Clinical trial NCT02513563
Conditions: Lung Cancer
Keywords: Squamous cell lung cancer
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2015-10-13; Completion date: 2023-11-28
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out what effects (good and bad) AZD1775 used in combination with carboplatin and paclitaxel will have on participants and their cancer.

Detailed description:

Arms: arm 1: Treatment: Combination of AZD1775 plus carboplatin and paclitaxel. Participants will be treated with this combination of drugs twice daily on days 1 and 2 and once on day 3 for a total of 5 doses during each 21 day cycle of treatment.
Interventions: intervention 1: Carboplatin intervention 2: Paclitaxel intervention 3: AZD1775
Intervention descriptions: intervention 1: Participants will be treated with carboplatin (area under the curve 5 (AUC5) will be used to determine the dosage) twice daily, days 1 and 2 and once a day on day 3 (5 doses) during each 21 day cycle of treatment. intervention 2: Participants will be treated with paclitaxel 175 mg/m\^2 twice daily, days 1 and 2 and once a day on day 3 (5 doses) during each 21 day cycle of treatment. intervention 3: Participants will receive AZD1775 225 mg twice daily, days 1 and 2 and once a day on day 3 (5 doses) during each 21 day cycle of treatment.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
A Phase II Trial of AZD1775 Plus Carboplatin-Paclitaxel in Squamous Cell Lung 
Cancer 
 
 
NCT02513563 
 
 
Version 6 
April 8, 2020  


1(64) 
 
 
Drug Substance 
AZD1775 
MCC Study 
Number 
18304 
Version Number 
6  
Date 
April 8, 2020  
A Phase II Trial of AZD1775 Plus Carboplatin- 
Paclitaxel in Squamous Cell Lung Cancer 
Sponsor: Moffitt Cancer Center 
PI: Jhanelle Gray, MD 


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Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE .............................................................................................................. 1 
TABLE OF CONTENTS ............................................................................................ 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................... 5 
1. 
INTRODUCTION ........................................................................................ 7 
1.1 
Background ...................................................................................... 7 
1.2 
Research hypothesis...................................................................... 14 
1.3 
Rationale for conducting this study ................................................ 14 
2. 
STUDY OBJECTIVES .............................................................................. 15 
2.1 
Primary objective ............................................................................ 15 
2.2 
Secondary objectives ..................................................................... 15 
2.3 
Exploratory objectives .................................................................... 15 
3. 
STUDY PLAN AND PROCEDURES......................................................... 16 
3.1 
Overall study design and flow chart ............................................... 16 
4. 
SUBJECT SELECTION CRITERIA .......................................................... 18 
4.1 
Inclusion criteria ............................................................................. 18 
4.2 
Exclusion criteria ............................................................................ 21 
5. 
STUDY CONDUCT ................................................................................... 23 
5.1 
Subject enrollment and initiation of investigational product ............ 23 
5.2 
Procedures for handling subjects incorrectly enrolled .................... 23 
5.3 
Treatments ..................................................................................... 23 
5.4 
Concomitant and post-study treatment(s) ...................................... 25 
5.5 
Dose Modifications ......................................................................... 26 
5.6 
Treatment compliance .................................................................... 31 
5.7 
Discontinuation of investigational product ...................................... 31 
5.8 
Withdrawal from study .................................................................... 32 
6. 
COLLECTION OF STUDY VARIABLES ................................................... 32 
6.1 
Recording of data ........................................................................... 32 
6.2 
Data collection at enrollment and follow-up .................................... 32 
6.3 
Efficacy .......................................................................................... 33 


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Drug Substance AZD1775 
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Edition Number 6  
Date: April 8, 2020  
6.4 
Safety ............................................................................................. 39 
 
 
6.5 
Instructions for Rapid Notification of Serious Adverse Events ........ 42 
7. 
DATA SAFETY MONITORING PLAN ....................................................... 45 
7.1 
Data Monitoring Board ................................................................... 45 
7.2 
Scientific Review Committee (SRC 
) 
46 
7.3 
PI Responsibility............................................................................. 46 
7.4 
Protocol Monitoring Committee (PMC) ........................................... 47 
7.5 
Research Compliance Division (RCD) ........................................... 47 
7.6 
The Institutional Review Board (IRB) ............................................. 47 
7.7 
Suspension/Termination................................................................. 48 
7.8 
Trial Discontinuation ....................................................................... 48 
7.9 
Monitoring of the Study and Regulatory Compliance ...................... 48 
7.10 
Protocol Modifications .................................................................... 49 
7.11 
Patient Privacy ............................................................................... 49 
7.12 
Records Retention ......................................................................... 49 
8. 
BIOLOGICAL SAMPLING PROCEDURES............................................... 49 
8.1 
Pharmacodynamics ........................................................................ 49 
8.2 
Handling, storage and destruction of biological samples ................ 50 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ......... 51 
9.1 
Description of analysis sets............................................................ 51 
9.2 
Methods of statistical analyses ....................................................... 51 
10. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY 
THE INVESTIGATOR ............................................................................... 52 
10.1 
Overdose ....................................................................................... 52 
10.2 
Pregnancy ...................................................................................... 53 
11. 
ADMINISTRATIVE PROCEDURES .......................................................... 53 
11.1 
Regulatory and Ethical Compliance ............................................... 53 
11.2 
Responsibilities of the Investigator and IRB/IEC/REB .................... 53 
11.3 
Informed Consent ........................................................................... 53 
11.4 
Optional Biopsy Consent ................................................................ 53 
11.5 
Amendments to the Protocol .......................................................... 54 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
11.6 
Monitoring ...................................................................................... 54 
11.7 
Study Drug Supply and Resupply, Storage, and 
Tracking/Drug Accountability ......................................................... 54 
12. 
PROTOCOL ADHERENCE ...................................................................... 55 
12.1 
Investigators ascertain they will apply due diligence to avoid 
protocol deviations ......................................................................... 55 
12.2 
Disclosure and Confidentiality ........................................................ 55 
13. 
ETHICS AND GOOD CLINICAL PRACTICE ............................................ 55 
14. 
LIST OF REFERENCES ........................................................................... 55 
15. 
APPENDIX A: DISALLOWED MEDICATIONS AND MEDICATIONS 
TO BE ADMINISTERED WITH CAUTION ................................................ 58 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this Clinical Study Protocol. 
 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APP 
Advanced Practice Provider 
AST 
Apartate Aminotransferase 
ASCO 
American Society of Clinical Oncology 
AUC 
Area Under the Curve 
BID 
Twice Daily 
BOR 
Best Confirmed Objective Response 
BRCT 
BRCA1 C Terminal 
CDK 
Cyclin-Dependent Kinases 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Cat Scan 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDR 
DNA Damage Response 
DLT 
Dose Limiting Toxicity 
ECOG 
Eastern Cooperative Group 
FDA 
Food and Drug Administration 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PARP 
Poly ADP Ribose Polymerase 
PAXIP1 
Paired Box Interacting protein 1 


