZD9008 and Section 5.2.1 Potential benefit: Clinical data are 
 
2) Section 3.1 Overall study design and flowchart and Section 5.1 Treatment: 
Supplementary information (including sample size and treatment) of the Part B optimal 
cohort is specified upon review and approval from IEC/IRB and/or local regulatory 
authority (as applicable) on the optimal RP2D selection. 
3) Section 4.2 Exclusion Criteria: Per Canadian regulatory requirement to exclude mean 
resting corrected QT interval (QTc): > 470 msec for women or > 450 msec for men, 
obtained from 3 electrocardiograms (ECGs) at screening (Canada only). 
4) Section 5.1.5 Toxicity management and dose modification and Section 5.3 
Discontinuation of investigational product and withdrawal from the study: Per 
Canadian regulatory requirement to specify conditions on AE leading to permanent 
discontinuation and continuation of treatment beyond disease progression. 
5) Section 6.3.1 Enrolment and screening: Added that subjects who have failed previous 
screening are permitted to be re-screened for once. 
6) Section 7.8 Analysis sets and Table 10 Analysis set definition:  
 
randomized NSCLC patients with documented EGFR Exon20ins mutation in tumor 
tissue who were previously treated with platinum-based chemotherapy, received at 
least 1 dose of DZD9008 and have measurable disease at baseline as identified by 
 
7) Table 14 Study Plan of Part B Dose Extension: Survival follow up is clarified to be 
performed within a visit window of ± 7 days. 
8) Appendix I (ophthalmic assessments): Per Canadian regulatory requirement to advise 
patients referral to the ophthalmologist for AE management. 
 
Version 11.0, December 21, 2022 
Summary of major changes from the previous version: 
1) Section 1 Study objective: 
was deleted to clarify the mutation diagnosis requirement for Part B. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
3 
 
2) Section 2.1 Background of NSCLC and Section 3.2.2 Rationale of Part B: These 
sections were updated to clarify current development of EGFR Exon20ins inhibitor 
treatment. 
3) Section 2.3.4 The key findings from Nonclinical toxicity studies: Additional new 
data were provided to reveal no toxicity findings when dosing duration was extended. 
4) Section 2.3.5 Clinical information of DZD9008: Food effect PK data were updated 
and added with a referral 
 for details. 
5) Section 3.2.2 Rationale of Part B, Dose Extension of DZD9008 and Section 6.6.1 
Exploratory analyses: Name of Sponsor designated central laboratory in mainland 
China was added per regulatory requirement. 
6) Section 4.1.1 Core inclusion criteria:  
 Criterion 7: The requirement of no evidence of progression was updated to provide 
clarity on at least 2 weeks after CNS-directed treatment as ascertained by clinical 
examination and brain imaging. 
 Criterion 8: Per updated safety risk assessment, the requirement was updated to 
 
measured or 
calculated by the Cockcroft-Gault method or others based on local practice. 
7) Section 4.1.2.2 Part B specific cohort inclusion criteria:  
 To align with target population for drug launch, the requirement is updated for Part 
B subjects to have progressed on, or be intolerant of, at least one prior line with 
platinum-based chemotherapy. 
 Duplicated France specific requirement on therapy type of treatment in prior lines 
were deleted as it would be covered under newly changed requirement.  
8) Section 4.2 Exclusion criteria:  
 Criterion 1: A typo in drug name: BDTX-198 was corrected. The exclusion was 
also added with patients who previously treated with furmonertinib which is an 
EGFR exon20ins inhibitor under development. Per updated clinical DDI study data, 
the required washout time was shortened for medications known to be potent 
inhibitors or inducers of CYP3A to within 1 week or 2 weeks respectively.  
 Criterion 4: To respect local practices for COVID-19, requirement of performing 
COVID-19 antigen testing to suspected subjects was removed. 
 Previous Criterion 14: Per updated safety risk assessment, the requirement 
Requires anticoagulation and anti-platelet therapy, i.e., with warfarin, heparin e
 
was removed. 
 Previous Criterion 15 had the order number updated to current Criterion 14 and 
variant spelling of hemorrhage was corrected. 
 Previous Criterion 16 had the number updated to current Criterion 15. 
9) Section 4.3 Restrictions and Section 5.2.2.10 Hemorrhage: Safety management was 
added that subjects receiving anticoagulation or anti-platelet therapy while receiving 
DZD9008 should be monitored for any signs of bleeding.

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
4 
 
10) Section 4.3.1 Concomitant treatment and Section 5.2.2.9 CYP450 
induction/inhibition: Per updated food effect data, the washout period of CYP3A4 
inducers and inhibitors was updated. 
11) Section 5.1 Treatment: Per updated pharmacokinetics data, the accepted window for 
subject to take the missed dose was extended to 12 hours. 
12) Figure 3 Dose modification for toxicity related to DZD9008: The figure was updated 
to clarify subjects either resuming same dose or at one dose level lower after dose 
interruption due to same AE in the past would have the exceptions to those already at 
the lowest possible dose. 
13) Section 6.3.3 Vital sign: To respect local practices, siting position was added for 
measuring blood pressure and pulse rate. 
14) Section 6.4.4 Reporting of serious adverse events: All SAEs was clarified to be 
recorded in both CRF and paper SAE form (Clinical Safety Event Report). 
15) Section 6.6.1 Exploratory analyses to support companion diagnostics 
development:  
 This section was updated to clarify mutation test in Part B used in Sponsor 
designated central laboratory being developed as companion diagnostics for 
DZD9008.  
 All Part B patients being asked to provide plasma samples was clarified to be at 
screening. 
 Study Plan for reference was corrected to Table 14 Study Plan of Part B Extension 
(from previous Table 13).  
16) Section 6.6.2.1 Achieved tumor tissue or fresh biopsy for exploratory biomarker 
research:  
 Duplicated reference to laboratory manual were deleted.  
 Sampling schedule in Part A had reference to Table 14 deleted as it was not 
applicable. 
17) Section 6.6.2.3. Blood sampling for other exploratory biomarker study, Table 14 
Study Plan and Table 18 Lab visits and clinical monitoring:  
 Based on tumor evaluation schedule, for Part B only, the blood samples collection 
plan was adjusted accordingly to be on Day 1 of each following odd Cycle (i.e., 
from previously even) until disease progression and updated table content. 
 Clarification on the exact subsequent sampling Cycle in both Part A and Part B was 
added. 
 Duplicated information of data be reported separately and not included in the 
Clinical Study Report was deleted as it had already been covered in Section 6.6 
Exploratory research. 
18) Section 6.7.2 Handling, storage and destruction of biological samples and Section 
6.7.2.4 Samples for pharmacogenetic study: Maximum time for samples retention 
was clarified as to align with local regulatory requirements. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
5 
 
19) Section 7.3 Calculation or derivation of safety variables: Creatinine clearance 
calculation was updated with clarity that it can be done per local practice. 
20) Section 7.8 Analysis sets and Table 10 Analysis set definition:  
 Definition of full analysis set was updated according to inclusion criteria to be All 
randomized NSCLC patients with documented EGFR Exon20ins mutation in tumor 
tissue from a local CLIA certified laboratory who were previously treated with 
platinum-based chemotherapy, received at least 1 dose of DZD9008 and have 
measurable disease at baseline as identified by IRC (applicable for Part B only) . 
 Centrally confirmed EGFR Exon20ins analysis set was separated into two sets and 
re-named by tumor tissue and by plasma ctDNA with updated definition. 
21) Section 7.9.7 Efficacy: Per new definition of analysis sets, the previous sensitivity 
analysis was updated to clarify as efficacy analysis in centrally confirmed EGFR 
Exon20ins by tumor tissue and by plasma ctDNA respectively. 
22) Section 7.9.7.2 Duration of response: Analysis population was added with clarity to 
be in Part A and in FAS of Part B. 
23) Section 7.9.7.4 Progression free survival and Section 7.9.7.5 Overall survival: 
Descriptions on survival analysis techniques was removed as it is not applicable. 
24) Section 7.9.7.5 Overall survival: Analysis population was updated with clarity to be 
FAS of Part B only.  
25) Section 8.1 Medical emergencies and Sponsor contacts: Contact person details were 
updated. 
26) Section 8.2 Overdose: Reporting time for other overdoses was deleted to avoid 
confusion. 
27) Table 11 - 14 Study Plan: Footnote for requirement on COVID-19 antigen testing for 
suspected COVID-19 infectious subjects was removed to respect local practices for 
COVID-19. 
28) Table 14 Study Plan of Part B Dose Extension and Table 18 Lab visits and clinical 
monitoring (Part B dose extension): Per regulatory requirement on safety monitoring, 
footnote was updated for collecting additional serum or urine samples for pregnancy 
testing (Italy only). 
29) Table 16 Lab visits and clinical monitoring (Part A dose expansion): Inconsistency 
to main text for PK sampling at pre-dose on C1D8 and C1D15, and at 3hr post-dose on 
C1D1 and C2D1 was filled out to correct. 
30) Table 18 Lab visits and clinical monitoring (Part B dose extension): Inconsistency 
to main text for PK sampling at pre-dose on C4 onwards D1 was filled out to correct. 
31) Appendix A Signature: The statement for 
protocol to maintain consistency. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
6 
 
32) Appendix H Guidance Regarding Potential Interactions with Concomitant 
Medication: Per clinical DDI study data, CYP3A4 metabolism and withdrawal period 
required prior to DZD9008 administration was updated. 
 
Version 10.0, April 18, 2022 
Summary of major changes from the previous version:  
1) Section 1.1.2.2: secondary study objectives of Part B  
 Added endpoint/variable DZD9008 metabolite concentration  to characterize the 
PK of DZD9008 
 Removed to assess the effect of DZD9008 on patients' disease related symptoms 
and health related quality of life (HRQoL)  and endpoint/variable the EORTC 
QLQ-C30 and the EORTC QLQ-LC13 questionnaires  from secondary objectives. 
2) Section 3.2.1 study design rationale: added In Part A, radiological scans (including 
those at unscheduled visits, or outside visit windows) for patients with EGFR 
Exon20ins will be collected on an ongoing basis.  
3) Section 3.2.2 study design rationale: updated enrollment of Part B NSCLC patients 
with EGFR Exon20ins which has been confirmed in a local CLIA-certified laboratory 
(or equivalent) or Sponsor designated central laboratory
ription of tumor 
sample handling procedure. 
4) Section 4.1.1 in the inclusion criteria: 
 R
s. 
 Updated a time window of  2 weeks and  4 weeks is required respectively if BM 
has been treated with radiation or surgery. 
5) Section 4.1.2.2 in Part B specific cohort inclusion criteria:  
 Updated mutation type confirmation for enrollment: Patients must have 
histologically or cytologically confirmed locally advanced or metastatic NSCLC 
with documented EGFR Exon20ins mutation in tumor tissue from a local CLIA-
certified laboratory (or equivalent) or Sponsor designated central laboratory. prior 
to the study entry . 
 Added the requirement on previous lines of treatment The prior lines of treatment 
must include at least one platinum-based chemotherapy associated to an anti-PD-
(L)1 therapeutic antibody  (France only) 
6) Section 4.2 in the exclusion criteria: 
 Added mean resting corrected QT interval (QTc): > 470 msec for women or > 450 
msec for men, obtained from 3 electrocardiograms (ECGs) at screening (France 
only). 
7) Section 4.3.1: limited the restriction of blood transfusions and hematopoietic growth 
factors during the screening phase to Part A escalation only.  

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
7 
 
8) Section 5.1.5: clarified the AE related dose reduction and permanent discontinuation 
(France only)  
9) Section 5.1: added the criteria for continuing treatment post progression (France only): 
(a) Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening of laboratory values) ; (b) Stable ECOG PS; (c) Absence of rapid 
progression of disease or of progressive tumor at critical anatomical sites that requires 
urgent alternative medical intervention; (d) Investigators must inform subjects that this 
practice is not considered standard in the treatment of cancer. 
10) Section 6.3.4: added description of pregnancy test criteria for female subjects of 
childbearing potential (Italy only). 
11) Section 6.5.2: added samples for determination of metabolite DZ0753 concentrations in 
plasma to be analyzed.  
12) Section 6.9, 7.6.1, 7.9, Appendix J: removed the description and calculation for the 
EORTC QLQ-C30 and the EORTC QLQ-LC13 questionnaires and removed previous 
Table 10 Visit Response for disease related symptoms and HRQoL. 
13) Section 7.2.2: clarified determination of sample size in Part B extension cohorts. 
14) Section 7.8 previous Table 11 (current Table 10) Analysis Set Definition:  
 updated the definition of full analysis set 
all randomized NSCLC patients who 
receive at least 1 dose of DZD9008 and have measurable disease at baseline as 
identified by IRC (applicable for Part B only)   
 added definition of centrally confirmed EGFR Exon20ins analysis set 
all 
patients in full analysis set with EGFR Exon20ins mutations confirmed by central 
laboratory (applicable for Part B only) .  
15) Section 7.10: added the publication policy (Spain only).  
16) Previous Table 15 (current Table 14) Study Plan of Part B Dose Extension: removed 
the schedule for the EORTC QLQ-C30 and the EORTC QLQ-LC13 questionnaires.  
17) Previous Table 15 (current Table 14) Study Plan of Part B Dose Extension and Table 
19 (current Table 18) Lab visit and clinical monitoring (Part B dose extension): added 
the footnote clarification of collecting additional serum or urine samples for pregnancy 
testing (Italy only). 
18) Appendix H: updated guidance regarding potential interaction with concomitant 
medication 
19) Appendix I: updated advice for patients with 
 be 
referred to the ophthalmologist (France only). 
 
Version 9.0, July 14, 2021  
Summary of major changes from previous version: 
1) Introduction: updated clinical study data to the cut-off date of 3 April 2021. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
8 
 
2) 
tumor DNA (ctDNA) for EGFR Exon20ins mutation testing and necessary technical 
studies, for liquid biopsy companion diagnostic development 
exploratory objectives. 
3) Section 2.3.5: updated clinical study data to the cut-off date of 3 April 2021. 
4) Section 6.3.5.1: added Cycle 1 Day 8 and Cycle 1 Day 15 into the ECG testing 
schedule. 
5) Section 6.6.1: added the description of collecting plasma samples for liquid biopsy 
companion diagnostics development. 
6) Section 7.1: added exploratory endpoints to Part B: 
 Collect and store tumor samples for diagnostics development and potential future 
exploratory research that may influence the development of DZD9008 
(exploratory). 
 To collect and store plasma samples for EGFR Exon20ins mutation testing and 
necessary technical studies for liquid biopsy companion diagnostic development 
and approval (exploratory). 
 To collect and store blood-based samples for future exploratory research on 
genes/genetic aberrations that may influence response to DZD9008 treatment 
and/or susceptibility to DZD9008 (exploratory). 
 To collect and store blood sample for future exploratory research into genes/genetic 
variation that may influence PK or response to DZD9008 (Pharmacogenetics study, 
exploratory). 
7) Table 15: added plasma sample collection for liquid biopsy companion diagnostic 
development; added Cycle 1 Day 8 and Cycle 1 Day 15 into the ECG assessment.  
 
 
Version 8.0, April 29, 2021  
Summary of major changes from previous version: 
1) Study flow chart: added the Part A expansion cohort 6 (NSCLC with EGFR Exon20ins, 
previously treated with Amivantamab, dosing at 300 mg with low-fat meal); Part B 
extension was updated to have 2 dose cohort (dosing at 200 mg and 300 mg DZD9008 
separately) for previously treated NSCLC with EGFR Exon20ins. 
2) 
ted symptoms and health related 
quality of life (HRQoL). 
3) Section 3.1: added expansion cohort 6 in Part A; updated the design of Part B extension 
(a) by changing from 1 dose cohort of 300 mg to 2 dose cohorts of 200 mg and 300 mg 
(b) and added Simon two- stage design. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
9 
 
4) Section 3.2.2: RP2D was updated from 300 mg to both 200 mg and 300 mg selected for 
Part B. 
5) Section 4.1.2.1: added inclusion criteria for Part A dose expansion cohort 6. 
6) Section 4.1.2.2: removed treatment naïve from the patient population of Part B 
extension. 
7) Added Table 3 to show the representative of dose intervention or modification. 
Updated the table listing. 
8) Section 5.3 and 6.3.1: safety follow up period was updated from 14 days to 28 days. 
9) Section 5.3.3: updated the interim analysis by adding futility analysis for Part B. 
10) Section 6.9: added the EQ-5D-5L collection. 
11) Section 7.2.2: updated the sample size calculation of Part B. Subjects will be 
randomized into two different dose cohorts. Each dose cohort uses a Simon two-stage 
design, and a sample size of 103 in each dose cohort is required to test a mull 
hypothesis 
one-sided significance level of 0.0125 and 80% power. 
12) Section 7.6: new added section to describe the calculation of derivation for EORTC 
QLQ-C30 and QLQ-LC13. 
13) Section 7.7: new added section to describe the calculation of EQ-5D-5L. 
14) Table 14 (study plan of Part A expansion): removed survival follow up from table to 
keep consistent with study objectives and assessment description. 
15) Appendix J: added EQ-5D-5L. 
 
 
Version 7.0, April 6, 2021 
Summary of major changes from previous version: 
1) Section 3.2.1 and section 5.1: updated the definition of low-fat meal (the low-fat meal 
is defined as approximatley 400 to 500 Kcal with about 25% of calories comes from 
11-14 grams of fat) to keep it consistent with FDA guidance. 
2) Appendix J: corrected the typing of answer to question of Nausea of CTCAE PRO  
Version 6.0, March 5, 2021 
Summary of major changes from previous version: 
1) Updated study flow chart: In the Part A expansion cohort, added cohorts dosing with 
DZD9008 at 200 mg and 300 mg, respectively, with low-fat meal (cohort 3 and 4) and 
treatment naïve cohort (cohort 5). The 200 mg and 300 mg expansion cohorts dosing 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
10 
 
under fasted condition in the previous flow chart (CSP version 4.0 and 5.0) are now the 
expansion cohort 1 and cohort 2. 
2) Updated clinical data, including exposure, PK, safety and efficacy using new cut-off 
date of February 5, 2021 in section 2.3.5. Updated preliminary PK data from food 
effect cohort (high-fat meal). 
3) Updated study objectives for Part A in section 1.1.1 
 Secondary objectives: added retrospective tumor assessment in patients with EGFR 
Exon20ins according to RECIST 1.1 by Independent Review Committee (IRC). 
 Exploratory objectives: added (a) To assess AEs of DZD9008 by using patient 
reported specific CTCAE symptoms and FACIT GP5 questionnaire. (b) To explore 
the relationship between DZD9008 exposure and selected endpoints (i.e., safety and 
efficacy), where deemed appropriate. 
4) Section 4.1.2: updated the inclusion criteria for different cohorts of dose expansion 
part. 
5) Section 5.1: updated the information of DZD9008 administration with low-fat meal. 
6) Section 5.1.5: reworded the guidance for toxicity management and dose modification to 
make it clearer. 
7) Section 6.3.5: added PRO-CTCAE and FACIT GP5 questionnaire in section 6.3.5.5 
and 6.3.5.6, respectively. 
 
 
Version 5.0, December 17, 2020 
Summary of major changes from previous version: 
1) Introduction and study flow chart 
 Updated study flow chart by only keeping cohort of NSCLC with EGFR Exon20ins 
and sample size of ~ 120. 
 Updated 13-week rat and dog toxicity study and genotoxicity study results. 
 Updated clinical study results of ongoing study of DZ2019E0001 and 
DZ2019E0002. 
2) Section 1.1.2: updated the study objectives for Part B. 
3) Section 2.1: added a paragraph of treatment status of NSCLC with EGFR Exon20ins. 
4) Section 2.3.3: updated key data of nonclinical pharmacokinetics study. 
5) Section 2.3.4: updated 13-week rat and dog toxicity study and genotoxicity study 
results. 
6) Section 2.3.5: updated results of ongoing clinical studies of DZD9008. 
7) Section 3.1: updated the study flow chart. 
8) Section 3.2.2: updated study rationale and study cohort for Part B by only keeping 
EGFR Exon20ins cohort. 
9) Section 4.1: updated inclusion and exclusion criteria. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
11 
 
 Added the description of stable brain metastasis 
 Updated the inclusion criteria of Part B by removing cohort with EGFR uncommon 
mutation, HER2 Exon20ins and POM cohort.  
10) Section 5.1.4: added the rationale for selecting 300 mg once daily as RP2D. 
11) Section 5.1.5: added the maximum dose reduction for part B. 
12) Section 5.2.1: added a paragraph of clinical efficacy data of DZD9008 from ongoing 
clinical studies. 
13) Section 5.2.2: added a paragraph of clinical safety data of DZD9008 from ongoing 
clinical studies. 
14) Section 5.3: updated the safety follow up time post last dosing from 28 days to 14 days. 
15) Section 5.4: updated the end of study for part B. 
16) Section 5.5: updated the post study access to study treatment. Updated the toxicity 
management for QTc prolongation. 
17) Section 6.3.3: added the schedule for Part B. 
18) Section 6.3.4: added Creatine phosphokinase into the lab testing in Table 3. 
19) Section 6.3.5: added the ECG visiting and ECG central review for Part B of the study.  
20) Section 6.3.6.3: updated the survival follow-up. 
21) 
. 
22) Section 6.5.2 updated the pharmacokinetics sampling time for Part B extension in both 
text and Table 7 & Table 8. 
23) Section 6.6 Exploratory research 
 Updated sample collection for tumor tissue. 
 Added a section for pharmacogenetics study. 
24) Section 7.2.2: added the sample size calculation for Part B dose extension part. 
25) Appendix H: added the gastric acid suppressive agents that may affect DZD9008 
absorption. 
 
 
Version 4.0, January 16, 2020  
Summary of major changes from previous version: 
1) Study flow chart and Figure 1: updated with new chart. Add Part A expansion into the 
 
2) Updated the list of abbreviations and definition of terms. 
3) 
-hydroxycholesterol 
to total cholesterol as a biomarker of cytochrome P450 (CYP)3A4 induction by 
ploratory objectives. 
4) Section 2.3: added clinical information of DZD9008 under 2.3.5. 
5) Section 3.1 and section 3.2.1: added a paragraph to describe Part A expansion. 
6) Inclusion criteria 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
12 
 
 Section 4.1.2.1 added the cohort specific inclusion criteria of Part A dose 
expansion. 
 
sequencing (NGS) assay in Clinical Laboratory Improvement Amendments (CLIA) 
certified laboratories (USA sites) or other similarly certified laboratories (outside of 
 
7) Section 4.2: exclusion criteria  
 Added exclusion criteria 
-3 years requires 
active treatment, except for adequately treated basal cell skin carcinoma, in situ 
cervical carcinoma, or other cancer type has been disease free for > 2 years with life 
 
 Updated the exclusion criteria. For Expansion cohort of Part A and cohort 1, 2, 4 of 
Part B: Patients who have received prior Poziotinib or TAK788 or other 
EGFR/HER2 exon20ins inhibitors treatment should be excluded. 
 
 
 Added the exclusion criteria of: Known history of bleeding diathesis, i.e., 
hemophilia, Von Willebrand disease. 
 
grapefruit juice, and orange marmalade 
Restriction. 
8) Section 5.1: updated the drug supply, packaging and labeling of DZD9008 by adding 
150 mg and 200 mg strength of tablet. 
9) Section 5.1.1.1: added a paragraph to describe Part A expansion. Added a paragraph to 
describe the prior setting of Bayesian logistic regression model. 
10) Updated Figure 2 with detailed description of treatment period 1 & 2. 
11) Section 6.5.1.1, Table 5 and Table 9: add pre-dose on Cycle 2 Day 1 to PK time point 
of Part A food effect cohort. 
12) Section 7.2.1: updated the sample size for Part A. 
13) Section 7.7: updated the definition for PK analysis set. 
14) Table 9: change the Cycle 1 duration from 28 days to 21 days. 
 
Version 3.1, October 9, 2019  
Summary of changes from previous version: 
1) Section 5.3, 
ed the typing error from Section 5.4.2 to Section 5.3.2. 
2) Section 5.3, 
tiated on investigational product (Section 5.4.1): 
corrected the typing error from Section 5.4.1 to Section 5.3.1. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
13 
 
3) Section 6.4.2, For definition of other significant adverse event (OAE), see section 
7.3.1 : corrected the typing error from Section 7.3.1 to Section 7.3. 
4) Table 9, RECIST assessments: corrected the typing error from Section 6.9.1 to Section 
6.8.1. 
5) Appendix F, Methods of measurement: corrected 
T
 
 
 
Version 3.0, September 6, 2019 
Summary of major changes from previous version: 
1) Title page: removed 
are too many investigators participating the study. The signature from each investigator 
will be obtained separately. 
2) Section 1.1.2.2: removed urine PK from the secondary objectives. The reason is to keep 
consistency with that described in section 6.5.1.1. 
3) Section 3.1, Part B, dose escalation: removed HER2 Exon20ins from Cohort 4. This is 
to align with that pEGFR is the applied PoM biomarker. 
4) Section 4.1.1.2:  
 Added 
fulfills local 
requirement.  
 Added 
ULN and activated partial 
activity on BTK in updated Investigator  Brochure.  
5) Section 4.2:  
 Exclusion criteria: changed 
DZD9008
patients staying untreated for a relatively shorter time 
while meeting the requirement for washout from prior treatment. 
 Added 
 
 Added 
and 
hemorrhage within 6 months befor
 
 4.2.12: changed QTcF to QTc, as the QTc interval will be measured by either 
 
6) Section 4.3 and section 4.3.1: to make consistency that patients must avoid concomitant 
use of medications, herbal supplements and/or ingestions of foods with known potent 
inducer/inhibitory effects on CYP3A4 activity whenever feasible. Changed the wording 
been discontinued for an appropriate period before patients 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
14 
 
drugs must have discontinued for a period of 2 weeks (CYP3A4 inhibitors) or 3 weeks 
(CYP3A4 inducers) prior to first administ
 
7) Section 5.1 Drug administration:  
 Added 
acceptable to take the dose. If it is more than 4 hours after the dose time, the missed 
dose should not be taken, protocol deviation will be recorded, and patients should 
be instructed to take the dose at the next scheduled time. If a subject vomits after 
taking their DZD9008, they should not make up for this dose, but should take the 
next scheduled dose . 
 Changed 
 fasted or 
fed condition 
patients may take DZD9008 under fast condition until the data from dose effect 
 
8) Table 1: corrected some errors of number. 
9) Section 5.1.4 Toxicity management 
 Changed 
e of the same AE subsequently requires 
dose interruption, patient should restart at one dose level lower (except cohort 1 
that in Figure 3.  
 Patients experiencing any of the following will not be permitted to restart study 
treatment: removed 
to keep consistent with the main paragraph 
 
10) Section 5.1.5: changed the 
make consistency across different parts. 
11) Section 5.2: added section 5.2.2.10 Hemorrhage and a whole paragraph description of 
 
12) Table 3: updated the laboratory safety assessments list by adding S/P- magnesium, 
lipase and amylase into the clinical chemistry list, adding Coagulation test (include 
APTT and INR) into the laboratory measurement list per updated risk assessment, and 
removing S/P Cystatin C from chemistry list considering there are S/P creatine and 
urine nitrogen already included for renal function testing. 
13) Section 6.3.5  
 ECG: removed 
in the study specific 
. This is to keep consistency across the protocol 
and considering no cardiac risk of QT prolongation from preclinical safety 
assessment. 
 Ophthalmologic examination: removed 
record any clinically significant findings. These photographs should be available for 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
15 
 
by ophthalmologist and not mandatory for Dizal representative to review. 
 Echocardiogram/MUGA Scan: changed the assessment frequency to 
(prior to first dose of DZD9008), on Cycle 3 Day 1 (± 7 days), then every 6 weeks 
 
 Pulmonary function tests (PFTs): changed 
(including spirometry and DLCO) will be performed at baseline (prior to first dose 
of DZD9008), on Cycle 3 Day 1 (± 7 days), and then every 6 weeks (± 1 week) and 
 
14) Section 6.7.1: updated the volume of blood due to additional coagulation test added 
into the laboratory variables. 
15) Section 6.8.1.1 Imaging assessment: changed the assessment frequency t
assessments will be performed using CT scan or MRI to assess extracranial lesions, 
such as chest, abdomen (including liver and adrenal glands), and MRI for the brain if 
brain metastasis presents at baseline (within 28 days of treatments start, ideally as close 
as possible to the start of study treatment), on Cycle 3 Day 1 (± 7 days) and then every 
6 weeks ± 7 days (relative to first dose of multiple dosing) until objective disease 
 
16) Section 7.3  
 ECG changes: added Bazett's to the formula of QTc calculation. 
 Creatine clearance: updated the calculation formula by adding the formula based on 
creatinine value in mg/dL. 
17) Section 7.4: updated the PK calculation by adding more PK parameter for calculation 
and adding more detailed description to the calculation. 
18) Secrion 7.5 Investigator RECIST based assessments: removed the paragraph of scaling 
up rule if  1/3 TL is missing. This will be included in the review charter of 
independent image review for Part B study. 
19) Section 7.8.4: updated the PK summary by adding more PK parameter and the detailed 
description. 
20) Table 4, 5, 6, 8, 9, 10: corrected some error to make it consistency between the 
description and tables; added foot note to clarify the visit or testing window; add 
HBV/HCV/HIV and APTT/INR into table 8, 9, 10. 
21) Table 11, 12 and 13: added APTT/INR into tables. 
 
Version 2.0, March 8, 2019 
Summary of major changes from previous version: 
1) Study flow chart:  

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
16 
 
 Removed previous cohort 1 (TKI treatment naïve EGFR sensitizing mutation or 
T790M mutation positive without Osimertinib treatment) from current Part B 
2) Section 1.1.2.1: added Independent Central Review for ORR and DOR. 
3) Section 2.3.4: added the new data of pathology analysis of 14 days dog DRF study into 
the summary. 
4) Section 3.1: removed the previous study flow chart and updated as above  
 Part A: removed 
 confirm 
safety or/and efficacy wi
 
 Part B: removed cohort 1, change total patient number from ~ 140 to ~ 120; remove 
patients may be enrolled into each cohort to further evaluate anti-tumor 
efficacy signals and/
 
5) Section 3.2.2: removed cohort 1 (TKI treatment naïve EGFR sensitizing mutation or 
T790M mutation positive without Osimertinib treatment) 
6) Section 4.1.1.4: removed collection of plasma samples from patients with EGFR 
L858R, 19del and T790M mutation diagnosed using plasma samples . 
7) Section 4.1.2.1 Part A: Patients must have documented histologically or cytologically 
confirmed locally advanced or metastatic NSCLC with EGFR or HER2 mutations, and 
have relapsed from, been refractory or intolerant to at least one line of standard therapy. 
8) Section 4.1.2.2 Part B: removed previous cohort 1. Patient enrolment in Part B using 
Next Generation Sequence (NGS) assay for mutation detection. 
9) Section 4.2: for exclusion criteria 2-8, changed 
 
10) Section 5.5.1.1: added additional point to 
predicted human free AUC and Cmax at 50 mg once daily are 0.12 µM*hr and 0.006 
µM, respectively, which are comparable or below the drug exposure at NOAEL in 
Added new table (exposure of DZD9008 at 
NOAEL from preclinical toxicity studies and margin to the predicted drug exposure in 
human at 50 mg once daily) into current protocol (Table 1). 
11) Section 5.1.1.2 DLT criteria:  
 Removed 
toxicity that is Common Terminology Criteria for Adverse Events (CTCAE 5.0) 
grade 4  
 Added Grade 3 platelet count decrease associated with clinically significant 
teria 
 Added 
-threatening 
 
12) Section 5.1.1.5: Changed DLT period from 21 day to 28 day (Cycle 1 of Part A). 
13) Section 5.1.2 The effect of food on PK of DZD9008:         
 Updated 
human PK data. In general, after single dose, at least 7 days or 5 x half-life 
whichever is longer will be allowed fo
 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
17 
 
 Updated Fasted condition 
 
 Updated Fed condition 
30 minutes prior to administration of DZD9008. Patients should finish this meal 
within 30 minutes or less; however, DZD9008 should be administered at 30 
 
14) Section 5.1.3: removed previous cohort 1 from Part B 
15) Section 5.2.2.8: added renal effect.  
 Patients with abnormal renal function as defined by creatinine >1.5 x upper limit of 
normal (ULN) concurrent with creatinine clearance < 50 mL/min at screening are 
excluded from participating in the study. During the study, kidney function tests 
(creatinine, urea nitrogen and Cystatin C) will be monitored regularly during the 
study and recorded at discontinuation. 
16) Section 5.3.3: updated 
In Part B, when the first 20 patients of cohort 1 or 2 
complete at least 12-week repeated dosing of DZD9008, and have two consecutive 
RECIST assessment available, interim data analysis will be performed to evaluate 
clinical efficacy and safety. Ongoing patients will be able to continue DZD9008 
 
17) Section 7.2.2.: changed sample size of Part B from ~140 to ~ 120.  
18) Section 7.5: added Independent Review Committee (IRC) and investigator RECIST 
based assessment 
Independent Central Review of RECIST based assessments (Part B) 
The Independent Central Review of all radiological imaging data will be carried out 
using RECIST version 1.1. All radiological scans for all patients (including those at 
unscheduled visits, or outside visit windows) will be provided to the IRC. Prior 
radiotherapy reports for patients (at baseline) and information on biopsied lesions will 
also be provided to the IRC to allow the selection of appropriate target lesions. The 
imaging scans will be reviewed by two independent radiologists using RECIST 1.1 
criteria and will be adjudicated if required. For each patient, the IRC will define the 
overall visit response data (CR, PR, SD, PD or NE) and the relevant scan dates for each 
time point (i.e. for visits where response or progression is/is not identified). If a patient 
has had a tumor assessment which cannot be evaluated then the patient will be assigned 
a visit response of not evaluable (NE) (unless there is evidence of progression in which 
case the response will be assigned as PD). Endpoints (ORR, DoR, DCR, PFS) will be 
derived from the overall visit response date and the scan dates. ORR will only include 
patients whose response has been confirmed by a second scan at least 4 weeks after the 
initial response. The endpoint of tumor shrinkage will be assessed from tumor size 
measurements based on the primary independent radiologist assessment. 
Investigator RECIST based assessments 
From the investigators review of the imaging scans, the RECIST tumour response data 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
18 
 
1.1. At each visit, patients will be programmatically assigned a RECIST 1.1 visit 
response of CR, PR, SD or PD depending on the status of their disease compared with 
baseline and previous assessments. If a patient has had a tumour assessment which 
cannot be evaluated then the patient will be assigned a visit response of not evaluable 
(NE) (unless there is evidence of progression in which case the response will be 
assigned as PD). 
19) Section 7.8.6.1: added 
 
20) Updated Table 8, 9, 10 to align with section 6.3.3, 6.3.4, 6.3.5. 
 
Version 1.0, January 16, 2019  
Initial creation 

Clinical Study Protocol
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
19
INTRODUCTION & STUDY FLOW CHART
A Phase I/II, Open-Label, Multicenter Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Anti-tumor Efficacy of DZD9008 in 
Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) with EGFR 
or HER2 mutation 
Study center (s) and number of patients planned:
Part A: 130 - 150 patients, Part B: 206 patients (providing approximately 103 patients are
enrolled to the optimal RP2D cohort)
Epidermal growth factor receptor (EGFR) Exon 20 insertions (Exon20ins), human epidermal 
growth factor receptor 2 (HER2) Exon20ins and EGFR uncommon mutations occurred in about 
7% patients with non-small cell lung cancer (NSCLC). Chemotherapy is the standard of care 
(SoC) for patients carrying EGFR or HER2 Exon20ins, but median progression free survival 
(PFS) and overall survival (OS) were only around 6 months and 24 months, respectively. For 
EGFR uncommon mutations, afatinib was approved as 1st line therapy in some regions, but 
there was no effective treatment after disease relapse. Therefore, there is an unmet medical need 
to develop more effective therapy. 
DZD9008 is an oral, potent, selective and irreversible EGFR tyrosine kinase inhibitor (TKI) 
targeting EGFR sensitizing mutation, T790M resistance mutation, Exon20ins and uncommon 
mutations as well as HER2 Exon20ins mutation, with weak activity against wild type EGFR. In 
vitro, DZD9008 modulates pEGFR with IC50 of
 in tumor cells carrying EGFR L858R, 
exon 19 deletion (Exon19del), L858R/T790M, Exon20ins or uncommon mutations, and inhibits 
pHER2 with IC50 of
 in tumor cells engineered with different subtypes of HER2 
Exon20ins. DZD9008 suppresses cell proliferation with GI50 of
 in tumor cells 
carrying EGFR L858R, Exon19del, L858R/T790M, Exon20ins or uncommon mutations, and 
GI50 of
 in tumor cells engineered with HER2 Exon20ins. In vivo, DZD9008 induces 
profound tumor regression in standard or patient derived xenograft models expressing EGFR 
Exon19del, L858R/T790M, Exon20ins or uncommon mutations, but demonstrates modest 
effect in a xenograft model carrying wild type EGFR. In addition, there is a good correlation 
between plasma PK and pEGFR modulation in tumor tissues of  xenograft models. 
DZD9008 has favorable drug metabolism and pharmacokinetics (DMPK) properties for oral 
dosing. Pharmacokinetic exposure increased approximately in proportion to oral dosing in rat 
and dog. Accumulation in terms of AUC was less than 2- folds on multiple daily dosing in rat 
and dog. In vitro data have indicated that CYP3A4/5 are the principal P450 isozymes 
responsible for human metabolism. Incubations with hepatocytes from rat, dog and humans 
have indicated that glutathione conjugation may be alternative/additional elimination pathways. 
Based upon in vitro data, DZD9008 DDI risk is considered unlikely to cause clinically 
significant hepatic drug interactions at clinically relevant concentrations through inhibition or
induction of cytochrome P450 enzyme activity.  
The key findings from the non-clinical toxicity studies were: diarrhea, low food intake and body 
weight loss. Histopathological findings include: gastrointestinal tract (inflammation, 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
20 
 
hemorrhage, ulcer, erosion, necrosis, gland dilatation), thyroid (follicular atrophy), lacrimal 
gland (acinal cell atrophy), vagina (epithelial atrophy), tongue/esophagus (epithelial 
atrophy/erosion/neutrophilic infiltrate), eye (cornea epithelial atrophy), pancreas (acinar 
atrophy, acinar cell secretory depletion), skin (crust formation in the epidermis), lung (alveolar 
infiltrates of macrophages), kidney (cortical tubular dilatation) and mandibular salivary gland 
acinar cell secretory depletion, which are considered EGFR inhibition related; lymphoid 
depletion of immune organs (thymus, spleen and lymph nodes) and adrenal gland hypertrophy 
were likely due to the stress; bone marrow myeloid hypercellularity could be the inflammatory 
response to gastrointestinal tract change; pancreas fibrosis was likely DZD9008 BTK inhibition 
related. Majority of findings observed during the 1-month studies were not present following 1-
month recovery period, with the exception of pancreas fibrosis. The results from preclinical 
toxicology studies support progression of DZD9008 into clinical trials in patients with advanced 
cancer. 
There are three clinical studies of DZD9008 monotherapy for which efficacy analysis has been 
conducted in NSCLC subjects with EGFR Exon20ins post platinum-based chemotherapy: 
(DZ2019E0001, and DZ2019E0002 and DZ2020E0001).  
DZ2019E0001 (ClinicalTrials.gov Identifier: NCT03974022) is a phase 1/2 study in NSCLC 
with EGFR or HER2 mutations, which is being conducted in US, Australia, Taiwan, and South 
Korea, etc. This study consists of two parts: Part A (dose escalation, food effect and dose 
expansion) and Part B (dose extension). In Part A, advanced NSCLC patients with EGFR or 
HER2 mutations who relapsed from or were refractory, or intolerant to standard systemic 
therapy will be enrolled for dose escalation. These patients will receive one single dose, and 
after a wash-out period, then multiple doses of DZD9008 with the objective to investigate its 
safety and tolerability, MTD, and preliminary anti-tumor efficacy. A separated cohort at defined 
dose level will be enrolled to evaluate food effect on PK. Further expansion of Part A will be 
triggered at well tolerated dose(s) with observed anti-tumor effect in patients with EGFR 
Exon20ins or HER2 Exon20ins mutant NSCLC. In Part B, advanced NSCLC patients with 
EGFR Exon20ins who have relapsed from or were refractory, or intolerant to 1 - 3 lines of prior 
systemic treatment will be enrolled. The objective of this part of study is to further assess anti-
tumor efficacy, safety and tolerability of DZD9008 at the Recommend Phase 2 Dose(s) (RP2Ds) 
of 200 mg and 300 mg. Following review and approval from IEC/IRB and/or local regulatory 
authority (as applicable) on the optimal RP2D selection, eligible patients can be enrolled into 
the optimal RP2D cohort. The results of Part B is planned to be used to support an NDA 
submission for accelerated approval of DZD9008 in NSCLC with EGFR Exon20ins. 
 
 

Clinical Study Protocol
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
21
Study flow chart (DZ2019E0001)
Patients will be dosed at 200 mg or 300 mg once daily in two separate cohorts in
phase 2 for Part B, but only the optimal RP2D cohort remains open for enrolling 
patients following review and approval from IEC/IRB and/or local authority (as 
applicable).
About 10 patients may participate in the proof-of-mechanism (PoM) study in each 
dose cohort of Part B.
Expansion cohort 5 will be triggered after the emerging data shows DoR of EGFR 
Exon20ins patients reaches 6 months, and the food effect cohort data is available.
DZ2019E0002 (Chinadrugtrial identifier: CTR 20192097) is a phase 1 study in Chinese NSCLC 
with EGFR or HER2 mutations. This study consists of dose escalation and expansion cohorts. 
Enrolled patients will first receive a single oral dose of DZD9008, followed by a 7-day wash 
out, then repeated daily dosing until disease progression, intolerable AEs, a discontinuation 
criterion is met or withdrawal of consent. The dose expansion will be initiated from the dose 
level where anti-tumor activity (PR or CR in patients with EGFR or HER2 Exon20ins) is 
observed. Data from dose escalation and dose expansion will be used to define RP2D.
As of data cut-off date April 3, 2023, in 74 prior platinum-based chemotherapy treated NSCLC 
subjects with EGFR Exon20ins, the confirmed ORR assessed by investigators was
 across 
all dose levels. At the dose level of 200 mg and 300 mg, the confirmed ORR was
 and
 
respectively.
DZ2020E0001 (Clinicaldrugtrial identifier: CTR20211009) is a phase 2, single arm, pivotal 
study in Chinese NSCLC with EGFR Exon20ins mutations.. As of April 3, 2023, in 97 patients 
of efficacy analysis set, the confirmed ORR was
 and the confirmed DCR was
 as 

Clinical Study Protocol
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
22
assessed by IRC. The median DoR was 
 months. The longest DoR already reached 
 
months, and subject is still responding. 
By the same DCO, a total of 313 advanced NSCLC subjects with EGFR or HER2 mutations 
were included in the safety analysis set. The most common (
20%) TEAEs across all dose 
levels were diarrhea, rash, anemia, blood creatine phosphokinase increased, paronychia, 
decreased appetite, vomiting, nausea, blood creatinine increased, and weight decreased. Refer 
to the current D
e (IB) for a complete summary of nonclinical 
and clinical information including safety, efficacy, and pharmacokinetics.