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PD 
Progressive Disease 
PFS 
Progression Free Survival 
PPI 
Protein-Protein Interactions 
PR 
Partial Response 
RECIST 
Response Criteria for Solid Tumors 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SD 
Stable Disease 
SQCLC 
Squamous Cell Lung Cancer 
ULN 
Upper Limit of Normal 


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Drug Substance AZD1775 
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Date: April 8, 2020  
 
 
1. 
INTRODUCTION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Clinical Study Protocol 
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Date: April 8, 2020  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Clinical Study Protocol 
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Edition Number 6  
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Clinical Experience with AZD1775 


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Clinical Study Protocol 
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Date: April 8, 2020  
 
 
AZD1775 has been administered to patients in 17 AstraZeneca-sponsored or Merck- 
sponsored clinical studies, 10 of which are ongoing. 
 
For details, please see the current Investigator’s Brochure. 
 
The initial clinical study of AZD1775 (PN001) was designed to assess the safety and tolerability 
of AZD1775 monotherapy and in combination with cytotoxic agents. Patients in the initial part 
of this study were assigned to a single cycle of AZD1775 monotherapy in order to establish the 
clinical safety profile of the study drug (Schellens et al., ASCO 2009. Abstract: 3510). Following 
the initial monotherapy treatment cycle, patients continued to combination treatment, 
comprising AZD1775 with cisplatin, carboplatin, or gemcitabine (Leijen S et al., ASCO 2010. 
Abstract: 3067; Brana I., ASCO 2013. Abstract: 5518). 
 
As of 11 November 2018, approximately 863 patients have been exposed to AZD1775 in 
AstraZeneca-sponsored or Merck-sponsored clinical studies. In addition, approximately 
706 patients have also received AZD1775 as part of externally-sponsored scientific research. 
Based on the safety data from the completed adavosertib clinical studies and preliminary data 
from ongoing studies adverse drug reactions to adavosertib monotherapy include: anemia, 
neutropenia and febrile neutropenia, thrombocytopenia, QTc prolongation,       
gastrointestinal events such as dyspepsia, diarrhea, nausea and vomiting (with or without 
dehydration or serum electrolyte decreases), as well as decreased appetite. In addition, the 
following events are also considered expected during treatment with adavosertib in 
combination with cytotoxic chemotherapy: febrile neutropenia, leukopenia, stomatitis, 
asthenia, fatigue, mucosal inflammation and myalgia. Based on information emerging during 
the clinical development programme of adavosertib, potential risks where a causal 
relationship with adavosertib monotherapy has not been established include asthenia/fatigue, 
gastrointestinal hemorrhage, lymphopenia/lymphocyte count decreased, leukopenia/WBC 
count decreased, myalgia, stomatitis, sepsis and transaminases elevation. In addition, the 
following events are also considered potential risks for adavosertib in combination with 
cytotoxic chemotherapy: pancytopenia. 
Refer to the IB for adavosertib for information on the potential benefits and assessment of 
potential and known risks. 
 
The single-dose maximum tolerated dose (MTD) in both gemcitabine and cisplatin combination 
therapy is 200 mg of AZD1775. Dose-limiting toxicities (DLTs) tended to be hematologic in the 
gemcitabine group and constitutional in the cisplatin group. The single-dose MTD in 
combination with carboplatin was 325 mg of AZD1775; DLTs in this group were related to 
serum chemistry. Similar DLTs have been observed in the multiple-dose chemotherapy 
combinations. These types of toxicities are not unexpected for therapies that include full-dose 
chemotherapy. Patients should therefore be closely monitored for signs of gastrointestinal 
(including diarrhea), hematologic, and laboratory toxicities and managed clinically with 
supportive care measures. Based on these studies and the current ongoing trial in ovarian 
cancer (NCI# NCT01357161), the recommended phase II dose is as follows: AZD1775 225 
mg twice daily (BID) day 1 to day 3 (5 doses) plus carboplatin AUC5 every 21 days/paclitaxel 
175 mg/m2 for 6 cycles followed by maintenance AZD1775. 