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
23 
 
TABLE OF CONTENTS 
PAGE
TITLE PAGE ........................................................................................................... 1 
INTRODUCTION & STUDY FLOW CHART .................................................... 19 
TABLE OF CONTENTS ....................................................................................... 23 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 30 
1. 
STUDY OBJECTIVES .......................................................................................... 34 
1.1 
Objectives .............................................................................................................. 34 
1.1.1 
Part A ..................................................................................................................... 34 
1.1.1.1 
Primary objectives ................................................................................................. 34 
1.1.1.2 
Secondary objectives ............................................................................................. 35 
1.1.1.3 
Exploratory objectives ........................................................................................... 35 
1.1.2 
Part B ..................................................................................................................... 36 
1.1.2.1 
Primary objectives ................................................................................................. 36 
1.1.2.2 
Secondary objectives ............................................................................................. 36 
1.1.2.3 
Exploratory objectives ........................................................................................... 36 
2. 
BACKGROUND ................................................................................................... 37 
2.1 
NSCLC with EGFR Exon20ins, HER2 Exon20ins, and EGFR uncommon 
mutation ................................................................................................................. 37 
2.2 
Investigational agent .............................................................................................. 38 
2.3 
Non-clinical and clinical information of DZD9008 ............................................... 38 
2.3.1 
The key data from primary pharmacology studies were as follows: ..................... 38 
2.3.2 
The key findings in the secondary and safety pharmacology studies were 
as follows: .............................................................................................................. 39 
2.3.3 
The key data from Nonclinical pharmacokinetics were as follows: ...................... 39 
2.3.4 
The key findings from Nonclinical toxicity studies were as follows:.................... 40 
2.3.5 
Clinical information of DZD9008.......................................................................... 42 
3. 
STUDY DESIGN AND RATIONALE ................................................................. 43 
3.1 
Overall study design and flowchart ....................................................................... 43 
3.2 
Rationale for conducting this study and for study design ...................................... 45 
3.2.1 
Part A, Dose escalation, dose expansion and food effect of DZD9008 ................. 45 
3.2.2 
Part B, Dose Extension of DZD9008 ..................................................................... 47 
4. 
PATIENT SELECTION AND RESTRICTIONS ................................................. 48 
4.1 
Inclusion criteria .................................................................................................... 48 
4.1.1 
Core inclusion criteria ............................................................................................ 48 
4.1.2 
Cohort specific inclusion criteria ........................................................................... 49 
4.1.2.1 
Part A ..................................................................................................................... 49 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
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4.1.2.2 
Part B ..................................................................................................................... 50 
4.2 
Exclusion criteria ................................................................................................... 50 
4.3 
Restrictions ............................................................................................................ 53 
4.3.1 
Concomitant treatment ........................................................................................... 54 
5. 
STUDY TREATMENT AND CONDUCT ........................................................... 55 
5.1 
Treatment ............................................................................................................... 55 
5.1.1 
Part A, Dose escalation, dose expansion and food effect ...................................... 56 
5.1.1.1 
Starting dose, dose escalation scheme and stopping criteria ................................. 56 
5.1.1.2 
Definition of dose limiting toxicity (DLT) ............................................................ 60 
5.1.1.3 
Definition of maximum tolerated dose (MTD) ...................................................... 61 
5.1.1.4 
Definition of maximum feasible dose .................................................................... 61 
5.1.1.5 
Definition of evaluable patient ............................................................................... 61 
5.1.1.6 
Safety Review Committee (SRC) .......................................................................... 61 
5.1.2 
Part A, dose expansion ........................................................................................... 62 
5.1.3 
The effect of food on PK of DZD9008 .................................................................. 63 
5.1.4 
Part B, Dose extension of DZD9008 ..................................................................... 64 
5.1.5 
Toxicity management and dose modifications....................................................... 65 
5.1.6 
Assessment timing if dosing is interrupted ............................................................ 66 
5.1.7 
Duration of treatment ............................................................................................. 68 
5.1.8 
Treatment compliance and accountability ............................................................. 68 
5.2 
Benefit/risk and ethical assessment........................................................................ 68 
5.2.1 
Potential benefit ..................................................................................................... 68 
5.2.2 
Potential risks identified non-clinically with DZD9008 ........................................ 69 
5.2.2.1 
Gastrointestinal tract effects................................................................................... 69 
5.2.2.2 
Dermatological effects ........................................................................................... 69 
5.2.2.3 
Ocular surface effects............................................................................................. 69 
5.2.2.4 
Cardiovascular effects ............................................................................................ 70 
5.2.2.5 
Respiratory effects ................................................................................................. 70 
5.2.2.6 
Liver effects ........................................................................................................... 70 
5.2.2.7 
Hematopoietic effects ............................................................................................ 70 
5.2.2.8 
Renal effect ............................................................................................................ 71 
5.2.2.9 
CYP450 induction/inhibition ................................................................................. 71 
5.2.2.10 Hemorrhage ............................................................................................................ 71 
5.2.3 
Safety data of DZD9008 in ongoing phase I/II clinical studies ............................. 71 
5.2.4 
Overall benefit/risk and ethical assessment ........................................................... 71 
5.3 
Discontinuation of investigational product and withdrawal from the study .......... 72 
5.3.1 
Procedures for handling patients incorrectly initiated on investigational 
product ................................................................................................................... 73 
5.3.2 
Procedures for withdrawal from study ................................................................... 74 
5.3.3 
Interim analysis ...................................................................................................... 74 
5.4 
End of study ........................................................................................................... 74 
5.5 
Post study access to study treatment ...................................................................... 75 

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Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
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6. 
STUDY PLAN AND COLLECTION OF STUDY VARIABLES ....................... 75 
6.1 
Study plan .............................................................................................................. 75 
6.2 
Recording of data ................................................................................................... 75 
6.3 
Safety assessment ................................................................................................... 75 
6.3.1 
Enrolment and screening ........................................................................................ 75 
6.3.2 
Physical examination ............................................................................................. 76 
6.3.3 
Vital sign ................................................................................................................ 76 
6.3.4 
Laboratory safety assessment ................................................................................ 78 
6.3.5 
Other safety assessments ........................................................................................ 79 
6.3.5.1 
Resting 12-lead ECG ............................................................................................. 79 
6.3.5.2 
Echocardiogram/MUGA Scan ............................................................................... 81 
6.3.5.3 
Pulmonary function tests (PFTs) ........................................................................... 81 
6.3.5.4 
Ophthalmologic examination ................................................................................. 82 
6.3.6 
Follow up ............................................................................................................... 82 
6.3.6.1 
Safety follow up ..................................................................................................... 82 
6.3.6.2 
Progression follow up ............................................................................................ 82 
6.3.6.3 
Survival follow up .................................................................................................. 83 
6.4 
Adverse events ....................................................................................................... 83 
6.4.1 
Definition of adverse events .................................................................................. 83 
6.4.2 
Definitions of serious adverse events..................................................................... 83 
6.4.3 
Recording of adverse events .................................................................................. 84 
6.4.3.1 
Time period for collection of adverse events ......................................................... 84 
6.4.3.2 
Follow-up of unresolved adverse events ................................................................ 84 
6.4.4 
Reporting of serious adverse events....................................................................... 87 
6.5 
Pharmacokinetics ................................................................................................... 87 
6.5.1 
Collection of pharmacokinetic samples ................................................................. 87 
6.5.1.1 
Part A (Dose escalation) ........................................................................................ 87 
6.5.1.2 
Part A expansion .................................................................................................... 89 
6.5.1.3 
Part B extension ..................................................................................................... 89 
6.5.2 
Determination of drug concentration in plasma and urine samples ....................... 93 
6.5.3 
Other parameters .................................................................................................... 93 
6.6 
Exploratory research .............................................................................................. 93 
6.6.1 
Exploratory analyses to support companion diagnostics development ................. 94 
6.6.2 
Exploratory biomarker research ............................................................................. 94 
6.6.2.1 
Archived tumor tissue or fresh biopsy for exploratory biomarker research .......... 94 
6.6.2.2 
Paired tumor tissue for proof-of-mechanism (PoM) biomarker study ................... 94 
6.6.2.3 
Blood sampling for other exploratory biomarker study ......................................... 95 
6.6.3 
Pharmacogenetics .................................................................................................. 95 
6.7 
Procedures for handling biological samples .......................................................... 96 
6.7.1 
Volume of blood .................................................................................................... 96 
6.7.2 
Handling, storage and destruction of biological samples ...................................... 96 
6.7.2.1 
Blood Sample for safety and PK ............................................................................ 96 

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Protocol No.: DZ2019E0001
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Date: July 24,2023
 
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6.7.2.2 
Blood-borne exploratory biomarker samples ......................................................... 97 
6.7.2.3 
Archived tumor tissue or fresh biopsy ................................................................... 98 
6.7.2.4 
Samples for pharmacogenetic study ...................................................................... 98 
6.7.3 
Labelling and shipment of biohazard samples ....................................................... 99 
6.7.4 
Chain of custody of biological samples ................................................................. 99 
6.7.5 
Withdrawal of informed consent for donated biological samples ......................... 99 
6.8 
Anti-tumor efficacy .............................................................................................. 100 
6.8.1 
Tumor assessments .............................................................................................. 100 
6.8.1.1 
Imaging assessment ............................................................................................. 100 
6.9 
Other assessments ................................................................................................ 101 
6.9.1 
EQ-5D-5L ............................................................................................................ 101 
6.9.2 
PRO-CTCAE ....................................................................................................... 101 
6.9.3 
FACIT-item GP5 ................................................................................................. 102 
7. 
EVALUATION AND CALCULATION OF VARIABLES AND 
STATISTICAL METHODS ................................................................................ 102 
7.1 
Definition of study endpoints ............................................................................... 102 
7.2 
Determination of sample size ............................................................................... 103 
7.2.1 
Part A Dose escalation, expansion and food effect cohort .................................. 103 
7.2.2 
Part B Dose extension cohort ............................................................................... 104 
7.3 
Calculation or derivation of safety variables ....................................................... 104 
7.4 
Calculation or derivation of pharmacokinetic variables ...................................... 105 
7.5 
Calculation or derivation of tumor response variables ........................................ 106 
7.5.1 
Objective response rate (ORR) ............................................................................ 107 
7.5.2 
Progression Free Survival (PFS) .......................................................................... 108 
7.5.3 
Duration of Response (DoR) ............................................................................... 108 
7.5.4 
Disease control rate (DCR) .................................................................................. 108 
7.5.5 
Change in tumor size ........................................................................................... 108 
7.5.6 
Overall Survival (OS) .......................................................................................... 108 
7.6 
Calculation of patient reported outcome (PRO) .................................................. 109 
7.6.1 
EQ-5D-5L ............................................................................................................ 109 
7.7 
Calculation or derivation of exploratory research variables ................................ 109 
7.8 
Analysis sets ......................................................................................................... 109 
7.9 
Methods of Statistical analysis ............................................................................. 110 
7.9.1 
Demographic data ................................................................................................ 110 
7.9.2 
Exposure .............................................................................................................. 110 
7.9.3 
Safety ................................................................................................................... 110 
7.9.4 
Pharmacokinetics ................................................................................................. 111 
7.9.5 
The effect of high fat meal ................................................................................... 113 
7.9.6 
The effect of low-fat meal .................................................................................... 114 
7.9.7 
Efficacy ................................................................................................................ 114 

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7.9.7.1 
Tumor response .................................................................................................... 114 
7.9.7.2 
Duration of response ............................................................................................ 115 
7.9.7.3 
Change in tumor size ........................................................................................... 115 
7.9.7.4 
Progression free survival ...................................................................................... 115 
7.9.7.5 
Overall survival .................................................................................................... 115 
7.9.8 
Patient Report Outcome (PRO) ........................................................................... 115 
7.9.9 
PoM biomarker .................................................................................................... 115 
7.9.10 
Exploratory biomarker research and pharmacogenetic study .............................. 116 
7.10 
Publication policy ................................................................................................ 116 
8. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................ 117 
8.1 
Medical emergencies and Sponsor contacts ........................................................ 117 
8.2 
Overdose .............................................................................................................. 117 
8.3 
Pregnancy ............................................................................................................. 118 
8.3.1 
Maternal exposure ................................................................................................ 118 
8.3.2 
Paternal exposure ................................................................................................. 118 
9. 
REFERENCES .................................................................................................... 119 
 
LIST OF FIGURES 
Figure 1 
Study Flowchart .............................................................................................. 44 
Figure 2 
Study plan of food effect cohort ..................................................................... 63 
Figure 3 
Dose modification for toxicity related to DZD9008 ....................................... 67 
 
LIST OF TABLES 
aTable 1 
Exposure of DZD9008 at NOAEL from preclinical toxicity studies and 
margin to the predicted drug exposure in human at 50 mg once daily ........... 57 
Table 2 
Indicative dose escalation scheme .................................................................. 59 
Table 3 
Dose interventions .......................................................................................... 66 
Table 4 
Laboratory variables to be measured .............................................................. 79 
Table 5 
Blood PK sampling schedule (Part A, dose escalation) .................................. 90 
Table 6 
Blood PK sampling schedule (Part A, food effect) ........................................ 90 
Table 7 
Blood PK sampling schedule (Part A expansion) ........................................... 91 

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Table 8 
Blood collection for intense PK (Part B extension) ........................................ 92 
Table 9 
Blood collection for sparse PK (Part B extension) ......................................... 93 
Table 10 
Analysis set definition .................................................................................. 109 
Table 11 
Study Plan of Dose Escalation Cohort (Part A, dose escalation) ................. 122 
Table 12 
Study Plan of Food Effect Cohort (Part A, food effect) ............................... 125 
Table 13 
Study Plan of Part A Dose Expansion .......................................................... 128 
Table 14 
Study Plan of Part B Dose Extension ........................................................... 131 
Table 15 
Lab visits and clinical monitoring (Part A, dose escalation) ........................ 134 
Table 16 
Lab visits and clinical monitoring (Part A dose expansion) ......................... 136 
Table 17 
Lab visits and clinical monitoring (Part A, food effect) ............................... 137 
Table 18 
Lab visits and clinical monitoring (Part B dose extension) .......................... 139 
Table 19 
Summary of Methods of Assessment ........................................................... 152 
Table 20 
Overall Visit Response for Target Lesions ................................................... 155 
Table 21 
Overall Visit Response for Non-Target Lesions ........................................... 156 
Table 22 
Overall Visit Response ................................................................................. 157 
Table 23 
Drugs that are strong inhibitors of CYP3A4 ................................................ 166 
Table 24 
Drugs that are strong inducers of CYP3A4 .................................................. 166 
Table 25 
Exposure, pharmacological action and toxicity may be increased or 
decreased by DZD9008 ................................................................................ 167 
Table 26 
Drugs prolonging QT interval ....................................................................... 168 
Table 27 
Drugs that may prolong QT interval ............................................................. 168 
 
 
 
LIST OF APPENDICES 
Appendix A SIGNATURE ................................................................................................ 141 
Appendix B FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE) ........................................................................... 142 
Appendix C INTERNATIONAL AIRLINE TRANSPORTATION ASSOCIATION 
(IATA) 6.2 GUIDANCE DOCUMENT ....................................................... 144 
Appendix D ETHICAL AND REGULATORY REQUIREMENTS ................................ 145 

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Appendix E PATIENT DATA PROTECTION ................................................................ 148 
Appendix F GUIDELINE FOR EVALUATION OF OBJECTIVE TUMOR 
RESPONSE USING RECIST 1.1 (RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS) ............................................................... 151 
Appendix G ACTIONS REQUIRED IN CASE OF COMBINED INCREASE OF 
AMINOTRANSFERASE AND TOTAL BILIRUBIN-
 ........... 161 
Appendix H GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH 
CONCOMITANT MEDICATIONS ............................................................ 165 
Appendix I GUIDANCE FOR THE SAFETY MONITORING AND 
MANAGEMENT OF ADVERSE EVENTS ................................................ 170 
Appendix J Patient Reported Outcomes (Selected PRO-CTCAE items, FACIT item 
GP5 and 5Q-5D-5L) ..................................................................................... 180 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this protocol. 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event  
Ae 
Cumulative amount of unchanged drug excreted into urine 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC(0-24) 
Area under the plasma concentration-time curve from time zero to 24 
hours 
AUC(0-72) 
Area under the plasma concentration-time curve from time zero to 72 
hours 
AUC(0-168) 
Area under the plasma concentration-time curve from time zero to 168 
hours 
AUC(0-t) 
Area under the plasma concentration-time curve from time zero to t 
[amount·time/volume] 
AUC(0-  
Area under the plasma concentration-time curve from time zero to 
infinity 
AUCss 
Area under the plasma concentration-time curve during any dosing 
interval at steady state [amount· time/volume] 
BOR 
Best Overall Response 
ctDNA 
Circulating free tumor deoxyribonucleic acid 
CL/F 
Total body clearance of drug from plasma after an oral dose 
CLss/F 
Total body clearance of drug from plasma after an oral dose at steady 
state 
CLR 
Renal clearance of drug from plasma 
Cmax 
Maximum plasma concentration 
CLIA 
Clinical Laboratory Improvement Amendments 
CPP 
Clinical Pharmacology and Pharmacometrics 
CR 
Complete response 
CRF 
Case Report Form (electronic/paper) 

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Abbreviation or 
special term 
Explanation 
CSP 
Clinical Study Protocol 
Css,max 
Maximum plasma concentration at steady state 
Css,min 
Minimum plasma concentration at steady state 
CSR 
Clinical Study Report 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of Response 
ECG 
Electrocardiogram 
Echo 
Echocardiogram 
ECOG 
Eastern Co-operative Oncology Group 
EGFR 
Epidermal growth factor receptor 
Exon19del 
Exon 19 deletion 
Exon20ins 
Exon 20 insertion 
Fe 
Percentage of the dose excreted unchanged in urine 
FFPE 
Formalin-fixed paraffin-embedded 
FTIP 
First Time in Patients 
GCP 
Good Clinical Practice 
GI50 
The concentration of a test agent for 50% of maximal inhibition of cell 
proliferation 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-seriously toxic dose 
HRQoL 
Health related quality of life 
IATA 
International Air Transport Association 
IB 
Investigator s Brochure 
IC50 
Half-maximal inhibitory concentration (the concentration of a test agent 
needed to inhibit a biological process or response by 50%) 

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Abbreviation or 
special term 
Explanation 
ICH 
International Conference on Harmonisation 
IRC 
Independent Review Committee 
INR 
International normalized ratio 
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRT 
Mean residence time 
MTD 
Maximum tolerated dose 
MUGA 
Multi gated acquisition scan 
NE 
Not evaluable 
NOAEL 
No Observed Adverse Effect Level 
NSCLC 
Non-Small Cell Lung Cancer 
NTL 
Non-target lesion 
OAE 
Other significant adverse event 
ORR 
Objective Response Rate 
PD 
Progression of disease 
PFS 
Progression free survival 
PK 
Pharmacokinetics 
PoM 
Proof of Mechanism 
PR 
Partial response 
PRO 
Patient Reported Outcomes 
QT 
ECG interval measured from the onset of the QRS complex to the end of 
the T wave 
QTc 
QT interval corrected for heart rate 
QTcB 
QTc interval with Bazett's correction 
QTcF 
QTc interval 
 
RAC 
Extent of accumulation on multiple dosing 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 

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Abbreviation or 
special term 
Explanation 
RP2D 
Recommended Phase II Dose 
SAE 
Serious adverse event  
SD 
Stable disease 
SRC 
Safety Review Committee 
STD10 
10% of the Severely Toxic Dose in rodents 
z 
terminal rate constant 
t½ z 
Terminal half-life  
TL 
Target lesion 
TKI 
Tyrosine kinase inhibitor 
tmax 
Time to maximum plasma concentration 
tss max 
Time to maximum plasma concentration at steady state 
ULN 
Upper limit of normal 
UVA 
Ultraviolet A 
UVB 
Ultraviolet B 
Vss/F 
Apparent volume of distribution   
WBDC 
Web Based Data Capture 
WHO 
World Health Organization 
~ 
Approximately 
 
 

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Protocol No.: DZ2019E0001
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Clinical Study Protocol 
 
A Phase I/II, Open-Label, Multicenter Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Anti-tumor Efficacy of DZD9008 in 
Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) with EGFR 
or HER2 mutation  
Part A: ~130 - 150 patients, Part B: 206 patients (providing approximately 103 patients are 
enrolled to the optimal RP2D cohort) 
1. 
STUDY OBJECTIVES 
Part A of the study is a first time in human study to assess safety, tolerability, pharmacokinetics 
and anti-tumor efficacy of DZD9008 in advanced non-small cell lung cancer (NSCLC) patients 
with epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 
(HER2) mutations, with preferential focusing on patients with EGFR and HER2 Exon20ins. 
Part B extension is a phase 2 study to assess the efficacy and safety of DZD9008 in NSCLC 
patients with EGFR Exon20ins mutation, who have relapsed from 1-3 lines of prior systemic 
therapy.  
This study includes two parts: Part A (dose escalation, food effect and dose expansion) and Part 
B (dose extension). 
1.1 
Objectives 
1.1.1 
Part A  
1.1.1.1 
Primary objectives 
Objectives 
Endpoint/Variable 
To investigate the safety and tolerability of 
DZD9008 when given orally to patients with 
advanced NSCLC with EGFR or HER2 mutations
 
Adverse Events (AEs)/Serious Adverse Events 
(SAEs) 
 
Laboratory data 
 
Vital signs 
 
Electrocardiogram (ECG) 
 
Physical examination  
 
Echocardiogram/MUGA 
 
Pulmonary function test  
To establish Maximum Tolerated Dose (MTD) (if 
possible) and Recommended Phase 2 Dose 
(RP2D) of DZD9008 when given orally in 
patients with advanced NSCLC with EGFR or 
HER2 mutations 
 
Dose Limiting Toxicities (DLTs) 
 
AEs/SAEs 

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1.1.1.2 
Secondary objectives 
Objectives 
Endpoint/Variable 
To characterize the pharmacokinetics (PK) of 
DZD9008 following a single oral dosing and at 
steady state after multiple oral dosing in the 
fasted state, and renal excretion of DZD9008  
 
Plasma and urine DZD9008 concentrations, and 
derived PK parameters  
To evaluate the effect of food on the exposure of 
DZD9008 at the defined doses 
 
Plasma DZD9008 concentrations, and derived 
PK parameters  
To assess preliminary anti-tumor activity of 
DZD9008 according to Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 by 
investigator 
 
Objective Response Rate (ORR) 
 
Best Overall Response (BOR) 
 
Duration of Response (DoR) 
 
Disease Control Rate (DCR)  
 
% Change in Size of tumor lesion  
 
Progression Free Survival (PFS) 
To retrospectively assess anti-tumor activity of 
DZD9008 in patients with EGFR Exon20ins 
according to RECIST 1.1 by Independent Review 
Committee (IRC) 
 
ORR, DCR, DoR by IRC 
1.1.1.3 
Exploratory objectives 
 
To collect and store diagnostic tumor samples (archived) or any fresh tumor biopsies 
(if archived tumor sample is not available) to confirm EGFR and HER2 mutations by 
central lab retrospectively, support the development of diagnostic test for pre-market 
approval by regulatory authorities and potential future exploratory research into 
factors that may influence development of DZD9008 in NSCLC and/or tumor 
response to DZD9008. 
 
To investigate the presence, and/or identity of the drug metabolites of DZD9008 in 
plasma and urine samples, if appropriate, characterize their PK. 
 
To in
-hydroxycholesterol to total cholesterol 
as a biomarker of cytochrome P450 (CYP)3A4 induction by DZD9008. 
 
To collect and store blood-based samples for future exploratory research on 
genes/genetic aberrations that may influence response to DZD9008 treatment and/or 
susceptibility to DZD9008. 
 
To assess AEs of DZD9008 by using patient reported specific CTCAE symptoms 
(PRO-CTCAE) and FACIT GP5 questionnaire.  

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To explore the relationship between DZD9008 exposure and selected endpoints, (i.e., 
safety and efficacy), where deemed appropriate. 
1.1.2 
Part B  
1.1.2.1 
Primary objectives 
Objectives 
Endpoint/Variable 
To evaluate anti-tumor activity of DZD9008 in 
advanced NSCLC patients with EGFR Exon20ins 
at defined dose(s) by assessment of Objective 
Response Rate (ORR) 
 
Objective Response Rate (ORR) according to 
RECIST 1.1 by an Independent Review 
Committee (IRC).  
 
1.1.2.2 
Secondary objectives 
Objectives 
Endpoint/Variable 
To assess anti-tumor efficacy of DZD9008 using 
additional endpoints  
 
DoR, Progression Free Survival (PFS), DCR, 
BOR and % of Change in Size of tumor lesion 
according to RECIST 1.1 using assessments 
performed by an IRC 
 
DoR, PFS, DCR, BOR and % of Change in Size 
of tumor lesion using investigators assessments 
according to RECIST 1.1 
 
Description of OS 
To determine the safety and tolerability of 
DZD9008  
 
AEs/SAEs 
 
Laboratory data 
 
Vital signs 
 
Physical examination 
 
ECG  
 
Echocardiogram/MUGA 
 
Pulmonary function test                        
To characterize the PK of DZD9008  
 
Plasma DZD9008 and metabolite concentration 
and derived PK parameters if deemed 
appropriately  
 
1.1.2.3 
Exploratory objectives 
 
To collect and store archived tumor samples (if more than one formalin-fixed 
paraffin-embedded (FFPE) block from a patient, tissue from the most recent one is 
preferred) or any fresh tumor biopsies (if archived tumor sample is not available) for 
EGFR Exon20ins confirmation in central laboratory and necessary technical studies 

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Drug Substance: DZD9008
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Edition Number: 12.0
Date: July 24,2023
 
37 
 
for companion diagnostics development and approval and potential future 
exploratory research into factors that may influence development of DZD9008.  
 
To collect and store plasma samples to isolate circulating free tumor DNA (ctDNA) 
for EGFR Exon20ins mutation testing and necessary technical studies, for liquid 
biopsy companion diagnostic development and approval. 
 
To collect and store blood-based samples for future exploratory research on 
genes/genetic aberrations that may influence response to DZD9008 treatment and/or 
susceptibility to DZD9008.  
 
To investigate the effect of DZD9008 on proof-of-mechanism (PoM) biomarkers in 
tumor biopsy (e.g., EGFR phosphorylation (pEGFR). 
 
To explore the relationship between DZD9008 exposure and selected endpoints 
(which may include efficacy, safety, QTc interval etc.), where deemed appropriate. 
 
To collect and store deoxyribonucleic acid (DNA) for future exploratory research into 
genes/genetic variation that may influence PK or response to DZD9008, (i.e., 
absorption, distribution, metabolism, excretion, safety and efficacy). 
 
To explore the impact of DZD9008 treatment and disease state on health state utility 
by using EQ-5D-5L health state utility index based on patient reported data. 
 
To assess AEs of DZD9008 by using subjects reported specific CTCAE symptoms 
(PRO-CTCAE) and FACIT GP5 questionnaire. 
2. 
BACKGROUND 
2.1 
NSCLC with EGFR Exon20ins, HER2 Exon20ins, and EGFR 
uncommon mutation  
Lung cancer is the most common cancer type in the world for several decades. It is also one of 
the most common causes of cancer death. NSCLC represents approximately 80% to 85% of all 
lung cancer. 
EGFR tyrosine kinase inhibitors (TKIs) have been proved to be effective therapy for NSCLC 
patients with EGFR sensitizing mutations, such as L858R and exon 19 deletion (Exon19del), 
and resistance mutation, T790M (1-9). However, beyond L858R, Exon19del and T790M, 
EGFR or HER2 Exon20ins, which together with EGFR G719X, S768I and L861Q uncommon 
mutations comprise of about 7% of NSCLC (10). Although amivantamab (JNJ-61186372), an 
EGFR and MET bispecific antibody, and mobocertinib (TAK-788), an EGFR TKI, both have 
recently received accelerated approval for NSCLC patients with EGFR Exon20ins, but the 
efficacy and safety of these two drugs should be further validated in phase 3 confirmatory 
studies with larger cohorts. Post-hoc analysis of afatinib phase 2 and phase 3 trials LUX-Lung 

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2, LUX-Lung 3 and LUX-Lung 6 demonstrated clinical activities in 1st line patients in certain 
types of uncommon EGFR mutations, such as G719X, S768I and L861Q, while there was no 
effective treatment after disease relapse. In addition, afatinib is not effective in patients with 
Exon20ins (11).
There is no standard regimen for the treatment of patients with EGFR Exon20ins. Platinum-
based doublet chemotherapies are commonly used in the clinic, however the treatment effect is 
not optimal. The first to third generation of EGFR TKIs as well as onco-immune therapy 
provides limited treatment effect in the above mentioned population. Real-world data showed 
that ORR of patients receiving the 2nd line therapies was ~ 14% (7% to 24%), and median PFS 
was ~ 3.7 months. In another retrospective real-world analysis of 165 Chinese NSCLC patients 
harboring EGFR Exon20ins who were diagnosed with advanced disease between 2015 and 
2018, data showed that ORR of 1st line platinum-based chemotherapy was 19.2%, DCR at 6 
months was 41.3%, and median PFS was 6.4 months (95% confidence interval: 5.7 to 7.1 
months). The ORR for 2nd line chemotherapy was 17.6%, ORR for 2nd line EGFR TKIs was 
5.9%. The median PFS for 2nd line chemotherapy was 4 months and for EGFR TKIs was 2 
months (12-13). These data suggest that highly effective targeted therapy against EGFR 
Exon20ins is urgently needed in the clinic.
2.2
Investigational agent
DZD9008 is an oral, potent, selective and irreversible EGFR TKI targeting EGFR sensitizing 
mutations, EGFR T790M mutation, EGFR Exon20ins, HER2 Exon20ins and EGFR uncommon 
mutations. DZD9008 demonstrates potent activities against all known EGFR or HER2 
mutations with less potent activity against wild type EGFR. 
2.3
Non-clinical and clinical information of DZD9008
2.3.1
The key data from primary pharmacology studies were as follows:
DZD9008 is a potent and selective irreversible EGFR TKI that targets various EGFR 
Exon20ins, uncommon mutation, or classical mutation with enzymatic IC50 of
.
DZD9008 shows good selectivity against kinase panel of 117 kinases. In addition to 
EGFR (L858R/T790M), only 14 other kinases were inhibited by greater than 50% at 
1 µM of DZD9008 (ranging from 51% - 96% inhibition). DZD9008 does not hit 
IGF1R (insulin growth factor receptor 1) and InsR (insulin receptor), demonstrated 
by both low kinase activity (IC50 > 100 nM) and low cellular pIGF1R and pInsR 
modulation activity (IC50 of ~ 5000 nM). 
DZD9008 downregulates pEGFR with IC50 ranging from
 in tumor cells 
expressing EGFR L858R, Exon19del, L858R/T790M, Exon20ins or uncommon 
mutations, and pHER2 with IC50 of 
 in tumor cells engineered with 
different subtypes of HER2 Exon20ins. In contrast, DZD9008 was less potent in 
modulating pEGFR in tumor cells expressing wild type EGFR, with IC50 of
 

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In cell proliferation assays, DZD9008 suppresses cell proliferation with GI50 of 
 in tumor cells carrying EGFR L858R, Exon19del, L858R/T790M, Exon20ins 
or uncommon mutations, and GI50 of 
 in tumor cells engineered with 
different subtypes of HER2 Exon20ins. 
In a number of standard and patient derived tumor xenograft models, DZD9008 
induces profound tumor regression in a dose dependent manner, while demonstrates 
only modest effect in xenograft model carrying wild type EGFR.
2.3.2
The key findings in the secondary and safety pharmacology studies were as 
follows:
In secondary pharmacology screening, DZD9008 had activity (a defined IC50 value) 
against 55 targets. No targets had activity within 50 folds of wild type EGFR 
biochemical enzyme activity IC50 (
).
DZD9008 inhibits the function of the hERG potassium channel with IC50 value of 
  Using manual patch clamping, DZD9008 showed activity at three other 
cardiac ion 
There were no notable effects on the cardiovascular system in conscious telemetered 
dogs following administration of single doses up to 30 mg/kg DZD9008. 
There were no notable effects on the respiratory and central nervous system (CNS) 
in rats following administration of single doses up to 100 mg/kg DZD9008.
2.3.3
The key data from Nonclinical pharmacokinetics were as follows:
DZD9008 has favorable drug metabolism and pharmacokinetics (DMPK) properties 
for oral dosing. Pharmacokinetic exposure approximately increased in proportion to 
oral dose in rats and dogs. Accumulation in terms of AUC was less than 2 folds on 
multiple daily dosing in rat and dog.  
In vitro data have indicated that CYP3A4/5 are the principal P450 isozymes 
responsible for human metabolism. Thus, co-administration with CYP3A4/5 
perpetrators may alter the exposure of DZD9008. The metabolism of DZD9008 in 
hepatocytes from mouse, rat, dog and human was primarily to N-dealkylated and N-
oxidative products with direct conjugation to a range of glutathione, cysteine and 
glucuronide conjugates. Glutathione conjugation may be an important pathway in 
DZD9008 metabolism in rat, dog and human. 
Based upon in vitro data and clinical exposure, DZD9008 DDI risk is considered 
unlikely to cause clinically significant hepatic drug interactions at clinically relevant 
concentrations through inhibition or induction of cytochrome P450 enzyme activity. 
Combination of In vitro data and DZD9008 clinical exposure indicated that 

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DZD9008 is likely a perpetrator of DDI through inhibition of P-gp, BCRP and 
OATP1B1 transporters, and induction of CYP3A4, CYP2C enzymes.  
 
Following intravenous and oral administration of [14C]-DZD9008 in intact and bile-
duct cannulated rats, the major route of excretion was via feces and/or biliary route, 
with urinary elimination being a minor component. Excretion was rapid in rats, with 
the majority radioactivity recovered in the first 48 hours. 
 
Concentration of radioactivity in tissues were quantified from the whole body auto-
radiography, using a validated image analysis system. Following oral administration 
of [14C]-DZD9008 to male and female non-pigmented rats in a QWBA study, drug 
related material was widely distributed to all tissues, with highest concentrations of 
radioactivity between 2 and 6 hours with elimination - GI tract, spleen, liver, kidney, 
lung and glandular tissue. Radioactivity in the brain and spinal cord remained below 
the limit of quantification. Following a single oral administration of [14C]-DZD9008 
to male partially-pigmented rats, distribution of radioactivity followed a similar 
pattern to that observed in the non-pigmented animals. Terminal half-life of 
radioactivity in tissues ranges from 2 to 1043 days. Radioactivity in the melanin-
containing uveal tract and meninges was measurable up to and including 60 days after 
dose administration, indicating affinity of the test material for melanin. 
2.3.4 
The key findings from Nonclinical toxicity studies were as follows: 
 
In both dog and rat toxicity studies, most observations and findings are consistent 
with consequences of the pharmacological inhibition of wild type EGFR by 
DZD9008 or sequelae to primary effects.  A wide range of organs and tissues 
containing epithelial cell lineages were affected with changes spanning epithelial 
atrophy through to erosion, inflammation and necrosis. Dose-limiting toxicity was 
principally deterioration of the animals from low food intake and body weight loss as 
a consequence of gastrointestinal (GI) toxicity resulting from effects of EGFR 
inhibition by DZD9008. 
 
In the 14-day dose range finding (DRF) study in dog, toxicity findings were 
associated to pharmacological inhibition of EGFR or sequelae secondary to primary 
effects.  Doses of 50 and 75 mg/kg were not tolerated and associated with moribund, 
notable body weight loss and decreased appetite, severe clinical signs (including 
moribund, weakness, deep breathing, lethargy, thin, decreased activity, diarrhea, oral 
mucosa color change, emesis); and macroscopic findings of diffused/multifocal dark 
red in GI tract.  Besides, altered clinical pathology parameters related to liver/kidney 
injury/inflammation at moribund condition were noted at 50 and 75 mg/kg. Major 
target organs identified by histology are: gastrointestinal tract (hemorrhage, ulcer, 
erosion, gland dilatation), thyroid (follicular atrophy), lacrimal gland (acinar cell 
atrophy), 
vagina 
(epithelial 
atrophy), 
tongue/esophagus 
(epithelial 
atrophy/erosion/neutrophilic infiltrate), eye (cornea epithelial atrophy), pancreas 
(acinar cell secretory depletion), kidney (cortical tubular dilatation), and mandibular 

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salivary gland acinar cell secretory depletion, which are considered EGFR inhibition 
related; Lymphoid depletion of immune organs (thymus, spleen and lymph nodes) 
and adrenal gland hypertrophy were likely due to the stress; bone marrow myeloid 
hypercellularity could be the inflammatory response to gastrointestinal tract change.  
At lower doses of 15 and 25 mg/kg, similar but milder or less findings presented.  
 
In the 4-week GLP dog study, dogs were dosed at 3, 6, 12/8 (males) or 12 (females) 
mg/kg.  The toxicity findings were similar with 14-day DRF dog study.  Up to 12 
mg/kg was tolerated in female dogs, while one female at 12 mg/kg showed severe 
body weight loss, low food consumption and diarrhea. Twelve mg/kg was intolerable 
in males due to EGFR inhibition related effects (including diarrhea, body weight loss 
and notable low food intake); when the dosage reduced to 8 mg/kg, males were well 
tolerated.  Mild ectasia of the glands of the colon was observed at one female dog 
given 12 mg/kg/day DZD9008.  Though exposure (Cmax and AUClast) was comparable 
with peers, one male dog dosed at 6 mg/kg showed EGFR inhibition related effect in 
the first two weeks including diarrhea, yellow/reddish mucus in feces, low food 
intake, body weight loss, and thin appearance, but these findings relieved in late stage 
of dosing phase. The GI findings are dose-limiting and reversible.  NOAEL is defined 
as 3 mg/kg and 6 mg/kg for males and females, respectively.   
 
In the 13-week GLP dog study, dogs were dosed at 1, 3 or 6 mg/kg/day for 13 weeks 
and well tolerated at all dose levels, with clinical signs limited to a non-adverse 
increase in the incidence of loose or liquid feces at 3 or 6 mg/kg/day, which were 
reversible during the treatment-free period. Slight decreases in primary red cell 
parameters at 6 mg/kg/day and slight decreases in potassium and albumin 
concentrations at 3 or 6 mg/kg/day at the end of the dosing period were reversible 
and considered not to be adverse.  There were no pathology findings to indicate target 
organ toxicity. NOAEL is 6 mg/kg/day. 
 
In the 4-week DRF rat study, male rats were dosed with 25, 50, 100 or 200 mg/kg 
DZD9008 for up to 28 days.  Dose level of 100 and 200 mg/kg were not tolerated.  
Moribund, notable body weight loss and adverse clinical signs (soft/watery feces) 
were observed at 100 and 200 mg/kg.  Reduction of alkaline phosphatase (47%), total 
cholesterol (16%) and triglyceride (48%) were observed at 100 mg/kg. Slightly 
decreases of albumin was noted at 50 mg/kg. DZD9008-related microscopic findings 
were present in the skin (crust formation in the epidermis), GI tract (erosion of 
mucosal epithelium, necrosis and inflammation), eye (corneal epithelial atrophy), 
thymus (lymphoid decrease) and pancreas (acinar atrophy) in 100 mg/kg or 200 
mg/kg dosing groups. Rats were well tolerated at 25 and 50 mg/kg. 
 
In the 4-week GLP rat study, animals were dosed at 25, 50/15, 65/35 mg/kg.  Similar 
to findings in 4-week DRF rat study, GI related changes (soft stool, low food intake, 
body weight loss) are dose limiting. High dosage (65 and 50 mg/kg) was intolerable 
due to remarked body weight loss and after 5 - 6 day dosing, doses were reduced to 
 35 mg/kg. Minimal 

Clinical Study Protocol
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
42
persistent pupillary membrane, iris synechia, or opacity of anterior lens capsule were 
observed at all dose levels. Minor clinical pathology changes (decreases in albumin, 
total protein, red blood cell count, hematocrit and/or hemoglobin concentration) 
along with minor histopathology findings in lung (diffuse, multifocal or focal alveolar 
infiltrates of macrophages in the lung, both sexes) and pancreas (focal or multifocal 
fibrosis, males only) were noted at all dose levels. Except for pancreas fibrosis, all 
above findings were not observed at the end of recovery phase. NOAEL is defined as 
35 mg/kg.  
In the 13-week GLP rat study, DZD9008 administered to animals at 15, 25 or 35 
mg/kg/day for 13 weeks resulted in reduced body weight gain at all dose levels and 
non-adverse clinical signs (flaky tails, tail riding and head scabbing) at 35 mg/kg/day.  
Slight changes in primary red cell parameters, neutrophil counts and liver, kidney and 
spleen weights were reversible and considered not to be adverse.  Target organs were 
identified as the mesenteric lymph nodes, lungs and mammary gland (males only) but 
based on the severity of the changes and apparent reversibility they were considered 
not to be adverse under the conditions of this study. NOAEL is 35 mg/kg/day.
When dosing duration was extended from 4 weeks to 13 week, no new toxicity 
findings were noted. In addition, the severity and frequency of the toxicity findings
did not change when the dosing duration increased.
DZD9008 showed no evidence of genotoxicity potential in AMES, in vitro 
chromosome aberration assay or in vivo micronucleus assay in rat studies.
DZD9008 showed no evidence of phototoxic potential in an in vitro 3T3 cell 
phototoxicity assay conducted in the presence or absence of UV light.
The results from the toxicology studies support progression into clinical trials in 
patients with advanced NSCLC. 
Furth
IB).
2.3.5
Clinical information of DZD9008
There are three clinical studies of DZD9008 monotherapy for which efficacy analysis has been 
conducted in NSCLC subjects with EGFR Exon20ins post platinum-based chemotherapy:
(DZ2019E0001, and DZ2019E0002 and DZ2020E0001).
As of April 3, 2023, in 74 prior platinum-based chemotherapy treated NSCLC subjects with 
EGFR Exon20ins from studies DZ2019E0001 and DZ2019E0002, the confirmed ORR assessed 
by investigators were
across all dose levels. At the dose level of 200 mg and 300 mg, the 
confirmed ORR was
 and
 respectively.
In another phase 2 pivotal study DZ2020E0001 in Chinese NSCLC with EGFR Exon20ins, in 
97 subjects of efficacy analysis set, the confirmed ORR was
 and the confirmed DCR was 

Clinical Study Protocol
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
43
 as assessed by IRC. The median DoR was 
months. The longest DoR already reached 
 months, and subject is still responding.
By the same DCO, a total of 313 advanced NSCLC subjects with EGFR or HER2 mutations 
were included in the safety analysis set. The most common (
20%) TEAEs across all dose 
levels were diarrhea, rash, anemia, blood creatine phosphokinase increased, paronychia, 
decreased appetite, vomiting, nausea, blood creatinine increased, and weight decreased.
As the bioanalytical sample cut-off dates of February 15, 2021 for study DZ2019E0001 and 
September 9, 2020 for study DZ2019E0002, preliminary PK analysis showed that the median 
tmax occurred about 
 post-dose. Following a single oral dosing, DZD9008 
exhibited low to moderate apparent clearance (CL/F) and extensive volume of distribution 
(V/F). Following once daily dosing, steady state was achieved by day
 DZD9008, with an 
accumulation of around
folds in AUC which was expected based on around 50-hour half-life.
At steady state, DZD9008 has flat PK profile and there was limited fluctuation between Css,max 
and Css,min, which is desirable PK properties to maintain effective concentrations during the 
dosing interval. DZD9008 exhibited approximately dose-proportional increases in exposure 
across the dose range investigated (50 - 400 mg) on multiple-dose. The impact of high-fat meal 
on the bioavailability of DZD9008 has been evaluated in healthy subjects (n = 20, study 
DZ2021E0004) as well as in NSCLC patients (n = 12) in this study at the 300 mg dose with the 
tablet (the proposed commercial formulation). Both studies showed high-fat meal has no to 
negligible effect on the Cmax and AUC of DZD9008. Since food might help to mitigate the GI 
related toxicity, it is recommended that DZD9008 be taken with food in this study.
nonclinical and clinical information including safety, efficacy, and pharmacokinetics.
3.
STUDY DESIGN AND RATIONALE
The clinical study protocol has finished peer review within Dizal Pharmaceuticals.
3.1
Overall study design and flowchart
This is a phase 1/2, open-label, multicenter study of DZD9008 administered orally in patients 
with advanced stage NSCLC with EGFR or HER2 mutation. The study design allows a dose 
escalation of DZD9008, with intensive safety monitoring to ensure the safety of the patients, 
followed by dose expansion at selected dose (s) in Part A, then move into cohort of patients 
with EGFR Exon20ins in Part B at defined RP2D.
There are two parts in this study. Part A, Dose escalation, dose expansion and food effect, and 
Part B, Dose extension. Approximately a total of 130 - 150 patients and ~206 patients are 
expected to be enrolled into Part A and Part B, respectively. Part B will be triggered when RP2D 
is defined. Following review and approval from IEC/IRB and/or local regulatory authority (as 
applicable) on the optimal RP2D selection, eligible patients can be enrolled into the optimal 
RP2D cohort to ensure approximately 103 patients be enrolled into this cohort.

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
44 
 
Figure 1 
Study Flowchart 
 
Part A, dose escalation  
The number of patients will depend upon the number of dose escalation necessary and potential 
expansion. Approximately 30 evaluable patients with advanced EGFR or HER2 mutant NSCLC 
who relapsed from or were refractory, or were intolerant to standard systemic therapy will be 
enrolled.  
Part A, food effect 
A separated cohort of ~10 evaluable patients will be enrolled to assess the effect of high-fat 
meal on PK of DZD9008 at a defined dose (i.e. predicted efficacious dose or RP2D). 
Part A, dose expansion 
To further evaluate safety, tolearbility, PK and preliminary anti-tumor efficacy of DZD9008 
and help define RP2D, a total of approximately 90 - 110 additional patients with EGFR or HER2 
Exon20ins will be enrolled into 6 different cohorts (see details in the study flow chart). There 
is no DLT assessment period for patients in Part A expansion cohorts. However, the incidence 
and type of DLT like toxicities will be taken into consideration by the SRC in determining dose 
escalation steps and RP2D.  
 
Dose expansion cohort 1 (n = ~10): patients with EGFR Exon20ins or HER2 
Exon20ins, previously treated with at least one line of systemic therapy, dose at 200 
mg in fasted state. 
 
Dose expansion cohort 2 (n = ~10): patients with EGFR Exon20ins or HER2 
Exon20ins, previously treated with at least one line of systemic therapy, dose at 300 
mg in fasted state. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
45 
 
 
Dose expansion cohort 3 (n = 10 ~ 20): patients with EGFR Exon20ins, previously 
treated with at least one line of systemic therapy, dose at 200 mg with low-fat meal.  
 
Dose expansion cohort 4 (n = 10 ~ 20): patients with EGFR Exon20ins, previously 
treated with at least one line of systemic therapy, dose at 300 mg with low-fat meal.  
 
Dose expansion cohort 5 (n = ~ 30): patients with EGFR Exon20ins, treatment naïve, 
dose at 300 mg with low-fat meal. This cohort will be triggered when the emerging 
data shows DoR reaches 6 months, and the food effect cohort data is available. 
 
Dose expansion cohort 6 (n= ~ 20): patients with EGFR Exon20ins, previously 
treated with at least one line of systemic therapy, and patients should be refractory to, 
relapsed from or intolerant to amivantamab treatment, DZD9008 will be dose at 300 
mg with low-fat meal. 
Part B, dose extension 
Part B is a phase 2, open-label, randomized pivotal study with 2 dose cohorts to evaluate the 
anti-tumor efficacy of DZD9008. Approximately 206 NSCLC patients with EGFR Exon20ins 
will be enrolled into 2 separate cohorts of this part of study. Simon two-stage design (14) will 
be used within each dose cohort respectively. When both dose cohorts pass stage 1, the response 
rate of two cohorts will be compared to identify the more effective arm. Alternatively, Dizal 
may trigger the earlier discussion with regulatory on the optimal RP2D selection upon emerging 
efficacy and safety data. 
Eligible patients will be stratified by the brain metastasis at baseline (Yes, No) and number of 
regimens of prior anti-cancer systemic therapy (<3, 3) and randomized to the DZD9008 200 mg 
or 300 mg arm at the ratio of 1:1. 
 
Cohort 1: patients with EGFR Exon20ins, previously treated with at least one line but 
no more than 3 lines of systemic therapy, DZD9008 will be dosed at 200 mg with 
food. 
 
Cohort 2: patients with EGFR Exon20ins, previously treated with at least one line but 
no more than 3 lines of systemic therapy, DZD9008 will be dosed at 300 mg with 
food.   
Following review and approval from IEC/IRB and/or local regulatory authority (as applicable) 
on the optimal RP2D selection, eligible patients can be enrolled into the optimal RP2D cohort 
to ensure approximately 103 subjects be enrolled into this cohort. 
3.2 
Rationale for conducting this study and for study design 
3.2.1 
Part A, Dose escalation, dose expansion and food effect of DZD9008 
Part A, Dose escalation 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
46 
 
This is a first time in patient study for DZD9008. The primary purpose of this part of the study 
is to assess safety, tolerability and determine MTD and/or RP2D of DZD9008. 
The preclinical data suggest DZD9008 has broad inhibition effect against different types of 
EGFR or HER2 mutations, including EGFR sensitizing mutation, T790M, EGFR and HER2 
Exon20ins, EGFR uncommon mutation etc. Thus, the target patient population of Part A 
includes any patients with locally advanced or metastatic NSCLC with all types of documented 
EGFR or HER2 mutations who have progressed despite prior systemic anti-cancer therapy (i.e. 
chemotherapy, with or without prior EGFR or HER2 target therapy), are relapsed or intolerant 
to current standard therapy.  
The starting dose, dose escalation and cohort size are based upon accepted methology for phase 
I oncology studies defined by the United States, European, Japanese and Chinese regulation 
(Section 5.2). This part of study will determine the MTD based upon assessment of the safety, 
tolerability and pharmacokinetic data collected during the first 28 days of daily dosing. The 28-
day assessment period was selected as the major toxicities leading to cessation of dose 
escalation in such studies (haematological, gastrointestinal, liver enzymes) are anticipated to 
present within this duration. The dose escalation method will utilize a Bayesian adaptive design, 
where the model provides a recommendation of the next dose (see Section 5.1.1 for more 
details).  
Part A, Food effect 
A cohort of NSCLC patients with EGFR or HER2 mutation (Food effect cohort, n = ~10) will 
be enrolled at the defined dose (ie. predicted efficacious dose etc) to evaluate the effect of high-
fat meal on exposure of DZD9008. Food effect study can be run in parallel with dose extension, 
and the emerging results from food effect study will guide optimization of dose scheme in Part 
B. The detailed process is specified in Section 5.1.1.2.  
Part A, Dose Expansion 
To further evaluate safety, tolerability, PK and preliminary anti-tumor efficacy of DZD9008 in 
fasted state or with low-fat meal (approximately 400 to 500 Kcal with about 25% of calories 
comes from 11-14 grams of fat), to help define and optimize RP2D, a total of approximately 
90~ 110 additional patients with EGFR or HER2 Exon20ins will be enrolled into 6 different 
cohorts (see details in the study flow chart). Cohort 6 aims to specifically evaluate the anti-
tumor activity of DZD9008 in amivantamb treated patients. There is no DLT assessment period 
for patients in Part A expansion cohorts. However, the incidence and type of DLT like toxicities 
will be taken into consideration by the SRC in determining dose escalation steps and RP2D.  
Preliminary results (n = 3) from the food effect study at 300 mg have shown that high-fat meal 
had limited effect on bioavailability of DZD9008. Hence, 300 mg once daily taken with low-
fat meal is not anticipated to increase the exposure of DZD9008 to clinically relevant extent, 
and is unlikely to increase safety risk. Additionally, experience from other TKIs showed that 
drug administered with food could improve GI tolerability (15).  
In Part A, Dizal plans to collect archived tumor tissue or fresh tumor biopsy to confirm the 
EGFR or HER2 mutation status retrospectively. This could be used to support the development 
of companion diagnostics. 

Clinical Study Protocol
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
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In Part A, radiological scans (including those at unscheduled visits, or outside visit windows)
for patients with EGFR Exon20ins will be collected on an ongoing basis for retrospective 
reviews by the Independent Review Committee. 
For specific part, Japan will follow Japan local CSP addendum in Part A.
3.2.2
Part B, Dose Extension of DZD9008
Although amivantamab (JNJ-61186372) and mobocertinib (TAK-788) have recently received 
accelerated approval for NSCLC patients with EGFR Exon20ins, the efficacy and safety of thse 
two drugs should be further validated in phase 3 confirmatory studies with larger cohorts.
From the real-world data analysis, current clinical treatment provides minimal benefit to 
NSCLC patients with EGFR Exon20ins. Platinum-based doublet chemotherapy is commonly 
used in the clinic, however, ORR was only around 14% (7.0% - 24.4%) and median PFS is 
around 3.7 months (2.6 - 5.9 months) for patients received prior treatment (13). In another real-
world study of Chinese patients with EGFR Exon20ins, ORR for patients received first-line and 
second line chemotherapy were 19.2% and 17.6%, respectively; median PFS for patients
received first-line and second line chemotherapy were 6.4 months (5.7 - 7.1 months) and 4.0 
months (3.2 - 4.8 months), respectively (12). Current available EGFR TKIs only confer ORR 
of around 8.7% and 5.9%, and median PFS of 2.9 months and 2.0 months for patients received 
first line and second line treatment, respectively (16). Data from Korea and Japan etc. shows 
similar results (17).
Given the unmet medical need in the aforementioned patient population alongside with the lack 
of well-proven treatment options, and the encouraging efficacy (BoR of
and
at 
selected RP2D of 200 mg and 300 mg once daily, separately, by DCO April 3, 2021) and well 
tolerated safety profile reported in the ongoing Part A of this study, it was considered resonable
to initiate Part B to further assess anti-tumor efficacy and safety of DZD9008 at both 200 mg 
and 300 mg. The Part B of DZ2019E0001 study is planned as a phase 2, open-label study of 
DZD9008 to assess its anti-tumor efficacy as primary objective using ORR by IRC in NSCLC 
patients with EGFR Exon20ins. PK will also be assessed in this Part of the study. The doses of
200 mg once daily and 300 mg once daily were selected as phase 2 dose (s) based on available 
safety, tolerability, PK and efficacy data from both DZ2019E0001 Part A and DZ2019E0002 
studies. In Part B, Dizal plans to enroll NSCLC patients with EGFR Exon20ins which has been
confirmed in a local CLIA-certified laboratory (or equivalent) or Sponsor designated central 
laboratory
). An adequate 
amount of archived tumor tissue or fresh biopsy must be available prior to the study entry for 
EGFR Exon20ins mutation confirmation in Sponsor designated central laboratory using the 
designated assay and for supporting future companion diagnostics development and approval.
If a pre-study written documentation of EGFR Exon20ins in tumor tissue is available from 
Sponsor designated central laboratory using the designated assay, no additional tumor sample 
needs to be submitted. In addition, collecting and storing plasma samples for isolation of ctDNA
to develop liquid biopsy diagnostic test is also planned. 
In addition, Dizal may perform genetic research in the DZD9008 clinical studies to explore if
genetic polymorphism/variations may affect the clinical parameters associated with DZD9008. 
Collection of ctDNA and DNA samples from populations with well described clinical 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
48 
 
characteristics may lead to improvements in the design and interpretation of clinical studies and 
possibly, to genetically guide treatment strategies.  
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to DZD9008 but also susceptibility to NSCLC for which DZD9008 may be 
evaluated. Thus, this genetic research may involve study of additional un-named genes or gene 
categories, but only as related to disease susceptibility and drug action. 
4. 
PATIENT SELECTION AND RESTRICTIONS 
Investigators should keep a record, e.g, patient screening log, of patients who entered pre-study 
screening. Eligibility should be reviewed and documented by the investigator, or appropriately 
qualified delegate, prior to enrolment. 
Each patient must meet all of the inclusion criteria (core inclusion criteria and cohort specific 
criteria) and none of the exclusion criteria at the time of starting study treatment. Under no 
circumstances there can be exceptions to this rule. 
4.1 
Inclusion criteria 
4.1.1 
Core inclusion criteria 
For inclusion in the study, patients must fulfil all of the following core criteria: 
1. 
Patients must be able to understand the nature of the trial and provide a signed and 
dated, written informed consent form prior to any study specific procedures, sampling 
and analyses. 
2. 
Aged at least 18 years old.  
3. 
Histological or cytological confirmed locally advanced or metastatic NSCLC. An 
adequate amount of tumor tissue (archived tumor tissue, or fresh biopsy if archived 
tissue is not available) must be available at the time of enrollment for central 
laboratory confirmation of mutations and/or companion diagnostics development.  
4. 
Patients must exhibit Eastern Cooperative Oncology Group (ECOG) performance 
status 0 - 1 at ICF signature with no deterioration over the previous 2 weeks. 
5. 
 12 weeks 
6. 
Patient must have measurable disease according to RECIST 1.1: At least one lesion, 
 10 mm in 
the longest diameter (except lymph nodes which must 
computed tomography (CT) or magnetic resonance imaging (MRI) and which is 
suitable for repeated measurement. 
7. 
Patients with brain metastasis (BM) can only be enrolled under the condition that BM 
is previously treated and stable e.g., no evidence of progression for at least 2 weeks 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
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49 
 
after CNS-directed treatment as ascertained by clinical examination and brain 
imaging (magnetic resonance image [MRI] or computed tomography [CT] scan) 
during the screening period, neurologically asymptomatic and not require 
corticosteroid treatment. If BM has been treated with radiation or surgery, there 
should be a time window of  2 weeks or 
4 weeks respectively, before the first 
grade 1. 
8. 
Adequate organ system functions, as outlined below 
 
 1.5 x 109/L 
 
 x 109/L 
 
 
 
Total bilirubin  1.5 x ULN if no liver metastases or  3 x ULN in the presence 
metastases  
 
Alanine aminotransferase (ALT) and aspartate aminotransfera
 x 
 x ULN with liver involvement 
 
Creati
 x ULN, or 
measured or 
calculated by the Cockcroft-Gault method or others based on local practice. 
 
International normalized 
 ULN and activated partial 
 
 
9. 
For inclusion in the optional genetic research study, patient must provide informed 
consent for genetic research. If a patient declines to participate in any voluntary 
exploratory research and/or genetic component of the study, there will be no penalty 
or loss of benefit to the patient and he/she will not be excluded from other aspect of 
the study. 
4.1.2 
Cohort specific inclusion criteria 
In addition to meet all of the core inclusion criteria, subjects must meet cohort specific inclusion 
criteria for their enrolment to specific cohort. 
4.1.2.1 
Part A 
Dose escalation 
Patients must have documented histologically or cytologically confirmed locally advanced or 
metastatic NSCLC with EGFR or HER2 mutations, and have relapsed from, been refractory to 
or are intolerant to prior standard therapy without preferred alternative therapy. 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
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50 
 
Dose expansion 
Dose expansion cohort 1 and cohort 2: NSCLC patients with EGFR Exon20ins or HER2 
Exon20ins, who have relapsed from, been refractory to or are intolerant to at least one line of 
prior systemic therapy. 
Dose expansion cohort 3 and cohort 4: NSCLC patients with EGFR Exon20ins, who have 
relapsed from,  been refractory to or are intolerant to at least one line of prior systemic therapy. 
Dose expansion cohort 5: NSCLC patients with EGFR Exon20ins, who have not received prior 
systemic therapy (treatment naïve). 
Dose expansion cohort 6: NSCLC patients with EGFR Exon20ins, who have recevied at least 
one line of prior systemic therapy, and must have relapsed from,  been refractory to or intolerant 
to Amivantamab treatment. 
4.1.2.2 
Part B 
Patients must have histologically or cytologically confirmed locally advanced or metastatic 
NSCLC with documented EGFR Exon20ins mutation in tumor tissue from a local CLIA-
certified laboratory (or equivalent) or Sponsor designated central laboratory prior to the study 
entry. 
An adequate amount of archived tumor tissue (if a patient has more than one FFPE blocks, the 
most recent tissue is preferred) or any fresh tumor biopsies (if archived tumor sample is not 
available) must be available prior to the study entry for EGFR Exon20ins mutation confirmation 
in Sponsor designated central laboratory using the designated assay and for supporting 
development of tumor tissue-based companion diagnostics for DZD9008. If a pre-study written 
documentation of EGFR Exon20ins in tumor tissue is available from Sponsor designated central 
laboratory using the designated assay, no additional tumor sample needs to be submitted. 
Patients should have received at least 1 line, but no more than 3 lines of systemic therapy for 
metastatic/locally advanced disease (who must have progressed on, or be intolerant of, at least 
one prior line with platinum-based chemotherapy). 
4.2 
Exclusion criteria 
1. 
Treatment with any of the followings: 
 
For expansion cohorts of Part A and Part B extension cohorts: Patients who have 
received prior Poziotinib, TAK-788, CLN-081, BDTX-189 or furmonertinib or 
any other EGFR/HER2 exon20ins small molecule inhibitors treatment should be 
excluded. Other EGFR TKIs, such as gefitinib, erlotinib, osimertinib, afatinib, 
dacomitinb are not considered EGFR or HER2 Exon20ins small molecule 
inhibitors, thus prior treatment with these drugs are allowed unless the patient 
had an objective response and subsequent progression as assessed by the 
investigator or treating physician during treatment with that prior TKI, and a 
minimum wash-out period of 8 days (approximately 5x half-life) prior to the first 
administration of DZD9008 is needed. 

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Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
51 
 
 
Treatment with EGFR or HER2 antibodies or other antibodies within 4 weeks 
before the first administration of DZD9008. 
 
Any cytotoxic chemotherapy, investigational agents or other anticancer drugs 
from a previous treatment regimen or clinical study within 14 days before the 
first administration of DZD9008. 
 
Major surgery (excluding placement of vascular access) within 4 weeks before 
the first administration of DZD9008. 
 
Radiotherapy with a limited field of radiation for palliation within 1 week of the 
first dose, with the exception of patients receiving radiation to more than 30% of 
the bone marrow or with a wide field of radiation which must be completed 
within 4 weeks before the first administration of DZD9008. 
 
Patients currently receiving (or unable to stop using) medications known to be 
potent inhibitors or inducers of CYP3A within 1 week or 2 weeks, respectively, 
before the first administration of DZD9008. 
 
Prior treatment with any onco-immunotherapy (e.g., immune checkpoint 
inhibitors PD-1, PD-L1, CTLA-4) within 4 weeks before the first administration 
of DZD9008.  
 
Treatment with any investigational drug within five half-lives of the compound 
(or discuss with Dizal Study team). 
 
Treatment with herbal supplements within 1 week and unable to stop using. 
2. 
Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time 
of starting DZD9008 with the exception of alopecia and grade 2 prior platinum-
therapy related neuropathy. 
3. 
Spinal cord compression or leptomeningeal metastasis.  
4. 
As judged by the investigator, any evidence of severe or uncontrolled systemic 
diseases, including uncontrolled hypertension and active bleeding diatheses, which 
desirable for the patient to participate in the 
trial or which would jeopardize compliance with the protocol, or active infection 
including hepatitis B, hepatitis C, human immunodeficiency virus (HIV) and 
COVID-19 (per local practice). Screening for chronic condition is not required. 
5. 
Any of the following cardiac criteria 
 
Mean resting corrected QT interval (QTc) > 470 msec (if in France and Canada: 
> 470 msec for women or > 450 msec for men) obtained from 3 
electrocardiograms (ECGs) at screening. 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
52 
 
 
Any clinically significant abnormalities in rhythm, conduction or morphology of 
resting ECG, e.g., complete left bundle branch block, third degree heart block, 
and second-degree heart block, PR interval > 250 msec. 
 
Any factors that increase the risk of QTc prolongation, such as heart failure, 
hypokalemia, congenital long QT syndrome, family history of long QT 
syndrome or unexplained sudden death under 40 years of age in first degree 
relatives or any concomitant medication known to prolong the QT interval.  
 
Prior history of atrial fibrillation within 6 months of first administration of 
DZD9008, except prior drug treatment related and recovered. 
6. 
For Part B, prior malignancy within 2 years requires active treatment, except for 
adequately treated basal cell skin carcinoma, in situ cervical carcinoma, or other 
cancer type which has been disease free for > 2 years with life expectancy >2 years.  
7. 
Past medical history of interstitial lung disease, drug-induced interstitial lung disease, 
radiation pneumonitis which required steroid treatment, or any evidence of clinically 
active interstitial lung disease. 
8. 
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to 
swallow the formulated product or previous significant bowel resection that would 
preclude adequate absorption of DZD9008. 
9. 
History of hypersensitivity to active or inactive excipients of DZD9008 or drugs with 
a similar chemical structure or class to DZD9008. 
10. 
Women who are pregnant or breast feeding. 
11. 
Involvement in the planning and conduct of the study (applies to Dizal staff or staff 
at the study site). 
12. 
Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements. 
13. 
Known history of bleeding diathesis, i.e., hemophilia, Von Willebrand disease. 
14. 
History of stroke or intracranial hemorrhage within 6 months before the first 
administration of DZD9008. 
15. 
In addition, the following is considered criteria for exclusion from the exploratory 
genetic research: 
 
Previous allogenic bone marrow transplant. 
 
Non-leukocyte depleted whole blood transfusion within 120 days of the date of 
the genetic sample collection. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
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4.3 
Restrictions 
The following restrictions apply while the patient is receiving study treatment for the specified 
time before and after: 
1. 
Male patients with female partners of child-bearing potential should be willing to use 
barrier contraceptives (i.e., by use of condoms), during their participation in this study 
and for 6 months following the last dose of the study drug. Patients should avoid 
procreation for 6 months after completion of trial treatment. Male patients must 
refrain from donating sperm during their participation in the study and at least for 6 
months after the last treatment. If male patients wish to father children, they should 
be advised to arrange for freezing of sperm samples prior to the start of study 
treatment. 
2. 
Females of child-bearing potential should use reliable methods of contraception from 
the time of screening until 6 weeks after discontinuation. Acceptable methods of 
contraception include total sexual abstinence, tubal ligation, hormonal contraceptives 
that are not prone to drug-drug interactions (IUS Levonorgestrel Intra Uterine System 
(Mirena), Medroxyprogesterone injections (Depo-Provera), copper-banded intra-
uterine devices and vasectomized partner. All hormonal methods of contraception 
should be used in combination with the use of a condom by their male sexual partner 
for intercourse. Female patients should not be breast feeding and must have a negative 
pregnancy test prior to start dosing if of child-bearing potential or must have evidence 
of non-child-bearing potential by fulfilling one of the following criteria at screening: 
 
Post-menopausal defined as aged more than 50 years and amenorrhea for at least 
12 months following cessation of all exogenous hormonal treatment. 
 
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation. 
3. 
All patients must avoid concomitant use of medications herbal supplements and/or 
ingestions of foods with known potent inducer/inhibitory effects on CYP3A4 activity 
whenever feasible. Such drugs must have discontinued for a period of 1 week 
(CYP3A4 inhibitors) or 2 weeks (CYP3A4 inducers) prior to first administration of 
DZD9008. Guidance on medications to avoid, medications that require close 
monitoring and on washout periods is given in Appendix H. Patients may receive any 
medication that is clinically indicated for treatment of adverse events. All 
concomitant medications should be captured on the eCRF. 
4. 
Patients should abstain from eating large amounts of grapefruit and Seville oranges 
(and other products containing these fruits, e.g., grapefruit juice or marmalade) 
during the study, e.g., no more than a small glass of grapefruit juice (120 mL) or half 
a grapefruit or 1 to 2 teaspoons (15 g) of Seville orange marmalade daily. 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
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5. 
Patients should avoid donating blood whilst participating in studies of DZD9008 and 
for at least 12 weeks after receiving the last dose of the study treatment. 
6. 
Patients who wear contact lens must discontinue wearing their lenses if they have any 
ment with 
DZD9008 until at least one week after symptoms have resolved. If a patient has a 
recurrence of eye symptoms or experiences any severe (CTCAE grade 
events, they must discontinue wearing their contact lenses until at least one week after 
treatment with DZD9008 is permanently discontinued. Patients must not use any eye 
drops or ointment for treatment of eye symptoms, unless agreed by a study doctor, at 
any time during the study until 1 week after DZD9008 has been permanently 
discontinued, Patient should consult the clinic promptly if they have any concerns. 
7. 
Patients require anticoagulation and anti-platelet therapy, i.e., with Warfarin, heparin 
etc. while receiving DZD9008 may be at increased risk of hemorrhage. They should 
be monitored for any signs of bleeding. 
For restrictions relating to concomitant medications, see next Section 4.3.1. 
4.3.1 
Concomitant treatment  
Information about any treatment within 4 weeks prior to starting of DZD9008 and all 
concomitant treatments given during the study along with reasons for the treatment will be 
recorded in the Case Report Form (CRF). After permanent discontinuation of DZD9008 and 28 
day follow up, only subsequent regimens of anti-cancer therapy will be recorded in CRF. If 
medically feasible, patients taking regular medication, with the exception of potent inhibitors 
and inducers of CYP3A4 (see Section 4.2 and Appendix H), should be maintained on it throught 
the study period.  
All patients must avoid concomitant use of medications, herbal supplements and/or ingestions 
of food with known potent inducer/inhibitory effects on CYP3A activity whenever feasible. 
Traditional Chinese Medicine should be avoided. Such drugs must have been discontinued for 
1 week (CYP3A4 inhibitors) or 2 weeks (CYP3A4 inducers) prior to first administration of 
DZD9008. Guidance on medications to avoid, medications that require close monitoring and on 
washout periods is given in Appendix H.  
Patients must avoid live vaccines whist receiving study drug and up to 30 days after the last 
dose of study drug. 
Patients may receive any medication that is clinically indicated for treatment of adverse events. 
All concomitant medications should be captured on the electronic CRF (eCRF). 
Other anticancer agents, investigational agents and radiotherapy should not be given while the 
patient is receiving DZD9008. The patient may be allowed to take localized palliative 
radiotherapy only if it has been confirmed local lesion is not progressing, and/or after overall 
response has been evaluated as disease progression. This is to avoid interfering tumor 
assessment in the event of disease progression. Study drug interruption is not required in the 
case of local palliative radiotherapy for pain control (excluding chest and brain). For local 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
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palliative radiotherapy to chest and brain, study drug should be interrupted during and up to 7 
days post the palliative radiotherapy. Definitive radiotherapy and other anticancer therapy is not 
allowed.  
Blood transfusions and hematopoietic growth factors are allowed as clinically indicated during 
the study but not during the screening phase (Part A escalation only) to support blood cell count 
for eligibility and the DLT assessment period (Cycle 1 in Part A) when transfusions should not 
be administered unless the patient experiences a hematological DLT or require emergency 
treatment for any condition.  
Patients may receive treatment with corticosteroids and/or bisphosphonates for the treatment of 
bone metastases.  Patients may also receive radiotherapy for painful bony metastases. 
Supportive care and other medications that are considered necessary for the 
l-
being, may be given at the discretion of the investigator. 
5. 
STUDY TREATMENT AND CONDUCT 
5.1 
Treatment 
Supply, Packaging and Labeling of DZD9008 
DZD9008 drug substance and drug product to be used for this clinical study are manufactured 
in accordance with Good Manufacturing Practice (GMP). 
DZD9008 will be supplied by Dizal as 25 mg, 50 mg, 100 mg, 150 mg and 200 mg tablet by 
IRT system. 
Labels will be prepared in accordance with GMP and local regulatory guidelines. The labels 
will fulfil GMP requirements for labelling. Label text will be translated into local language. 
The label will include the Name of the Sponsor, Study Code, for clinical trial use only and /or 
any other specific requirements. 
DZD9008 tablets of 25 mg, 50 mg, and 100 mg strengths are presented as yellow, round shaped, 
biconvex, and film-coated tablets. Each HDPE bottle contains 25 units of one strength of the 
above mentioned 3 different tablets, and with 1 g of pre-packed silica-gel. DZD9008 tablets of 
150 mg and 200 mg strengths are presented as yellow, caplet shaped ,biconvex ,and film-coated 
tablets, 
on the other side. The tablet core is off-white to pale yellow after removing the coating film. 
Each HDPE bottle contains 30 units of one strength of the mentioned 150 mg or 200 mg tablets, 
and with 1 g of pre-packed silica-gel. 
DZD9008 tablet must be stored at storage condition of up to 30 C in the original container(s). 
The stability study of DZD9008 clinical batches is on-going and will be continued to at least 
cover the whole clinical trial. The shelf life will be evaluated when stability data becomes 
available.  
All study drugs should be kept in a secure place under appropriate storage conditions. The 
investigational product label specifies the appropriate storage condition. 

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Protocol No.: DZ2019E0001
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Drug administration 
DZD9008 will be given orally, once daily except for Cycle 0 in Part A dose escalation and food 
effect cohort.  
In Part A dose escalation cohort and dose expansion cohorts 1 and 2, patients are required to 
 dosing. Water is permitted during 
this fasted period.  
In Part A dose expansion cohorts 3 - 6, patients are recommended to take DZD9008 with a low-
fat meal. The low-fat meal is defined as approximately 400 to 500 Kcal with about 25% of 
calories comes from 11 - 14 grams of fat. Meal record will be collected at clinic site on PK 
sampling days as described in Table 7. Compliance with prandial conditions for non-PK 
sampling days is to be confirmed by the study personnel during the study visits (e.g., through 
patient diaries). 
In Part B, patients will receive repeat daily dosing of DZD9008 at 200 mg and 300 mg with 
food to further investigate its anti-tumor efficacy, safety/tolerability and PK.  
Following review and approval from IEC/IRB and/or local regulatory authority (as applicable) 
on the optimal RP2D selection (i.e., dropping the suboptimal dose), patient who is under 
screening will start treatment at optimal dose level. Patient who has been enrolled in optimal 
RP2D cohort can stay and maintain the pre-defined treatment course. The ongoing patient who 
has been randomized to another (suboptimal) Part B dose cohort can maintain the same dose 
level, or shift to receive the optimal dose if (a) judged by the investigator that it is of the best 
-consent is obtained. 
Dose should be taken approximately 24 hours apart at the same time point each day. On PK and 
plasma ctDNA sampling day, the dose should be instructed to take by site personnel. Doses 
should not be missed. If a subject misses taking a scheduled dose, within a window of 12 hours, 
it is acceptable to take the dose. If it is more than 12 hours after the dose time, the missed dose 
should not be taken and should be recorded, and subjects should be instructed to take the dose 
at the next scheduled time. If a subject vomits after taking their DZD9008, they should not make 
up for this dose. 
Enrollment of patients into Part A dose expansion cohort 5 will be triggered when emerging 
data shows DoR reaches 6 months. 
5.1.1 
Part A, Dose escalation, dose expansion and food effect 
5.1.1.1 
Starting dose, dose escalation scheme and stopping criteria 
Part A, dose escalation 
A dose of 50 mg once daily is proposed as the starting dose in this first time in patient study. 
This is based on international guidance of starting dose selection for agents in cancer patients 
(ICH S9) which recommends that the starting dose should be either 1/10th of the severely toxic 
dose (STD10) in rodent toxicity studies or 1/6th of the highest non-severely toxic dose (HNSTD) 
in non-rodent studies. From the preclinical GLP toxicity studies, STD10 in rat is defined as 
35~50 mg/kg, and HNSTD in dog is defined as 8 mg/kg. HED derived from 1/10th of STD10 in 
rat or 1/6th of HNSTD in dog is 35 mg or 43 mg once daily respectively. A dose of 50 mg once 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
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daily which is slightly higher than the ICH S9 recommended starting dose, is proposed in this 
first time in patient study. The rationales are as follows: 1) The predicted human free AUC and 
Cmax at 50 mg once daily are 0.12 µM*hr and 0.006 µM, respectively, which are comparable to 
or below the drug exposure at NOAEL in preclinical toxicity studies of rat and dog (see below 
table); 2) The non-clinical GLP tox findings of DZD9008 are similar to that of other EGFR 
TKIs, such as gefitinib and osimertinib, with dose limiting toxicities related to inhibition of wild 
type EGFR; 3) The wild type EGFR related toxicities are consistently translatable from non-
clinic to clinic across multiple EGFR TKIs; 4) Wild type EGFR related toxicities are generally 
monitorable, reversible and manageable, and there are extensive clinical knowledge and 
experience of monitoring and managing these toxicities based on more than 10 years of using 
EGFR TKIs in clinical practice; 5) From PK/PD modeling, 50 mg once daily is expected to 
derive biological effect.  
Table 1 
Exposure of DZD9008 at NOAEL from preclinical toxicity studies and 
margin to the predicted drug exposure in human at 50 mg once daily 
Study 
NOAEL 
(mg/kg) 
Mean free 
AUC 
(µM*hour) 
Mean free 
Cmax (µM) 
Fold to the 
predicted drug 
exposure in human 
at 50 mg daily 
(calculated by free 
AUC) 
Fold to the 
predicted drug 
exposure in 
human at 50 mg 
daily (calculated 
by free Cmax) 
Rat 1 month 
GLP toxicity 
study 
35 mg/kg 
0.64 
0.053 
5.3X 
8.8X 
Dog 1 month 
GLP toxicity 
study 
3 mg/kg (M) 
0.086 
0.007 
0.7X 
1.2X 
6 mg/kg (F) 
0.122 
0.011 
1.0X 
1.8X 
 
The dose escalation scheme will not exceed doubling of the dose, in principle. However, up to 
a quadrupling of the dose may be permitted in the first two escalations only, if the drug 
concentrations from the first or second dose level are not measurable or are below the predicted 
drug exposure for biological effect. This will ensure the fewest possible cohorts are exposed to 
DZD9008 below the presumed therapeutic dose. Non-clinical modelling provides only an 
approximate prediction of human PK, therefore the planned dose escalation scheme has the 
flexibility to be amended in light of emerging data. 
This study will utilize a Bayesian logistic regression model (BLRM) with overdose control 
(EWOC) similar to that proposed by Babb (18) for dose escalation to improve the efficiency 
and accuracy of MTD estimation compared to a traditional 3+3 design. The dose-limiting 
toxicity (DLT) relationship in the dose escalation part of the study is described by the following 
model:  
 
-
 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
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d* is the reference dose level, setting as 400mg. 
 based on prior 
guesses from preclinical data and clinical PK/PD modelling: 
 
The probability for DLT at lowest dose level 50 mg is very low, we assume it as 0.05 
 
 
400 mg may be a reasonable MTD justified for DZD9008. 
Using EAST 6.5, setting number of Beta samples as 1000, we will get the parameters of the 
prior distributions of model parameters as provided as below: 
Parameters 
Means 
Standard deviations 
Correlation 
 
(-1.101,0.191) 
(1.838, 1.07) 
0.488 
The target toxicity level is 30%. The following 3 intervals are defined: 
1. [0, 20%) under-dosing 
2. [20%, 35%) targeted toxicity 
3. [35%, 100%] excessive toxicity 
Dose recommendation will be based on posterior summaries for each dose, primarily the 
posterior probabilities for the above three intervals. 
Following the principle of escalation with overdose control (EWOC), after each cohort of 
patients, the recommended dose is the one with the highest posterior probability of the DLT rate 
falling in the target interval (20%, 35%) among the doses fulfilling EWOC, i.e., it is unlikely (< 
25% posterior probability) that the DLT rate at the dose falls in the excessive toxicity interval.   
The operating characteristics will include the accuracy (percentage of correct recommendations) 
and the safety profile (percentages of subjects experiencing DLTs and subjects exposed to 
overdosing doses in the trial) under various scenarios. 
Patients will be enrolled to ensure approximately minimum of 3 and maximum of 6 evaluable 
patients per cohort (additional patients may be enrolled to confirm safety and efficacy as agreed 
by SRC). Dosing will begin at 50 mg once daily. Table 2 shows an example of dose escalation 
scheme. However, all potential dose escalation or de-escalation levels after the starting dose 
may be adjusted in light of emerging safety, tolerability and/or PK data. 
For the purpose of planning, every 3 week period (21-day repeated dosing) will be called a 
Cycle (except Cycle 0, a single dosing followed by a 7-day washout period, and Cycle 1 [28-
day DLT assessment period]). In the first two patients of each dose cohort, a minimum of 7-day 
time interval is required between the first dosing of these two patients. Providing that there are 
no serious or unexplained safety issues, dosing of the remaining patients of the same cohort will 
continue without requirement in dosing time interval. However, should ambiguous findings 
occur, the SRC may choose to stagger the start of dosing remaining patients of the same cohort.   

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Dose escalation decision will be made by the Safety Review Committee once the last patient in 
a cohort has completed Cycle 1. Patients are evaluable if they have completed the first multiple 
dosing cycles and meet the evaluability criteria (see Section 4.1). Any patient experiencing a 
DLT is also considered evaluable. SRC will review the overall safety of the last completed 
cohort and any other safety signals from patients treated at other dose levels, as well as the 
recommendation provided by the adaptive Bayesian model. The final decision on next dose 
level will be made by SRC. 
Table 2 
Indicative dose escalation scheme 
Cohort 
Dose mg (once daily) 
1 
50 
2 
100 
3 
200 
4 
300 
5 
400 
 
Stopping criteria have been set in accordance with traditional oncology phase 1 study 
methodology. 
The overall dose-escalation and de-escalation paradiam is described below: 
 
If no dose-limiting toxicity (DLT) at any dose has been observed, then dose escalation 
may occur without further modelling. 
 
After the first DLT has been observed (at any dose), the Bayesian Logistic Regression 
model will be run to inform subsequent dose selections. Cumulative data on the 
evaluable patients will be used to estimate the predicted probability of a DLT and the 
posterior probabilities of DLT in the under-dosing, target and overdosing toxicity 
intervals at each study dose level. The recommendation for the next dose will then be 
based on the following principles, e.g. 
 
No dose may be chosen where the predicted probability of a DLT exceeds 50%. 
 
The posterior DLT risk in the overdosing toxicity level should not exceed pre-
specified tolerated risk level (e.g., 25%). 
 
The recommendation for the next dose will be chosen to have the maximum 
posterior probability of DLT level in the target toxicity interval.  
 
Dose increases will be permitted after review of data from a minimum of 3 evaluable 
patients. 
 
Prior to a dose escalation decision, the SRC will review all available safety and PK 
data. 

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Escalations will not exceed doubling of the dose in principle. However, up to a 
quadrupling of dosing may be permitted in the first two escalations only, if the drug 
concentrations of the first or second level are not measurable or are deemed to be far 
from predicted drug exposure (e.g., greater than 2-fold difference) and there have 
been no significant safety or tolerability issues. 
 
Dose escalation and de-escalation will be completed when any of the following occur: 
 
The required precision of the estimated MTD is achieved (e.g., the posterior 90% 
credible interval for the MTD is between 0.05 and 0.6). 
 
The maximum absorbable dose is achieved (i.e., when no increase in exposure 
with increasing dose is observed and a change in scheduling is conducted) 
 
Unfeasible number of tablets required to deliver dose.  
 
No anticipated improvement in efficacy with increasing dose. 
 