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In Study PN001, of 176 evaluable patients who received AZD1775 (either single or multiple 
doses) as monotherapy or in combination with gemcitabine, cisplatin, or carboplatin, a partial 
response (PR) (confirmed and unconfirmed) was observed in 17 (9.7%) patients, and stable 
disease (SD) was observed in 94 (53.4%) patients. 
 
No complete or PRs were observed in either of Studies PN005 or PN008 at the time that they 
were terminated. 
 
Significance 
 
SQCLC is an incurable disease, with current therapy producing a survival benefit, although it 
is small. In addition, there is no FDA-approved triplet combination in this patient population. It 
was demonstrated that carboplatin in combination with paclitaxel has significant clinical activity 
in this disease with an overall response rate of 26%. This is remarkable; however, 74% of 
patients do not respond. Therefore, it is important to develop combination therapies to improve 
the efficacy and to discover resistance mechanisms. One potential class of agents that could 
be used in combination with platinum chemotherapy is WEE1 inhibitors. As it is likely that 
combination therapies will need to be developed to produce significant effects, we thus propose 
to perform a phase II study in which the combination is evaluated. 
 
As a single agent, AZD1775 has not been extensively studied in clinical trials. Carboplatin has 
significant activity in lung cancer due to its ability to create DNA adducts that lead to DNA 
damage and cytotoxicity. p53 mutant SQCLC may be more dependent on the G2/M checkpoint 
for correction of DNA damage. In the setting of DNA damage occurring though platinum- 
induced adducts, a medication such as a WEE1 inhibitor, which further prevents functionality 
of this checkpoint, may lead to enhanced effects. There have been trials extensively testing 
the combination of a WEE1 inhibitor plus platinum chemotherapy in SQCLC patients. 
 
Innovation 
 
The sensitivity and resistance mechanisms to AZD1775 in combination with platins are 
currently unknown. Several possibilities exist, including the expression of key regulators of the 
cell cycle. We will perform pre- and post-treatment tumor biopsies of the patients, which will 
allow us to characterize the biomarkers in the clinical responders and the nature of the 
resistance mechanisms in the clinical non-responders. 
 
1.2 
Research hypothesis 
Hypothesis: In patients with p53-mutant SQCLC with high expression of G2/M checkpoint 
proteins WEE1 and PAXIP1 (defined as WEE1 and/or PAXIP1 positive), we expect to find that 
treatment with carboplatin-paclitaxel and AZD1775 will improve progression-free survival 
(PFS). 
 
 
 
Rationale 
1.3 
Rationale for conducting this study 


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The overall 5-year survival for non-small-cell lung cancer (NSCLC), which is used as a 
benchmark for putative cure from this disease, is presently only 15%10. The majority of patients 
will present with late-stage disease. SQCLC represents the second most common type of 
NSCLC. The trial's rationale is based on the fact that standard of care in first-line treatment for 
patients with advanced-stage SQCLC is platinum doublet chemotherapy11-13. While the phase 
II trial by Johnson et al demonstrated that compared to carboplatin-paclitaxel, carboplatin- 
paclitaxel plus bevacizumab offered statistically significantly improved time to progression in 
chemo-naive NSCLC patients (n = 67; 4.2 vs. 7.4 months; P = 0.023; respectively), the majority 
of the major bleeding events including hemoptysis occurred in those patients with squamous 
histology. Based on these findings, the phase III trial excluded patients with SQCLC. 
Furthermore, complete responses are rare and eventual progression is inevitable in patients 
with advanced SQCLC. Hence, there is a great need for the development of newer agents and 
innovatively designed clinical trials to test these newer agents. 
 
In the lab, AZD1775 is a powerful anticancer drug; clinical trials are underway. The 
identification of a key molecular event that determines the biological response of cells to WEE1 
inhibitor treatment may help to identify clinically relevant PD markers to assess tumor sensitivity 
or resistance at the early stages of therapy. In NSCLC cell lines, we have demonstrated that 
cisplatin has exhibited enhanced effects in combination with the AZD1775 (a WEE1 inhibitor). 
 
 
 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Determine the progression-free survival of carboplatin-paclitaxel plus AZD1775 in patients with 
advanced/metastatic SQCLC. 
 
2.2 
Secondary objectives 
1. Estimate time-to-event variables, such as overall survival time, duration of overall 
response, and duration of stable disease. 
 
 
2. Estimate the disease control rates (complete response, partial response, and 
stable disease). 
2.3 
Exploratory objectives 
1. Assess pharmacodynamic endpoints in tumor tissue. 
 
 
a. Determine the frequency of tissue biomarkers (including WEE1, PAXIP1, 
phospho-Y15-CDK1). 
 
 
b. Examine potential resistance mechanisms in the tumors of clinical non- 
responders. 


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c. Compare tissue biomarkers with clinical covariates and outcomes. 
 
 
3. 
STUDY PLAN AND PROCEDURES 
 
 
 
Study Design 
3.1 
Overall study design and flow chart 
 
This is a multicenter-center phase II trial of carboplatin, paclitaxel, and AZD1775 in patients 
with advanced/metastatic SQCLC. Patients will be treated with carboplatin AUC5 and paclitaxel 
175 mg/m2 plus AZD1775 225 mg once daily for one day and twice daily for two days for a total 
of 5 doses over days 1-3. Each cycle will be 21 days (Table 1). The doses of carboplatin, 
paclitaxel, and AZD1775 are based on prior phase I studies of AZD1775 in patients with 
advanced solid tumors (Schellens et al, ASCO 2011, #3068; Leijen et al., ASCO 2010. 
Abstract: 3067; Brana, ASCO 2013, Abstract: 5518) and ongoing phase II studies in ovarian 
cancer. Following 6 cycles of treatment, patients will then go on to continue maintenance 
treatment with AZD1775. Treatment will continue until disease progression, intolerable toxicity, 
or withdrawal from study. Radiographic evaluation will occur on days 0 (baseline), 42, and 
every two cycles there after by CT. The data will be summarized as clinical response measured 
continuously. Toxicities will be evaluated according to CTCAE v.4 guidelines. Archival tumor 
will be collected for correlative studies. In addition, serial pre- and post-treatment tumor 
biopsies will be performed in a minimum of 7-10 patients. 
 
Inclusion of Women and Minorities: Both men and women of all races and ethnic groups 
are eligible for this trial. 
 
Safety: CTCAE v.4 will be used to monitor patients for safety and tolerability. Careful toxicity 
assessment will be performed with standard laboratory studies (CBC, BUN, creatinine, 
electrolytes, and LFTs) before each treatment. In addition, a medical history and physical 
examination will be performed before each cycle. 
 
Patients will receive intravenous (IV) treatments in a clinical research unit or infusion center, 
which is staffed by nurses experienced in the management of infusion reactions and cytokine 
release syndrome. All SAEs with a determination of SAE-relatedness to the investigational 
therapy will be reported as described in the data and safety monitoring plan detailed in the 
protocol. 
 
Efficacy: Radiographic assessments will be performed every 2 cycles and will be assessed 
by RECIST v1.1. Patients who are found to have stable disease (SD), partial response (PR), 
or complete response (CR) at re-staging after the initial 4-6 cycles will receive additional 
AZD1775 every 21 days until evidence of disease progression. More specifically, as per 
standard of care practice, for patients who are noted to have additional tumor regression 
following 4 cycles of treatment and are tolerating the triplet combination, then 2 additional 
cycles will be administered per treating physician/PI discretion. Response rate, overall survival, 
and progression-free survival will be determined. 


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Table 1. Study Calendar. All screening and on study visits, labs, procedures, and scans 
windows are +/- 7 days unless otherwise specified in the footnotes. 
 
Intervention 
Screening 
C1 
D1 
C1 
D2-D3 
C1 
D15 
C2-6 
D1 
C2-6 
D2-D3 
C7 D1 
and 
beyond 
End 
of 
treatment 
N 
30+/-14 
days 
Post 
study 
follow- 
upN 
Survial 
Follow 
upO 
Informed Consent 
X 
History and Physical 
(H&P), including 
weight and heightA; 
X 
X 
X 
X 
X 
X 
CBC 
XB 
X 
X 
X 
X 
XB 
CMPC 
XB 
X 
X 
X 
X 
XB 
PT/INRD 
X 
X 
Urinalysis 
XB 
X 
X 
X 
X 
X 
Pregnancy TestE 
XB 
X 
X 
X 
X 
X 
Muga or ECHO 
XF 
ECG 
X 
X 
X 
X 
X 
X 
X 
CT chest/abdomen 
(tumor assessments) 
XG 
XH 
X H 
X 
X 
ECOG PSI 
XB 
X 
X 
X 
X 
X 
Toxicity AssessmentsJ 
XB 
X 
X 
X 
X 
X 
X 
X 
X 
Magnesium, 
Phosphorus 
X 
X 
X 
X 
X 
X 
Archival Tissue 
Collection 
X 
X 
AZD1775K 
X 
X 
X 
X 
X 
Carboplatin/Paclitaxel 
K 
X 
X 
Optional Tumor 
Biopsy 
XL 
XM 
Survival follow-up 
X 
A Interval H&P can be performed by the treating physician or APP in the Moffitt Clinical Research Unit or the Thoracic 
Clinic. A physician or APP H&P must be performed within 14 days of cycle 1, day 1. Physical exam will include 
weight and vital signs. Height will need to be collected at screening. 
B CBC, CMP, ECG, ECOG PS, urinalysis, PS, and serum pregnancy test (only for women of child bearing potential) 
will be performed every 21 days on day 1+/- 7 days of every subsequent cycle as long as patients remains on study 
drug. Toxicity Assessments will be continuous measure that is collected throughout the patients time on study. 
C CMP includes sodium, potassium, chloride, bicarbonate, BUN, Cr, glucose, calcium, total protein, albumin, AST, 
ALT, total bilirubin, and alkaline phosphatase. 
D The coagulation profile includes a prothrombin time or International Normalized Ratio (INR), and activated partial 
thromboplastin time (for only those who will undergo a biopsy). 
E Pregnancy test is indicated only for female patients of child bearing age who are premenopausal. There must be 
negative serum pregnancy test within 72 hours prior to first study dose in all WOCBP. 
F A baseline Echo or MUGA scans will be completed on or prior to C1D1. Results must be known prior to dosing the 
patient. 
G Tumor measurements must occur no more than 30 days prior to starting the trial. 
HTo be completed on day 1 cycle 3 +/-7 days and then every other cycle +/- 7 days. After completing cycles of 
therapy, CT imaging will occur every 3 cycles. [EG:For those patients where shifts in the window do not occur, CT 