Decision made by SRC to stop the dose escalation.  
5.1.1.2 
Definition of dose limiting toxicity (DLT) 
A DLT is defined as any toxicity not attributable to the disease or disease-related processes 
under investigation, which occurs from the first dose of study treatment (Day 1, Cycle 0) up to 
the last day of Cycle 1 (28 days after start of multiple dosing) in dose escalation cohorts and 
which includes, despite optimal therapeutic intervention: 
 
Hematological toxicity that is Common Terminology Criteria for Adverse Events 
(CTCAE 5.0) grade 4  
 
Non-hematological 
 
 
Infection including febrile neutropenia 
 
Confirmed QTc prolongation (> 500 msec absolute or > 60 msec above baseline) 
 
Grade 3 platelet count decreased associated with clinically significant bleeding  
 
Grade 4 laboratory abnormalities per CTCAE 5.0 including life-threatening 
consequences. 
 
Any other toxicity that is 
 
Is greater than that of baseline, is clinically significant, and/or unacceptable, does 
not respond to supportive care, results in a disruption of dosing schedule of more 
than 7 days or is judged to be a DLT by the Safety Review Committee (SRC). 

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That is a protocol defined stopping criteria  
A DLT excludes: 
 
Alopecia of any grade 
 
Isolated grade 3 laboratory changes without clinical sequelae or clinical 
significance 
However, the incidence and type of DLT-type toxicity post DLT period and beyond will be 
taken into consideration by the SRC in determining dose escalation steps. 
5.1.1.3 
Definition of maximum tolerated dose (MTD) 
The MTD is defined as the highest dose at which the frequency of a dose limiting toxicity 
(DLT) is less than 30%. 
5.1.1.4 
Definition of maximum feasible dose 
A dose will be considered to be the maximum feasible dose and dose escalation will stop if: 
 
Delivery of the next dose level would require dosing of > 8 tablets per administration, 
or 
 
There is evidence in the dose-exposure relationship of saturation of absorption. 
5.1.1.5 
Definition of evaluable patient 
In order to be evaluable for determining dose escalation, an evaluable patient is defined as a 
patient who has received study treatment as appropriate: 
 
Received the single dose and at least 80% of planned doses of DZD9008 in Cycle 1 
(first 28-day of repeat dosing) of Part A 
 
Completed minimum required safety evaluations 
OR  
 
Experienced a DLT during the single dose to the end of Cycle 1 of Part A 
Any unevaluable patients could be replaced in the dose escalation phase to meet minimum 
required patient number for dose escalation. 
5.1.1.6 
 Safety Review Committee (SRC) 
The SRC will consist of: 
 
Study Team Physician, who will chair the committee, or delegate 
 
Principal Investigator or delegate from each investigational site 
 
Sponsor Safety Physician or delegate  

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The Chief Medical Officer, Clinical Pharmacology Scientist, Study Statistician, Study Leader, 
and Tox Project Lead, further internal or external experts may be invited as appropriate.  
Once there are at least 3 evaluable patients at a dose level, the SRC will review and assess all 
available safety data from the cohort together with available PK data to make a decision on the 
dose for the next cohort. Any dose interruptions and reductions will be taken into consideration. 
The decision may be to: 
 
Proceed with dose escalation  refer to Section 5.1.1.1. 
 
De-escalate the dose either to a previous lower dose level or to an intermediate lower 
dose level 
 
Recommend intermediate dose level, dosing interval and/or schedules prior to 
declaring the RP2D which will be guided by the evolving safety, preliminary efficacy 
and PK data 
 
Further expand the dose cohort to confirm safety and efficacy 
 
Stop the dose escalation part of the study 
 
Consider alternative dosing frequencies or intermittent dosing schedules 
 
Declare MTD 
 
Declare RP2D 
 
Approve the treatment ongoing patients in lower dose level cohort to escalate 
DZD9008 to a higher dose level if it is well tolerated. 
When there are other patients that are ongoing at the time of this review, the SRC may decide 
to defer their decision until these further patients become evaluable. 
Any patient started on treatment in error, as he/she failed to comply with all of the selection 
criteria but meets the criteria of an evaluable patient, will be reviewed on a case by case basis 
by the SRC to determine if the patient should be included or excluded in the decision for dose 
escalation.  
The decisions and decision-making of the SRC on the next dose level will be documented and 
provided to the investigators prior to dosing any new patients. 
5.1.2 
Part A, dose expansion 
To further evaluate safety, tolearbility, PK and preliminary anti-tumor efficacy of DZD9008 
and define RP2D, a total of approximately 90 - 110 additional patients with EGFR or HER2 
Exon20ins will be enrolled into 6 different cohorts (Figure 1, study flow chart) at selected doses 
under fasted or low-fat meal condition. There is no DLT assessment period for patients in Part 
A expansion cohorts. However, the incidence and DLT-like toxicities will be taken into 
consideration by the SRC in determining dose escalation steps and RP2D.  

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Patients will receive repeated dosing of DZD9008 until disease progression, intolerable AEs, 
discontinuation criteria have met or withdrawal of consent.  
5.1.3 
The effect of food on PK of DZD9008 
An additional cohort (n = ~10) in Part A will be enrolled at the defined dose (i.e. predicted 
efficacious dose, RP2D, etc) to evaluate food effect on PK of DZD9008.  
Figure 2 
Study plan of food effect cohort 
 
Note: ~10 patients are planned to be enrolled   
* 
The washout time of each treatment period might be updated in light of emerging human PK data. In 
general, after single dose, at least 7 days or 5 x half-lives will be allowed for drug elimination.  
 
This is a food effect cohort following cross-over study design. Patients in this cohort will firstly 
be randomized to receive a single dose of DZD9008 under either fasted or fed condition (a high 
fat meal), with 5 patients in each condition. After a 7-day washout period or 5 x half-lives 
(whichever is longer), these patients will be switched to receive a single dose of DZD9008 under 
cross-over condition. Blood samples will be taken in both conditions at defined time points for 
the assessment of DZD9008 plasma concentrations.  
Fasted condition: Patients must fast for  1 hours prior to taking a dose and to  2 hour post 
dose.  
Fed condition: Patients should start ingestion of a recommended meal 30 minutes prior to 
administration of DZD9008. Patients should finish this meal within 30 minutes or less; however, 
DZD9008 should be administered at 30 minutes after start of  high fat meal. DZD9008 should 
be administered with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 
2 hours post-dosing. 
Water will be restricted from 1 hour pre-dose until 1 hour post dose, except for the water 
administered with DZD9008, and any drink provided as part of the meal in the fed portion of 
the study. 
Patients should receive standardized meals. A high-fat (approximately 50 percent of total caloric 
content of the meal) and high-calorie (approximately 800 to 1000 calories) meal is 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
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recommended as a test meal. This test meal should derive approximately 150, 250, and 500-600
calories from protein, carbohydrate, and fat, respectively. The caloric breakdown of the test 
meal should be provided in the study report. An example test meal would be 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. Substitutions in this test meal can be made as long as the meal 
provides a similar amount of calories from protein, carbohydrate, and fat and has comparable 
meal volume and viscosity.
After completion of PK sampling, patients may continue receiving DZD9008 treatment until 
disease progression, intolerable AEs, discontinuation criteria have met or withdrawal of 
consent.
5.1.4
Part B, Dose extension of DZD9008
Based on the clinical data from phase 1 study, both 200 mg and 300 mg once daily dosing are
selected to further evaluate anti-tumor efficacy, safety and tolerability as well as PK of 
DZD9008 in EGFR Exon20ins NSCLC in Part B of this study: Following review and approval 
from IEC/IRB and/or local regulatory  authority (as applicable) on the optimal RP2D selection,
eligible patients can be enrolled into the optimal RP2D cohort.
Dose and Dosing Regimen
In the three clinical studies in NSCLC patients (DZ2019E0001, DZ2019E0002 and 
DZ2020E0001), DZD9008 was well tolerated at doses ranging from 50 mg to 400 
mg. Exploratory dose/exposure-safety analysis indicated a positive relationship of
DZD9008 exposure with incidence and severity of gastrointestinal (GI) TEAEs. A 
higher percentage of patients at 400 mg experienced TEAEs which required dose 
interruption and reduction, compared with patients at other dose levels. Although the 
400 mg was comparable with that of afatinib (19) and dacomitinib (20), it was not 
optimal for NSCLC patients with EGFR Exon20ins who require continuous therapy 
to control this aggressive disease. At the dose level of 200 mg and 300 mg, the 
incide
lower than that of afatinib (19), dacomitinib (20) and mobocertinib (TAK-788) (21).
Pooled efficacy analysis of the two studies (study DZ2019E0001 [Part A] and 
DZ2019E0002) showed tumor response at the doses of 100 mg to 400 mg in prior 
platinum-based chemotherapy treated NSCLC subjects with EGFR Exon20ins. At
the dose level of 200 mg and 300 mg,
In the phase 2, pivotal study 
DZ2020E0001 in Chinese NSCLC with EGFR Exon20ins, the confirmed ORR at 300
mg QD was 
. This anti-tumor activity was significantly 
better than current standard therapy, e.g. chemotherapy (12), and comparable to that 
of
mobocertinib (TAK-788)
(21) and amivantamab (JNJ-61186372)
(22).
Noteworthily, tumor response was also observed in patients who relapsed from 
amivantamab (JNJ-61186372) treatment. 

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Higher incidence of dose reduction and interruption occurred at 400 mg cohort was 
observed as compared to 200 mg and 300 mg cohort, which presumably led to lower 
clinical efficacy at the 400 mg cohort (ORR 25% at 400 mg ).As the doses of 100 mg 
or above demonstrated clinical activity, and 200 mg or 300 mg is expected to 
overcome PK variability of DZD9008 to achieve pharmacological relevant exposure 
required from different subtypes of Exon20ins, thus selecting both 200 mg and 300 
mg is appropriate to further evaluate DZD9008 dose optimization for the phase 2 
pivotal study. 
 
DZD9008 elimination half-life is approximately 50 hours following a single dose 
across the doses investigated, which supports the once daily dosing regimen of 
DZD9008 in clinical development.  
Ethnic sensitivity 
 
Based on the available data, no obvious difference in safety, PK and anti-tumor 
efficacy of DZD9008 was observed between Asian and White patients across 
different regions/countries. Therefore, Dizal believes that the use of same dose and 
schedule across different regions and countries is appropriate. 
Patients enrolled to Part B will receive repeated dosing of DZD9008 at 200 mg or 300 mg once 
daily. Following review and approval form IEC/IRB and/or local regulatory authority (as 
applicable) on the optimal RP2D selction, eligible patients can be enrolled into the optimal 
RP2D cohort. The ongoing patients previously randomized to the suboptimal Part B dose cohort 
can maintain the same dose level, or shift to receive the optimal RP2D, if judged by the 
investigator that it is of the best clinical benefit to patients and re-consent is needed (see section 
5.1). DZD9008 will be administrated with food as dosing with high fat food in Part A showed 
limited effect on DZD9008 exposure. Patients with prior therapy may be stratified into sub-
cohorts when data is analyzed.  
Patients will receive repeated daily dosing of DZD9008 until disease progression, intolerable 
AEs, discontinuation criteria have met or withdrawal of consent. 
5.1.5 
Toxicity management and dose modifications 
If a patient experiences a CTCAE  grade 3 and/or unacceptable toxicity including a DLT not 
attributable to the disease or disease-related processes under investigation, where the 
investigator considers the AE of concern to be specifically associated with DZD9008, dosing 
should be interrupted and supportive therapy will be administered as required in accordance 
with local practice/guidelines.  
If the toxicity 
AE grade 2 within 21 days, then the patient should be 
withdrawn from the study and observed until resolution of the toxicity.  
If the dose reduction is due to drug related AE, the dose is not allowed to escalate back to the 
original level after AEs resolve. 
On resolution of toxicity within 21 days during treatment, DZD9008 may be restarted at the 
same dose or a lower dose: 

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If a further episode of the same AE subsequently requires dose interruption, patient 
should restart at one dose level lower (except cohort 1 dose, restart at cohort 1 dose 
level). (Refer to Table 3). For cohort 2 of Part B, the dose could be reduced to 200 
mg and then 150 mg if needed; for cohort 1 of Part B, dose could be reduced to 150 
mg). 
 
If a different AE subsequently requires dose interruption or no prior AE related dose 
interruption, DZD9008 may restart at same dose level or one dose level lower (unless 
in Part A Cohort 1, when restart will be at Cohort 1 dose) on improvement of the AE 
at the discretion of the Investigator. 
 
Patients who are at the lowest possible dose, and who have demonstrated clinical 
benefit and an acceptable recovering of AEs to the dose interruption may be permitted 
to restart at the lowest dose level at the discretion of the Investigator. 
 
After a second occurrence of CTCAE grade 4 AE, patient must be permanently 
withdrawn from study treatment (France and Canada only). 
Patients with QTc prolongation fulfilling the following criteria (i.e., confirmed QTc 
prolongation to > 500 msec absolute or a > 60 msec increase from baseline) should have study 
treatment interrupted and regular ECGs performed until resolution to baseline. If the toxicity 
1 within 3 weeks, the patient will be permanently withdrawn from 
study treatment. Patients who develop QTc interval prolongation with signs/symptoms of life-
threatening arrhythmia will permanently discontinue DZD9008. 
Patients experiencing corneal ulceration or Interstitial Lung Disease (ILD) will not be permitted 
to restart study treatment. 
Table 3 shows the representative of dose intervention or modification for Part B.  
Table 3 
Dose interventions 
Dose level  
DZD9008 dose 
Dose level 1 (starting dose for extension cohort 2) 
300 mg 
Dose level 2 (starting dose for extension cohort 1) 
200 mg 
Dose level 3 
150 mg 
 
5.1.6 
Assessment timing if dosing is interrupted 
If a patient misses any doses of DZD9008 during the 28-day evaluation period of Cycle 1 of 
Part A, please contact the Dizal Study Team for advice regarding the evaluability of the patient 
and appropriate timing of the PK assessments. All other assessments, including laboratory 
safety assessments, vital signs and RECIST should continue to be performed as per study plan, 
relative to the baseline assessments. 
 

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Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
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Figure 3
Dose modification for toxicity related to DZD9008
Resolution to CTCAE Grade 2 or 
below within 21 days?
Further adverse event
Yes
Previous dose interruption in the study 
due to same AE in the past
No
Permanent discontinuation of 
study treatment
Must restart at one dose level lower 
(except lowest possible dose)
May restart at the same dose or one 
dose level lower (except lowest possible 
dose)

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5.1.7
Duration of treatment
Patients may continue on treatment with DZD9008 until RECIST 1.1 defined disease 
progression or until treatment discontinuation criteria are met or withdrawal of consent, or 2 
years post study completion or first indication market available (if patients are still on treatment 
when study completion).
5.1.8
Treatment compliance and accountability
The investigational product should only be used as directed in this protocol. Details of treatment 
with investigational product for each patient will be recorded in the CRF.
All patients will be requested to complete a dosing diary, including the date and time that each 
dose is taken. If a dose is missed, the reason must be noted in the diary. A copy of the dosing 
diary is provided in the study reference material.
Patients should return all unused medication and empty containers to the investigator. The study 
personnel at the investigational site will account for all drugs dispensed and returned. Unless 
otherwise authorized by Sponsor, all investigational product supplies unallocated or unused by 
the patients must be destroyed by procedures approved by Sponsor or returned to Sponsor or its 
designee. Certificates of delivery and destruction should be signed.
5.2
Benefit/risk and ethical assessment
5.2.1
Potential benefit
EGFR Exon20ins and HER2 Exon20ins occurred in about 4% patients with NSCLC. The 
prognosis of these patients is poor as there lacks effective treatment. Chemotherapy is the 
standard of care, but median PFS and OS were only around 6 months and 24 months, 
respectively. 
In preclinical setting, DZD9008 shows in vitro activity in cells expressing EGFR sensitizing 
mutations, T790M mutation, Exon20ins and uncommon mutations as well as HER2 Exon20ins, 
with weak activity in cells carrying wild type EGFR. In vivo, DZD9008 demonstrates promising 
anti-tumor efficacy in xenograft models carrying EGFR aberrations. 
In the two ongoing phase 1 studies of DZD9008 in NSCLC patients with EGFR and HER2 
mutations (by April 3, 2023), DZD9008 demonstrated promising anti-tumor efficacy in patients 
with EGFR Exon20ins with confirmed ORR of
and
 selected dose level of 200 mg 
and 300 mg, separately. In the phase 2, pivotal study DZ2020E0001 in Chinese NSCLC with 
EGFR Exon20ins, the confirmed ORR at 300 mg QD was 
as assessed by IRC. Anti-
tumor activity of DZD9008 was also observed in patients with EGFR sensitizing mutation, 
T790M, as well as in patients with HER2 Exon20ins. DZD9008 was well tolerated up to 400 
mg once daily. The incidences of TEAEs at grade 3 and above, TEAEs leading to dose 
interruption or reduction were lower than the other EGFR TKIs. The types of TEAEs reported 
were considered to be related to inhibition of wild type EGFR, and majority of TEAEs were 
mild or moderate, and could be managed or recover.
These data suggest that DZD9008 has a potential to bring clinical benefit to patients with 
different types of EGFR or HER2 aberrations, especially in patients with EGFR Exon20ins.

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5.2.2 
Potential risks identified non-clinically with DZD9008 
Section 2.3.4 of this protocol summarizes potential risks based upon non-clinical toxicity studies 
with DZD9008 in rats and dogs, and in vitro experiments, with further detailed information 
available in the IB. The monitoring and management of the potential risks based on preclinical 
findings and clinical EGFR TKIs class effect are discussed below: 
5.2.2.1 
Gastrointestinal tract effects 
Patients with refractory nausea, vomiting and chronic gastrointestinal diseases are excluded 
from participating in this study. Detailed information on the treatment of gastrointestinal 
ors. This guidance is for 
information sharing only, and investigator can manage these AEs according to their local 
practice. Investigator will also be advised to follow the general toxicity management guidelines 
regarding dose interruption and reduction as detailed in Section 5.1.5.  
5.2.2.2 
Dermatological effects 
No specific dermatological exclusion criteria are included in this study, however, patients with 
any unresolved adverse events from prior therapy greater than CTCAE grade 1 will be excluded 
from participation. Dermatological treatment should be instituted for patients with any CTCAE 
grade skin reactions, considered by the investigator to be causally related to DZD9008. Detailed 
information on the treatment of dermatological adverse events will be included i
advised to follow the general toxicity management guideline regarding dose interruption and 
reduction as detailed in Section 5.1.5.  
5.2.2.3 
Ocular surface effects 
Full ophthalmic assessment, including slit lamp examination, will be performed at screening 
and should be repeated if a patient experiences any visual symptoms (including blurring of 
vision), with additional tests if clinically indicated. Any clinically significant findings, including 
those confirmed by the ophthalmologist must be reported as an AE. Photographs may be 
performed to record any clinically significant findings. Ophthalmology examination results 
should be collected in the eCRF. Any patient developing corneal ulceration will be permanently 
discontinued from study treatment and should be followed regularly until resolution of the 
event. 
Patients who wear contact lenses will be advised to discontinue wearing lenses if they have any 
until at least one week after symptoms have resolved. If a patient has recurrence of eye 
symptoms or experiencing any severe (CTCAE grade 
wearing their contact lenses until at least one week after treatment with DZD9008 is 
permanently discontinued. Patients should not use any eye drops or ointment for treatment of 
eye symptoms has been permanently discontinued. Patient will be advised to consult the 
investigator promptly if they have any concerns. 

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5.2.2.4 
Cardiovascular effects 
Patients who have unstable cardiac conditions and risk factors for QT prolongations will be 
excluded from participation in this study. Concomitant use of regular medications that may 
prolong the QT interval will be restricted whenever feasible (See Appendix H), but patients may 
receive any medication that is clinically indicated for the treatment of AEs. Electrolyte and vital 
sign assessments, including pulse rate and blood pressure, will be monitored regularly 
throughout the study. Regular digital ECG assessments will be as described in Section 6.3.4. 
The investigator or designated physician will review each ECG prior to discharge from the clinic 
and may refer to a local cardiologist if appropriate for immediate management of the patient. A 
All digital ECG data will be 
analyzed. If an abnormal ECG finding at screening or baseline is considered to be clinically 
significant by the investigator, it should be reported as a concurrent condition. 
5.2.2.5 
Respiratory effects 
Patients with a past medical history of interstitial lung disease, drug-induced interstitial lung 
disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically 
active interstitial lung disease will be excluded from participation in this study. 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality 
suggestive of interstitial lung disease, an interruption in study treatment dosing is recommended, 
and the Sponsor study team should be informed. A questionnaire regarding the results of the 
full diagnostic workup (including high-resolution computed tomography (HRCT), blood and 
sputum culture, hematological parameters, bronchoscopy with biopsy as needed) will be sent to 
investigators. It is strongly recommended to perform a full diagnostic workup, to exclude 
alternative causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, 
or pulmonary hemorrhage. In the presence of confirmatory HRCT scans where other causes of 
respiratory symptoms have been excluded, a diagnosis of interstitial lung disease should be 
considered, and study treatment permanently discontinued. In the absence of a diagnosis of 
interstitial lung disease, study treatment may be restarted following consultation with Sponsor 
Study Physician. 
5.2.2.6 
Liver effects  
Patients with any evidence of severe or uncontrolled systemic liver disease, including those with 
known hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or abnormal liver 
enzymes (defined as AST or ALT > 2.5 x upper limit of normal (ULN), total bilirubin >1.5 x 
ULN if no evidence of liver metastases; AST or ALT > 5 x ULN, total bilirubin > 3 x ULN in 
the presence of liver metastases) at screening are excluded from participating in the study.  
During the study, liver function tests will be monitored regularly during the study and recorded 
Guidance for Drug Induced Liver Injury (FDA Guidance 2005) with the process described in 
detail in Appendix G. 
5.2.2.7 
Hematopoietic effects  
Patients with inadequate bone marrow reserve as demonstrated by any of the following laboratory 
values (absolute neutrophil count < 1.5 x 109/L; platelet count < 100 x 109/L; hemoglobin < 90 g/L) 

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will be excluded from the study. Hematological parameters will be monitored prior to administration 
of the first dose, weekly during the first cycle of multiple dosing, at the start of each subsequent cycle, 
and at discontinuation. 
5.2.2.8 
Renal effect 
Patients with abnormal renal function as defined by creatinine > 1.5 x upper limit of normal 
(ULN) concurrent with creatinine clearance < 50 mL/min at screening are excluded from 
participating in the study. During the study, kidney function tests (creatinine and urea nitrogen) 
will be monitored regularly during the study and recorded at discontinuation. In addition, 
creatine kinase will be routinely monitored throughout the study. 
5.2.2.9 
CYP450 induction/inhibition 
All patients must try to avoid concomitant use of medications, herbal supplements and/or 
ingestions of foods with known potent inducer or inhibitors on CYP3A4 activity whenever 
feasible.  Such drugs must have been discontinued for a period of 1 week (CYP3A3 inhibitors) 
or 2 weeks (CYP3A4 inducers) prior to first administration of DZD9008. Patients taking 
concomitant medications whose disposition is dependent upon intestinal CYP3A4 and/as or 
transporter proteins and which have a narrow therapeutic index should be closely monitored for 
signs of changed tolerability as a result increased exposure of the concomitant medication whilst 
receiving DZD9008. Guidance on medications to avoid, medications that require close 
monitoring and on washout periods is given in Appendix H. If medically feasible, patients 
taking regular medication, with the exception of potent inhibitors or inducers of CYP3A4, 
should be maintained on them throughout the study period.  Patients may receive any 
medication that is clinically indicated for treatment of adverse events. 
5.2.2.10 Hemorrhage 
DZD9008 was reported to be a potent BTK inhibitor (Investigator's Brochure). Bleeding events, 
some fatal, including central nervous system, respiratory, and gastrointestinal hemorrhage, have 
been reported in patients treated with other BTK inhibitors in clinic. Patients receiving 
antiplatelet or anticoagulant therapies may be at increased risk of hemorrhage. As a precaution, 
it is suggested per protocol that DZD9008 be withheld for at least 3 days pre- and post-surgery. 
Patients require anticoagulation or anti-platelet therapy while receiving DZD9008 should be 
monitored for any signs of bleeding. Patients with hemorrhage should be managed per 
institutional guidelines or as clinically indicated. 
5.2.3 
Safety data of DZD9008 in ongoing phase I/II clinical studies 
 
5.2.4 
Overall benefit/risk and ethical assessment 
For advanced stage NSCLC patients with EGFR or HER2 Exon20ins, there is no effective 
treatment, and thus prognosis is poor. DZD9008 is a potent, selective and irreversible EGFR 
TKI which is designed to treat this population of patients with high unmet medical need. 

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This study is a first-time in-patient study to evaluate DZD9008 in advanced NSCLC with EGFR 
or HER2 mutation, preferentially focusing on patients with EGFR Exon20ins or HER2 
Exon20ins. The starting dose and steps for dose escalation of DZD9008 are defined based on 
non-clinical toxicity studies. The selected starting dose is predicted to hit the target, in 
accordance with the ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals Section 
III.A p
addition, patients will continue the treatment as long as they are deriving benefit from the 
t can continue according 
-life of DZD9008 is ~50 
hours, which could potentially achieve continuous inhibition of mutant EGFR pathway and 
derive clinical activity by once daily dosing. The non-clinical safety profile has not identified 
any risks that would preclude investigation of DZD9008 in this setting. The study design aims 
to minimize potential risks, and monitoring is in place for those risks deemed to be most likely 
or serious.
The selected dose of 200 mg or 300 mg once daily is considered to be appropriate doses with 
good risk-benefit balance for phase 2. At these two dose levels, by April 3, 2023, the reported 
incidence of grade 3 and above TEAEs, TEAEs leading to dose interruption and reduction were 
lower than that of mobocertinib (TAK-788) and other EGFR inhibitors, e.g. afatinib or 
dacomitinib (19-21); the confirmed ORRs
of 200 mg and
of 300 mg dose cohort, 
respectively) in platinum pretreated patients were superior or comparable to that reported in 
mobocertinib (TAK-788) (21) and amivantamab (JNJ-61186372) (22) studies. Noteworthily, in 
patients relapsed from or not responded to amivantamab (JNJ-61186372), DZD9008 also 
showed tumor response.
The investigation of DZD9008 in this patient population appears acceptable, based upon the 
emerging safety, PK and anti-tumor efficacy of clinical studies, non-clinical safety profile, the 
lack of effective alternative treatments available to patients, the limited life expectancy due to 
malignant disease, and the strength of the specific hypothesis under evaluation. Thus, the
benefit/risk assessment for this first-into-human Phase 1 study support the oral administration 
of DZD9008 to patients with advanced EGFR or HER2 mutant NSCLC. The data generated 
from phase 1 studies support the evaluation of DZD9008 in phase 2 study, focusing on 
previously treated EGFR Exon20ins mutant NSCLC, according to the proposed study design.
5.3
Discontinuation of investigational product and withdrawal from 
the study
Patients may withdraw from the study at any time, without prejudice to further treatment and 
independent of any decision concerning participation in other aspects of the main study. 
Procedures for withdrawal from the exploratory research are outlined in Section 5.3.2.
Patients may be discontinued from investigational product in the following situations:
Patient decision. The patient is at any time free to withdraw his/her participation in
the study, without prejudice
Adverse events

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Severe non-compliance to this protocol as judged by the investigator and/or Study 
Team 
 
Confirmed disease progression as per RECIST 1.1, unless, in the opinion of the 
investigator, the patient is still deriving clinical benefit. For France and Canada 
only: fulfil the following criteria: (a) Absence of clinical symptoms and signs of 
disease progression (including clinically significant worsening of laboratory values); 
(b) Stable ECOG PS; (c) Absence of rapid progression of disease or of progressive 
tumor at critical anatomical sites that requires urgent alternative medical intervention; 
(d) Investigators must inform subjects that this practice is not considered standard in 
the treatment of cancer. 
 
Patients incorrectly initiated on investigational product (Section 5.3.1) 
 
Pregnancy 
Patients who withdraw from the study but are evaluable for safety assessment in Part A 
escalation will not be replaced. Any patient that is not evaluable in Part A escalation will be 
replaced to ensure a minimum number of evaluable patients. Once study medication is 
permanently discontinued it cannot be restarted. 
In Part A expansion and Part B, any patient who discontinues study treatment for reasons other 
than disease progression should have RECIST assessment performed as scheduled in Table 13 
and Table 14 of the protocol until disease progression is documented or death occurs, or consent 
is withdrawn. Study procedure related SAEs and anti-cancer treatment must be captured until 
the patient no longer has RECIST 1.1 tumor assessment (disease progression or permanent 
withdrawal from the study). 
After database lock, there may be some patients remaining on study treatment. For these patients 
who are continuing to receive the study treatment, Sponsor will collect information during the 
treatment period and for 28 days after last dose on SAEs, death (including those due to disease 
progression), discontinuation due to AEs/SAEs and drug accountability. 
5.3.1 
Procedures for handling patients incorrectly initiated on investigational 
product 
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, 
be enrolled or receive study medication. There can be no exceptions to this rule. 
Where patients who do not meet the inclusion criteria are enrolled in error or incorrectly started 
on treatment, or where patients subsequently fail to meet the study criteria post initiation, the 
investigator should inform the Sponsor Study Physician immediately. The decision on when to 
discontinue the ineligible patient from the study is based on the medical/safety risk for the 
patient. The Sponsor Study Physician is to ensure all such contacts are appropriately 
documented. 
Any patient who is found to have failed to comply with all of the selection criteria, but has not 
started treatment, will be removed from the study. 

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Any patient started on treatment in error, as he/she subsequently been found to have failed to 
comply with all the eligibility criteria, will undergo a risk/benefit assessment by the SRC: if the 
patient is judged to be receiving clinical benefit, the investigators may choose to continue to 
dose them with DZD9008. 
5.3.2 
Procedures for withdrawal from study 
Patients are at any time free to withdraw from the study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent). Such patients will 
always be asked about the reason(s) and the presence of any adverse events. If possible, they 
will be seen by an investigator and undergo the assessments and procedures scheduled for the 
post study assessment (see Section 6.3.6). Adverse events should be followed up and study 
drugs should be returned by the patient. 
5.3.3 
Interim analysis 
An interim data analysis will take place when the last evaluable patient in Part A escalation 
completes the 28-day continuous dosing (DLT phase) with DZD9008 and finishes all the safety 
evaluation. Data analysis will be performed and a SRC meeting will be held with the decision 
of RP2D. 
To check futility and also inform the dose selection, one interim analysis will be performed in 
Part B when 39 patients in full analysis set completed at least 2 RECIST assessments in each 
cohort. If the number of responses is less than or equal to 7 out of 39 patients in the first stage, 
then the dose cohort will be stopped. A dose cohort passing the first stage is considered as a 
titiv
cohort. When both dose cohorts become competitive, the response rate of two 
cohorts will be compared to identify the more effective dose. The less effective dose may be 
dropped after the interim analysis. 
Dizal may trigger the discussion with regulatory on the optimal RP2D selection upon emerging 
efficacy and safety data before interim analysis. 
5.4 
End of study 
The earliest data cut-off for the primary analysis of ORR may take place 3 months after the last 
patient enrolled, to allow all patients to complete two follow-up RECIST assessments. At this 
time, DoR and safety/tolerability will also be summarized. The CSR of primary analysis may 
include, but not limited to, ORR, DoR, safety and tolerability data.  
The full CSR of Part B will report the analysis of all primary and secondary endpoints (including 
updated ORR and DoR, DCR, tumor shrinkage, PFS and OS). The data cut-off for this analysis 
will take place approximately 8 months after the last patient is enrolled to ensure that the last 
responder could be followed up for at least 6 months after initial documented response. All 
patients will continue to be followed up for an updated analysis based on cut-off that will occur 
between 12 - 24 months after the last patient is enrolled. All endpoints will be updated and 
summarized in an addendum to the CSR.The study may be terminated at individual centers if 
the study procedures are not being performed according to GCP, or if recruitment is slow. Dizal 
may also terminate the entire study permaturely if concerns for safety arise within this study or 
in any other study with DZD9008. 

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5.5 
Post study access to study treatment 
Any patients still receiving investigational product at the time of end of the study will be able 
to continue to receive DZD9008 if in the opinion of investigator they continue deriving clinical 
benefit with agreement with Dizal study physician. Re-consent is required. Such patients will 
continue to be monitored for safety assessments until DZD9008 is discontinued. These patients 
will then be followed up for treatment-related Serious Adverse Events up to 28 days after the 
last dose of investigational product. A CSR addendum will be prepared to summarize any 
additional safety data collected. 
6. 
STUDY PLAN AND COLLECTION OF STUDY VARIABLES 
6.1 
Study plan 
Descriptions of the procedures are included in Table 11, Table 12, Table 13 Table 14. The 
schedule of assessments may change in response to emerging data, updated assessment tables 
will be provided outside of the protocol. All study visits from Cycle 2 Day 1 onwards may be 
performed within a visit window of ± 2 days.  
6.2 
Recording of data 
Web Based Data Capture (WBDC) will be used for data collection on the observations, tests 
and assessments specified in the protocol and query handling. The investigator will ensure that 
data are recorded on the CRFs as specified in the protocol and in accordance with the 
instructions provided. 
The investigator will ensure the accuracy, completeness, and timeliness of the data recorded 
and for the provision of answers to data queries according to the Clinical Study Agreement or 
applicable information.  
The investigator will sign the completed CRFs. A copy of the completed CRFs will be archived 
at the study site. 
For details of data and study management, see Appendix E of this Clinical Study Protocol. 
6.3 
Safety assessment 
6.3.1 
Enrolment and screening 
At enrollment, each potential patient will provide informed consent prior to starting any study 
specific procedures (see Appendix D of this Clinical Study Protocol for Ethics and Regulatory 
Requirements). 
IRT system will be used in this study to assign patient enrollment code. Each potential patient 
will be assigned an unique enrollment number. If a patient withdraws from the study, then the 
enrollment code cannot be reused. 
Demographic data and other characteristics will be recorded and will include date of birth or 
age, gender, race and/or ethnicity according to local regulations, and smoking history. 

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A standard medical, medication and surgical history will be obtained with review of the 
selection criteria with the patient. 
Each patient will undergo screening (Table 11, Table 12, Table 13, Table 14) during the 28 days 
prior to first dosing to confirm eligibility. Screen failure reason needs to be recorded in EDC 
system. Tumor assessment and other clinical data obtained as standard of care prior to consent 
may be used for the study provided the assessments fall within the protocol specified period 
prior to the first dose of study drug. 
All patients should have brain MRI or contrast-enhanced CT within 28 days of first dose to 
exclude leptomeningeal metastasis or active brain metastasis. 
Prior to discharge from each in-patient and clinic visit, the Investigator or their deputy will be 
responsible for reviewing all available data including vital signs and ECG tracings. 
Subjects who have failed previous screening are permitted to be re-screened for once. ICF 
should be re-signed, and an updated subject code will be assigned. Screening procedures must 
be repeated (unless the study procedures meet the time window requirement for the second 
screening). If subjects have provided tumor tissues and/or plasma samples for EGFR Exon20ins 
mutation confirmation, then no additional tumor tissue and/or plasma samples need to be 
provided at the re-screening. 
6.3.2 
Physical examination 
A physical examination will be performed and include an assessment of the followings: general 
appearance, skin, head and neck (including ears, eyes, nose and throat), respiratory, 
cardiovascular, abdomen, lymph nodes, thyroid, musculo-skeletal (including spine and 
extremities) and neurological systems. Performance status will be assessed at the visits as 
indicated in the Study Plan according to ECOG criteria as follows: 
 
0 = Fully active, able to carry out all pre-disease activities without restrictions 
 
1 = Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light housework, office work 
 
2 = Ambulatory and capable of self-care, but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
 
3 = Capable of only limited self-care, confined to bed or chair more than 50% of 
waking Hours 
 
4 = Completely disabled, cannot carry on self-care, totally confined to bed or chair 
6.3.3 
Vital sign 
Blood pressure and pulse rate 
Blood pressure and pulse rate will be measured in supine or siting position after 10 minutes rest. 
Assessments will be performed at the visits as shown in the Study Plan (Table 11, Table 12, 
Table 13, Table 14). Observations will be recorded at the following times: 

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Part A 
 
Screening 
 
First dosing day (Cycle 0 Day 1) for dose escalation: pre-dose, 1, 2, 4, 6, 10 and 24 
hours post-dosing 
 
On day 1 and day 9 of food effect cohort in Part A: pre-dose, 1, 2, 4, 6, 10 and 24 
hours post-dosing (treatment time might be updated upon emerging human PK data). 
 
First day of multiple dosing (Cycle 1 Day 1): pre-dose, 1, 2, 4, 6, 10 and 24 hours 
post-dosing 
 
Cycle 1 Day 8 and 15: pre-dose, 1, 2, 4, 6, 10 and 24 hours post-dosing 
 
On Day 1 of each subsequent cycles: one assessment at any time during day 
 
On occurrence of any cardiac AE or clinically indicated at the discretion of the 
investigator 
 
Discontinuation visit 
Part B 
 
Screening 
 
Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 1 Day 15: Pre-dose 
 
On Day 1 of each subsequent cycles: one assessment at any time during the day 
 
On occurrence of any cardiac AE or clinically indicated at the discretion of the 
investigator 
 
Discontinuation visit 
 
The timing and frequency of vital signs assessment may be adjusted in response to 
emerging PK and safety data. 
Weight 
Weight will be assessed at screening and then Day 1 of each cycle and at the discontinuation 
visit. 
Height 
Height will be assessed at screening only. 
Any changes in vital signs should be recorded as an AE if applicable. 

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6.3.4 
Laboratory safety assessment 
Blood and urine samples for determination of clinical chemistry, hematology and urinalysis will 
be taken at the visits as indicated in the Study Plan (see Table 11, Table 12, Table 13, Table 
14).Laboratory tests do not need to be repeated at baseline if the baseline visit is within 7 days 
of the screening sample. 
Blood and urine samples for safety assessment will be collected at the following times: 
 
Screening 
 
First dosing day (Cycle 0 Day 1) for dose escalation: pre-dose (baseline) 
 
On day 1 and day 9 of food effect cohort in Part A: pre-dose (treatment time might 
be updated upon emerging human PK data). 
 
First day of multiple dosing (Cycle 1 Day 1, both Part A and Part B): pre-dose 
 
Multiple dosing, day 8 and 15 of Cycle 1 (both Part A and Part B): pre-dose 
 
On Day 1 of each subsequent cycles: pre-dose 
 
Discontinuation visit 
The date of each collection will be recorded in the appropriate CRF. 
Following review of data from a group of patients the timing of blood samples may be adjusted 
for subsequent groups of patients. Additional sampling times may be added if indicated by the 
emerging data. 
Laboratory values that meet the criteria for CTCAE 5.0 grade 3 or have changed significantly 
from baseline and are considered to be of clinical concern will be repeated/confirmed within 7 
days and followed up as appropriate. 
The following laboratory variables (Table 4) will be measured: 

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Date: July 24,2023
 
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Table 4 
Laboratory variables to be measured 
Clinical chemistry 
 
Hematology 
Serum (S)/Plasma (P)- Albumin 
S/P-Alkaline phosphatase 
S/P-ALT 
S/P-AST  
S/P-Bicarbonate 
S/P-Urea nitrogen 
S/P-Calcium  
S/P-Creatinine  
S/P-Glucose  
S/P-Potassium  
S/P-Magnesium 
S/P-Sodium 
S/P-Total bilirubin 
S/P-Total serum protein 
S/P-Lipase 
S/P-Amylase 
S/P-Creatine phosphokinase 
 
Urinalysis 
U-Glucose 
U-Protein 
U-Blood 
Blood (B)-Hemoglobin  
B-Hematocrit  
B-Platelet count 
B-Reticulocyte 
B-Red blood cell count  
B-White blood cell count  
B-Absolute leukocyte differential cell count: 
 
Basophils 
 
Eosinophils 
 
Lymphocytes  
 
Monocytes 
 
Neutrophils 
 
Coagulation 
APTT 
INR  
 
* 
Beyond what listed in the table, additional urine/serum samples will be collected from all females of 
childbearing potential at screening (within 7 days of the first dosing), and at treatment discontinuation for 
a pregnancy test. 
For Italy only, the female subject should only be included or continue receiving study treatment after a 
confirmed menstrual period and a negative highly sensitive urine or serum pregnancy test upon local 
practice.  
 
6.3.5 
Other safety assessments 
6.3.5.1 
Resting 12-lead ECG  
Twelve-lead ECGs will be performed at the visit indicated in the Study Plan (see Table 11, 
Table 12, Table 13, Table 14).  
Twelve-lead ECGs will be recorded at the following times: 
Part A 
 
Screening 

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Protocol No.: DZ2019E0001
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Date: July 24,2023
 
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First dosing day (Cycle 0 Day 1) for dose escalation: pre-dose, 1, 2, 4, 6, 10 and 24 
hours post-dosing 
 
On day 1 and day 9 of food effect cohort in Part A: pre-dose, 1, 2, 4, 6, 10 and 24 
hours post-dosing (treatment time might be updated upon emerging human PK data). 
 
First day of multiple dosing (Cycle 1 Day 1): pre-dose, 1, 2, 4, 6, 10 and 24 hours 
post-dosing 
 
Cycle 1 Day 8 and Day 15: pre-dose, 1, 2, 4, 6, 10 and 24 hours post-dosing 
 
On Day 1 of each subsequent cycles: one assessment at any time during the day 
 
On occurrence of any cardiac AE 
 
Discontinuation visit 
Part B 
 
Screening:  
 
For sparse PK group: any time on that day for sparse PK group 
 
For intense PK group: pre-dose, 2, 4, 6 and 8 hours post dosing (Since there is 
no dosing at screening, ECG recording should start at a time that would be 
consistent with planned dosing times at Cycle 1 Day 1 and Cycle 3 Day1 (for 
baseline purpose). 
 
Cycle 1 Day 1 and Cycle 3 Day 1: Pre-dose, 2, 4, 6 and 8 hours post-dosing 
 
Cycle 1 Day 8 and Cycle 1 Day 15: Pre-dose 
 
Cycle 2 Day 1: Pre-dose 
 
On Day 1 of each subsequent cycles after Cycle 3: one assessment at any time during 
the day 
 
On occurrence of any cardiac AE 
 
Discontinuation visit 
The timing and number of ECGs may be adjusted depending on the emerging PK and safety 
data. 
A 30 minute window will be allowed for ECGs performed at pre-dose and 15 minute window 
for 1-10 h, and 1 hour window for ECG performed at 24 hours. 