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Date: April 8, 2020  
 
 
scans will occur on:  D1C3 (after 6 weeks), D1C5 (after 12 weeks),  D1C7 (after 18 weeks), D1C10 (after 27 
weeks), D1C13 (after 36 weeks), D1C16 (after 45 weeks) and so forth.] 
I ECOG Performance status will be collected at time of physical exams. 
JToxicity will be measured against the Common Terminology Criteria for Adverse Events 4.0. SAE collection will 
initiate at time of consent while AE collection will initiate on C1D1 per section 6.4. Toxicity assessments will be a 
continuous measurement. On days 2-3 of each cycle, toxicity assessment details will be collected by patient 
documenting on pill diary. A specific visit is not required. 
K The X in the study calendar implies agent dosing. Carboplatin AUC5 and paclitaxel 175 mg/m2 plus AZD1775 225 
mg once daily for 1 day and twice daily for two days for a total of 5 doses over days 1-3 every 21 days for 4-6 cycles 
followed by maintenance AZD1775 every 21 days. 
L Pre-treatment tumor biopsy will be performed anytime within 30 days of beginning cycle 1 day 1 +/-7 days. 
M Post-treatment tumor biopsy will be obtained on cycle 1 day 15+/-7 days. 
N Patients are allowed to continue treatment until disease progression, until the patient is discontinued due to 
unacceptable toxicity, or until a decision to discontinue treatment by the patient or investigator. After withdrawal 
from or completion of protocol treatment, patients must be followed for any new AEs for 30 calendar days after the 
last dose of study drug or until initiation of new therapy, whichever occurs first. The 30- D a y  Post Study Follow-
Up visit will be performed 30 days (+/- 14 days) from last treatment dose. 
OPatients will be followed every 3 months (±2 weeks) from the last disease assessment of response until death or 
until the study is terminated.  Patients without disease progression at the time of study drug discontinuation should 
have CT Scan (if applicable) repeated at follow-up visits until disease progression has been observed OR until 
initiation of a subsequent line of systemic cancer therapy. Survival Follow-up visits will occur to collect survival 
status (e.g., date and cause of death), an information pertaining to the type and date of any post-study alternative 
cancer therapy administered. Patients may be contacted during outpatient visits or by telephone or  the data can 
be collected from the electronic medical (if available. 
 
 
 
 
 
 
 
4. 
SUBJECT SELECTION CRITERIA 
 
All inclusion and exclusion criteria will be assessed within 28 days before initiation of 
therapy with the exception of radiographic studies. All eligibility criteria must be met prior to 
enrolling a subject. The study will be conducted in accordance with Good Clinical Practice 
(GCP), as defined by the International Conference on Harmonisation (ICH), WHO and any local 
directives and in compliance with the protocol. This clinical study will require IRB and IND 
approval. Informed consent will be obtained from each patient enrolled onto the study. 
 
4.1 
Inclusion criteria 
For inclusion in the study, subjects should fulfill the following criteria: 
 
1. 
Provision of informed consent prior to any study specific procedures. 
 
2. 
Histologic or cytological diagnosis of SQCLC with advanced/metastatic stage, with 
no known curative treatment options. 
Prior platinum-containing adjuvant, 
neoadjuvant, or definitive chemoradiation therapy given for locally advanced disease 
is considered first line therapy only if recurrent (local or metastatic) disease 
developed within 6 months of completing therapy. Subjects with recurrent disease > 
6 months from completion on chemotherapy will be eligible. 
 
3. 
Female or male aged >18 years. 


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4. 
ECOG performance status of 0/1. 
 
5. 
Prior chemotherapy in the adjuvant/neoadjuvant/consolidation setting is allowed. 
 
6. 
Any prior palliative radiation must have been completed at least 7 days prior to the 
start of studies drugs and patients must have recovered from any acute adverse 
effects prior to the start of the study treatment. 
 
7. 
Prior Immunotherapy with PD1i, PDL1i, anti-CTLA-4 or vaccines is allowed. 
 
8. 
Patients must have normal organ and marrow function as defined below: 
 
 
a) leukocytes 
>3,000/μL 
b) absolute neutrophil count 
>1,000/μL 
c) platelets 
>100,000/μL 
d) total bilirubin 
≤ 1.5 X normal institutional limits 
(except subjects with Gilbert 
Syndrome, who can have total 
bilirubin < 3.0 mg/dL) 
e) AST(SGOT)/ALT(SGPT) 
≤ 2.5 X institutional upper limit of 
normal, 
or 
≤ 5 X institutional upper limit of 
normal for patients with liver 
metastases. 
f) creatinine 
≤ 2.0 
 
 
9. Have archival tissue available or undergo a fresh biopsy where clinically feasible after 
discussion with the sponsor. 
 
10. No reproductive toxicology nor teratogenic studies have been conducted with AZD1775 
to date, and it is unknown whether the drug is excreted in human milk. Therefore, women 
of childbearing potential and men should agree to use adequate contraception prior to 
study entry and for the duration of study participation and women who are breast feeding 
are excluded from the study. Both women and men should be fully informed of the lack of 
reproductive toxicity testing, and women must have a negative pregnancy test prior to 
enrolment. 
 
Female patients are considered to be of childbearing potential unless: 
 
• 
they are post-menopausal (defined as older than 50 years and amenorrhoeic 
for at least 12 months following cessation of all exogenous hormonal 
treatments), 
 
• 
there is documentation of irreversible surgical sterilization by hysterectomy, 
bilateral oophorectomy or bilateral salpingectomy (but not tubal ligation), or 


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• 
they are 50 years or younger but have been amenorrhoeic for at least 12 months 
following the cessation of exogenous hormonal treatments and have serum 
follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in the 
postmenopausal range for the institution. 
 
Female patients who are of childbearing potential must agree to use adequate 
contraceptive measures (as defined below) for the duration of study participation, 
and for 90 days after the final dose of study drug; cessation of birth control after this 
point should be discussed with a responsible physician. They also may not be breast 
feeding and must have a negative serum or urine pregnancy test within 72 hours 
prior to start of study treatment. 
 
Male patients who are sexually active with a female partner of childbearing potential 
must be either surgically sterilized or agree to use barrier contraception (i.e., 
condoms) for the duration of study participation, and for 90 days after the final dose 
of study drug; cessation of birth control after this point should be discussed with a 
responsible physician. 
 
Female patients who are of child-bearing potential (as defined above) should use 
enhanced methods of contraception from the time of screening until 90 days after 
the final dose of study drug; cessation of birth control after this point should be 
discussed with a responsible physician. Acceptable methods of contraception 
include true abstinence in line with the preferred and usual lifestyle choice of the 
subject, tubal ligation, vasectomized partner, and methods listed in the table below. 
All methods of contraception (with the exception of total abstinence) should be used 
in combination with the use of a condom by their male sexual partner for intercourse. 
Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control. 
 
Should a woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician immediately. 


21(64) 
Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
Effective Methods of Contraception 
 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
• 
Cap plus spermicide 
• 
Sponge plus spermicide 
• 
Diaphragm plus spermicide 
• 
Copper T 
• 
Levonorgestrel-releasing 
intrauterine system (e.g., 
Mirena®)a 
Any registered and marketed 
contraceptive agent that 
contains an estrogen and/or a 
progestational agent (including 
oral, subcutaneous, 
intrauterine, or intramuscular 
agents) such as 
• 
Implants 
• 
Hormone shot or injection 
• 
Combined pill 
• 
Minipill 
• 
Patch 
a 
This is also considered a hormonal method. 
 
 
 
Male patients should be asked to avoid unprotected sex with all sexual partners but use 
condoms plus spermicide during the study, and for a washout period of 90 days after 
the last dose of study drug. Where a sexual partner of a male participant is a woman 
of child-bearing potential, patients should avoid procreation for 90 days after completion 
of study drug treatment. Patients should refrain from donating sperm from the start of 
dosing until 90 days after discontinuing study 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. 
 
4.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
 
1. Progressive, symptomatic untreated brain metastases. 
 
2. Pregnancy or breast feeding. 
 
3. A serious uncontrolled medical disorder or active infection that in the investigator’s opinion 
would impair the patient’s ability to receive study treatment. 
 
4. Prior use of platinum or paclitaxel for stage IV NSCLC or concurrent use of other anticancer 
approved or investigational agents. 
 
5. Use of anti-cancer treatment drug ≤21 days or 5 half-lives (whichever is shorter) prior to the 
first dose of AZD1775. For drugs for which 5 half-lives is ≤21 days, a minimum of 10 days 
between termination of the prior treatment and administration of AZD1775 treatment is 
required. 


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Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
6. Major surgical procedures ≤28 days of beginning study treatment, or minor surgical 
procedures ≤7 days. No waiting period required following port-a-cath or other central venous 
access placement. 
 
7. Grade >1 toxicity from prior therapy EXCEPT: Alopecia, anorexia, and/or endocrinopathies 
on replacement therapy. 
 
8. Unable to swallow oral medications. Note: Patient may not have a percutaneous endoscopic 
gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN). 
 
9. Patients with known Hepatitis B or C or HIV infection. 
 
10. Second primary malignancy, other than in situ malignancies or adequately treated basal cell 
carcinoma of the skin or other malignancy treated at least 2 years previously with no 
evidence of recurrence. 
 
11. Any of the following cardiac diseases currently or within the last 6 months: unstable angina 
pectoris, acute myocardial infarction, congestive heart failure ≥ Class 2 (as defined by New 
York Heart Association (NYHA)), conduction abnormality not controlled with pacemaker or 
medication, significant ventricular or supraventricular arrhythmias (patients with chronic 
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible.) 
 
12. Patient has had prescription or non-prescription drugs or other products (i.e., grapefruit 
juice) known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow 
therapeutic index, or to be moderate to strong inhibitors or inducers of CYP3A4, which 
cannot be discontinued 2 weeks before Day 1 of dosing and withheld throughout the study 
until 2 weeks after the last dose of study drug (See Appendix A). 
 
13. Co-administration of aprepitant and fosaprepitant during this study is prohibited (See 
Appendix A). 
 
14. AZD1775 is an inhibitor of breast cancer resistance protein (BCRP). The use of statins 
including Atorvastatin which are substrates for BCRP are therefore prohibited and patients 
should be moved on to non-BCRP alternatives (See Appendix A). 
 
15. Herbal preparations are not allowed throughout the study. These herbal medications 
include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng (See Appendix A). 
 