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Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 10 
minutes prior to times indicated. All ECGs should be recorded with the patient in the same 
physical position. For each time point three ECG recordings should be taken at about 5 minute 
intervals. A standardised ECG machine should be used and the patient should be examined 
using the same machine throughout the study if possible. 
After paper ECGs have been recorded, the investigator or designated physician will review each 
of the ECGs and may refer to a local cardiologist if appropriate. A paper copy should be filed 
 if applicable. If an abnormal ECG finding at screening or 
baseline is considered to be clinically significant by the investigator, it should be reported as a 
concurrent condition. For all ECGs details of rhythm, ECG intervals and an overall evaluation 
will be recorded. 
All ECG data will also be collected digitally. Heart rate, PR, R-R, QRS and QT intervals will 
be determined and reviewed by a cardiologist wherever needed.   
For Part B, prior to primary analysis, ECG data will be collected electronically, analyzed and 
stored by a central ECG vendor as described in the study specific ECG manual. Post primary 
analysis, ECGs will be collected locally and stored at the site. 
6.3.5.2 
Echocardiogram/MUGA Scan  
Echocardiogram or MUGA scan to assess LVEF will be conducted at baseline (prior to first 
dose of DZD9008), on Cycle 3 Day 1 (± 7 days), then every 6 weeks (± 1 week) and whenever 
clinically indicated.  
The modality of the cardiac function assessments must be consistent within a patient i.e. if 
echocardiogram is used for the screening assessment then echocardiogram should also be used 
for subsequent scans if required. The patients should also be examined using the same machine 
and operator whenever possible, and a quantitative measurement should be taken. 
Recommendations include having complete high quanlity standardized 2-D with Doppler 
echocardiographic examinations performed by an experienced sonographer and include 
evaluation of both systolic and diastolic left ventricular function. Ejection fraction 
determinations should be determined quantitatively based on bi-plane measurements of end 
diastolic and end systolic left ventricular volumes. 
Any symptomatic decrease in LVEF will prompt the discontinuation of the treatment and a 
cardiac consultation. 
6.3.5.3 
Pulmonary function tests (PFTs) 
Signs and symptoms (cough, short breath and pyrexia, etc) including auscultation for lung field 
will be checked at each visit. 
PFTs (including spirometry and DLCO) will be performed at baseline (prior to first dose of 
DZD9008), on Cycle 3 Day 1 (± 7 days), and then every 6 weeks (± 1 week) and whenever 
clinically indicated. 
HRCT scan will be performed at baseline and then when clinically indicated (see below) 

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If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality 
suggestive of interstitial lung disease on RECIST scan or decrease in lung function 
tests 
treatment dosing should be interrupted and a full diagnostic workup (including chest 
X-Ray with PA and lateral view, cardiac, infectious and hematological workups) will 
be performed. A full diagnostic workup is strongly recommended to exclude 
alternative causes such as disease progression, pleural effusion and cardiac causes. 
Alternative clinical diagnosis will be managed according to local practice. 
 
If other causes of respiratory changes have been excluded, an HRCT scan should be 
performed. If a diagnosis of interstitial lung disease is confirmed study treatment 
should be permanently discontinued. In the absence of a diagnosis of interstitial lung 
disease, study treatment may be restarted. 
6.3.5.4 
Ophthalmologic examination  
Full ophthalmologic assessment, including slit lamp examination, should be performed at 
screening, study drug discontinuation and if a patient experiences any visual symptoms 
(including blurring of vision), with additional tests if clinically indicated. Any clinically 
significant findings, including those confirmed by the ophthalmologist must be reported as an 
AE.  
Patients experiencing corneal ulceration will not be permitted to restart study treatment. 
Ophthalmology examination results should be collected in the eCRF. 
6.3.6 
Follow up 
6.3.6.1 
Safety follow up 
A post study assessment will be performed at the time investigational product is permanently 
discontinued. 
As a minimum, telephone contact should be made with the patient for 28 days following the 
discontinuation of DZD9008 to collect new AEs and follow up on any ongoing AEs and 
concomitant medications (including any subsequent cancer therapy). Refer to Section 6.4.3 for 
full details on AE recordings during follow-up. 
Beyond the 28 day follow up, only ongoing AEs or study procedure-related SAE should be 
collected. Any SAE will be followed to resolution where possible. 
6.3.6.2 
Progression follow up 
Patients who discontinue DZD9008 for reasons other than progression will continue RECIST 
1.1 assessments on Cycle 3 Day1 (  7 days), then every 6 weeks (± 1 week) until objective 
disease progression.   
Details of concomitant medications (including any subsequent cancer therapy) should continue 
to be collected as detailed in the study plan up to the 28-day follow up visit. Beyond the 28-day 
follow up visit only subsequent cancer therapy and new SAEs due to study procedures should 
be collected.   

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6.3.6.3 
Survival follow up 
In Part B extension 
 physician must be contacted every 6 weeks for survival information. 
Subsequent treatment regimens received following withdrawal and subsequent treatment will 
also be collected every 6 weeks. Survival data will be collected up to the time of the final OS 
analysis. Patients should be contacted in the week following the data cut-off for the final 
survival analyses to provide complete survival data. 
6.4 
Adverse events 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
6.4.1 
Definition of adverse events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition during or following exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition can 
be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, electrocardiogram). In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. 
Any deterioration of the disease under study and associated symptoms or findings should not 
be regarded as an adverse event as far as the deterioration can be anticipated. 
The term adverse event is used generally to include any AE whether serious or non-serious. 
6.4.2 
Definitions of serious adverse events 
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in, 
treatment, washout, and follow-up), that fulfils one or more of the following criteria: 
 
Results in death 
 
Is immediately life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/ incapacity or substantial disruption of 
the ability to conduct normal life functions 
 
Is or results in a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix B of this Clinical Study Protocol. 
For definition of other significant adverse event (OAE), see Section 7.3. 

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6.4.3 
Recording of adverse events 
6.4.3.1 
Time period for collection of adverse events 
AEs will be collected from the first dosing of DZD9008 until the end of the follow-up period. 
SAEs will be collected from ICF sign. From the phase 1 data, terminal half-life of DZD9008 in 
human is around 50 hours. The safety follow-up duration would like to cover at least 5 folds of 
half-life to ensure the safety monitoring until elimination of DZD9008, Thus, the follow-up 
period is defined as 28 days after study treatment is discontinued.  
SAEs occurring in the follow-up period should be reported to Dizal in the usual manner (see 
Section 6.4.4). 
6.4.3.2 
Follow-up of unresolved adverse events 
investigator for as long as medically indicated, but without further recording in the CRF. 
Dizal retains the right to request additional information for any patient with ongoing AE(s) at 
the end of the study, if judged necessary. 
If an investigator learns of any SAEs, including death, at any time after a patient has completed 
the study and he/she considers there is a reasonable possibility that the event is related to 
DZD9008, the investigator should notify Dizal Patient Safety Team or representatives. 
Variables 
The following variables will be collected for each AE: 
 
AE diagnosis/description 
 
The date when the AE started and stopped 
 
CTCAE grade, grade change and its associated date 
 
Whether the AE is serious or not 
 
Investigator causality rating against the investigational product (yes or no) 
 
Action taken with regard to investigational product 
 
Outcome 
For SAEs other variables will be collected including treatment given for the event. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 6.4.2. An AE of severe intensity need 
not necessarily be considered serious. For example, nausea that persists for several hours may 
be considered severe nausea, but not a SAE. On the other hand, a stroke that results in only a 
limited degree of disability may be considered a mild stroke but would be a SAE. 
The grading scales found in the current National Cancer Institute CTCAE 5.0 version will be 
utilized for all events with an assigned CTCAE grading. For those events without assigned 

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CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the current CTCAE version can 
be downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
Causality collection 
The investigator will assess causal relationship between investigational product and each 
adverse event, and an
reasonable 
 
For SAEs causal relationship will also be assessed for other medication and study procedure. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
 
A guide to the interpretation of the causality question is found in Appendix B of this Clinical 
Study Protocol. 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from th
visit/you were last asked? , or revealed by observation will be collected and recorded in the 
CRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to recording 
a list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
Adverse events based on examinations and tests 
The results from protocol mandated laboratory tests, vital signs, ECGs and other safety 
assessments will be summarized in the Clinical Study Report. 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 to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or 
 
Test result is considered 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. 
If deterioration in a laboratory value, vital sign, ECG or other safety assessment is associated 
with clinical signs and symptoms, the sign or symptom will be reported as an AE and the 
associated laboratory result or other finding will be considered as additional information. 

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Wherever possible the reporting investigator uses the clinical, rather than the laboratory term 
(e.g., anemia versus low hemoglobin value). In the absence of clinical signs and symptoms, 
clinically relevant deteriorations in non-mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
Disease progression 
Disease progression can be considered as a worsening of 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE. Events that are unequivocally 
due to disease progression should not be reported as AEs during the study. 
New cancers 
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study tre
 in 
this study. They do not include metastases of the original cancer. 
 
Cases where a patient 
need to be reported as SAEs. 
SAE 
expedited reporting system) is required for compliance with regulatory guidelines. The 
investigator is responsible for, without delay, determining whether a patient meets potential 
riteria. 
s and actions to take are detailed in Appendix 
G. 
Handling of deaths 
All deaths that occur during the study, or within the follow-up period after the administration 
of the last dose of investigational product, should be reported as follows: 
 
Death, which is unequivocally due to disease progression, should be communicated 
to the study monitor at the next monitoring visit and should be documented in the 
CRF module, but should not be reported as a SAE during the study. 
 
Where death is not clearly due to disease progression of the disease under study the 
AE causing the death should be reported to the study monitor as an SAE within 24 
hours. The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign a single primary cause of 
death together with any contributory causes. 

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Deaths with an unknown cause should always be reported as a SAE but every effort 
should be made to establish a cause of death. A post-mortem may be helpful in the 
assessment of the cause of death, and if performed a copy of the post-mortem results 
(with translation of important parts into English) should be reported in an expedited 
fashion to Sponsor representative within the usual timeframes. 
6.4.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF and paper SAE 
form (Clinical Safety Event Report). 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate Sponsor representatives (study physician, patient safety, operation manager etc) 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated Sponsor representative works with the investigator to ensure that all the 
necessary information is provided to appropriate patient safety database within one calendar 
day of initial receipt for fatal and life threatening events and within five calendar days of initial 
receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
Sponsor representatives of any follow-up information on a previously reported SAE 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The Sponsor representative will advise the investigator/study site personnel how to proceed. 
The reference doc
DZD9008. 
6.5 
Pharmacokinetics 
6.5.1 
Collection of pharmacokinetic samples 
For detailed sample collection and processing please refer to lab manual. 
A 30 min window is allowed for pre-dose sampling. A 5 min window will be allowed for 
samples taken at 0.5 hour and 1 hour; a 10 min window for samples taken at 2 - 10 hours; a 1-
hour window for samples taken at 12 hours and 24 hours, a 2-hour window at 48 hours, 72 
hours, 120 hours and 168 hours. 
6.5.1.1 
Part A (Dose escalation) 
Blood samples 
Venous blood samples will be taken at the time points shown Table 5. Discussion with the 
Clinical Pharmacologist from Dizal Pharmaceuticals is required as to any impact if dose 
interruption occurs within 3 days of scheduled time points for PK sampling. The date and time 
of dosing and collection of each sample will be recorded. 

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Time points on Cycle 0 Day 1 are pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120 and 168 
hours post-dose. 
Time points on Cycle 2 Day 1 are pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose. 
On Cycle 1 Day 1, Day 8, Day 15, and Cycle 3, 4, 5 Day 1, pre-dose samples are collected. 
The timing for PK sampling may be adjusted with emerging data during the study, in order to 
ensure appropriate characterization of the plasma concentration-time profiles of DZD9008 
(Table 5). 
Hospitalization can be allowed for out of business time PK collection. 
Blood samples (approximately 4 mL at each time point) will be collected and put into lavender 
top (EDTA) Vacutainer® evacuated collection tubes at the time points indicated. After 
processing, plasma samples will be split, for quantification of DZD9008 and identification and 
semi-quantification of all possible metabolites. The timing for PK sampling may be adjusted 
with emerging data during the study, in order to ensure appropriate characterization of the 
plasma concentration-time profiles of DZD9008. 
Urine samples 
Urine samples (approximately 5 mL) for the determination of concentrations of DZD9008 and 
characterization of its metabolites will be taken from the total urine samples provided during 0-
24 h at Cycle 2 Day 1. The date and time of collection and the weight of each urine collection 
will be recorded. Samples will be split into aliquots, for quantification of DZD9008 and for 
identification and semi-quantification of all possible metabolites. 
The interval for urine collection on Cycle 2 Day 1 are 0 - 4, 4 - 12, and 12 - 24 hours. The timing 
for PK sampling may be adjusted with emerging data during the study, in order to ensure 
appropriate characterization of urine excretion DZD9008. 
In addition, the pharmacokinetic samples may be subjected to further analyze by Dizal 
Pharmaceuticals or CROs in order to investigate the presence and/or identity of additional drug 
metabolites. Any results from such analyses will be reported separately from the Clinical Study 
Report. 
Food effect 
Venous blood samples will be taken at the time points shown in Table 6. The date and time of 
dosing and collection of each sample will be recorded. 
A 30 min window is allowed for pre-dose sampling. A 5 min window will be allowed for 
samples taken at 0.5 hour and 1 hour; a 10 min window for samples taken at 2 - 10 hour; an 1 
hour window for samples taken at 12 hour and 24 hour, a 2 hour window at 48 hour, 72 hour, 
120 hour and 168 hour (Table 6). 
Time points on day1 and 9 are pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120 and 168 
hours post-dose (treatment time might be updated upon emerging human PK data). 
Time point on Cycle 2 Day 1: pre-dose. 

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The timing for PK sampling may be adjusted with emerging data during the study, in order to 
ensure appropriate characterization of the plasma concentration-time profiles of DZD9008. 
Blood samples (approximately 2 mL at each time point) will be collected and put into lavender 
top (EDTA) Vacutainer® evacuated collection tubes at the time points indicated. 
6.5.1.2 
Part A expansion  
Blood samples 
Venous blood samples will be taken at the time points shown in Table 7. Discussion with the 
Clinical Pharmacologist from Dizal Pharmaceuticals is required as to any impact if dose 
interruption occurs within 3 days of scheduled time points for PK sampling. The date and time 
of dosing and collection of each sample will be recorded. 
Time points on Cycle 1 Day 1 and Cycle 2 Day 1 are pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 
24 hour post-dose. On Cycle 1 Day 8 Day 15, and Cycle 3, 4 Day 1, pre-dose samples are 
collected (Table 7). 
The timing for PK sampling may be adjusted with emerging data during the study, in order to 
ensure appropriate characterization of the plasma concentration-time profiles of DZD9008. 
Blood samples (approximately 2 mL at each time point) will be collected and put into lavender 
top (EDTA) Vacutainer® evacuated collection tubes at the time points indicated. 
6.5.1.3 
Part B extension 
Patients at selected sites will be invited for intense PK studies (approximately 10% - 30% of 
patients for each arm) and the remaining for sparse PK to characterize DZD9008 
pharmacokinetics as shown in Table 8 and Table 9. 
Throughout the treatment, the PK sampling time might be time-matched with the PRO-CTCAE 
assessments as described in Table 14. Beyond Cycle 3, the PK sampling time might be time-
matched with efficacy assessment as described in section 6.8.1. Flexible sampling schedule will 
be implemented to improve the site feasibility. For example, if the patient already took the study 
drug before the on-site visit, the patient is still eligible for PK sample collections if the accurate 
dosing time and sample collection time are recorded accurately. 
If there is a dose interruption, dose reduction, or an early termination due to an AE or there is 
an SAE, the investigator may choose to collect an unplanned blood sample (if possible) within 
the 24 hour after the last dose, which will be used to explore the exposure-response relationship 
between study drug exposure and AEs.  

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Table 5 
Blood PK sampling schedule (Part A, dose escalation) 
Time 
relative to 
dose 
Single dosing (Part A, Dose escalation) 
Multiple dosing 
Multiple dosing 
Cycle 1 
Multiple 
dosing 
Cycle 2 
Multiple 
dosing 
Cycle 3, 
4, 5 
 
D1 
D2 
D3 
D4 
D6 
D8 
D1 
D8 
D15 
D1 
D1 
Pre-dose 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
0.5 hour 
X 
 
 
 
 
 
 
 
 
X 
 
1 hour 
X 
 
 
 
 
 
 
 
 
X 
 
2 hours 
X 
 
 
 
 
 
 
 
 
X 
 
3 hours 
X 
 
 
 
 
 
 
 
 
X 
 
4 hours 
X 
 
 
 
 
 
 
 
 
X 
 
6 hours 
X 
 
 
 
 
 
 
 
 
X 
 
8 hours 
X 
 
 
 
 
 
 
 
 
X 
 
10 hours 
X 
 
 
 
 
 
 
 
 
X 
 
12 hours 
X 
 
 
 
 
 
 
 
 
X 
 
24 hours 
 
X 
 
 
 
 
 
 
 
X (D2, 
pre-dose) 
 
48 hours 
 
 
X 
 
 
 
 
 
 
 
 
72 hours 
 
 
 
X 
 
 
 
 
 
 
 
120 hours 
 
 
 
 
X 
 
 
 
 
 
 
168 hours 
 
 
 
 
 
X 
 
 
 
 
 
Note: 
The treatment date and sample collection time for each period might change upon emergent human 
PK data. 
a. A 30 min window is allowed for pre-dose sampling.  
b. A 5 min window is allowed for samples taken at 0.5 hour and 1 hour;  
c. A 10 min window for samples taken at 2-10 hours;  
d. A 1 hour window for samples taken at 12 hours and 24 hours,  
e. A 2 hour window for samples taken at 48 hours, 72 hours, 120 hours and 168 hours. 
 
Table 6 
Blood PK sampling schedule (Part A, food effect) 
Time 
relative to 
dose 
Period 1 
Period 2 
Cycle2 
D1 
D2 
D3 
D4 
D6 
D8 
D9 
D10 
D11 
D12 
D14 
D16 
D1 
Pre-dose 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 

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Time 
relative to 
dose 
Period 1 
Period 2 
Cycle2 
D1 
D2 
D3 
D4 
D6 
D8 
D9 
D10 
D11 
D12 
D14 
D16 
D1 
0.5 hour 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
1 hour 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
2 hours 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
3 hours 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
4 hours 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
6 hours 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
8 hours 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
10 hours 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
12 hours 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
24 hours 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
48 hours 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
72 hours 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
120 hours 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
168 hours 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Note: 
The treatment date and sample collection time for each period might change upon emergent human PK 
data. 
a. A 30 min window is allowed for pre-dose sampling.  
b. A 5 min window is allowed for samples taken at 0.5 hour and 1 hour;  
c. A 10 min window for samples taken at 2-10 hours;  
d. A 1 hour window for samples taken at 12 hours and 24 hours,  
e. A 2 hour window for samples taken at 48 hours, 72 hours, 120 hours and 168 hours. 
 
Table 7 
Blood PK sampling schedule (Part A expansion) 
Time relative 
to dose 
Cycle 1 
Cycle 2 
Cycle 3, 4 
D1 
D8 
D15 
D1 
D1 
Pre-dose 
X 
X 
X 
X 
X 
0.5 hour 
X 
 
 
X 
 
1 hour 
X 
 
 
X 
 
2 hours 
X 
 
 
X 
 
3 hours 
X 
 
 
X 
 
4 hours 
X 
 
 
X 
 
6 hours 
X 
 
 
X 
 

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Time relative 
to dose 
Cycle 1 
Cycle 2 
Cycle 3, 4 
D1 
D8 
D15 
D1 
D1 
8 hours 
X 
 
 
X 
 
10 hours 
X 
 
 
X 
 
12 hours 
X 
 
 
X 
 
24 hours 
X (prior to 
next dose) 
 
 
X (prior to 
next dose) 
 
Note: 
The treatment date and sample collection time for each period might change upon emergent human PK 
data. 
a. A 30 min window is allowed for pre-dose sampling.  
b. A 5 min window is allowed for samples taken at 0.5 hour and 1 hour;  
c. A 10 min window for samples taken at 2-10 hours;  
d. A 1 hour window for samples taken at 12 hours and 24 hours.  
 
Table 8 
Blood collection for intense PK (Part B extension) 
Time 
relative 
to dose 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 5 
Cycle 7 
Cycle 9 
Cycle 11 
D1 
D8 
D15
D1 
D1 
D1 
D1 
D1 
D1 
Pre-dosea 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 hourb 
X 
 
 
 
X 
 
 
 
 
2 hoursc 
X 
 
 
 
X 
 
 
 
 
3 hoursc 
X 
 
 
 
X 
 
 
 
 
4 hoursc 
X 
 
 
 
X 
 
 
 
 
6 hoursc 
X 
 
 
 
X 
 
 
 
 
8 hoursc 
X 
 
 
 
X 
 
 
 
 
24 hoursd 
X 
(prior 
to next 
dose) 
 
 
 
X (prior 
to next 
dose) 
 
 
 
 
a. A 30 min window is allowed for pre-dose sampling.  
b. A ±5 min window is allowed for samples taken at 1 hour;  
c. A ±10 min window for samples taken at 2-8 hours;  
d. A ±1 hour window for samples taken at 24 hours.  
Note: 
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG 
measurements, the ECG will be completed before the collection of the blood samples.   
 

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Table 9 
Blood collection for sparse PK (Part B extension) 
Time 
relative 
to dose 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 5 
Cycle 7 
Cycle 9 
Cycle 11 
D1 
D8 
D15 
D1 
D1 
D1 
D1 
D1 
D1 
Pre-dosea 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4 hoursb 
X 
 
 
 
X 
 
 
 
 
8 hoursb 
X 
 
 
 
X 
 
 
 
 
a. A 30 min window is allowed for pre-dose sampling.  
b. A ±10 min window for samples taken at 2-8 hours;  
Note:  
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG 
measurements, the ECG will be completed before the collection of the blood samples.   
 
6.5.2 
Determination of drug concentration in plasma and urine samples 
Samples for determination of DZD9008 and/or metabolite DZ0753 concentrations in plasma 
will be analyzed using a validated bioanalytical method. All samples within the known stability 
of the analysts of interest at the time of receipt by the bioanalytical laboratory will be analyzed. 
Full details of the analytical method used will be described in a separate bioanalytical report. 
In addition, the pharmacokinetic samples may be subjected to further analyses by Dizal or CROs 
in order to investigate the presence and/or identity of additional drug metabolites. Any results 
from such analyses will be reported separately from the Clinical Study Report. 
Details on sample processing, handling, shipment and storage are provided in the Laboratory 
Manual. 
6.5.3 
Other parameters 
A biomarker to determine CYP3A induction, the ratio of 4- -hydroxy cholesterol / total 
cholesterol, will be measured at pre-dose of Cycle 0 Day 1, Cycle 1 Day 1, Day 8 and Day 15, 
Cycle 2 Day 1 (Part A Dose escalation only). 
Blood samples (approximately 6 mL at each time point) will be collected and put into lavender 
top (EDTA) Vacutainer® evacuated collection tubes at the time points indicated. 
6.6 
Exploratory research 
If a patient agrees to participate in the exploratory biomarker research, component of the study 
biological samples (e.g., blood, plasma, archived and study-obtained tumor, etc.) will be 
collected and may be analyzed for exploratory biomarkers to assess correlations with disease 
activity, effects of study drug and clinical outcomes. 
The results of this exploratory biomarker research will be reported separately and will not form 
part of the Clinical Study Report. 
The results of this exploratory biomarker research may be pooled with biomarker data from 
other studies with the study drug to generate hypotheses to be tested in future studies. 

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6.6.1
Exploratory analyses to support companion diagnostics development
In Part B, all patients will be asked to provide consent to mandatorily donate archived tumor 
samples (if more than one FFPE blocks from a patient, tissue from the most recent one is 
preferred) or any fresh tumor biopsies (if archived tumor sample is not available) for 
confirmation of EGFR Exon20ins status in Sponsor designated central laboratory
 using the designated assay and for the development and approval of tissue-
based companion diagnostics for DZD9008. If a pre-study written documentation of EGFR 
Exon20ins in tumor tissue is available from Sponsor designated central laboratory using the
designated assay, no additional tumor sample needs to be submitted. The prior treatment must 
be clearly indicated for each archival tumor sample provided.
In Part B, the mutation test used in Sponsor designated central laboratory to select EGFR 
Exon20ins positive patients for this study will be developed for future approval as a companion 
diagnostics for DZD9008. Some residual tissue and/or DNA will be used for necessary technical 
studies for future companion diagnostics development and approval.
In addition, all patients in Part B will be asked to provide plasma samples at screening. These 
samples will be used for the extraction of circulating free tumor DNA (ctDNA) and assessing 
EGFR Exon20ins status for the development and approval of liquid biopsy companion
diagnostics. The plasma samples may also be used for future exploratory research into factors 
that may influence development of DZD9008 in NSCLC or tumor response to DZD9008.
Details of sample collection, processing, shipping and storage will be described in the 
Laboratory Manual. For sampling schedule, see Study Plan (Table 14).
6.6.2
Exploratory biomarker research
6.6.2.1
Archived tumor tissue or fresh biopsy for exploratory biomarker research
All patients will be asked to provide consent to mandatorily donate tumor tissue (archived tumor 
tissue, or fresh biopsy if archived tissue is not available). In each case the prior treatment must 
be clearly indicated for each sample provided. 
In Part A, the tumor samples will be used for the confirmation of EGFR and HER2 mutations 
by central lab retrospectively, for the development of diagnostic test for pre-market approval by 
regulatory authorities and/or potential future exploratory research into factors that may 
influence development of DZD9008 in NSCLC and/or tumor response to DZD9008 For 
sampling schedule, see Study Plan (Table 11, Table 12, Table 13).
In Part B, the tumor samples are for potential future exploratory research into factors that may 
influence development of DZD9008 (Table 14).
Details on sample processing, handling, shipment and storage are provided in the Laboratory 
Manual. For sampling schedule, see Study Plan (Table 11, Table 12, Table 13, Table 14).
6.6.2.2
Paired tumor tissue for proof-of-mechanism (PoM) biomarker study
In Part B, around 10 patients in each dose cohort are requested to provide paired tumor biopsy 
at pre- and post-dosing to further understand the potential mechanism of DZD9008. For patients 

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joining the PoM study in Part B, paired tumor biopsy samples will be collected at screening and 
Cycle 2 Day 1 (± 2 days) (If for any reason the biopsy cannot be collected at Cycle 2 Day 1, it 
may be taken at any visit within Cycle 2) or discuss with Dizal study team. 
Details of sample collection, processing, shipping and storage will be described in the 
Laboratory Manual. For sampling schedule, see Study Plan (Table 14). 
6.6.2.3 
Blood sampling for other exploratory biomarker study 
This part of study is optional.  
In Part A, if patients consent to donate samples, blood samples will be collected at screening, 
Cycle 0 Day 1 (pre-dose, Part A dose escalation and food effect cohorts), Cycle 1 Day 1 (pre-
dose), Cycle 1 Day 8, Cycle 1 Day 15, Day 1 of each cycle from Cycle 2 to Cycle 6, then Day 
1 of each following even Cycle (every 6 weeks) until disease progression, according to RECIST 
assessment to determine exploratory biomarkers, including EGFR and HER2 (and other genes) 
mutation status/copy in ctDNA.  
In Part B, if patients consent to donate samples, blood samples will be collected on Cycle 1 Day 
1 (pre-dose), Cycle 1 Day 8, Cycle 1 Day 15, Day 1 of each cycle from Cycle 2 to Cycle 6, then 
Day 1 of each following odd Cycle until disease progression, according to RECIST assessment 
to determine exploratory biomarkers, including EGFR or other gene mutation status/copy in 
ctDNA.  
For Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1, a window of ± 2 days will be allowed.  
For Day 1 of each cycle from Cycle 3 to Cycle 6, and then Day 1 of each following indicated 
Cycle (i.e., Cycle 8 Day 1, Cycle 10 Day 1 and so on for Part A; Cycle 7 Day 1, Cycle 9 Day 1 
and so on for Part B) until disease progression, according to RECIST assessment, a window of 
± 7 days will be allowed.  
The blood samples collected prior to dosing may be used to retrospectively confirm EGFR and 
HER2 mutation by central laboratory.  
Patients will also be asked to consent for using these samples to further investigate the 
relationship between drug exposure and/or disease progression, blood-borne biomarkers and 
resistant mechanism.  
Details of sample collection, processing, shipping and storage will be described in the 
Laboratory Manual. For sampling schedule, see Study Plan (Table 11, Table 12, Table 13, Table 
14). 
6.6.3 
Pharmacogenetics 
Pharmacogenetic sample evaluation could assist in drug development in NSCLC. If a patient 
agrees to participate in the host pharmacogenetics research component of the study, a blood 
sample will be collected.  
Dizal intends to perform genetic research in the DZD9008 clinical development program to 
explore how genetic variations may affect the clinical parameters associated with DZD9008. 

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The potential benefits of exploring the associations between genes and clinical outcomes in the 
DZD9008 program include: 
 
analysis of genes that may affect efficacy, safety and tolerability, and variability (for 
example, but not limited to, drug metabolizing enzymes and drug transporters). 
The single blood sample will be obtained from the subjects prior to the first administration of 
DZD9008 in the study (pre-dose at Cycle 1 Day 1 in Part B). If for any reason the sample is not 
drawn prior to dosing, it may be taken at any time visit until the last study visit. Although 
genotyping is a stable parameter, early sample collection is preferred to avoid introducing bias 
by excluding patients who may withdraw due to an adverse event. Such patients would be 
important to be included in any genetic analysis. Only one sample should be collected per 
subject for pharmacogenetic evaluation during the study. 
This part of data will be reported separately and will not form part of the Clinical Study Report. 
For information about sample collection, labeling, storage and shipment are detailed in the 
Laboratory Manual. For sampling schedule, see Study Plan (Table 14). 
6.7 
Procedures for handling biological samples 
6.7.1 
Volume of blood 
The number of samples taken, as well as the volume required for each analysis, may be changed 
during the study as new data becomes available. The estimated total volume of blood that will 
be drawn from each patient from screening until end of Cycle 6 is around 270 mL in Part A 
dose escalation, 150 mL in Part A food effect and 170 mL in Part A expansion and Part B 
extension (Details in Table 15, Table 16, Table 17, Table 18). 
6.7.2 
Handling, storage and destruction of biological samples 
The samples will be used up, or disposed of after analyses or retained for further use as described 
below. 
maximum of 15 years following the finalization of the Clinical Study Report or per local 
regulatory requirements, whichever is the earliest. The results from future analysis will not be 
reported in the Clinical Study Report but separately in a bioanalytical report. 
6.7.2.1 
Blood Sample for safety and PK 
After collection, blood samples will be aliquoted and put into different tubes for safety and PK.  
Safety assessment 
S
of their established methods. The number of samples/blood volumes is therefore subject to site-
specific change. 

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Pharmacokinetic assessment 
PK samples will be disposed of after the Bioanalytical Report finalization or 6 months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses. 
PK samples may be disposed of or destroyed and anonymized by pooling. Additional analyses 
may be conducted on the anonymized, pooled pharmacokinetic samples to further evaluate and 
validate the analytical method. Any results from such analyses may be reported separately from 
the CSR. Anonymized samples will be retained for no more than 5 years after the CSR is 
finalized. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test samples and reported in a separate bioanalytical report. 
Samples for metabolite identification and/or analysis will be shipped to and retained by Sponsor 
for a maximum of one year following the finalization of CSR. The results from the investigation 
will not be reported in CSR but in a separate report. 
Any PK sample remaining after analysis of DZD9008 and its metabolites may be used for 
biomarker analyses. These analyses are for Sponsor use only and will not be included in the 
Clinical Study Report. 
6.7.2.2 
Blood-borne exploratory biomarker samples 
Details of sample collection, processing, shipping and storage are described in the Laboratory 
Manual. set 
Each sample for exploratory research will be identified with the study number and patient 
enrolment number. In this way, exploratory biomarker and genetic data may be correlated with 
clinical data, samples destroyed in the case of withdrawal of consent and regulatory audit 
enabled. 
Where genetic analysis will be undertaken, the processes adopted for the coding and storage of 
samples will be more stringent in order to maintain patient confidentiality. As an added 
precaution, irrespective of the type of sample, the DNA sample will be assigned a unique 
number replacing the information on the sample tube. Thereafter, the DNA sample will be 
identifiable by the unique DNA number only. The DNA number will be used to identify the 
sample and corresponding data at the Sponsor genetics laboratories, or at the designated contract 
laboratory. No personal details identifying the individual will be available to any person 
(Sponsor employee or contract laboratory staff) working with the DNA. 
The samples and data for genetic analysis in this study will be single coded. The link between 
the patient enrolment code and the DNA number will be maintained and stored in a secure 
environment, with restricted access within Dizal biobank system. The link will be used to 
identify the relevant DNA samples for analysis, facilitate correlation of genotypic results with 
clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent when the patient has requested disposal/destruction of collected samples 
not yet analyzed. 

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6.7.2.3 
Archived tumor tissue or fresh biopsy 
In Part A, archived tumor samples or any fresh tumor biopsies (if archived tumor sample is not 
available) will be used to retrospectively confirm EGFR and HER2 mutations by central 
laboratory, support the development of diagnostic test for pre-market approval by regulatory 
authorities and potential future exploratory research into factors that may influence 
development of DZD9008 in NSCLC and/or tumor response to DZD9008. 
In Part B, EGFR Exon20ins will be confirmed by central laboratory testing using analytically 
validated next generation sequencing-based assay. Archived tumor samples or fresh tumor 
biopsed tissue will be collected to support companion diagnostics development for approval and 
potential future exploratory research.  
In Part B, around 10 patients of each dose cohort are requested to provide paired pre-and post-
treatment tumor biopsies for PoM study. Tumor tissue biopsy should be conducted at screening 
or post dose on Cycle 2 Day 1, and tissues should be submitted for pEGFR (or other EGFR 
pathway related biomarkers) IHC testing.  
Following biopsy sample taken, tissues should be placed in 10% neutral buffered formalin 
fixative as quick as possible in order to ensure antigen preservation. Samples should be 
remained in fixative for 24 to 48 hours at room temperature, then follow a standard overnight 
processing schedule into paraffin wax.  When formalin fixed paraffin embedded (FFPE) block 
is not possible, unstained sections should be prepared from the FFPE sample block. Tissue 
sectioning will be cut onto positively-charged glass slides at appropriate time upon S
request. All blocks or sections must be put into appropriate containers with clear labelling. 
Finally, the blocks or slides should be shipped in an appropriate condition.  
Details of sample collection, processing, shipping and storage will be described in the 
Laboratory Manual. For sampling schedule, see Study Plan (Table 11, Table 12, Table 13, Table 
14). 
6.7.2.4 
Samples for pharmacogenetic study 
is optional but will be beneficial of drug development in NSCLC.   
The single blood sample for genetic research will be obtained from the subjects prior to the first 
administration of DZD9008 in the study (pre-dose at Cycle 1 Day 1 in Part B). If for any reason 
the sample is not drawn prior to dosing, it may be taken at any time visit until the last study 
visit.  Although genotyping is a stable parameter, early sample collection is preferred to avoid 
introducing bias by excluding patients who may withdraw due to an adverse event. Such patients 
would be important to be included in any genetic analysis. Only one sample should be collected 
per subject for pharmacogenetic evaluation during the study.  
The processes adopted for the coding and storage of samples for genetic analysis will be strictly 
adhered to maintain subject confidentiality. Samples will be stored for a maximum of 15 years 
following the finalization of the Clinical Study Report or per local regulatory requirements, 
whichever is the earliest, after which they will be destroyed. The results of these optional 
analyses will be reported either in the Clinical Study Report or as an addendum, or separately 

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in a scientific report or publication. Samples will be stored and used until depletion, or the 
maximum storage time has been reached.  
For information about sample collection, labelling, storage and shipment are detailed in the 
Laboratory Manual.  
6.7.3 
Labelling and shipment of biohazard samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with the 
Laboratory Manual and the Biological Substance, Category B (materials containing or 
suspected to contain infectious substances that do not meet Category A criteria), see Appendix 
C 
 
Any samples identified as Infectious Category A materials are not shipped and no further 
samples taken from the patient unless agreed with Sponsor and appropriate labelling, shipment 
and containment provisions are approved. 
All archival tumor samples should be shipped at ambient temperatures as per the Laboratory 
Manual to the Dizal or designated Central Contract Research Organization. 
6.7.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Principal Investigator at each center keeps full traceability of collected biological samples 
from the patients while in storage at the center until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
Sponsor keeps oversight of the entire life cycle through internal procedures, monitoring of study 
sites and auditing of external laboratory providers. 
Samples retained for further use are registered in the Sponsor biobank system during the entire 
life cycle. 
6.7.5 
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of voluntarily donated biological samples, then the 
samples will be disposed of/destroyed, and the action will be documented. If samples are already 
analyzed, Sponsor is not obliged to destroy the results of this research. 
If collection of the biological samples is an integral part of the study, then the patient may be 
withdrawn from further participation in the study. 
The Principal Investigator: 
 
consent to the use of donated biological samples.  
 
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented.  

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Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action 
documented, and the signed document returned to the study site.  
 
Ensures that the patient and Sponsor are informed about the sample disposal 
Sponsor ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the action 
documented and the document returned to the study site. 
Sponsor designated research center will conduct potential exploratory biomarker studies if 
required. Samples will be stored for a maximum of 15 years following the finalization of the 
Clinical Study Report or per local regulatory requirements, whichever is the earliest. The results 
from future analysis will not be reported in the CSR but separately in a CSR Addendum 
/Scientific Report or Scientific Publication.  
At the end of the study, or in the event of a subject withdrawing consent, or as required by law, 
the Sponsor will return any samples and delete the Study Data in a sensitive way, according to 
local laws and protocols. 
6.8 
Anti-tumor efficacy 
6.8.1 
Tumor assessments 
6.8.1.1 
Imaging assessment 
RECIST 1.1 criteria will be used to assess tumor response to treatment by determining Objective 
Response rate (ORR), Disease Control Rate (DCR), Duration of Response (DOR) and 
Progression Free Survival (PFS). The RECIST 1.1 guidelines for measurable, non-measurable, 
target and non-target lesions and the objective tumor response criteria (complete response, 
partial response, stable disease or progression of disease) will be used for the assessment of 
tumors according to Appendix F. 
Imaging assessments will be performed using CT scan or MRI to assess extracranial lesions, 
such as chest, abdomen (including liver and adrenal glands). MRI is the preferred method for 
analyzing the brain lesion if brain metastasis presents at baseline (within 28 days of treatments 
start, ideally as close as possible to the start of study treatment), on Cycle 3 Day 1 (± 7 days) 
and then every 6 weeks ± 7 days until objective disease progression or withdrawal from study. 
Contrast-enhanced CT can be used if MRI is not feasible. In addition, additional areas should 
be investigated based on the signs and symptoms of the patient. Any other sites at which new 
disease is suspected should also be appropriately imaged. If an unscheduled assessment is 
performed and the patient has not progressed, every attempt should be made to perform the 
subsequent assessments at their scheduled visits. 
Categorization of objective tumor response assessment will be based on the RECIST 1.1: CR 
(complete response), PR (partial response), SD (stable disease) and PD (progression of disease). 
Target lesion (TL) progression will be calculated in comparison to when the tumor burden is at 
a minimum (i.e. smallest sum of diameters previously recorded on study). In the absence of 
progression, tumor response (CR, PR, SD) will be calculated in comparison to the baseline 

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tumor measurements obtained before starting treatment. For objective response rate (ORR), a 
visit response of CR or PR must be confirmed by a later scan conducted at the next scheduled 
visit and no less than 4 weeks after the initial visit response of CR or PR. 
If the Investigator is in doubt as to whether progression has occurred, particularly with response 
to NTL (non-target lesion) or the appearance of a new lesion, it is advisable to continue 
treatment until the next scheduled assessment or sooner if clinically indicated and reassess the 
us. If repeated scans confirm progression, then the date of the initial scan should 
be declared as the date of progression.  
-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation 
-target lesions is usually not 
sufficient to quality for unequivocal progression status. 
It is important to follow the assessment schedule as closely as possible. Please refer to the study 
plan (Table 11, Table 12, Table 13, Table 14). 
All images for RECIST 1.1 assessment will be reviewed at site. Duplicates will be collected on 
an ongoing basis and stored by a Sponsor appointed representative, and sent for Independent 
Review Committee. 
6.9 
Other assessments 
6.9.1 
EQ-5D-5L 
The EQ-5D-5L is a standardised measure of health status developed by the EuroQol group in 
order to proivde a simple, generic measure of health for clinical and economic appraisal (23-
25). Applicable to a wide range of health conditions and treatments, it provides a simple 
descriptive profile and a single index value for health status that can be used in the clinical and 
economic evaluation of health care as well as in population health surveys. 
The questionaire assesses 5 dimension: mobility, self-care, usual activities, pain/disconfort and 
anxiety/depression. Each dimension has 5 response options (no problems, slight problems, 
moderate problems, severe problems, and extreme problems) that reflect increasing levels of 
difficulty. 
The patients will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionaire also includes a visual analogue 
scale, where the patient will be asked to rate currrent health status on a scale of 0 to 100, with 0 
being the worst imaginable health state (Appendix J). EQ-5D-5L will be collected at the 
timepoints shown in Table 14. 
6.9.2 
PRO-CTCAE 
The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse 
Event (PRO-CTCAE) system will be appied to patients in Part A expansion cohorts and Part B. 
Patients will be asked to complete those items which are considered relevant to TEAEs observed 
in this study, i.e. Rash, skin dryness, acne, itching, nail loss, nail ridging, decrease appetite, 

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nausea, vomiting, diarrhea, constipation, abdominal pain, mouth/throat sores, cracking at the 
corner of the mouth, bloating, fatigue, blurred vision, nosebleed (Appendix J). 
PRO-CTCAE will be collected at the timepoint shown Table 13 and Table 14. 
6.9.3 
FACIT-item GP5  
A single PRO questionnaire that can inform the overall tolerability of a dose from Functional 
Assessment of Cancer Therapy- item GP5 (FACIT- item GP5) will be collected at the timepoint 
shown in Table 13 and Table 14. 
7. 
EVALUATION AND CALCULATION OF VARIABLES AND 
STATISTICAL METHODS 
7.1 
Definition of study endpoints 
In Part A, the primary endpoints for determining the MTD and RP2D are the incidence of dose-
limiting toxicities (DLTs), adverse events (AEs), serious adverse events (SAEs) and abnormal 
laboratory test results. The RP2D definition will be based on integrated analysis of PK, 
tolerability or anti-tumor efficacy data. 
The secondary and exploratory endpoints are as following: 
 
PK assessment includes concentrations of DZD9008 in plasma and/or urine of 
individual patient (secondary). 
 
Preliminary assessment of anti-tumor efficacy includes the objective response rate 
(ORR), which includes the number of CR and PR based on RECIST 1.1, disease 
control rate (DCR), and duration of response (DoR) (secondary). 
 
The effect of food on PK of DZD9008 (secondary). 
 
To retrospectively assess anti-tumor activity of DZD9008 in patients with EGFR 
Exon20ins according to RECIST 1.1 by Independent Review Committee (IRC) 
(secondary). 
 
Retrospective confirmation of EGFR or HER2 Exon20ins in archived tumor tissue or 
fresh tumor biopsy or plasma sample (exploratory). 
 
Metabolite identification (exploratory). 
 
Other biomarkers (exploratory). 
 
To explore the relationship between DZD9008 exposure and selected endpoints. 
In Part B, the primary endpoints for determining anti-tumor efficacy is ORR according to 
RECIST 1.1 by Independent Review Committee (IRC). 

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The secondary and exploratory endpoints are as following: 
 
Safety and tolerability, including adverse events (AEs), serious adverse events 
(SAEs) and abnormal laboratory test results (secondary). 
 
PK assessment includes concentrations of DZD9008 in plasma of individual patient 
(secondary). 
 
Additional anti-tumor efficacy endpoints include BOR, DOR, PFS and overall 
survival (OS) (secondary). 
 
Collect and store tumor samples for companion diagnostics development and 
potential future exploratory research that may influence the development of 
DZD9008 (exploratory). 
 
To collect and store plasma samples for EGFR Exon20ins mutation testing and 
necessary technical studies for liquid biopsy companion diagnostic development and 
approval (exploratory). 
 
To collect and store blood-based samples for future exploratory research on 
genes/genetic aberrations that may influence response to DZD9008 treatment and/or 
susceptibility to DZD9008. 
 
Other exploratory biomarker data if needed (pEGFR or other pathway biomarker 
modulation in tumor tissue by DZD9008 (at defined dose[s]) (exploratory). 
 
To collect and store blood sample for future exploratory research into genes/genetic 
variation that may influence PK or response to DZD9008 (pharmacogenetics study, 
exploratory). 
 
To explore the effect of DZD9008 treatment and disease state on health state utility 
by using EQ-5D-5L health state utility index based on patient reported data. 
 
To assess AEs of DZD9008 by using subjects reported specific CTCAE symptoms 
(PRO-CTCAE) and FACIT GP5 questionnaire (exploratory). 
7.2 
Determination of sample size 
7.2.1 
Part A Dose escalation, expansion and food effect cohort 
In Part A, all patients dosed with DZD9008 will be included. The total number of patients will 
depend upon the number of dose escalation necessary. It is anticipated that there will be 
approximately 5 escalation cohorts, hence approximately 30 evaluable patients will be included 
for escalation.  
To better evaluate the safety and anti-tumor efficacy to help define the RP2D, approximately 
90 - 110 patients will be enrolled into 6 different expansion cohorts of Part A to explore safety, 

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PK and efficacy of DZD9008 under fasted or low-fat meal condition at 200 mg and 300 mg 
dose level, respectively. In addition, a separated cohort of 10 patients will be recruited to 
evaluate food effect on the PK. 
7.2.2
Part B Dose extension cohort
In Part B, subjects will be randomized into one of the two dose cohorts. Each dose cohort uses 
a Simon two-stage design.
Considering there are two dose cohorts in the pivotal study and the primary endpoint will be 
analyzed within each cohort independently, Bonferroni method is employed to control the 
family-wise type I error (at one-sided 0.025). The analysis in two cohorts will be performed 
independently, at one-sided significance level of 0.0125.
7.3
Calculation or derivation of safety variables
Safety and tolerability will be assessed in terms of AEs, SAEs, laboratory data, vital signs, ECG 
changes. These will be collected for all patients. Appropriate summaries of these data will be 
presented as described in Section 7.8.
ECG Changes
Immediate clinical management of patients will be according to local assessment of the QT
interval. For the Clinical Study Report QTc will be 
or Bazett's 
formulae.
Creatinine Clearance
Estimated creatinine clearance will be calculated using the Cockcroft and Gault formula;
For creatinine values in mol/L
Men: [(140 
Women: [(140 
For creatinine values in mg/dL
Men: [(140 age) x weight (kg)] / (creatinine x 72)
Women: [(140 age) x weight (kg) x 0.85] / (creatinine x 72)

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Or others per local practice. 
Other significant adverse events 
During the evaluation of the AE data, in addition to CRO medical monitor, a Dizal medically 
qualified or designated expert or designated will review the list of AEs that were not reported 
as SAEs and AEs leading to 
judgement, adverse events of particular clinical importance may, after consultation with the 
Study Physician, be considered other significant adverse events (OAEs) and reported as such in 
the Clinical Study Report. A similar review of laboratory values, vital signs, ECGs and other 
safety assessments will be performed for identification of other significant adverse events. 
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.  
7.4 
Calculation or derivation of pharmacokinetic variables 
The actual sampling times will be used in the parameter calculations and PK parameters will be 
derived using standard non-compartmental methods. 
Where possible the following PK parameters will be determined for DZD9008. 
Following the single dose part (or first dose) of the study: 
Maximum plasma concentration (Cmax), time to Cmax (tmax
half-life (t
), area under the plasma concentration-time curve from zero to 24 hours (AUC(0-
24)), area under the plasma concentration-time curve from zero to 168 hours (AUC(0-168)), from 
zero to the time of the last measurable concentration (AUC(0-t)) and from zero to infinity (AUC(0-
), apparent plasma clearance (CL/F), apparent volume of distribution (Vss/F), mean residence 
time (MRT) , as well as  the regression based 
q adj, 
, tlast, AUCextr). 
For Part A dose expansion and Part B dose extension, maximum plasma concentration (Cmax), 
time to Cmax (tmax), area under the plasma concentration-time curve from zero to 24 hours 
(AUC(0-24)). 
Following the multiple dose part of the study: 
Maximum plasma concentration at steady state (Css,max), time to Css,max (tss,max), minimum 
plasma concentration at steady state (Css,min), area under the plasma concentration-time curve 
from zero to the end of the dosing interval (AUCss), apparent plasma clearance at steady state 
(CLss/F), extent of accumulation on multiple dosing for AUC and Cmax (RAC(AUC) and RAC 
(Cmax)), time dependency of the pharmacokinetics, and urinary PK parameters: amount excreted  
(Ae) [by collection interval and cumulatively over the collection intervals], percentage of the 
dose excreted unchanged in urine (Fe [%]) [by collection interval and cumulatively over the 
collection intervals] and urinary clearance (CLR).  
The maximum plasma concentration (Cmax), the Cmax at steady state (Css,max), the time of 
maximum concentration (tmax) and the tmax at steady state (tss max) will be determined by 

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inspection of the concentration-time profiles. Where 
-
linear regression of the terminal portion of the concentration-time profiles where there are 
sufficient data and the t
 
All AUC (0-t) values ((AUC(0-t), AUC(0-
24), AUC(0-168), AUCss)  will be calculated using the linear up/log down rule. Where appropriate, 
the AUC (0-t) 
(0-
 The CL/F following 
the single dose and CLss/F following multiple dosing will be determined from the ratio of 
dose/AUC(0-  and dose/AUCss, respectively. The volume of distribution (Vss/F) will be 
determined from the mean residence time (MRT) x CL/F. The RAC will be calculated as the 
ratio of the AUCss or Cmax on Cycle 2 Day 1 and AUC(0-24) or Cmax on Cycle 0 Day 1. The time 
dependency of the pharmacokinetics on multiple dosing will be assessed by the calculation of 
the ratio of AUCss on Cycle 2 Day 1/AUC(0-  on Cycle 0 Day 1. 
The equation for calculating the amount excreted in the urine is: Ae (µmol or ng) = urine volume 
(mL) * concentration (µmol/mL or ng/mL). The weight/volume of urine and the concentration 
of drug in urine are usually recorded assuming that 1 g corresponds to 1 mL of urine. Urine 
concentrations below LLOQ will be treated as numerical zero. The percentage of dose excreted 
unchanged in the urine (e.g. Fe [%]) will be calculated by dividing the corresponding Ae in the 
collection period by the dose administered and multiplying by 100. 
Renal clearance can be calculated by:. CLR (L/h) = Ae0-t (µmol or ng) / AUC0-t (µmol.h/L or 
ng.h/L) where the 0-t interval is the same for both Ae and AUC.   
Where possible the appropriate pharmacokinetic parameters will also be determined for the 
metabolites of DZD9008. 
Additional PK parameters may be derived where appropriate. 
7.5 
Calculation or derivation of tumor response variables 
Independent Central Review of RECIST based assessments  
The Independent Review Committee (IRC) will review all the images collected from Part B of 
the study and images collected from patients with EGFR Exon20ins in Part A of the study when 
needed. IRC review of all radiological imaging data will be carried out using RECIST version 
1.1. All radiological scans for all patients (including those at unscheduled visits, or outside visit 
windows) will be provided to the IRC. Prior radiotherapy reports for patients (at baseline) and 
information on biopsied lesions will also be provided to the IRC to allow the selection of 
appropriate target lesions. The imaging scans will be reviewed by two independent radiologists 
using RECIST 1.1 criteria and will be adjudicated if required. For each patient, the IRC will 
define the overall visit response data (CR, PR, SD, PD or NE) and the relevant scan dates for 
each time point (i.e. for visits where response or progression is/is not identified). If a patient has 
had a tumor assessment which cannot be evaluated then the patient will be assigned a visit 
response of not evaluable (NE) (unless there is evidence of progression in which case the 
response will be assigned as PD). Endpoints (ORR, DoR, DCR, PFS) will be derived from the  
scan dates. ORR will only include patients whose response has been confirmed by a second 
scan at least 4 weeks after the initial response. The endpoint of tumor shrinkage will be assessed 
from tumor size measurements based on the primary independent radiologist assessment.  

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Results from the independent review will not be communicated to investigators. The 
management of patients will be based solely on the results of the RECIST 1.1 assessment 
conducted by the investigator. 
For more detailed information refers to recent IRC charter. 
Investigator RECIST based assessments 
From the investigators review of the imaging scans, the RECIST tumor response data will be 
 visit response according to RECIST version 1.1. At each visit, 
patients will be assigned a RECIST 1.1 visit response of CR, PR, SD or PD depending on the 
status of their disease compared with baseline and previous assessments.  
Progression of TLs will be calculated in comparison to when the tumor burden was at a 
minimum (i.e., smallest sum of diameters previously recorded on study). In the absence of 
progression, tumor response (CR, PR, SD) will be calculated in comparison to the baseline 
tumor measurements obtained before starting treatment.  
If a patient has had a tumor assessment, which cannot be evaluated, then the patient will be 
assigned a visit response of not evaluable (NE) unless there is evidence of progression in which 
case the response will be assigned as PD. 
 
A visit response of CR will not be allowed if any of the TL data is missing 
7.5.1 
Objective response rate (ORR) 
Objective response rate is defined as the percentage of patients who have best overall response 
of CR or PR prior to any evidence of progression (as defined by RECIST 1.1).  
A visit response of CR is defined when all TL and NTL lesions present at baseline have 
disappeared (with the exception of lymph nodes which must be < 10 mm to be considered non-
pathological) and no new lesions have developed since baseline. A visit response of PR is 
defined when the sum of diameters of the TLs has decreased by 30% or more compared to 
baseline (with no evidence of progression) and the NTLs are at least stable with no evidence of 
new lesions. A confirmed response of CR/PR means that a response of CR/PR is recorded by 
 
When the investigator is in doubt as to whether progression of disease has occurred and 
therefore reassesses the patient at a later date, the date of the initial scan should be declared as 
the date of progression if the repeat scans confirm progression. 
Any CR or PR which occur after a further anticancer therapy is received will not be included in 
numerator of the ORR calculation. 
Best overall response (BOR) will be calculated as the best response recorded from study 
treatment starts until RECIST assessed progression is documented for each patient, prior to any 
subsequent cancer therapy received and irrespective of whether patients discontinued treatment 
of DZD9008. When confirmation of CR/PR is required, BOR of CR or PR will only be claimed 
only if the criterion for confirmed response is met. When SD is believed to be the best response, 
at least 6 weeks from baseline (with ± 7 day visit window) is required. 

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7.5.2 
Progression Free Survival (PFS) 
PFS is defined as the time from date of first dosing until the date of objective disease progression 
as defined by RECIST 1.1 or death (by any cause in the absence of progression) regardless of 
whether the subject withdraws from the study treatments or receives another anticancer therapy 
prior to progression. 
Patients who have not progressed or died at the time of analysis will be censored at the time of 
the latest date of assessment from their last evaluable RECIST assessment. If the patient 
progresses or dies after two or more consecutively missed RECIST assessments visits, the 
patient will be censored at the time of latest evaluable RECIST assessment before the missed 
visit. If the patient has no evaluable visits or does not have baseline data they will be censored 
on the first dosing date unless they die within two RECIST assessment visits after baseline. 
If a patient discontinues treatment prior to progression and/or receives a subsequent therapy 
prior to progression then these patients will continue to be followed until evidence of objective 
disease progression as defined by RECIST 1.1 and their PFS time will be derived as defined 
above. 
The PFS will always be derived based on scan/assessment dates not visit dates. 
Note: Symptomatic deterioration will not be regarded as a progression event. 
7.5.3 
Duration of Response (DoR) 
Duration of response will be defined as the time from the date of first documented response, 
that is subsequently confirmed until the date of documented progression or death in the absence 
of disease progression, the end of response should coincide with the date of progression or death 
from any cause used for the PFS endpoint. The time of the initial response will be defined as 
the latest of the dates contributing towards the first visit response of PR or CR. 
If a patient does not progress following a response, then his/her duration of response will use 
the PFS censoring time. 
7.5.4 
Disease control rate (DCR) 
Disease control rate is defined as the proportion of patients with a best overall response of CR, 
PR or SD. 
7.5.5 
Change in tumor size 
Tumor size is defined as the sum of the lengths of the longest diameters of the RECIST 1.1 
target lesions. Percentage change in tumor size will be determined for patients with measurable 
disease at baseline and is derived at each visit by the percentage change in the sum of the 
diameters of TLs compared to baseline. 
For further details see Appendix F of this Clinical Study Protocol. 
7.5.6 
Overall Survival (OS) 
Overall survival will be assessed based on the date of first dose and survival status at the time 
of analysis. 

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Overall survival is defined as the interval between the date of first dose and the date of patient 
death due to any cause. Patients who have not died at the time of the statistical analysis will be 
censored at the time they were last known to be alive. 
7.6 
Calculation of patient reported outcome (PRO) 
7.6.1 
EQ-5D-5L 
The EQ-5D-5L index comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression). For each dimension, respondent select which 
statement best describes their health on that day from a possible 5 options of increasing levels 
of severity (no problems, slight problems, moderate problems, severe problems and unable 
problems). A unique EQ-5D health state is referred to by a 5-digit code allowing for a total of 
3125 health states. For example, state 11111 indicates no problems on any of the 5 dimensions.  
In addition to the descriptive system, respondents also assess their health on the day of 
assessment on a visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best 
imaginable health). The score is reported separately. 
7.7 
Calculation or derivation of exploratory research variables 
Results from the exploratory biomarker and pharmacogenetic research etc.may be reported 
separately from the Clinical Study Report for the main study. 
7.8 
Analysis sets 
The analysis of data will be based on different subsets according to the purpose of the analysis. 
Throughout the safety result sections, erroneously treated patients (eg, those assigned to receive 
dose A who actually received dose B, those who failed to meet the selection criteria) will be 
accounted for in the actual dose group received. 
Table 10 
Analysis set definition 
Analysis Set 
Definition 
All patients 
All patients screened 
All randomized patients 
All patients who were randomized (applicable for Part B only) 
Safety 
All patients who received at least 1 dose of DZD9008 
Full analysis set (FAS) 
All randomized NSCLC patients with documented EGFR Exon20ins 
mutation in tumor tissue who were previously treated with platinum-
based chemotherapy, received at least 1 dose of DZD9008 and have 
measurable disease at baseline as identified by IRC  
(applicable for Part B only) 
Centrally confirmed EGFR 
Exon20ins by tumor tissue 
All patients in full analysis set with EGFR Exon20ins mutations 
confirmed in tumor tissue by central laboratory (applicable for Part B 
only) 
Centrally confirmed EGFR 
Exon20ins by plasma ctDNA 
All patients in full analysis set with EGFR Exon20ins mutations 
confirmed in plasma ctDNA by central laboratory (applicable for Part B 
only)  

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Analysis Set 
Definition 
Pharmacokinetics 
All dosed patients who has at least one measurable plasma 
concentration of DZD9008 post dose with no protocol deviations or AE 
thought to impact the analysis of the PK data 
Food effect 
Patients from the food effect cohort for whom a PK profile is available 
on at least one of the fed and fasted dosing days 
Evaluable for response 
Dosed patients with measurable disease at baseline and follow up 
RECIST assessment (Part A) 
Exploratory biomarkers 
All patients that participate in the exploratory biomarker research 
Paired biopsy (PoM cohort) 
Dosed patients with a pre-study tumor biopsy and one tumor biopsy on 
study treatment 
7.9 
Methods of Statistical analysis  
The statistical analyses will be performed by Dizal statistical group or designated third party 
provider, under the direction of Dizal. Data from Part A and Part B will be provided separately. 
Summary statistics will be presented by dose group in Part A and by study cohort in Part B. 
7.9.1 
Demographic data 
Characteristics of the patients, including medical history, disease characteristics at baseline, 
prior and concomitant medications will be listed for each patient and summarized. 
Reasons for discontinuation of investigational product will be listed including the day of 
treatment discontinuation and will be summarized. 
7.9.2 
Exposure 
Dose administration data for the investigational product, including the cycle number, start/end 
dates, dose (unit), dose modifications will be listed for all patients in the safety analysis set. 
Total exposure duration (date of last dose minus date of first dose + 1, regardless of any 
intermittent interruptions) and the total administered dose, as well as treatment compliance will 
be summarized by the following: mean, standard deviation, minimum, maximum, median and 
number of observations. In addition, the number and percentage of patients with at least one 
dose interruption and at least one dose reduction will be presented separately for the initial 
period defined as 21 days of multiple dosing (cycle 1) and for any time following this initial 
period of the study. 
7.9.3 
Safety 
All patients who receive at least one dose of DZD9008 will be included in the assessment of the 
safety profile (safety analysis set). At the end of the study, appropriate summaries of safety data 
will be produced, as defined below. 
Data from all cycles of initial treatment will be combined in the presentation of safety data. AEs 
will be listed individually by patient and dose group. For patients who have a dose modification, 
all AEs (due to drug or otherwise) will be assigned to the initial dose group. The number of 
patients experiencing each AE will be summarized by the Medical Dictionary for Regulatory 

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Activities (MedDRA) system organ class, MedDRA preferred term and CTCAE grade. The 
number and percentage of patients with adverse events in different categories (eg, causally 
in Part B, and events in each category will be further summarized by MedDRA system organ 
class and preferred term, by dose group. SAEs will be summarized separately if a sufficient 
number occur. 
Any AE occurring within the defined 28-day follow-up period after discontinuation of 
investigational product will be included in the AE summaries. Any adverse events in this period 
that occur after a patient has received further therapy for cancer (following discontinuation of 
investigational product) will be flagged in the data listings. AEs occurring after the 28 day 
follow-up period after discontinuation of investigational product will be listed separately, but 
not included in the summaries. 
Hematology, clinical chemistry, vital signs and ECG data will be listed individually by patient 
and suitably summarized. For all laboratory variables, which are included in CTCAE 5.0, the 
CTCAE grade will be calculated. Summary statistics such as mean, median, standard deviation, 
minimum, maximum and number of observations will be used for continuous variables, 
frequency and percentages will be used for categorical variables. 
Details of any deaths will be listed for all patients. 
Any qualitative assessments will be summarized using the number and proportion of patients 
with results of negative, trace or positive. 
Graphical presentations of safety data will be presented as is deemed appropriate. This may 
include, but is not restricted to, presentation of parameters against time, concentration or shift 
plots. Appropriate scatter plots will also be considered to investigate trends in parameters 
compared to baseline. 
7.9.4 
Pharmacokinetics 
This will be summarized in the Pharmacokinetics analysis set. 
Plasma concentrations of DZD9008 will be summarized by nominal sample time. Plasma 
concentrations and derived PK parameters will be summarized. Parameters following single and 
multiple dosing will be summarized separately. Plasma concentrations at each time point will 
be summarized according to dose by the following summary statistics: 
 
The geometric mean (Gmean
n of the data on 
a logarithmic scale) 
 
2)-1], where s is the standard 
deviation of the data on a log scale) 
 
Gmean 
 
 
Arithmetic mean calculated using untransformed data 
 
Standard Deviation calculated using untransformed data 

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Median 
 
Minimum 
 
Maximum 
 
Number of observations 
The following summary statistics will be presented for AUC(0-
 AUC(0-24), AUC(0-72), AUC(0-
168), AUC(0-t), AUCss, Cmax, Css max, and Css min : 
 
Gmean
 
 
2)-1], where s is the standard deviation of the data on a 
log scale) 
 
Arithmetic mean calculated using untransformed data 
 
Standard deviation calculated using untransformed data 
 
Median 
 
Minimum 
 
Maximum 
 
Number of observations 
The following summary statistics will be presented for CL/F, CLss/F, Vss/F, t
, RAC (AUC) 
and RAC(Cmax), time dependency, CLR, Ae and Fe: 
 
Arithmetic mean 
 
Standard deviation 
 
Minimum 
 
Maximum 
 
Number of observations 
The following summary statistics will be presented for tmax and tss max: 
 
Median 
 
Minimum 
 
Maximum 
 
Number of observations 

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Regression based 
AUCextr) will be listed only and not summarized. 
The pharmacokinetic data for DZD9008 after a single-dose and separately, at steady state will 
also be displayed graphically. Displays will include plasma concentration patient profiles (on 
the linear and log-scale) versus time and Gmean concentration (+/-standard deviation) versus 
time, stratified by dose. 
Scatter plots of PK parameters versus dose, or log-dose will also be considered following both 
single (escalation only) and multiple dose administration of DZD9008 to assess dose 
proportionality in Part A. 
In a preliminary assessment of dose proportionality, log-transformed AUC(0-  and/or AUC(0-t) 
and Cmax parameter estimates will be examined using the Power Model: 
parameter = ea (dose)b 
i.e., log(parameter) = a + (b * log(dose)) 
where a is the intercept, depending on patients, and b is the slope, measuring the extent of dose 
proportionality. Dose proportionality implies that b=1 and will be assessed by estimating b 
along with its confidence interval. 
If there is evidence of departures from dose proportionality, log-transformed dose-normalized 
AUC and Cmax of DZD9008 will be analysed separately using a mixed effects model. Dose will 
be fitted as a fixed effect and patient as a random effect. Point estimates and associated 90% 
confidence intervals (CIs) for the differences between each dose level and the reference dose 
(the lowest dose) will be constructed using the residual variance. The estimates will then be 
back-transformed to provide point estimates and corresponding 90% CIs for the ratios of each 
dose level to the reference dose on the original scale. No adjustments for pre-planned multiple 
comparisons will be made. This analysis will only be performed provided there are sufficient 
data. 
If there are more than 20% patients whose AUC(0-  values are not calculable for either treatment 
due to large extrapolated area (> 20%), Rsq adjusted <0.80 or any other reason, AUC(0-t) will 
also be analyzed statistically and presented in the same way as AUC(0- . Otherwise, AUC(0-t) 
will not be statistically analyzed. 
The same analysis will be performed on AUCss and Css,max from Cycle 2 Day 1 PK data. 
7.9.5 
The effect of high fat meal 
For the assessment of the effect of high fat meal, the primary PK variables AUC(0-  and/or 
AUC(0-t) and/or AUC(0-72), and Cmax of plasma DZD9008 will be analyzed in food effect analysis 
set. These parameters will be natural log-transformed and analyzed using a linear mixed effects 
model with fixed effects for sequence, period and treatment, and random effect for patient 
nested within sequence. The difference in treatment means will be determined along with its 
associated 90% CI and back-transformed to give an estimate of the effect of food on the 
exposure of DZD9008. The results of this analysis will be presented in terms of geometric 
means for both treatments, the effect of food on the exposure of DZD9008 (ie, the ratio of the 
treatment geometric means) and its 90% CI. 

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In the event of relevant carry-over exposure across periods (predose concentration exceeds 5% 
of Cmax for DZD9008 in period  2), the primary analysis will be performed excluding the Period 
2 data for patients meeting the carry-over criteria. A secondary statistical analysis may be 
performed including all patients, irrespective of the degreee of carry-over. If appropiorate, an 
exploratory analysis on carry-over adjusted concentrations and PK parameters may also be 
performed. 
7.9.6 
The effect of low-fat meal 
Additional cohorts from Part A investigate PK exposure of DZD9008 at 200 mg and 300 mg, 
respectively, with low-fat meal. For the assessment of the effect of low-fat meal, the primary 
PK parameters at steady state (AUCss and Css,max at cycle 2 day 1) will be analyzed. These 
parameters will be natural log-transformed and analyzed using a linear model, with the dose 
level (200 mg or 300 mg) and food condition (fed or fasted) included as independent variables. 
The between-food condition difference and 90% confidence intervals (CIs) will be provided. 
An evaluable full PK profile between fasted and fed was defined as: 
On C2D1 of Part A expansion, the patient took DZD9008 under the originally assigned prandial 
conditions. 
No vomiting occurred within four hours following dose administration on the full PK sampling 
day. 
Additionally, an entire PK profile could be considered non-evaluable as per scientific judgment 
of clinical pharmacology expert even if the above criteria were fulfilled. 
7.9.7 
Efficacy 
Efficacy endpoints related to RECIST tumor assessment will be analyzed and reported based 
on the evaluation by IRC and investigators, respectively.  
Unless otherwise specified, the efficacy analysis population will be the evaluable for response 
anlaysis set for Part A and full analysis set for Part B. To support companion diagnostics 
development, efficacy analysis in centrally confirmed EGFR Exon20ins by tumor tissue and 
centrally confirmed EGFR Exon20ins by plasma ctDNA analysis sets may be performed for 
Part B. 
7.9.7.1 
Tumor response 
The analysis population will be the evaluable for response anlaysis set for Part A and FAS for 
Part B.  
Summaries of the number of patients with best overall response in each part will be provided in 
the following categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), 
Progressive Disease (PD) and Non-Evaluable (NE). Objective response rate and disease control 
rate will be summarized.  
For Part B, p value for the test against the null hypothesis of ORR 17% will reported based on 
-stage method. ORR and two-
method (26) 
-stage design and 
provide the uniformly minimum variance unbiased estimator. 

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Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
115 
 
Data will be analyzed by subgroup (e.g. taken into consideration of the prior treatment) in Part 
B. 
7.9.7.2 
Duration of response 
The analysis population for duration of response will be the subset of the evaluable for response 
population (Part A) or FAS (Part B) with a best overall response of confirmed CR/PR. Duration 
of response will be summarized and the number (%) of responding patients with a duration of 
response > 3, > 6, > 9 and > 12 months will be presented. Or if data are appropriate, response 
ongoing rates at 6, 9 and 12 months will be estimated based on Kaplan-Meier method. A Kaplan 
Meier plot and median duration of response (calculated from the Kaplan-Meier) will be 
presented.  
7.9.7.3 
Change in tumor size 
The analysis population for change in tumor size will be the evaluable for response set for Part 
A and FAS for Part B.  
The absolute values and percentage change in target lesion tumor size from baseline will be 
summarized using descriptive statistics and presented at each time point. The best change will 
also be summarized. 
Tumor size will also be presented graphically u
percentage change in tumor size as a separate bar, with the bars ordered from the largest increase 
to the largest decrease. Reference line at the -30% change in tumor size levels will be added to 
the plots, which corresponds to the definition of partial response.  
7.9.7.4 
Progression free survival 
The analysis populations for PFS will be the safety analysis set for Part A and FAS for Part B.  
PFS will be displayed using a Kaplan-Meier plot. The progression-free survival rates at 6, 9 and 
12 months (calculated from the Kaplan-Meier estimator), median and quartiles (if estimable 
from the Kaplan-Meier estimator) will be summarized.  
7.9.7.5 
Overall survival 
Overall survival will be analyzed and reported in FAS for Part B. The survival status (dead, 
alive, lost to follow-up, etc) at the end of the study will be summarized. In addition, the number 
and percentage of patients prematurely censored before data cut-off will be summarized.  
Overall survival will be displayed using a Kaplan-Meier plot. The  overall survival rates at 6, 9 
and 12 months (calculated from the Kaplan-Meier estimator), median and quartiles (if estimable 
from the Kaplan-Meier estimator) will be summarized.  
7.9.8 
Patient Report Outcome (PRO)  
Descriptive analysis will be perfomed by treatment group and visit for each item and the VAS 
score in EQ-5D-5L. 
7.9.9 
PoM biomarker 
The pharmacodynamic effect of DZD9008 on pEGFR in tumor tissue from paired biopsies will 
be evaluated. The technological platform for the pharmacodynamics analysis will be 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
116 
 
immunohistochemistry, but may not be limited to this. The biomarker study will include, but 
not limit to pEGFR. pEGFR expression in tumor tissue with DZD9008 treatment will be 
summarized and displayed graphically in subset of patient population who have paired tumor 
tissue biopsies. The baseline and post-treatment pEGFR levels will be compared for individual 
patient and will be also summarized by dose cohort.  
PoM biomarker study result will not constitute the Clinical Study Report. 
7.9.10 
Exploratory biomarker research and pharmacogenetic study 
The number of patients who will agree to participate in the exploratory biomarker and genetic 
research is unknown. It is therefore not possible to establish whether sufficient data will be 
collected to allow a formal statistical evaluation or whether only descriptive statistics will be 
generated. The exploratory biomarker study results will not be included in CSR. 
7.10 
Publication policy  
This policy applies to Spain. 
All information concerning the product as well as any matter concerning the operation of the 
Sponsor, such as clinical indications for the drug, its formula, methods of manufacture and other 
scientific data relating to it, that have been provided by the Sponsor and are unpublished, are 
confidential and must remain the sole property of the Sponsor. The Investigator will agree to 
use the information only for the purposes of carrying out this study and for no other purpose 
unless prior written permission from the Sponsor is obtained.  
Samples and/or data will be processed centrally, and the results will be sent electronically to the 
Sponsor or designated CRO. Data that will be processed centrally includes central imaging 
review data (CT/MRI), central ECG data and centrally analyzed laboratory data including PK 
and blood/tumor biomarker samples.  
The Sponsor has full ownership of the original eCRFs completed as part of the study.  
By signing the clinical study protocol, the Investigator agrees that the results of the study may 
be used for the purposes of national and international registration, publication, and information 
for medical and pharmaceutical professionals. The authorities will be notified of the 
Investigator's name, address, qualifications, and extent of involvement.  
After conclusion of the clinical trial, an integrated clinical and statistical study report will be 
prepared by the Sponsor or designee. As soon as possible and no later than one year, the trial 
results must be entered in European Clinical Trials Database clinicaltrialsregister.eu. 
All materials, documents and information supplied by the Sponsor to the Investigator, and all 
materials, documents and information prepared or developed in the course of the study to be 
performed under this protocol, shall be the sole and exclusive property of the Sponsor. Subject 
to obligations of confidentiality, the Investigator reserves the right to publish only the results of 
the work performed pursuant to this protocol, provided, however, that the Investigator provides 
an authorized representative of the Sponsor with a copy of any proposed publication for review 
and comment at least 45 days in advance of its submission for publication. In addition, if 
requested, the Investigator will withhold publication an additional 90 days to allow for filing a 

Clinical Study Protocol
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
117
patent application or taking such other measures as Sponsor deems appropriate to establish and 
preserve its proprietary rights. 
It is agreed that, consistent with scientific standards, publication of the results of the study shall 
be made only as part of a publication of the results obtained by all sites performing the protocol.
8.
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY 
THE INVESTIGATOR
8.1
Medical emergencies and Sponsor contacts
The Principal Investigator(s) is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes a SAE and is to be reported as such, see Section 6.4.4.
In the case of a medical emergency the investigator may contact the Study Team Physician. If 
the Study Team Physician is not available, contact the Study Leader at Dizal Pharmaceuticals.
Name 
Role in the study 
Address & telephone number
Study Team Physician 
responsible for the 
protocol at Dizal 
Global Study Leader 
responsible for the 
protocol at Dizal
Chief Medical Officer
Responsible for the high 
level strategy
8.2
Overdose
There are no data on overdosing since this is the first study in humans with DZD9008. There is 
no definition of what constitutes an overdose. There is no known antidote. Investigators will be 
advised that any patient who receives a higher dose than that intended should be monitored 
closely, managed with appropriate supportive care and followed up expectantly.
Such overdoses should be recorded as follows:

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
118 
 
 
An overdose with associated AEs/SAEs is recorded as the AE diagnosis/symptoms 
on the relevant AE/SAE modules in the CRF and on the overdose CRF module. 
 
An overdose with no associated symptoms is only reported on the overdose CRF 
module. 
If an overdose occurs in the course of the study, then investigators or other site personnel inform 
appropriate Dizal representatives immediately, or no later than 24 hours of when he or she 
becomes aware of it. 
The designated Dizal representative works with the investigator to ensure that all relevant 
information is provided to the Dizal Patient Safety team or representatives.  
For overdoses associated with an SAE, standard reporting timelines apply, see Section 6.4.4.  
8.3 
Pregnancy 
All pregnancies and their subsequent outcome (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth or congenital abnormality) should be reported to Dizal using 
the appropriate forms. 
8.3.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study, investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous miscarriages 
should be reported and handled as SAEs.  Elective abortions without complications should not 
be handled as AEs. The outcome of a pregnancy should be followed up and documented even 
if the patient was withdrawn from the study.  
If a pregnancy occurs during exposure to investigational product or in the 28 days after 
discontinuing investigational product, then investigators or other site personnel inform 
appropriate Dizal representatives immediately, or no later than 24 hours of when he or she 
becomes aware of it. 
The designated Dizal representative works with the investigator to ensure that all relevant 
information is provided to the Dizal Patient Safety team within 1 or 5 days for SAEs, (see 
Section 6.4.4) and within 28 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
8.3.2 
Paternal exposure 
Pregnanc
conception occurring from the date of dosing until 16 weeks after dosing should be reported to 
Dizal and followed up for its outcome. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
119 
 
9. 
REFERENCES 
1. Maemondo M, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated 
EGFR. N. Engl. J. Med. 2010; 362(25):2380-8. 
2. Mitsudomi T, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell 
lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): 
an open label, randomised phase 3 trial. Lancet Oncol. 2010; 11(2):121-8. 
3. Mok TS, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. 
J. Med. 2009; 361(10): 947-57. 
4. Rosell R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European 
patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a 
multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13(3): 239-46. 
5. Wu YL, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian 
patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-
Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014; 15(2): 213-22. 
6. Zhou C, et al., Erlotinib versus chemotherapy as first-line treatment for patients with 
advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-
0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12(8): 
735-42. 
7. Soria JC, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung 
Cancer. N. Engl. J. Med. 2018;378(2):113-125. 
8. Sequist LV, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with 
metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31(27): 3327-
34. 
9. Wu YL, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced 
EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, 
randomized, open-label, ENSURE study. Ann Oncol. 2015; 26 (9): 1883- 1889. 
10. Arcila ME, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, 
molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013; 
12(2):220-9. 
11. Yang JC, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung 
cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-
Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015; 16 (7): 830-8. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
120 
 
12. Yang G, et al. Chinese advanced non-small cell lung cancer patients: molecular 
heterogeneity and treatment outcome from nationwide real-world study. Lung Cancer. 
2020, 145:186-194. 
13. Horn L, et al. Indirect comparison of Mobocertinib (TAK-788) vs real-world data outcomes 
in refractory NSCLC with EGFR Exon20 insertions. 2020 ASCO.  
14.  Simon R. Optimal two stage designs for phase II clinical trials. Controlled clinical trials. 
1989, 10(1): 1-10. 
15. Cho, et al. Efficacy and Safety of Certinib (450 mg/d or 600 mg/d) with Food Versus 750 
mg /d Fasted in Patients with ALK Recepetor Typrosin Kinase (ALK)-Positive NSCLC. J 
Thorac Oncol. 2019;14(7):1255-1265. 
16. Naidoo J, et al. Epidermal growth factor receptor exon 20 insertions in advanced lung 
adenocarcinomas: Clinical outcomes and response to erlotinib. Cancer. 2015; 
121(18):3212-20. 
17. Udagawa H, et al. Clinical outcome of non-small cell lung cancer with EGFR/HER2 exon 
20 insertions identified in the LC-SCRUM-Japan. 2019 WCLC.  
18. Babb J, et al. Cancer phase I clinical trials: efficient dose escalation with overdose control. 
Stat Med. 1998;17 (10):1103-20.  
19. Afatinib NDA package.  
20. Dacomitinib NDA package.  
21. Riely RJ, et al. Anti-tumor activity of the EGFR/HER2 inhibitor, TAK-788 in NSCLC with 
EGFR Exon20 insertion. 2019 WCLC.   
22. Park K, et al. Amivantinib (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in 
patients with EGFR Exon20 insertion (Exon20ins)-mutant non-small cell lung cancer 
(NSCLC). 2020 ASCO.  
23. EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16(3): 199-208. 
24. EQ-5D-5L User Guide: Basic information on how to use EQ-5D-5L instrument. URL 
http://www.euroqol.org/fileadmin/user-
upload/Documenten/PDF/Folders_Flyers/UserGuide_EQ-5D-5L_V2.0_Octber_2013.pdf 
25. Osoba D, et al. Interpreting the Significance of Changes in Health-Related Quality-of-Life 
Scores. J Clin Oncol. 1998; 16(1):139-144. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
121 
 
26. Jung SH, et al. On the estimation of the binomial probability in multistage clinical trials. 
Stat Med. 2004;23(6): 881-896.

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Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
122 
 
Table 11 
Study Plan of Dose Escalation Cohort (Part A, dose escalation) 
Assessment 
Screen 
Cycle 0 
Days (cycle 0=8 days) 
Cycle 1 (28 days) 
Cycle 2 (21 
days) 
onwards 
Discontinuat
ion 
28 day 
follow 
up 
Details in 
section 
Day 
-28~ -1 
1h 
2 
3 
4 
6 
8 
1h 
8a 
15a 
1b 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.1.1 
Demography & baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.1 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.1 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 & 4.2 
Physical examination 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
6.3.2 
ECOG performance status 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
6.3.2 
Brain MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Pregnancy test (premenopausal females 
only)c 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
6.3.4 
Ophthalmologic assessment i 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
6.3.5 
Archival tumor tissue or fresh biopsy 
collection (mutation confirmation) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Vital signs 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
6.3.3 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.3 
Weight 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
6.3.3 
ECG 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
6.3.5 
Clinical chemistry/ 
Hematology/Urinalysis 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
6.3.4 
Echocardiogram/MUGAe 
X 
 
 
 
 
 
 
on Cycle 3 Day1, then every 6 weeks 
 
6.3.5 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
123 
 
Assessment 
Screen 
Cycle 0 
Days (cycle 0=8 days) 
Cycle 1 (28 days) 
Cycle 2 (21 
days) 
onwards 
Discontinuat
ion 
28 day 
follow 
up 
Details in 
section 
Day 
-28~ -1 
1h 
2 
3 
4 
6 
8 
1h 
8a 
15a 
1b 
 
 
 
Lung function test (LFT) e 
X 
 
 
 
 
 
 
on Cycle 3 Day1, then every 6 weeks 
 
6.3.5.3 
HBV, HCV, HIV, COVID-19d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.2 
APTT/INR 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
6.3.4 
Blood PK samples 
(including metabolites) 
 
X# 
X 
X 
X 
X 
X 
X 
X 
X 
X#* 
 
 
6.5.1 
PK Urine (including metabolites) 
 
 
 
 
 
 
 
 
 
 
X# 
 
 
6.5.1 
4-
 
 
X 
 
 
 
 
 
X 
X 
X 
X (C2 only) 
 
 
6.5.3 
Dose with DZD9008 
 
X 
 
 
 
 
 
----------- X (daily dosing) ---------------
 
 
5.1 
Blood samples for ctDNA & 
Biomarkers (optional) 
X 
X 
 
 
 
 
 
X 
X 
X 
X (C2D1-C6D1 and continuous every 
even cycle D1 until disease progression) 
6.6.2.3 
RECIST assessments f 
X 
 
 
 
 
 
 
--on Cycle 3 Day1, then every 6 weeks until disease 
progression
 
6.8.1 
Concomitant medication 
----------------------------------------------------------------------------------------------------------------
 
4.3.1 
Adverse eventsg 
----------------------------------------------------------------------------------------------------------------
 
6.4 
#: Multiple time point for PK sampling. Hospitalization can be allowed for out of business time PK collection. 
*: Day 1 of Cycle 2, 3, 4 and 5  
a. 
±1 day visit window is allowed for C1D8 & D15.  
b. 
All study visits from Cycle 2 Day 1 onwards may be performed within a visit window of ± 2 days. 
c. 
Pregnancy test needs to be within 3 days of the first dosing. 
d. 
HBV/HCV/HIV/COVID-19 tests can be done based on local practice.  
e. 
Echo/MUGA and LFT at baseline needs to be done within 14 days of the first dosing. 
f. 
CT is preferred. Same scan modality is required to use for tumor scan and RECIST assessment from baseline till follow up for one patient. Please refer to Appendix F of 
CSP about the details of RECIST assessment.  