16. History of Torsades de pointes unless all risk factors that contributed to Torsades have 
been corrected. 
 
17. Mean resting corrected QTc interval using the Fridericia formula (QTcF) >450 msec/male 
and >470 msec/female (as calculated per institutional standards) obtained from 1 
electrocardiogram (ECGs). 


23(64) 
Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
5. 
STUDY CONDUCT 
5.1 
Subject enrollment and initiation of 
investigational product 
After screening patient will be treated with AZD1775 PO in combination with IV 
carboplatin and paclitaxel every 3 weeks for 4-6 cycles at the discretion of the 
treating physician. Patients will be treated with carboplatin AUC5 and paclitaxel 175 
mg/m2 plus AZD1775 225 mg once daily for one day and twice daily for two days for 
a total of 5 doses over days 1-3. Following 4-6 cycles of treatment, AZD1775 will be 
continued for 5 doses over Days 1-3 for each subsequent cycle until disease 
progression, study withdrawal, or intolerance. The carboplatin and paclitaxel will be 
administered in the CRU or Infusion center and AZD1775 will be distributed to the 
patient by the investigational pharmacy. 
 
 
5.2 
Procedures for handling subjects 
incorrectly enrolled 
Any patient identified to be incorrectly enrolled will be counted as a screen failure 
and be replaced. Any patients falling into this category may continue on treatment 
as long as there is no evidence of progressive disease by RECIST v 1.1 or evidence 
of intolerance. Patients will be allowed to re-screen. 
 
5.3 
Treatments 
5.3.1 
Identity of investigational product(s) 
 
 
 
Investigational product 
Dosage form and strength 
Supplied by 
AZD1775 
225mg 
AstraZeneca 
Non-Investigational 
products 
Dosage form and strength 
Supplied by 
Carboplatin* 
Paclitaxel* 
AUC 5 
175 mg/m2 
Standard of Care 
Standard of Care 
*Premedications are according to the institutional standards on Day 1 of each 21-day 
cycle. Chemotherapy will be infused per Institutional standards. 
 
5.3.2 
Doses and treatment regimens 
Patient will receive AZD1775 225 mg once daily for one day and twice daily for two 
days  for  a  total  of  5  doses  over  days  1-3. 
AZD1775 
will be  administered 


24(64) 
Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
concomitantly with the Day 1 infusion of paclitaxel +carboplatin, followed by four 
additional doses of AZD1775 to be taken in approximate 12-hour intervals (BID for a 
total of 5 doses). 
 
All patients must receive a 5-HT3 antagonist, ondansetron (Zofran) 8 mg PO BID or 
granisetron (Kytril) 1 mg PO BID prior to each dose of AZD1775. In addition, 
dexamethasone 4 mg PO will be given with each AZD1775 dose unless 
contraindicated or not well-tolerated. Dexamethasone or the 5-HT3 antagonist may 
be given by IV. 
Please note: aprepitant [Emend] and fosaprepitant are not permitted due to known 
DDIs. 
 
Due to frequent reports of diarrhea with AZD1775 administration, vigorous anti- 
diarrheal treatment loperamide (Imodium) is required at the first onset of diarrhea 
according to American Society of Clinical Oncology (ASCO) guidelines. Patients 
should be instructed to take oral loperamide (Imodium) 2 mg every 2 hours until 
diarrhea-free for at least 12 hours. Patients should be instructed to notify the 
Investigator or research staff for the occurrence of blood or black stools, symptoms 
of dehydration, fever, inability to take liquids by mouth, and inability to control 
diarrhea within 24 hours of using loperamide  or  other prescribed antidiarrheal 
medications. 
 
 
 
If the patient misses a dose of AZD1775, the patient should take the dose as soon 
as possible, but not more than 6 hours after the missed scheduled dose, If greater 
than 6 hours, the missed dose should be skipped and the patient should take the 
next dose when scheduled. 
 
If vomiting occurs after the patient takes the AZD1775, the patient should be 
instructed not to retake the dose, but to wait until the next scheduled dose of 
AZD1775.  If vomiting persists, the patient should contact the Investigator. 
 
5.3.3 
Labeling and storage 
Investigational drugs are properly labeled as provided by AstraZeneca at all times 
and properly stored according to the supplier’s recommendations. They are 
administered only upon written order of the authorized principal investigator, or 
his/her designee, who must be a member of the medical staff. All investigational drug 
supplies for patient use are kept in the pharmacy. Each drug is stored separately for 
each protocol. The pharmacy maintains a separate Drug Accountability Record 
Form, which reflects drug supply for each investigational agent and protocol. The 
form contains all of the necessary information regarding the disposition of the drug 
and the storage site. Other drug documentation (e.g., receipt of drug, internal 
transfers, returns, broken vials, etc.) is recorded on this form. 


25(64) 
Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
5.4 
Concomitant and post-study 
treatment(s) 
Formal drug-drug interaction studies have not yet been performed with AZD1775; 
therefore, the potential for drug-drug interaction described in this protocol are 
based on findings from in vitro studies and clinical experience. 
 