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
124 
 
g. 
AE will be collected from first dosing of DZD9008; SAE is required to be collected from inform consent  
h. 
For C0D1 and C1D1, -1 day window is allowed for laboratory safety testing and physical examination 
i. 
Eye examination includes: Visual acuity, Pupils, Intraocular pressure, External examination, Slit-lamp examination, and Fundoscopic examination (pupil dilate is not 
required) and others if clinically indicated. 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
125 
 
Table 12 
Study Plan of Food Effect Cohort (Part A, food effect) 
Assessment 
Screen 
Cycle 0 
* Days (cycle 0=16 days) 
Cycle 1 
(21 days) 
Cycles 2 
(21 days) 
onwards 
Disconti
nuation 
28-day 
Follow Up 
Details in 
section 
Day 
 
1h 
2 
3 
4 
6 
8 
9 
10 
11 
12 
14 
16 
1 h 
8a 
15a 
1b 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.1.1 
Demography & baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.1 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.1 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 & 4.2 
Physical examination 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
6.3.2 
ECOG performance status 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
6.3.2 
Brain MRI or contrast-
enhanced CT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Pregnancy test 
(premenopausal females 
only)c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
6.3.4 
Ophthalmologic assessment 
i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
6.3.5.4 
Archival tumor tissue or 
fresh biopsy (mutation 
confirmation) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Vital signs 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
6.3.3 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.3 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
6.3.3 
ECG 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
6.3.5 
HBV, HCV, HIV, COVID-
19d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
126 
 
Assessment 
Screen 
Cycle 0 
* Days (cycle 0=16 days) 
Cycle 1 
(21 days) 
Cycles 2 
(21 days) 
onwards 
Disconti
nuation 
28-day 
Follow Up 
Details in 
section 
Day 
 
1h 
2 
3 
4 
6 
8 
9 
10 
11 
12 
14 
16 
1 h 
8a 
15a 
1b 
 
 
 
Clinical chemistry/ 
Hematology/Urinalysis 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
6.3.4 
APTT/INR 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
6.3.4 
Echocardiogram/MUGAe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
On Cycle 3 Day1, then every 6 weeks 
 
6.3.5.2 
Lung function test (LFT) e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
On Cycle 3 Day 1, then every 6 weeks 
 
6.3.5.3 
PK blood samples 
 
X# 
X 
X 
X 
X 
X 
X# 
X 
X 
X 
X 
X 
 
 
 
Xj 
 
 
6.5.1.1 
Blood sample for ctDNA & 
Biomarkers (optional) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X (C2D1-C6D1 and continuous every 
even cycle D1 until disease 
progression) 
6.6.2.3 
RECIST assessmentsf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
On Cycle 3 Day 1, then every 6 weeks until progression 
6.8.1 
Dose with DZD9008 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
---------X (daily dosing) ------------
 
 
5.1.1 
Concomitant medication 
----------------------------------------------------------------------------------------------------------------
 
4.3.1 
Adverse events g 
----------------------------------------------------------------------------------------------------------------
 
6.4 
#: Multiple time point for PK sampling. Hospitalization can be allowed for out of business time PK collection. 
* Treatment date might be update in light of emerging human PK data 
a. 
±1 day visit window is allowed for C1D8 & D15.  
b. 
All study visits from Cycle 2 Day 1 onwards may be performed within a visit window of ± 2 days. 
c. 
Pregnancy test needs to be within 3 days of the first dosing. 
d. 
HBV/HCV/HIV/COVID-19 tests can be done based on local practice.  
e. 
Echo/MUGA and LFT at baseline needs to be done within 14 days of the first dosing. 
f. 
CT is preferred. Same scan modality is required to use for tumor scan and RECIST assessment from baseline till follow up for one patient. Please refer to Appendix F of 
CSP about the details of RECIST assessment.  
g. 
AE will be collected from first dosing of DZD9008; SAE is required to be collected from inform consent  

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
127 
 
h. 
For C0D1 and C1D1, -1 day window is allowed for laboratory safety testing and physical examination 
i. 
Eye examination includes: Visual acuity, Pupils, Intraocular pressure, External examination, Slit-lamp examination, and Fundoscopic examination (pupil dilate is not 
required) and others if clinically indicated. 
j. 
Pre-dose on Cycle 2 day 1. 
 

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Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
128 
 
Table 13 
Study Plan of Part A Dose Expansion 
Assessment 
Screen 
Cycle 1 
(21 days) 
Cycle 2 (21 days) onwards 
Discontinuation 
28-day 
follow 
up 
Details in 
section 
Day 
-28 to -1 
1 h 
8a 
15a 
1b 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
4.1.1 
Demography & baseline 
characteristics 
X 
 
 
 
 
 
 
6.3.1 
Medical/surgical history 
X 
 
 
 
 
 
 
6.3.1 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
4.1 & 4.2 
Physical examination 
X 
X 
 
 
X 
X 
 
6.3.2 
ECOG performance status 
X 
X 
 
 
X 
X 
 
6.3.2 
Brain MRI or contrast-enhanced CT 
X 
 
 
 
 
 
 
4.1 
Pregnancy test (premenopausal 
females only)c 
X 
 
 
 
 
X 
 
6.3.4 
Ophthalmology assessment i 
X 
 
 
 
 
X 
 
6.3.5.4 
Archival tumor tissue or fresh biopsy 
(mutation confirmation) 
X 
 
 
 
 
 
 
6.6.2 
Vital signs 
X 
X 
X 
X 
X 
X 
 
6.3.3 
Height 
X 
 
 
 
 
 
 
6.3.3 
Weight 
X 
X 
 
 
X 
X 
 
6.3.3 
ECG 
X 
X 
X 
X 
X 
X 
 
6.3.5 
Clinical chemistry/ 
Hematology/Urinalysis 
X 
X 
X 
X 
X 
X 
 
6.3.4 
HBV/HCV/HIV/COVID-19d 
X 
 
 
 
 
 
 
4.2 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
129 
 
Assessment 
Screen 
Cycle 1 
(21 days) 
Cycle 2 (21 days) onwards 
Discontinuation 
28-day 
follow 
up 
Details in 
section 
Day 
-28 to -1 
1 h 
8a 
15a 
1b 
 
 
 
APTT/INR 
X 
X 
X 
X 
X 
X 
 
6.3.4 
Echocardiogram/MUGA e 
X 
----------------On Cycle 3 Day 1, then every 6 weeks  -----------------
 
 
6.3.5.2 
Lung function test (LFT) e 
X 
---------------- On Cycle 3 Day 1, then every 6 weeks -----------------
 
 
6.3.5.3 
PRO-CTCAE and FACIT GP5 
questionsj 
 
X 
X 
X 
Weekly until the end of cycle 6, 
then on day 1 of each cycle 
X 
 
6.9.2 & 6.9.3 
PK blood samples 
 
X# 
X 
X 
X#* 
 
 
6.5.1.2 
Blood sample for ctDNA & 
exploratory Biomarkers (optional) 
X 
X 
X 
X 
X (C2D1-C6D1 and continuous every even cycle D1 until disease 
progression) 
6.6.2 
RECIST assessments f 
X 
----------------On Cycle 3 Day 1, then every 6 weeks ------------------
 
6.8.1 
Dose with DZD9008 
 
----------------X (daily dosing) ------------------
 
 
5.1.2 
Concomitant medication 
-------------------------------------------------------- X --------------------------------------
 
4.3.1 
Adverse events g 
------------------------------------------------------- X ---------------------------------------
 
6.4 
#: multiple time point for PK sampling. Hospitalization can be allowed for out of business time PK collection. 
*: Day 1 of Cycle 2, 3, 4 
a. 
±1-day visit window is allowed for C1D8 & D15.  
b. 
All study visits from Cycle 2 Day 1 onwards may be performed within a visit window of ± 2 days. 
c. 
Pregnancy test needs to be within 7 days of the first dosing. 
d. 
HBV/HCV/HIV/COVID-19 test can be done based on local practice.  
e. 
Echo/MUGA and LFT needs to be done within 14 days of the first dosing. 
f. 
CT is preferred. Same scan modality is required to use for tumor scan and RECIST assessment from baseline till follow up for one patient. Please refer to Appendix F of 
CSP about the details of RECIST assessment.  
g. 
AE will be collected from the first dosing of DZD9008; SAE is required to be collected from inform consent  

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
130 
 
h. 
For C1D1, -1 day window is allowed for laboratory safety testing and physical examination 
i. 
Eye examination includes: Visual acuity, Pupils, Intraocular pressure, External examination, Slit-lamp examination, and Fundoscopic examination (pupil dilate is not 
required) and others if clinically indicated. 
j. 
PRO-CTCAE and FACIT GP5 questionnaire will be collected weekly for the first 18 weeks (to cycle 6), and then on day 1 of each subsequent cycle (expansion cohort 3-
6). 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
131 
 
Table 14 
Study Plan of Part B Dose Extension 
Assessment 
Screen 
Cycle 1 
(21 days) 
Cycle 2 (21 days) 
onwards 
Discontinuation 
28-day follow up 
Details in 
section 
Day 
-28 to -1 
1 h 
8a 
15a 
1b 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
4.1.1 
Demography & baseline 
characteristics 
X 
 
 
 
 
 
 
6.3.1 
Medical/surgical history 
X 
 
 
 
 
 
 
6.3.1 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
4.1 
Physical examination 
X 
X 
 
 
X 
X 
 
6.3.2 
ECOG performance status 
X 
X 
 
 
X 
X 
 
6.3.2 
Brain MRI or contrast enhanced CT 
X 
 
 
 
 
 
 
4.1 
Pregnancy test (premenopausal 
females only) 
X c 
 
 
 
 
X 
 
6.3.4 
Ophthalmology assessment i 
X 
 
 
 
 
X 
 
6.3.5.4 
Archival tumor tissue or fresh biopsy 
(mutation confirmation and/or 
companion diagnostics development)m 
X 
 
 
 
 
 
 
6.6.1 
Vital signs 
X 
X 
X 
X 
X 
X 
 
6.3.3 
Height 
X 
 
 
 
 
 
 
6.3.3 
Weight 
X 
X 
 
 
X 
X 
 
6.3.3 
ECG 
X 
X## 
X 
X 
X## 
X 
 
6.3.5 
Clinical chemistry/ 
Hematology/Urinalysis 
X 
X 
X 
X 
X 
X 
 
6.3.4 
HBV/HCV/HIV/COVID-19d 
X 
 
 
 
 
 
 
4.2 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
132 
 
Assessment 
Screen 
Cycle 1 
(21 days) 
Cycle 2 (21 days) 
onwards 
Discontinuation 
28-day follow up 
Details in 
section 
Day 
-28 to -1 
1 h 
8a 
15a 
1b 
 
 
 
APTT/INR 
X 
X 
X 
X 
X 
X 
 
6.3.4 
Echocardiogram/MUGA e 
X 
----------------On Cycle 3 Day 1, then every 6 weeks  -----------------
 
 
6.3.5.2 
Lung function test (LFT) e 
X 
---------------- On Cycle 3 Day 1, then every 6 weeks -----------------
 
 
6.3.5.3 
EQ-5D-5L 
 
X 
Every 6 weeks relative to first dose 
X 
 
6.9.1 
PRO-CTCAE and FACIT GP5 
questions 
 
X 
X 
X 
Weekly until the 
end of cycle 6, than 
on day 1 of each 
cycle 
X 
 
6.9.2 & 6.9.3 
PK blood samples l 
 
X 
X 
X 
X 
 
 
6.5.1.3 
Paired tumor biopsy (Subject joins PoM 
study only) 
X 
 
 
 
X (C2D1) 
 
 
6.6.2.2 
Plasma sample for the development of 
liquid biopsy companion diagnostic 
X 
 
 
 
 
 
 
6.6.1 
Blood sample for ctDNA & exploratory 
Biomarkers (optional) 
 
X 
X 
X 
X (C2D1-C6D1 and continuous every odd cycle D1 until disease 
progression) 
6.6.2.3 
Blood sample for pharmacogenetics 
(optional) 
 
Xj 
 
 
 
 
 
6.6.3 
RECIST assessments f 
X 
----------------On Cycle 3 Day 1, then every 6 weeks ------------------
 
6.8.1 
Dose with DZD9008 
 
----------------X (daily dosing) ------------------
 
 
5.1.4 
Concomitant medication 
-------------------------------------------------------- X --------------------------------------
 
4.3.1 
Adverse events g 
------------------------------------------------------- X ---------------------------------------
 
6.4 
Survival status k 
------------------------------------------------------- X ---------------------------------------
 
6.3.6.3 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
133 
 
 ##: multiple time points for ECG. Refer to section 6.3.5.1 for details. 
*: Day 1 of Cycle 2, 3, 4 
a. 
±1-day visit window is allowed for C1D8 & D15.  
b. 
All study visits from Cycle 2 Day 1 onwards may be performed within a visit window of ± 2 days. Survival follow up may be performed within a visit window of ± 7 
days. 
c. 
Pregnancy test needs to be within 7 days of the first dosing. For Italy only: additional tests at pre-dose on Day 1 of Cycle 2 and each subsequent cycle, as clinically 
indicated, and during the safety follow-up period (2 weeks ± 3 days after the last dosing). 
d. 
HBV/HCV/HIV/COVID-19 test can be done based on local practice.  
e. 
Echo/MUGA and LFT needs to be done within 14 days of the first dosing. 
f. 
It is suggested that site to conduct the first tumor assessment no earlier than C3D1 (±7days). CT is preferred for extracranial tumor. Same scan modality is required to use 
for tumor scan and RECIST assessment from baseline till follow up for one patient. Please refer to Appendix F of CSP about the details of RECIST assessment.  
g. 
AE will be collected from the first dosing of DZD9008 and SAE is required to be collected from inform consent  
h. 
For C1D1, -1 day window is allowed for laboratory safety testing and physical examination 
i. 
Eye examination includes: Visual acuity, Pupils, Intraocular pressure, External examination, Slit-lamp examination, and Fundoscopic examination (pupil dilate is not 
required) and others if clinically indicated. 
j. 
If for any reason the sample is not drawn prior to first dose (pre-dose at C1D1) it may be taken at any visit until the last study visit. 
k. 
Survival status including anti-cancer therapy will be collected every 6 weeks following disease progression or withdrawal from treatment. 
l. 
Multiple time point for PK sampling on C1D1 and C3D1, details refer to Table 8 and Table 9. Hospitalization can be allowed for out of business time PK collection. If 
there is a dose interruption, dose reduction, or an early termination due to an AE, or there is an SAE, the investigator may choose to collect an unplanned blood sample (if 
possible) within the 24 hour after the last dose. 
m. Adequate amounts of archived tumor tissue or fresh biopsy (if archived tissue is not available) will be collected for Sponsor designated central laboratory confirmation of 
EGFR Exon20ins mutations. If a pre-study written documentation of EGFR Exon20ins in tumor tissue is available from Sponsor designated central laboratory using the 
designated assay, no additional tumor sample needs to be submitted. Requirements of tumor tissue sample collection can be referred to the Laboratory Manual. 
 
 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
134 
 
Table 15 
Lab visits and clinical monitoring (Part A, dose escalation) 
Measurement 
Screening 
C0D1 
C1D1 
C1D8 
C1D15 
C2D1 
C2D8 
C2D15 
C3D1 
C4 & C5 
onwards 
D1 
End of 
treatment 
 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
Hematology 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
 
 
 
 
x 
4ml 
x 
4ml 
x 
4ml 
Clinical chemistry 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
 
 
 
 
x 
4ml 
x 
4ml 
x 
4ml 
APTT/INR 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
 
 
 
 
x 
4ml 
x 
4ml 
x 
4ml 
HBV, HCV, HIV 
screening 
x 
6ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Pregnancy Test 
(Urine) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK Pre 
 
 
x 
4ml 
x 
2ml 
x 
2ml 
x 
2ml 
x 
4ml 
 
 
 
 
x 
2ml 
x 
2ml 
 
 
Plasma PK 0.5h post 
 
 
x 
4ml 
 
 
 
 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
Plasma PK 1h post 
 
 
x 
4ml 
 
 
 
 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
Plasma PK 2hr post 
 
 
x 
4ml 
 
 
 
 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
Plasma PK 3hr post 
 
 
x 
4ml 
 
 
 
 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
Plasma PK 4hr post 
 
 
x 
4ml 
 
 
 
 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
Plasma PK 6hr post 
 
 
x 
4ml 
 
 
 
 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
Plasma PK 8hr post 
 
 
x 
4ml 
 
 
 
 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
Plasma PK 10hr post 
 
 
x 
4ml 
 
 
 
 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
Plasma PK 12hr post 
 
 
x 
4ml 
 
 
 
 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
Plasma PK 24hr post 
 
 
x 
4ml 
 
 
 
 
 
 
x 
4mlc 
 
 
 
 
 
 
 
 
 
 
Plasma PK 48hr post 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 72hr post 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK120hr post 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
135 
 
Measurement 
Screening 
C0D1 
C1D1 
C1D8 
C1D15 
C2D1 
C2D8 
C2D15 
C3D1 
C4 & C5 
onwards 
D1 
End of 
treatment 
 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
Plasma PK168hr post 
 
 
x 
4ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine PK 
 
 
 
 
 
 
 
 
 
 
x d 
 
 
 
 
 
 
 
 
 
 
 
4- -
hydroxycholesterol / 
total cholesterol 
 
 
x 
6ml 
x 
6ml 
x 
6ml 
x 
6ml 
x 
6ml 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
ctDNA & 
Exploratory 
Biomarker 
x 
10ml 
x 
10ml 
x 
10ml 
x 
10ml 
x 
10ml 
x 
10ml 
 
 
 
 
x 10ml (C3-C6 D1 and continuous every 
even cycle D1 afterwards)b 
BP/HR  
x 
 
x a 
 
x a 
 
x a 
 
x a 
 
x 
 
 
 
 
 
x 
 
x 
 
x 
 
ECG 
x 
 
x a 
 
x a 
 
x a 
 
x a 
 
x 
 
 
 
 
 
x 
 
x 
 
x 
 
a: time point: pre-dose, 1, 2, 4, 6, 10, 24 hours post dose. The 24 
 point falls on the 2nd day. 
b: detailed time points see Section 6.6 
c: 24hr post dosing should be collected before dosing on C2D2 
d: The interval for urine collection on cycle 2 day 1 are 0-4, 4-12, and 12-24 hours. Next dosing on C2D2 should be given after the urine collection.  
 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
136 
 
Table 16 
Lab visits and clinical monitoring (Part A dose expansion) 
Parameters 
Screening 
C1D1 
C1D8 
C1D15 
C2D1 
C3D1 
C4 onwards 
D1 
End of 
treatment 
 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
Hematology 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
Clinical chemistry,  
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
APTT/INR 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
x 
4ml 
HBV, HCV, HIV screening 
x 
6ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Pregnancy Test (Urine) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK Pre 
 
 
x 
2ml 
x 
2ml 
x 
2ml 
x 
2ml 
x 
2ml 
x 
2ml (only 
C4) 
 
 
Plasma PK 0.5hr Post 
 
 
x 
2ml 
 
 
 
 
x 
2ml 
 
 
 
 
 
 
Plasma PK 1hr Post 
 
 
x 
2ml 
 
 
 
 
x 
2ml 
 
 
 
 
 
 
Plasma PK 2hr Post 
 
 
x 
2ml 
 
 
 
 
x 
2ml 
 
 
 
 
 
 
Plasma PK 3hr Post 
 
 
x 
2ml 
 
 
 
 
x 
2ml 
 
 
 
 
 
 
Plasma PK 4hr Post 
 
 
x 
2ml 
 
 
 
 
x 
2ml 
 
 
 
 
 
 
Plasma PK 6hr Post 
 
 
x 
2ml 
 
 
 
 
x 
2ml 
 
 
 
 
 
 
Plasma PK 8hr Post 
 
 
x 
2ml 
 
 
 
 
x 
2ml 
 
 
 
 
 
 
Plasma PK 10hr Post 
 
 
x 
2ml 
 
 
 
 
x 
2ml 
 
 
 
 
 
 
Plasma PK 12hr Post 
 
 
x 
2ml 
 
 
 
 
x 
2ml 
 
 
 
 
 
 
Plasma PK 24hr Post 
 
 
x 
2mlb 
 
 
 
 
x 
2mlc 
 
 
 
 
 
 
Blood sample for ctDNA & Exploratory Biomarker 
x 
10ml 
x pre-
dose 
10ml 
x 
10ml 
x 
10ml 
x 
10ml 
x 10ml (C3-C6 D1 and continuous every even 
cycle D1 afterwards)a 
BP/HR 
x 
 
x d 
 
x d 
 
x d 
 
x 
 
x 
 
x 
 
x 
 
ECG 
x 
 
x d 
 
x d 
 
x d 
 
x 
 
x 
 
x 
 
x 
 
a: detailed time points see Section 6.6 
b: 24hr post dosing should be collected before dosing on C1D2 
c: 24hr post dosing should be collected before dosing on C2D2 
d: time points: pre-dose, 1, 2, 4, 6, 10, 24 hours post dose. 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
137 
 
Table 17 
Lab visits and clinical monitoring (Part A, food effect) 
 
 
Cycle 0 
Cycle 1 
Cycle 2 & onward 
 
Scree
ning 
D1 
D2 
D3 
D4 
D6 
D8 
D9 
D10 
D11 
D12 
D14 
D16 
C1D1 
C1D8 
C1D15 
C2D1 
C3D1 
and 
onward 
End of 
study 
Plasma PK Pre 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
2 ml 
 
 
Plasma PK 0.5hr post 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 1hr post 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 2hr post 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 3hr post 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 4hr post 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 6hr post 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 8hr post 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 10hr post 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 12hr post 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 24hr post 
 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
 
Plasma PK 48hr post 
 
 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
 
Plasma PK 72hr post 
 
 
 
 
2ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
 
Plasma PK 120hr post 
 
 
 
 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
 
Plasma PK 168hr post 
 
 
 
 
 
 
2 ml 
 
 
 
 
 
2 ml 
 
 
 
 
 
 
Pregnancy test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
4 ml 
4 ml 
 
 
 
 
 
 
 
 
 
 
 
4 ml 
 
 
4 ml 
4 ml 
4 ml 
Clinical chemistry 
4 ml 
4 ml 
 
 
 
 
 
 
 
 
 
 
 
4 ml 
 
 
4 ml 
4 ml 
4 ml 
Blood sample for 
ctDNA & Exploratory 
Biomarker 
10ml 
10ml 
 
 
 
 
 
 
 
 
 
 
 
10ml 
10ml 
10ml 
× 10ml (C2-C6 D1 and 
continuous every even cycle 
D1 afterwards)b 
BP/HR 
 
xa 
xa 
 
 
 
 
xa 
xa 
 
 
 
 
xa 
xa 
xa 
x 
x 
x 
ECG 
 
xa 
xa 
 
 
 
 
xa 
xa 
 
 
 
 
xa 
xa 
xa 
x 
x 
x 
HBV/HCV/HIV 
6 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
138 
 
 
 
Cycle 0 
Cycle 1 
Cycle 2 & onward 
 
Scree
ning 
D1 
D2 
D3 
D4 
D6 
D8 
D9 
D10 
D11 
D12 
D14 
D16 
C1D1 
C1D8 
C1D15 
C2D1 
C3D1 
and 
onward 
End of 
study 
APTT/INR 
4 ml 
4 ml 
 
 
 
 
 
 
 
 
 
 
 
4 ml 
 
 
4 ml 
4 ml 
4 ml 
a: time point: pre-dose, 1, 2, 4, 6, 10, 24 hours post dose. The 24hour time point falls on the 2nd day. 
b. detailed time points see Section 6.6 
 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
139 
 
Table 18 
Lab visits and clinical monitoring (Part B dose extension) 
Parameters 
Screening 
C1D1 
C1D8 
C1D15 
C2D1 
C3 D1 
C4 onwards 
D1 
End of 
treatment 
 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
 
Blood 
Vol. 
Hematology 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
Clinical chemistry,  
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
APTT/INR 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
x  
4ml 
HBV, HCV, HIV, COVID-19 screening 
x  
6ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x  
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Pregnancy Test (Serum/ Urine) 
x d 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Plasma PK Pre 
 
 
x 
2ml# 
x 
2ml# 
x 
2ml# 
x 
2ml# 
x 
2ml# 
x 
2ml# 
(C5, C7, 
C9 and 
C11) 
 
 
Plasma PK 1hr Post 
 
 
x  
2ml* 
 
 
 
 
 
 
x  
2ml* 
 
 
 
 
Plasma PK 2hr Post 
 
 
x  
2ml* 
 
 
 
 
 
 
x  
2ml* 
 
 
 
 
Plasma PK 3hr Post 
 
 
x  
2ml* 
 
 
 
 
 
 
x  
2ml* 
 
 
 
 
Plasma PK 4hr Post 
 
 
x  
2ml# 
 
 
 
 
 
 
x  
2ml# 
 
 
 
 
Plasma PK 6hr Post 
 
 
x  
2ml* 
 
 
 
 
 
 
x  
2ml* 
 
 
 
 
Plasma PK 8hr Post 
 
 
x  
2ml# 
 
 
 
 
 
 
x  
2ml# 
 
 
 
 
Plasma PK 24hr Post 
 
 
x  
2ml* 
 
 
 
 
 
 
x  
2ml* 
 
 
 
 
Blood sample for the development of liquid biopsy 
companion diagnostic  
x 
20ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for pharmacogenetics (optional) 
 
 
x 
(pre-
dose) 
5ml 
 
 
 
 
 
 
 
 
 
Blood sample for ctDNA & Exploratory Biomarker 
(optional) 
 
 
x 
(pre-
dose) 
10ml 
x 
10ml 
x 
10ml 
x 
10ml 
x 10ml (C3-C6 D1 and 
continuous every odd cycle D1 
afterwards)a 
 
 
BP/HR 
x 
 
x 
 
x 
 
x  
 
x  
 
x 
 
x  
 
x  
 
ECG 
xc 
 
xb 
 
x 
 
x  
 
x  
 
x b 
 
x  
 
x  
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
140 
 
#: PK sample collection for both sparse and intense PK group* PK sample collection for intense PK group only. 
a. detailed time points see section 6.6 
b. multiple time for ECG. Details refer to section 6.3.5 
c: multiple time point (pre- and 2, 4, 6, 8 hr post) for ECG of intense PK cohort. pre-dose ECG for sparse PK cohort. Details description refer to section 6.3.5. 
d: pregnancy testing needs to be performed within 7 days of the first dosing, For Italy only: additional tests at pre-dose on Day 1 of Cycle 2 and each subsequent cycle, as 
clinically indicated, and during the safety follow-up period (2 weeks ± 3 days after the last dosing).  
 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
141 
 
Appendix A 
SIGNATURE 
INVESTIGATOR STATEMENT 
Principal investigator Signature 
Protocol Number: DZ2019E0001 
Protocol title: A Phase I/II, Open-Label, Multicenter Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Anti-tumor Efficacy of DZD9008 in Patients with Advanced Non-Small 
Cell Lung Cancer (NSCLC) with EGFR or HER2 mutation. 
 
I understand that all information concerning DZD9008 in connection with this study and not 
previously published is confidential. This confi
Brochure, Clinical Study Protocol, Case Report Form, clinical methodology, and basic scientific 
data. 
I will not initiate this study without approval from the Institutional Review Board/Ethics 
Committee and I understand that any changes in the protocol must be approved in writing by 
Dizal (Jiangsu) Pharmaceutical Co., Ltd and the Institutional Review Board/Ethics Committee 
before they can be implemented, except when necessary to eliminate immediate hazards to the 
subjects. 
By my signature below, I attest that I have read, understand, and agree to abide by all the 
conditions, instructions, and restrictions contained in Protocol Number DZ2019E0001, and will 
conduct the trial in accordance with Good Clinical Practice (GCP) and applicable regulatory 
requirements.   
 
 
 
 
 
Principal investigator/Signature 
 
Date 
 
 
 
Principal investigator/Printed Name 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
142 
 
Appendix B 
FURTHER GUIDANCE ON THE DEFINITION OF A 
SERIOUS ADVERSE EVENT (SAE) 
Life threatening 
-
(AE) as it occurred or it is suspected that use or continued use of the product would result in the 
-
at had an AE occurred in a more severe form 
it might have caused death (e.g., hepatitis that resolved without hepatic failure). 
Hospitalization 
Out-patient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement should be used. 
Examples of such events are: 
 Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
 Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
 Intensive treatment in an emergency room or at home for allergic bronchospasm 
 Blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
 Development of drug dependency or drug abuse. 
A guide to interpreting the causality QUESTION 
that an AE may have been caused by the drug. 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
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 Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug? 
 Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
 Dechallenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
 No alternative cause.  The AE cannot be reasonably explained by another etiology such 
as the underlying disease, other drugs, other host or environmental factors. 
 Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped?   
 Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship? 
ore of these 
factors exist. 
usality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of the 
AE. 
In difficult cases, other factors could be considered such as: 
 Is this a recognized feature of overdose of the drug? 
 Is there a known mechanism? 
relationship unless further evidence becomes available to refute this.  Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility. 
 
 

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Appendix C 
INTERNATIONAL AIRLINE TRANSPORTATION 
ASSOCIATION (IATA) 6.2 GUIDANCE DOCUMENT 
Labelling and Shipment of Biohazard Samples  
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories. For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B or Exempt. There is 
no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are e.g., Ebola, Lassa fever virus 
are to be packed and shipped in accordance with IATA Instruction 602 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2. They are assigned the following UN 
number and proper shipping name: 
 
UN 3373  Biological Substance, Category B 
 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
 
Clinical trial samples will fall into Category B or exempt under IATA regulations. 
 
Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging. 
 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content. 
 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable. 
 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used. 
 

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Appendix D 
ETHICAL AND REGULATORY REQUIREMENTS 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the International Conference on Harmonisation 
(ICH)/Good Clinical Practice (GCP) guidelines, applicable regulatory requirements and the 
Dizal policy on Bioethics and Human Biological Samples. 
Ethics and regulatory review 
An Ethics Committee should approve the final Clinical Study Protocol, including the final 
version of the Informed Consent Form and any other written information and/or materials to be 
provided to the patients.  This will include approval of the exploratory biomarker and 
pharmacogenetic research and associated consent(s) forms. The investigator/The Head of the 
study site will ensure the distribution of these documents to the applicable Ethics Committee, 
and to the study site staff. In Japan, the head of the study site will ensure the distribution of 
these documents to the applicable IRB, and the Principal Investigator to the Investigator and 
study site staff. 
The opinion of the Ethics Committee should be given in writing. The investigator should submit 
the written approval to Dizal before enrolment of any patient into the study. In Japan, the Head 
of the study site should submit a notification of direction/determination as well as the 
Institutional Review Board (IRB) written approval to Dizal. If applicable this approval should 
clearly state that the exploratory biomarker and pharmacogenetic research is approved.  
The Ethics Committee should approve all advertising used to recruit patients for the study. 
Dizal should approve any modifications to the Informed Consent Form that are needed to meet 
local requirements. 
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually. 
In Japan, the Head of the study site should seek the opinion of the IRB with respect to the 
appropriateness of continuing the study at the study site at least once a year when the duration 
of the study exceeds one year. The Principal Investigator should submit progress reports to the 
IRB via the Head of the study site at the time of the protocol re-approval.  
Before enrolment of any patient into the study, the final Clinical Study Protocol, including the 
final version of the Informed Consent Form, is approved by the national regulatory authority or 
a notification to the national regulatory authority is done, according to local regulations. 
Dizal will handle the distribution of any of these documents to the national regulatory 
authorities. 
Dizal will provide Regulatory Authorities, Ethics Committees and Principal Investigators (in 
Japan, also the Head of the study site) with safety updates/reports according to local 
requirements, including SUSARs (Suspected Unexpected Serious Adverse Reactions), where 
relevant. 

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Each Principal Investigator is responsible for providing the Ethics Committees/Institutional 
Review Board (IRB) with reports of any serious and unexpected adverse drug reactions from 
any other study conducted with the investigational product. Dizal will provide this information 
to the Principal Investigator so that he/she can meet these reporting requirements. In Japan, the 
Head of the study site should submit a written report to the IRB providing the details of all 
safety relative information reported by Dizal. 
Informed consent 
Any incentives for patients who participate in the study as well as any provisions for patients 
harmed as a consequence of study participation should be described in the informed consent 
form that is approved by an Ethics Committee. 
The Principal Investigator at each center will: 
 Ensure that each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study and the optional exploratory 
biomarker and genetic research component(s) 
 Ensure that each patient is notified that they are free to withdraw from the study or the 
research components at any time 
 Ensure that each patient is given the opportunity to ask questions and allowed time to 
consider the information provided 
 Ensure each patient provides signed and dated informed consent before conducting any 
procedure specifically for the study 
 Ensure each original, signed Informed Consent Form 
Study File/medical records 
 Ensure a copy of each signed Informed Consent Form is given to the patient 
The exploratory biomarker and genetic research component(s) of this study are voluntary, and 
the patient may participate in the main study without participating in the exploratory biomarker 
and/or genetic research part(s) of the study. To participate in the exploratory biomarker and/or 
genetic component of the study the patient should sign and date the consent form for the main 
study and as applicable separate consent forms for the exploratory biomarker and/or the genetic 
components of the study. 
Changes to the protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and Dizal Pharmaceuticals. 
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a Clinical Study Protocol Amendment and where required in a new version of 
the protocol (Revised Protocol). 

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The amendment should be approved by each Ethics Committee and if applicable, also the 
national regulatory authority, before implementation. Local requirements should be followed 
for Revised Protocols. 
Dizal will distribute any subsequent amendments and new versions of the protocol to each 
Principal Investigator.  For distribution to Ethics Committee see Section 2.2. 
If a protocol amendment requires a change to a 
 Informed Consent Form, Dizal and the 
 Ethics Committee should approve the revised Informed Consent Form before the 
revised form is used.  
If local regulations require, any administrative change will be communicated to or approved by 
each Ethics Committee. 
In Japan, study procedures will not be changed without the mutual agreement of the Principal 
Investigator and Dizal. If it is necessary for the study protocol to be amended, the amendment 
should be submitted to the Head of the study site and be approved by its IRB. If applicable, 
Dizal should submit a notification to the regulatory authority before it is implemented. If a 
protocol amendment requires a change to a study site's Informed Consent Form, then Dizal and 
the 
 IRB should be notified by the Principal Investigator. Approval of the revised 
Informed Consent Form by Dizal and by the IRB is required before the revised form is used.  If 
an administrative change is required, such a change should be notified to or approved by each 
IRB according to local requirements. 
Audits and inspections 
Authorized representatives of Dizal, a regulatory authority, or an Ethics Committee may 
perform audits or inspections at the center, including source data verification.  The purpose of 
an audit or inspection is to systematically and independently examine all study-related activities 
and documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonisation (ICH), and any applicable 
regulatory requirements.  The investigator will contact Dizal immediately if contacted by a 
regulatory agency about an inspection at the center. 
 

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Appendix E 
PATIENT DATA PROTECTION 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a separate 
document incorporating) wording that complies with relevant data protection and privacy 
legislation.  
Due to the exploratory nature of the biomarker and genetic research, there will be no routine 
communication of these results to patients. Dizal will not provide individual results to patients, 
any insurance company, any employer, their family members, general physician or any other 
third party, unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a patient.  For example, in the case of a 
also have access to his or her genetic data. Also, regulatory authorities may require access to 
the relevant files, t
physically separate.  
Pre-study activities 
Before the first patient is entered into the study, it is necessary for a representative of Dizal to 
visit the investigational study site to: 
 Determine the adequacy of the facilities 
 Determine availability of appropriate patients for the study 
 Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of Dizal or its 
representatives.  This will be documented in a Clinical Study Agreement between Dizal 
and the investigator 
Training of study site personnel 
Before the first patient is entered into the study, a Dizal representative will visit the study site 
to review and discuss the requirements of the Clinical Study Protocol and related documents 
with the investigational staff and also to train them in any study specific procedures including 
collection of samples and the WBDC system utilized. The additional requirements for the 
be clarified. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of the staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all staff members involved in the study 
(medical, nursing and other staff). 

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Source data 
Refer to the Clinical Study Agreement for location of source data. 
Monitoring of the study 
During the study, a Dizal representative will have regular contacts with the study sites, including 
visits to: 
 Provide information and support to the investigator(s) 
 Confirm that facilities remain acceptable 
 Confirm that the investigational team is adhering to the protocol including the specific 
requirements of the biomarker and genetic research, that data are being accurately and 
timely recorded in the CRFs, and that investigational product accountability checks are 
being performed 
 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of the Informed Consent Form(s)of participating patients.  This 
will require direct access to all original records for each patient (e.g., clinic charts) 
 If applicable, ensure withdrawal of informed consent to the use of 
biological samples is reported and biological samples are identified and disposed 
of/destroyed accordingly, and the action is documented, and reported to the patient 
The Dizal representative will be available between visits if the investigator(s) or other staff at 
the center needs information and advice about the study conduct. 
Data management by Dizal /delegate  
Data management will be performed by the CRO Data Management team. 
Data entered in the WBDC system or data captured electronically will be immediately saved to 
the applicable database and changes tracked to provide an audit trail.   
The data collected through third party sources will be obtained and reconciled against study 
data. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA). Medications 
will be classified according to the latest version of WHODrug. All coding will be performed by 
the Medical Coding Team at the CRO Data Management team. 
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the study 
database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan. Quality control procedures 
will be applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly. 

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When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment-revealing data may thereafter be added, and the final database will be locked. 
Genotype data generated in this study will be stored in the appropriate secure system, separate 
from the database used for the main study. 
Some or all of the clinical datasets from the main study may be merged with the genetic data in 
a suitable secure environment separate from the clinical database. The results from this genetic 
research will be reported separately from the Clinical Study Report for the main study.  
Study agreements 
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
Clinical Study Protocol shall prevail with respect to the conduct of the study and the treatment 
of patients and in all other respects, the terms of the Clinical study Agreement shall prevail. 
Specific reference to requirements relating to this optional biomarker and genetic research will 
be included in the study agreement(s). 
Agreements between Dizal and the Principal Investigator should be in place before any study-
related procedures can take place, or patients be enrolled. 
Archiving of study documents 
The investigator follows the principles outlined in the Clinical Study Agreement. 
End of study 
The end of the study is defined as the last visit of the last patient undergoing the study. 
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow. Dizal may also 
terminate the entire study prematurely if concerns for safety arise within this study or in any 
other study with DZD9008. 
 

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Appendix F 
GUIDELINE FOR EVALUATION OF OBJECTIVE 
TUMOR RESPONSE USING RECIST 1.1 (RESPONSE 
EVALUATION CRITERIA IN SOLID TUMORS) 
Introduction 
This appendix details the implementation of RECIST (Response Evaluation Criteria in Solid 
Tumors) 1.1 guidelines (Eisenhauer et al 2009) for the study with regards to investigator 
assessment of tumor burden including protocol-specific requirements for this study. 
Definition of measurable, non-measurable, target and non-target lesions 
Patients with at least one lesion measurable that can be accurately assessed at baseline by 
computerized tomography (CT), magnetic resonance imaging (MRI) or plain X-ray should be 
included in this study. 
Measurable lesions 
At least one lesion, not previously irradiated, that can be accurately measured at baselin
10 
with computered tomograpghy (CT) or magnetic resonance imaging (MRI) which is suitable 
for accurate repeated measurements. 
Non-measurable lesions 
 All other lesions, including small lesions (longest diameter < 10 mm or pathological 
ith < 10 mm 
short axis are considered non-pathological and should not be recorded as non-target 
lesions (NTLs) 
 Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural / pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that are not measurable by CT or MRI 
 Previously irradiated lesions as localized post-radiation changes, which affect lesion 
sizes, may occur.  Therefore, lesions that have been previously irradiated will not be 
considered measurable and should be selected as NTLs at baseline and followed up as 
part of the NTL assessment 
 Skin lesions assessed by clinical examination 
 Brain metastasis 
Special cases 
 Lytic bone lesions or mixed lytic blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. Blastic lesions are considered non-measurable. 

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 Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in 
the same patient, these non-cystic lesions should be selected as the target lesions (TLs). 
Target lesions 
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline. 
Non-target lesions 
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. 
Methods of measurement 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
The methods to be used for RECIST assessment are summarized in Table 19 and those excluded 
for tumor assessments in this study are discussed below, with the rationale provided. 
Table 19 
Summary of Methods of Assessment 
Target Lesions 
Non target lesions 
New Lesions 
CT (preferred) 
MRI 
 
CT (preferred) 
MRI 
Clinical examination  
X-ray, chest X-ray 
CT (preferred) 
MRI 
Clinical examination 
X-ray, chest X-ray 
Ultrasound 
Bone scan 
FDG-PET 
 
CT and MRI  
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TLs selected for response assessment and to assess NTLs and identification 
of new lesions. 
In this study it is recommended that CT examinations of the chest and abdomen will be used to 
assess tumor burden at baseline and follow-up visits.  CT examination with intravenous contrast 
media administration is the preferred method.  MRI should be used where CT is not feasible, or 
it is medically contra-indicated.  For assessment of brain lesions MRI is the preferred method. 
Clinical examination  
Clinical examination will not be used for assessment of TLs. Clinically detected lesions can be 
selected as TLs if they are then assessed by CT or MRI scans.  Clinical examination can be used 

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to assess NTLs in patients that also have other lesions assessable by CT, MRI or plain X-ray 
and to identify the presence of new lesions. 
X-rays 
Plain X-ray 
Plain X-rays may be used as a method of assessment for bone NTLs and to identify the presence 
of new bone lesions.  
Chest X-ray 
Chest X-rays will not be used for assessment of TLs as they will be assessed by CT or MRI 
examination.  Chest X-rays can, however, be used to assess NTLs and to identify the presence 
of new lesions. 
Ultrasound  
Ultrasound examination will not be used for assessment of TLs and NTLs as it is not a 
reproducible method, does not provide an accurate assessment of tumor size and it is subjective 
and operator dependent. Ultrasound examination can, however, be used to identify the presence 
of new lesions.  If new clinical symptoms occur and an ultrasound is performed then new lesions 
should be confirmed by CT or MRI examination. 
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated in 
the context of tumor measurements. 
Tumor markers  
Tumor markers will not be used for tumor response assessments per RECIST 1.1. 
Cytology and histology  
Histology will not be used as part of the tumor response assessment per RECIST 1.1.  
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment is required when the measurable tumor has met criteria for response or stable disease.  
In such circumstances, the cytology is necessary to differentiate between response / stable 
disease (an effusion may be a side effect of the treatment) and progressive disease (if the 
neoplastic origin of the fluid is confirmed).  Where cytology findings are not available, any 
effusion that significantly worsens (from trace to large) or the appearance of a clinically 
significant effusion (requiring change in drug therapy) during the study treatment will be 
considered to be progression of NTLs or disease progression due to new lesions. 
Isotopic bone scan  
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or X-
ray at baseline should be recorded as NTLs and followed by the same method as per baseline 
assessment. 
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits.  New lesions will be recorded where a positive hot-spot that 

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was not present on the baseline bone scan assessment is identified on a bone scan performed at 
any time during the study.  The Investigator should consider the positive hot-spot to be a 
significant new site of malignant disease and represent true disease progression in order to 
record the new lesion.  Confirmation by CT, MRI and x-ray is recommended where bone scan 
findings are equivocal. 
FDG-PET scan  
FDG-PET (fluorodeoxyglucose positron emission tomography) scans may be used as a method 
for identifying new lesions, according with the following algorithm: New lesions will be 
recorded where there is positive FDG uptake (defined as when an uptake greater than twice that 
of the surrounding tissue is observed) not present on baseline FDG-PET scan or in a location 
corresponding to a new lesion on CT/MRI at the same follow-up visit.  If there is no baseline 
FDG-PET scan available, and no evidence of new lesions on CT/MRI scans then follow-up 
CT/MRI assessments should be continued, scheduled as per protocol or clinical indicated, in 
order to confirm new lesions. 
Tumor response evaluation  
Schedule of evaluation 
CT examinations of the chest and abdomen (including liver adrenal glands) will be used to 
assess tumor burden at baseline and follow-up visits.  CT examination with intravenous contract 
media administration is the preferred method.  MRI should be used where CT is no feasible or 
it is medically contra-indicated. 
Baseline tumor assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients and should be performed no more than 28 
days before the start of study treatment. Follow-up assessments should be performed every 6 
weeks (± 7 days) after the start of treatment until discontinuation of study treatment or 
withdrawal of consent.  Any other sites at which new disease is suspected should also be 
adequately imaged at follow-up. Following the 24 month DCO, tumor assessment will be 
performed in accordance with clinical practice with the exception of those in the Phase I first 
line expansion cohort.  For the Phase I first line expansion cohort RECIST 1.1 assessments will 
continue every 12 weeks (± 7 days) until disease progression.   
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments as their scheduled visits.  This schedule 
is to be followed in order to minimize any unintentional bias caused by some patients being 
assessed at different frequency than other patients. 
Target lesions 
Documentation of target lesions 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes), representative of all lesions involved, should be identified as TLs at baseline.  Target 
lesions should be selected on the basis of their size (longest diameter for non-nodal lesions or 
short axis for nodal lesions) but in addition should be those that lend themselves to reproducible 

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repeated measurements.  It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion, which can be 
measured reproducibly, should be selected. 
The site and location of each TL should be documented as well as the longest diameter for non-
nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimeters.  At baseline, the sum of the diameters for all TLs will be calculated and reported 
as the baseline sum of diameters.  At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.   
Special cases: 
 For TLs measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis.  
 If the CT/MRI slice thickness used is > 5mm, the minimum size of measurable disease 
at baseline should be twice the slice thickness of the baseline scan. 
 If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm. 
 If a TL splits into two or more parts, then record the sum of the diameters of those parts 
 If two or more TLs merge then the sum of the diameters of the combined lesion should 
be recorded for one of the lesions and 0 mm recorded for the other lesion(s) 
 If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned.  If an accurate measure can be given, this should be 
recorded, even if it is below 5mm. 
 If a TL cannot be measured accurately due to it being too large, provide an estimate of 
the size of the lesion 
 When a TL has had any intervention e.g., radiotherapy, embolization, surgery etc., 
during the study, the size of the TL should still be provided where possible 
Evaluation of target lesions 
Table 20 provides the definitions of the criteria used to determine objective tumor visit response 
for TLs. 
Table 20 
Overall Visit Response for Target Lesions 
Complete Response (CR) 
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to < 10 
mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of TLs, taking as 
reference the baseline sum of diameters. 

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Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at 
least 5mm. 
Not Evaluable (NE) 
Only relevant if any of the TLs were not assessed or not evaluable or 
had a lesion intervention at this visit. 
Note: If the sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL response 
Non-Target lesions 
Evaluation of non-target lesions 
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.  Measurements are not required for these lesions but their status should be followed at 
subsequent visits.  At each visit, an overall assessment of the NTL response should be recorded 
by the investigator. Table 21 provides the definitions of the criteria used to determine and record 
overall response for NTLs at the investigational site at each visit. 
Table 21 
Overall Visit Response for Non-Target Lesions 
Complete Response (CR) 
Disappearance of all NTLs since baseline.  All lymph nodes must be 
non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more NTLs. 
Progressive Disease (PD) 
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases the progression MUST 
clinically significant for the physician to consider changing or 
stopping therapy. 
Not Evaluable (NE) 
Only relevant when one or some of the NTLs were not assessed and 
evaluable overall NTL assessment at this visit. 
Note: For patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression criteria 
have not been met. 
 
NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 
 one or more NTLs is usually not sufficient to qualify for unequivocal 
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New Lesions 
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
The finding of a new lesion should be unequivocal: i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor. 
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of the 
initial scan. 
Symptomatic deterioration 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for stopping 
study therapy. 
objective evidence of disease progression at that time should continue to undergo RECIST 1.1 
assessments according to the clinical study protocol until objective disease progression is 
observed. 
Evaluation of Overall Visit Response 
The overall visit response will be derived using the algorithm shown in Table 22. 
Table 22 
Overall Visit Response 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
CR 
Non-CR/Non PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non PD or NE 
No 
PR 
SD  
Non PD or NE 
No 
SD 
NA 
Non CR/Non PD 
No 
SD (Non CR/non PD) 
NE 
Non-PD or NE 
No 
NE 
NA 
NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease 

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IR = incomplete response, NE = not evaluable, NA = not applicable (relevant when no NTLs at baseline) 
 
Specifications for radiological imaging 
These notes are recommendations for use in clinical studies.  The use of standardized protocols 
for CT and MRI allows comparability both within and between different studies, irrespective of 
where the examination has been undertaken. 
CT Scan 
CT scans of chest and abdomen (including liver and adrenal glands) should be contiguous 
throughout all the anatomical regions of interest. 
The most critical CT image acquisition parameters for optimal tumor evaluation using RECIST 
1.1 are anatomic coverage, contrast administration, slice thickness, and reconstruction interval. 
Anatomic coverage 
Optimal anatomic coverage for most solid tumors is the chest, abdomen and pelvis.  Coverage 
should encompass all areas of known predilection for metastases in the disease under evaluation 
and should additionally investigate areas that may be involved based on signs and symptoms of 
individual patients.  Because a lesion later identified in a body part not scanned at baseline 
would be considered as a new lesion representing disease progression, careful consideration 
should be given to the extent of imaging coverage at baseline and at subsequent follow-up time 
points.  This will enable better consistency not only of tumor measurements but also 
identification of new disease. 
Intravenous contrast administration 
Optimal visualization and measurement of metastases in solid tumors requires consistent 
administration (dose and rate) of intravenous contrast as well as timing of scanning.  Typically, 
most abdominal imaging is performed during the portal venous phase and (optimally) about the 
same time frame after injection on each examination.  An adequate volume of a suitable contrast 
agent should be given so that the metastases are demonstrated to best effect and a consistent 
method is used on subsequent examinations for any given patient.  It is very important that the 
same technique be used at baseline and on follow- up examinations for a given patient.  For 
patients who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) should be 
performed should also be based on the tumor type, anatomic location of the disease and should 
be optimized to allow for comparison to the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward.  Care must 
be taken in measurement of TLs on a different modality and interpretation of non-target disease 
or new lesions, since the same lesion may appear to have a different size using a new modality.  
Oral contrast is recommended to help visualize and differentiate structures in the abdomen. 
If iodine contrast media is medically contraindicated at baseline or at any time during the course 
of the study, then the recommended methods are: CT thoracic examination without contrast and 
abdominal and pelvic MRI with contrast.  If MRI cannot be performed then CT without 

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intravenous contrast is an option for the thorax, abdomen and pelvic examinations.  For 
assessment of brain lesions MRI is the preferred method. 
Slice thickness and reconstruction material 
It is recommended that CT scans be performed at 5mm contiguous slice thickness, and this 
guideline presumes a minimum 5 mm thickness in recommendations for the measurable lesion 
definition.  Exceptionally, particular institutions may perform medically acceptable scans at 
slice thicknesses greater than 5 mm.  If this occurs, the minimum size of measurable lesions at 
baseline should be twice the slice thickness of the baseline scans. 
All window settings should be included in the assessment, particularly in the thorax where lung 
and soft tissue windows should be considered.  When measuring lesions, the TLs should be 
measured on the same window setting for repeated examinations throughout the study.  All 
of the apparent lesion. 
MRI Scan 
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement.  Furthermore, the availability of MRI is variable globally.  The modality used 
at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  Generally, axial imaging of the abdomen and 
pelvis with T1 and T2 weighted imaging along with gadolinium-enhanced imaging should be 
performed.  The field of view, matrix, number of excitations, phase encode steps, use of fat 
suppression and fast sequences should be optimized for the specific body part being imaged as 
well as the scanner utilized.  It is beyond the scope of this appendix to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts and diseases.  Ideally, the same type of 
scanner should be used, and the image acquisition protocol should be followed as closely as 
possible to prior scans.  Body scans should be performed with breath-hold scanning techniques 
if possible. 
For these reasons, CT is the imaging modality of choice. 
FDG-PET scans 
FDG-PET has gained acceptance as a valuable tool for detecting, staging and restaging several 
malignancies.  If FDG-PET scans are included in a protocol, an FDG uptake period of 60 min 
prior to imaging has been decided as the most appropriate for imaging of patients with 
malignancy.  Whole-body acquisition is important since this allows for sampling of all areas of 
interest and can assess if new lesions have appeared thus determining the possibility of interval 
progression of disease.  Images from the base of the skull to the level of the mid-thigh should 
be obtained 60 min post injection.  PET camera specifications are variable and manufacturer 
specific, so every attempt should be made to use the same scanner, or the same model scanner, 
for serial scans on the same patient.  Whole-body acquisitions can be performed in either 2- or 
3-dimensional mode with attenuation correction, but the method chosen should be consistent 
across all patients and serial scans in the clinical trial. 

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PET/CT scans 
At present, low dose or attenuation correction CT portions of a combined PET CT are of limited 
use in anatomically based efficacy assessments, and it is therefore suggested that they should 
not be substituted for dedicated diagnostic contrast enhanced CT scans for tumor measurements 
by RECIST 1.1.  In exceptional situations, if a site can document that the CT performed as part 
of a PET CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) 
then the CT portion of the PET CT can be used for RECIST measurements.  However, this is 
not recommended because the PET portion of the CT introduces additional data that may bias 
an investigator if it is not routinely or serially performed. 
REFERENCES 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J.  
New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1).  
European Journal of Cancer.  45 (2009) 228-247. 
 
 

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Appendix G 
ACTIONS REQUIRED IN CASE OF COMBINED 
INCREASE OF AMINOTRANSFERASE AND TOTAL 
BILIRUBIN-
 LAW 
Introduction 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets potential 
tudy. 
The Investigator participates, together with Dizal clinical project representatives, in review and 
HL) criteria are met.  HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product 
(IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
Definitions 
(PHL) 
 x Upper Limit of 
Normal (ULN) and 
 x ULN at any point during the study irrespective 
of an increase in Alkaline Phosphatase (ALP).  
 
AST or AL
 x ULN and 
 x ULN, where no other reason, other than the IMP, can 
be found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral 
hepatitis, another drug.  
Identification of potential H
 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in isolation 
or in combination: 
 
 ULN 
 
 ULN 
 
 ULN 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
 Notify the Dizal representative 

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 Determine whether the patient meets PHL criteria (see Section Definitions of this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
 Promptly enter the laboratory data into the laboratory CRF 
Follow-up 
met 
If the patient does not meet PHL criteria the Investigator will: 
 Inform the Dizal representative or delegate that subject has not met PHL criteria. 
 Perform follow-up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol. 
P
 
If the patient does meet PHL criteria the Investigator will: 
 Determine whether PHL criteria were met at any study visit prior to starting study 
treatment in the presence of liver metastases (See Section Actions required when 
po
) 
 Notify the Dizal representative who will then inform the central Study Team  
 The Study Physician contacts the Investigator, to provide guidance, discuss and agree 
-up and the continuous review of data.  
Subsequent to this contact the Investigator will: 
 Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated  
 Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician 
 Complete the three Liver CRF Modules as information becomes available  
 If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
Review and Assessment of potential H
 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP.  The 
Dizal Medical Science Director and Global Safety Physician will also be involved in this review 
together with other subject matter experts as appropriate. 

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According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
 If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
 If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the standard processes 
 If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
 
 
 
hould be used if no other serious criteria 
apply 
 
should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
 
ty 
assessment as per above 
 Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review 
Actions required when po
treatment  
This section is applicable to patients who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit prior to starting study treatment.  
At the first on study treatment occurrence of PHL criteria being, even if there has been no 
# compared with pre-study treatment visits, the 
Investigator will: 
 Notify the Dizal representative who will inform the central Study Team.  

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 Follow the subsequent process described is Section P
 of 
this Appendix. 
#  
 to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or 
in combination, or a clinically relevant change in associated symptoms.  The determination 
of whether there has been a significant change will be at the discretion of the Investigator, 
this may be in consultation with the Study Physician if there is any uncertainty. 
law 
This section is applicable when a patient meets PHL criteria on study treatment and has already 
met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
 
Was the alternative cause for the previous occurrence of PHL criteria being met 
chronic or progressing malignant disease or did the patient meet PHL criteria prior to 
starting study treatment and at their first on study treatment visit as described in 
Section Actions required when po
starting study treatment? 
If No: follow the process described in Section P
 of this Appendix. 
If Yes: 
Determine if there has been a significant change in the p
# compared with when 
PHL criteria were previously met 
 
If there is no significant change no action is required 
 
If there is a significant change follow the process described in Section P
Law Criteria met of this Appendix 
#  
liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a clinically 
relevant change in associated symptoms.  The determination of whether there has been a significant change 
will be at the discretion of the Investigator, this may be in consultation with the Study Physician if there is 
any uncertainty. 
References 
FDA G
-induced liver injury: Premarketing 
 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf. 
 

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Appendix H 
GUIDANCE REGARDING POTENTIAL INTERACTIONS 
WITH CONCOMITANT MEDICATIONS 
aged but use 
of these products (e.g., herbal supplement), as well as use of all vitamins, nutritional 
supplements, and all other concomitant medications must be recorded in the eCRF. 
DZD9008 is an investigational drug for which no data on in vivo drug-drug interactions (DDI) 
are currently available. In vitro data have shown that the principal CYP enzymes responsible 
for the Phase I metabolism of DZD9008 are CYP 3A4/5, and glutathione conjugation may be 
alternative pathway for DZD9008 metabolism.  
In vitro DZD9008 showed either no inhibition or a low level reversible inhibition of CYPs 1A2, 
2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 activity. DDI risk is considered low with these 
CYP enzymes, although the risk of a clinical interaction via inhibition CYP2D6 and intestinal 
CYP3A4 cannot be excluded at clinically relevant exposure. 
There was not time dependent inhibition observed for DZD9008 in vitro with CYPs 1A2, 2C9 
and 2C19. Time dependent inhibition was observed for CYP2D6 only at 50 µM and CYP3A4/5 
at both 10 and 50 µM, however at clinically relevant exposure of DZD9008 the risk of a 
clinically meaningful drug interaction arising from CYP3A4/5 inhibition is minimal. 
DZD9008 was shown to be an inhibitor of the active efflux transport protein P-gp and BCRP. 
It has also been determined to be an inhibitor of the active uptake transport mediated by 
OATP1B1. A clinical meaningful interaction with both intestinal P-gp, BCRP and OATP1B1 
transporter cannot be excluded. 
Restrictions regarding drug affecting CYP3A4 metabolism  
CYP3A4/5 is considered to be the predominant metabolic pathway, thus modulation of 
CYP3A4/5 activity may increase or decrease exposure to DZD9008, respectively. In clinical 
DDI study, when co-administered with multiple doses of strong CYP3A4 inhibitor itraconazole, 
DZD9008 Cmax and AUC increase by 32% and 51%, respectively. DZD9008 Cmax and AUC 
decrease by 38% and 48%, respectively, when co-administered with multiple doses of strong 
CYP3A4 inducer carbamazepine.   
Strong inhibitors and strong inducers of CYP3A4/5 should not be combined with DZD9008. 
Moderate inhibitors and inducers of CYP3A4/5 are permitted but caution should be exercised, 
and patients monitored closely for possibly drug interactions. Strong inhibitors or inducers of 
CYP3A4 should be stopped at least 1 week for inhibitors or 2 weeks for inducers before the 
first dose of DZD9008 (Table 23 & Table 24). 
These lists are not intended to be exhaustive, and a similar restriction will apply to other agents 
that are known to strongly modulate CYP3A4 activity. Appropriate medical judgment is 
required. Please contact Dizal with any queries you have on this issue. 
If the investigator feels that concomitant administration of medications or herbal supplements 
that strongly modulate CYP3A4/5 is essential during the trial, DZD9008 treatment should be 
discontinued. 

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Table 23 
Drugs that are strong inhibitors of CYP3A4 
Contraindicated drugs  
Withdrawal period prior to DZD9008 start 
Boceprevir, clarithromycin, conivaptan, 
1 week 
grapefruit juice*, indinavir, itraconazole, 
ketoconazole, lopinavir/RIT, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin,  
Voriconazole, elvitegravir/RIT, fluconazole 
* 
Double-strength grapefruit juice 
* 
Patients should abstain from eating large amounts of grapefruit and Seville oranges (and other products 
containing these fruits e.g., grapefruit juices or marmalade) during the study 
 
Table 24 
Drugs that are strong inducers of CYP3A4 
Contraindicated drugs  
Withdrawal period prior to DZD9008 start 
Avasimibe, Carbamazepine, phenobarbital, 
phenytoin, Rifampicin, rifabutin, rifapentin 
, Phenobarbitone 
2 weeks 
 
Drugs whose exposure may be affected by DZD9008 that Dizal considers may be allowed 
with caution, see Table 25. 
In vitro data shows that DZD9008 is a weak inhibitor of CYP3A4/5, DZD9008 has the potential 
to increase the exposure of CYP3A4/5 substrate whose absorptive process is restricted by 
CYP3A4/5 metabolism in the intestine which includes some of the statins. 
DZD9008 induces CYP3A4 and 2C8 but not CYP1A2, 2B6, 2C9 and 2C19 isoforms in vitro in 
human primary hepatocytes. The exposure of co-medications where disposition is dependent on 
CYP3A4, or CYP2C8 isoforms and P-gp which may also be induced, may be reduced when co-
administrated with DZD9008. 
CYP2C8 and P-gp substrate 
Sensitive CYP2C8 and P-gp substrate with narrow therapeutic range are permitted but caution 
should be exercised, and patients monitored closely for possible drug interactions. 
CYP3A4 substrate and P-gp and/or BCRP substrates 
In vitro data suggests DZD9008 has the potential to cause drug interactions at the intestinal 
level through CYP3A4. It has also been shown that there is a potential for a DDI when dosed 
with sensitive substrates of P-gp, BCRP or OATP1B1. DDI was predicted following more 
conservative approaches recommended by EMA and PMDA. Although a potential interaction 
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predicted values are close to cut-off and therefore DDI risks with these transporter substrates 
are considered to be low. Table 25 outlines some of the drugs that are sensitive substrates of 
CYP3A4, CYP2C8, P-gp, BCRP, OATP1B1/3, MATE1 and MATE2 K. This list is not 
intended to be exhaustive, and a similar restriction will apply to other agents that are known to 
depend on CYP3A4 and/or transporter proteins for disposition and/or metabolism. Appropriate 
medical judgement is required. Please contact Dizal with any queries you have on this issue. 
Patients taking concomitant medications such as statins whose disposition is dependent upon 
Breast Cancer Resistance Protein (BCRP) and which have a narrow therapeutic index should 
be closely monitored for signs of changed tolerability as a result of increased exposure of the 
concomitant medication whilst receiving DZD9008. If the patient experiences any potentially 
relevant AEs suggestive of muscle toxicity including unexplained muscle pain, tenderness or 
weakness, particularly if accompanied by malaise or fever, statins must be stopped, and any 
appropriate further management should be taken  
Table 25 
Exposure, pharmacological action and toxicity may be increased or 
decreased by DZD9008 
Warning of possible interaction 
Advice 
CYP3A4 substrate: alfentanil, 
cyclosporine, dihydroergotamine, 
ergotamine, everolimus, fentanyl, 
pimozide, quinidine, sirolimus and 
tacrolimus 
Drugs are permitted but caution should be exercised, and 
patients monitored closely for possible drug interactions. 
Please refer to full prescribing information for all drugs prior 
to co-administration with DZD9008. 
CYP2D6 substrate: Pimozide, 
thioridazine 
CYP2C8 substrate: Repaglinide 
P-gp substrate: Digoxin 
Monitor for increased digoxin concentrations if increase in 
intolerability is observed due to increased systemic exposure. 
Monitor for adverse reactions if concomitant use of 
DZD9008 with other P-gp substrates with a narrow 
therapeutic index cannot be avoided 
BCRP substrate: Methotrexate, 
topotecan, or irinotecan, rosuvastatin, 
sulfasalazine 
Drugs are permitted but caution should be exercised, and 
patients monitored closely for possible drug interactions.  
Please refer to full prescribing information for all drugs prior 
to co-administration with DZD9008. 
MATE1 and MATE2-K substrate: 
metformin  
OATP1B1/3: atorvastatin, pitavastatin, 
pravastatin, simvastatin acid 
Drugs that may prolong QT interval 
The drugs listed in this section are taken from information provided by The Arizona Center for 
Education and Research on Therapeutics and The Critical Path Institute, Tucson, Arizona and 
Rockville, Maryland. Ref: https://crediblemeds.org/. 
Drugs known to prolong QT interval 

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The following drugs are known to prolong QT interval or induce Torsades de Pointes and should 
not be combined with DZD9008.  Recommended withdrawal periods following cessation of 
treatment with these agents are provided in Table 26 & Table 27. 
Table 26 
Drugs prolonging QT interval 
Contraindicated drug  
Withdrawal period prior to DZD9008 start 
Clarithromycin, droperidol, erythromycin, 
procainamide 
2 days 
Cisapride, disopyramide, dofetilide, domperidone, 
ibutilide, quinidine, sotalol, sparfloxacin, 
thioridazine 
7 days 
Bepridil, chlorpromazine, halofantrine, 
haloperidol, mesoridazine 
14 days 
Levomethadyl, methadone, pimozide 
4 weeks 
Arsenic trioxide   
6 weeks* 
Pentamidine 
8 weeks 
Amiodarone, chloroquine 
1 year 
* 
Estimated value as pharmacokinetics of arsenic trioxide has not been studied 
Drugs that may possibly prolong QT interval 
The use of the following drugs is permitted (notwithstanding other exclusions and restrictions) 
provided the patient has been stable on therapy for the periods indicated. 
Table 27 
Drugs that may prolong QT interval  
Drug 
Minimum treatment period on 
medication prior to DZD9008 
start 
Alfuzosin, chloral hydrate, ciprofloxacin, dolasetron, foscarnet, 
galantamine, gemifloxacin, isridipine, ketoconazole, levofloxacin, 
mexiletine, nicardipine, octreotide, ofloxacin, ondansetron, 
quetiapine, ranolazine, telithromycin, tizanidine, vardenafil, 
venlafaxine, ziprasidone 
2 days 
Amantadine, amitriptyline, amoxapine, clozapine, doxepin, 
felbamate, flecainide, fluconazole, fosphenytoin, gatifloxacin, 
granisetron, imipramine, indapamide, lithium, moexipril/HCTZ, 
moxifloxacin, risperidone, roxithromycin, sertraline, trimethoprim-
sulfa, trimipramine, voriconazole 
7 days 
Azithromycin, citalopram, clomipramine, itraconazole, 
nortriptyline, paroxetine, solifenacin, tacrolimus 
14 days 
Fluoxetine  
5 weeks 
Protriptyline 
6 weeks 

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Drug 
Minimum treatment period on 
medication prior to DZD9008 
start 
Tamoxifen 
8 weeks 
Restriction regarding drugs may affect DZD9008 absorption 
DZD9008 exhibited pH-dependent solubility, thus the absorption may be affected by altered 
intragastric pH. When intragastric pH is elevated, DZD9008 GI solubility, bioavailability and 
eventually treatment efficacy may be influenced. To avoid reduced oral absorption of DZD9008 
and safeguard optimal DZD9008 therapy, intake of gastric acid suppressive agents relative to 
DZD9008 treatment is suggested to be managed (Table 28). 
Table 28 
Gastric acid suppressive agents that may affect DZD9008 exposure 
Type of gastric acid suppressive agents 
Dosage management relative to DZD9008 
administration 
Proton pump inhibitors 
PPIs should be avoided. 
H2- antagonists 
DZD9008 should be taken at least 2 h before or 10 
h after the H2- antagonist intake. 
Antacids 
DZD9008 should be administrated at least 2 h 
before or 2 h after antacid intake. 
 
 
 

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Appendix I 
GUIDANCE FOR THE SAFETY MONITORING AND 
MANAGEMENT OF ADVERSE EVENTS 
Introduction 
DZD9008 is an oral, potent, selective and irreversible EGFR tyrosine kinase inhibitor (TKI) 
targeting EGFR sensitizing mutations, T790M resistance mutation, EGFR Exon20ins and 
uncommon mutations as well as HER2 Exon20ins. It is intended for the treatment of advanced 
non-small cell lung cancer (NSCLC) patients with EGFR or HER2 mutation as monotherapy. 
Whilst there is no clinical experience with DZD9008, preclinical studies suggest a potential 
association between the use of DZD9008 and adverse events of skin, gastro-intestinal tract, 
liver, lung, eyes etc. been observed. When the appropriate treatment of these events is instituted, 
they can be tolerable, allowing patients to continue receiving treatment. 
The purpose of these treatment guidelines is: 
 To prevent tolerable adverse events becoming intolerable for the patient and leading to 
discontinuation of treatment. 
 To promote consistency of monitoring and treatment for specific adverse events across 
DZD9008 clinical development program. 
 
ILD/Pneumonitis Assessments Flow Chart 
 
 
 
 

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Diarrhea Treatment Guidance 
An association between the use of EGFR inhibitor and the occurrence of diarrhea has been 
observed, as a result, Dizal has chosen to include the following in the clinical study during using 
with DZD9008. 
 
 
 Dietetic measures: 
 
Stop all lactose-containing products 
 
Drink 8 to 10 large glasses of clear liquids per day 
 
Eat frequent small meals 
 
Recommend low fat regimen enriched with rice, bananas, and apple sauce 
 Pharmacological treatment 
 
Administer loperamide: initial dose 4 mg, followed by 2 mg every 4 hours or after 
every unformed stool. 
 
Grade 1 intermittent diarrhea may not require treatment 
 
Consider continuous of loperamide until diarrhea-free for 12 hours 
 
Consider electrolyte replacement, as appropriate 
CTCAE (V5
neutropenia): 
 
Dietetic measures: 
 
 
 
Pharmacological treatment: 
 
 
 
If dehydration is severe, administer octreotide and use intravenous fluids as 
appropriate 
 
Consider prophylactic antibiotics, especially if diarrhea is persistent beyond 24 
hours or there is fever or grade 3-4 neutropenia 
 
Consider electrolyte replacement, as appropriate, and consider more frequent 
measurement of electrolyte until AE resolves 
Skin effects- Rashes & Acnes 
An association between the use of EGFR inhibitor and the occurrence of skin adverse events 
has been observed. As a result, Dizal has chosen to include the following in the clinical study 
when DZD9008 is used: 
 
Patients should be informed that skin reactions are not contagious or not result from 
allergy to treatment. 
 
Patients should be encouraged to report any instance of skin reaction as soon as they 
arise so that appropriate treatment can be promptly initiated. 
 
Patients should be instructed to contact the site if a skin reaction changes (e.g., if is 
spreads or becomes painful). 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
172 
 
 
Any occurrence of a skin event should be recorded as an Adverse Event b completing 
the AE CRF, and the severity captured using the CTCAE (v5) grading system. 
 
Sponsor will be reviewing dermatological adverse events on an ongoing basis and may 
ask for additional information to be provided.  
 
Treatment administered should be recorded. 
 
It may be beneficial to avoid irritating skin products (e.g., irritating soaps, products 
containing retinol or retinoic acid). Use of topical benzoyl peroxides and other irritating 
anti-acne agents should be avoided. 
 
Camouflage make-up (non-comedogenic or non-pore blocking) can be used during 
study treatment. 
 
Patients may consider applying over-the-counter moisturizing cream to face, hands and 
feet twice daily from the start of study. 
 
Investigators may consider issuing a prescription for topical treatment to patients. 
However, topical steroids and topical or oral antibiotics should not be implemented 
prophylactically, and treatment should only be started when confirmed with Investigator. 
 
As soon as an acneiform/papulopustular rash occurs, treatment with moderate strength 
topical steroids and antibiotics should be implemented. 
 
The occurrence of non-papulopustular skin reactions should be treated appropriately, as 
defined by the treating physician, and in consultation with a dermatologist where 
necessary. 
 
 
 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
173 
 
Skin effects- Rash Treatment Guidance 
 
  
 CTCAE (v5) Grade 1 
 <10% body surface area (BSA) 
papules/pustules 
 With or without symptoms of pruritus 
or tenderness 
Emollient cream application 
and/or 
Topical steroid moderate strength bid 
and/or 
CTCAE (v5) Grade 2 
 10 to 30% BSA papules/pustules with 
or without symptoms of pruritus or 
tenderness 
 Psychosocial impact 
 Limiting instrumental activities of 
daily living (ADL) 
Treatment same as Grade 1 
 
Consider using oral antibiotic for 6 weeks 
CTCAE (v5) Grade 3 
 > 30% BSA papules/pustules with or 
without symptoms of pruritus or 
tenderness 
 Limited self-care ADL 
 Associated with local superinfection 
Topical steroid moderate strength bid  
and 
Oral antibiotics for 6 weeks 
Switch to broad spectrum/gram negative 
cover if infection suspected (yellow crusts, 
purulent discharge, painful skin/nares) 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
174 
 
Skin effect-- Dry Skin/ Xerosis Treatment Guidance 
 
  
 CTCAE (v5) Grade 1
 Mild or localized 
 Topical intervention indicated 
 Topical steroid moderate strength bid or 
topical antipruritic bid 
CTCAE (v5) Grade 2 
 Intense or widespread 
 Intermittent 
 Skin changes from scratching (e.g., 
oedema, 
papulation, 
excoriation, 
lichenification, oozing/crusts) 
 Oral intervention indicated  
Limited instrumental ADL
 Topical steroid moderate strength bid or 
topical antipruritic bid  
 Oral antihistamine 
CTCAE (v5) Grade 3 
 Intense or widespread 
 Limiting self-care ADL or sleep  
 Oral 
corticosteroid 
or 
immunosuppressive therapy indicated 
 Oral antihistamine 
 GABA agonist (gabapentin 300mg or 
pregabalin 50-75 mg every 8 hours) 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
175 
 
Skin effect-- Paronychia Treatment Guidance 
 
  
 CTCAE (v5) Grade 1
 Nail fold oedema or erythema 
 Disruption of the cuticle 
 Topical antibiotic bid and vinegar soaks# 
CTCAE (v5) Grade 2 
 Localized intervention indicated 
 Nail fold oedema or erythema with 
pain  
 Associated with discharge or nail 
plate separation 
 Limiting instrumental activities of 
daily living (ADL)
 Topical antibiotic bid and vinegar soaks # 
 Topical silver nitrate weekly 
CTCAE (v5) Grade 3
 Surgical intervention or IV antibiotics 
indicated 
 Limiting self-care ADL 
 Topical antibiotics bid and vinegar soaks # 
 Topical silver nitrate weekly 
 Consider nail avulsion/ removal 
# Soaking fingers or toes in a 1:1 solution of white vinegar in water for 15 minutes every 
day 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
176 
 
Ophthalmic assessments 
The ophthalmic adverse events were observed in the preclinical safety assessment of DZD9008. 
As a result, Dizal has chosen to include the following in the clinical study when DZD9008.  
 
Full ophthalmological assessments at baseline for all patients. 
 
Follow-up assessments for those patients reporting any clinically significant and/or 
persistent ophthalmic symptom. 
The purpose of these guidelines is to: 
 
Provide guidance on when to perform follow-up ophthalmic assessments 
 
Promote consistency of assessment across the study. 
Some key points for Ophthalmic Guidance 
 
It is important that patients are fully informed that ophthalmic event may occur during 
treatment with DZD9008. 
 
DZD9008 should not be administered on the first scheduled day if the patient has any 
clinically significant eye symptoms. 
 
Patients should be encouraged to report any instance of ophthalmic symptoms and/or 
vision changes to allow the appropriate treatment to be initiated. Symptoms may 
include: 
o Burning/ itching/ irritation/ smarting 
o Redness with / without discharge 
o Blurred vision 
o Light sensitivity 
 
Patients who wear contact lenses must discontinue wearing them if they have any mild 
 2) until at least one week after symptoms 
have been resolved. 
 
Only after agreement with the investigator, patients may use eye drops or ointment for 
treatment of eye symptoms. 
 
If a patient has a recurrence of eye symptoms or experiences any severe (CTCAE grade 
 3) ocular events they must discontinue wearing their contact lenses until at least one 
week after treatment with DZD9008 is permanently discontinued. 
 
Ulcerative events must result in permanent discontinuation from study. 
 
(For France and Canada only: 
or eye symptoms that are clinically significant and/or persistent (>7 
days) should be referred to the ophthalmologist. For example: 
o Deterioration in near or distant visual activity by more than one level  
o Persistence or worsening of: 
 Burning/irritation/smarting 
 Itching 
 Redness with or without discharge 
 Light sensitivity (photophobia) 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
177 
 
 Blurred vision 
 
Ophthalmology examination findings sh
reported to Dizal team if required. 
Baseline assessment 
 
Full ophthalmological assessment, including slit lamp examination performed by an 
ophthalmologist (or appropriately qualified individual) 
 
Date of assessment should be recorded on the CRF  
 
 
Follow-up assessment 
 
If the patient reports any eye symptoms during treatment with DZD9008 or if signs are 
observed during a study visit, the investigator should perform a clinical examination 
including a repeat best corrected near and distant visual acuity assessment if appropriate 
 
Eye drops or ointment for treatment of eye symptoms may be used, ONLY after it is 
agreed with a study doctor. 
 
Findings and treatment should be d
 
Post-baseline Ophthalmic assessment 
 
Any clinically significant post-baseline ophthalmic findings, including those confirmed 
by the ophthalmologist, must be recorded as an Adverse Events by completing the AE 
module, and the severity captured using CTCAE 5.0 grading system. 
 
In addition, a report should be provided to Dizal detailing: 
o Ophthalmic examination performed 
o Findings 
 
Treatment administered should be captured on the CRF. 
 
 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
178 
 
Ophthalmic Assessment Flow Chart 
 
 
Full ophthalmological assessment including slit lamp 
examination performed by ophthalmologist or appropriately 
qualified individual using site standard methodology
Patient-reported eye symptoms or eye signs 
Investigator to perform clinical examination as appropriate 
 
 3 or 
Clinically significant adverse event 
CTCAE grade < 3 or  
Finding is not clinically significant  
Monitor for up to 7 days  
Initiate treatment as appropriate
Referral to Ophthalmologist 
As clinically appropriate, possible follow-
up assessment may include: 
 
Slit lamp-/+ fluorescein 
 
Amsler grid; fundoscopy 
 
Sch
-
up time 
Findings to be documented in patient 
notes  
Confirmation of findings may trigger dose 
adjustments as agreed with study 
physician or SRC review board 
Symptom worsening or persistence 
for >7 days 
 
Burning/ irritation/ smarting 
 
Itching 
 
Blurred vision 
 
Light sensitivity 
 
Redness with or without 
discharge 
 
Reduced visual acuity 
Refer to ophthalmologist
All eyes symptoms should be reported as an Adverse Event
Baseline 
Follow-up 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
179 
 
Guidance on Ophthalmic Dose Adjustments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 
OR 
Clinically significant or persistent (present for > 7 days) Adverse Event and considered 
causally related to DZD9008 
Initiate ophthalmic treatment as appropriate and withhold DZD9008 dose for up to 3 
weeks 
 
DZD9008 at the current dose maintaining treatment as appropriate 
 
 
If adverse event improves to CTCAE Grade 2 within 3 weeks reinstate DZD9008 
at a reduced dose, maintaining treatment as appropriate 
 
 
 3 or clinically significant or persistent adverse event does 
not improve to a lower CTCAE Grade within 3 weeks of DZD9008 interruption, 
DZD9008 should be permanently discontinued. 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
180 
 
Appendix J 
Patient Reported Outcomes (Selected PRO-CTCAE items, FACIT item GP5 and 5Q-5D-
5L) 
Selected PRO-CTCAE items 
As individuals go through treatment for their cancer, they sometimes experience different symptoms and side effects. For each 
question, please check or mark an X in the one box that best describes your experiences over the past 7 days. 
Rash 
a. In the last 7 days, did you have any RASH? 
      Yes 
      No 
 
Skin dryness 
a. In the last 7 days, what was the SEVERITY of your DRY SKIN at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
 
Acne 
a. In the last 7 days, what was the SEVERITY of your ACNE OR PIMPLES ON THE FACE OR CHEST at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
 
Itching 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
181 
 
a. In the last 7 days, what was the SEVERITY of your ITCHY SKIN at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
 
Nail loss 
a. In the last 7 days, did you LOSE ANY FINGERNAILS OR TOENAILS? 
      Yes 
      No 
 
Nail ridging 
a. In the last 7 days, did you have any RIDGES OR BUMPS ON YOUR FINGERNAILS OR TOENAILS? 
      Yes 
      No 
 
Nail discoloration 
a. In the last 7 days, did you have any CHANGE IN THE COLOR OF YOUR FINGERNAILS OR TOENAILS? 
      Yes 
      No 
 
Decreased appetite 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
182 
 
a. In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
b. In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual or daily activities? 
        Not at all 
         A little bit 
        Somewhat 
        Quite a bit 
        Very much 
 
Nausea 
a. In the last 7 days, how OFTEN did you have NAUSEA? 
        Never 
       Rarely 
       Occasionally 
       Frequently 
      Almost constantly 
b. In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
        None 
       Mild 
        Moderate 
        Severe 
       Very severe 
 
Vomiting 
a. In the last 7 days, how OFTEN did you have VOMITING? 
        Never 
         Rarely 
        Occasionally 
        Frequently 
        Almost constantly 
b. In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
183 
 
Diarrhea 
a. In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS (DIARRHEA/DIARRHOEA)? 
        Never 
         Rarely 
        Occasionally 
        Frequently 
        Almost constantly 
 
Constipation 
a. In the last 7 days, what was the SEVERITY of your CONSTIPATION at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
 
Abdominal pain 
a. In the last 7 days, how OFTEN did you have PAIN IN THE ABDOMEN (BELLY AREA)? 
        Never 
         Rarely 
        Occasionally 
        Frequently 
        Almost constantly 
b. In the last 7 days, what was the SEVERITY of your PAIN IN THE ABDOMEN (BELLY AREA) at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
c. In the last 7 days, how much did PAIN IN THE ABDOMEN (BELLY AREA) INTERFERE with your usual or daily activities? 
        Not at all 
         A little bit 
        Somewhat 
        Quite a bit 
        Very much 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
184 
 
Mouth/throat sores 
a. In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at their WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
b. In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your usual or daily activities? 
        Not at all 
         A little bit 
        Somewhat 
        Quite a bit 
        Very much 
 
Cracking at the corners of the mouth (cheilosis/cheilitis) 
a. In the last 7 days, what was the SEVERITY of SKIN CRACKING AT THE CORNERS OF YOUR MOUTH at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
 
Bloating 
a. In the last 7 days, how OFTEN did you have BLOATING OF THE ABDOMEN (BELLY)? 
        Never 
         Rarely 
        Occasionally 
        Frequently 
        Almost constantly 
b. In the last 7 days, what was the SEVERITY of your BLOATING OF THE ABDOMEN (BELLY) at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
185 
 
Fatigue 
a. In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF ENERGY at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
b. In the last 7 days, how much did FATIGUE INTERFERE with your usual or daily activities? 
        Not at all 
         A little bit 
        Somewhat 
        Quite a bit 
        Very much 
 
Blurred vision 
a. In the last 7 days, what was the SEVERITY of your BLURRY VISION at its WORST? 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 
b. In the last 7 days, how much did BLURRY VISION INTERFERE with your usual or daily activities? 
        Not at all 
         A little bit 
        Somewhat 
        Quite a bit 
        Very much 
 
Nosebleed 
a. In the last 7 days, how OFTEN did you have NOSEBLEEDS 
        Never 
         Rarely 
        Occasionally 
        Frequently 
        Almost constantly 
b. In the last 7 days, what was the SEVERITY of your NOSEBLEEDS at their WORST? 

Clinical Study Protocol
Drug Substance: DZD9008 
Protocol No.: DZ2019E0001 
Edition Number: 12.0 
Date: July 24,2023 
 
186 
 
        None 
         Mild 
        Moderate 
        Severe 
        Very severe 

Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
187 
 
FACIT-Item GP5 (Version 4) 
Functional Assessment of Cancer Therapy - Item GP5 
Item GP5 from the FACIT Measurement System 
 
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
 
              I am bothered by side effects of treatment
  
 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
0 
1 
2 
3 
4 
 
 
 
GP5 

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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
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Clinical Study Protocol 
Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
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Drug Substance: DZD9008
Protocol No.: DZ2019E0001
Edition Number: 12.0
Date: July 24,2023
 
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