 
5.4.1 
The following treatments are prohibited while 
in this study (for a full list, see Appendix “A”) 
Prescription and non-prescription agents known to be moderate to strong 
inhibitors/inducers of CYP3A4 or sensitive CYP3A4 substrates or substrates of 
CYP3A4 with a narrow therapeutic window that cannot be discontinued 2 weeks 
before first dose of AZD1775 and withheld throughout the study until 2 weeks after 
the last dose of AZD1775 are prohibited. The use of grapefruit juice is prohibited 2 
weeks prior to, during the study, and 2 weeks after the last dose of AZD1775. 
– Strong Inhibitors of CYP3A4 include: azole antifungals (ketoconazole, fluconazole, 
voriconazole, 
and 
itraconazole), 
macrolide 
antibiotics 
(clarithromycin 
and 
erythromycin), calcium channel blockers, HIV protease inhibitors (indinavir, 
nelfinavir, and ritonavir), and cimetidine, aprepitant, and nefazodone. 
– 
Inducers of CYP3A4: phenytoin, barbiturates, and rifampicin 
– Substrates of CYP3A4: statins (lovastatin, simvastatin), midazolam, terfenadine, 
astemizole, and cisapride 
Refer to Appendix “A” for a list of inhibitors, inducers and substrates of CYP3A4. 
Supportive care with a CYP3A4 inhibitor/inducer/substrate according to institutional 
guidelines in the context of standard of care chemotherapy will be exempt; however, 
concomitant treatment with aprepitant is not allowable per protocol. See AZD1775 
IB for additional information. 
• In vitro data suggest that AZD1775 may also be a weak reversible inhibitor of 
CYP2C19. Caution should be exercised with concomitant administration of AZD1775 
and agents that are sensitive substrates of CYP2C19, or substrates of this enzyme 
with narrow therapeutic range; please refer to Appendix A for a list of sensitive 
substrates of CYP2C19, or substrates of this enzyme with narrow therapeutic range. 
• In vitro studies have shown that AZD1775 may be a substrate and inhibitor for 
human P-glycoprotein (P-gp). Caution should be exercised when inhibitors or 
substrates of P-gP are administered with AZD1775. 
• Use of metformin is prohibited in this study as recent in vitro transporter data have 
shown that AZD1775 is an inhibitor of Multidrug and Toxin Extruder 1 (MATE1) and 
MATE2K. Caution should be used when administering drugs that are substrates of 
these transporters (e.g., cimetidine, acyclovir, fexofenadine) as the clinical relevance 
of AZD1775 inhibition of the MATE pathway is not known in these compounds. 
• 
Aprepitant or Fosaprepitant use is prohibited in this study. No formal clinical 
drug interaction studies have been performed with AZD1775. An exploratory 
assessment of the effect of aprepitant on AZD1775 exposure in oncology patients 
suggests that there is a drug interaction between AZD1775 and aprepitant, as 


26(64) 
Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
exposure to AZD1775 increased by ~40% when aprepitant was co-administered 
with AZD1775. The observed increase in AZD1775 exposure is likely the result of 
CYP3A4 inhibition by aprepitant. This increase in exposure is statistically 
significant. At the selected MTDs, this increase may also be of clinical importance. 
Therefore, concomitant treatment with aprepitant is not allowable per protocol until 
further evaluation. See AZD1775 Investigator’s Brochure for more information. 
• Atorvastatin use is prohibited in this study. Recent in vitro transporter studies have 
shown AZD1775 to be an inhibitor of BCRP (IC50=5.1 μM). This finding is particularly 
relevant for drugs administered orally where exposure is normally limited by BCRP- 
mediated efflux, in particular some statins. Modeling has predicted a substantial 
increase in the exposure of atorvastatin when coadministered with AZD1775, and 
the use of atorvastatin is therefore prohibited in the current study. Other drugs where 
the disposition is mediated via BCRP should be administered with caution, with dose 
modification considered or substituted by an alternative drug. 
• Herbal preparations/medications are not allowed throughout the study. These 
herbal medications include, but are not limited to: St. John’s wort, kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, 
and ginseng. Patients should stop using these herbal medications 7 days before first 
dose of AZD1775. 
• AZD1775 has been shown to be a weak inducer of CYP1A2 in vitro. Taking into 
account the anticipated plasma concentrations (Cmax<1.5 μM) and the intermittent 
nature of the AZD1775 dosing schedule, however, the risk of induction in the clinic 
is considered low. No specific precautions are recommended at this time, except to 
be initially vigilant when using substrates of CYP1A2 with a narrow therapeutic 
range. 
• Caution must be exercised with the concomitant use of aminoglycosides in keeping 
with the treatment guidelines for carboplatin. 
• Paclitaxel is metabolized by CYP2C8 (mainly) and CYP3A4. Appendix D provides 
a list of CYP2C8 inhibitors that should be excluded as concomitant medications. This 
list is not all-inclusive, and for other concomitant medications, the Investigator and 
AstraZeneca will determine if they are known to significantly influence CYP2C8. 
In addition, Investigators should look at a frequently updated drug reference such as 
Lexicomp to see if any medicine they want to prescribe is on a list of drugs to avoid. 
 
5.4.2 
Growth factors for neutrophils or RBCs used in 
accordance with established guidelines are 
allowed. 
5.4.3 
Palliative (limited-field) radiation therapy is 
permitted, if all of the following criteria are met: 
1. Repeat imaging demonstrates no new sites of bone metastases. 
2. The lesion being considered for palliative radiation is not a target lesion. 
5.5 
Dose Modifications 
Dose adjustments will be based on the organ system exhibiting the greatest degree of toxicity. 
Dose reductions or holds and initiation of supportive care are allowed as clinically indicated by 


27(64) 
Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
the treating physician. A maximum of 2 dose reductions for the AZD1775 and chemotherapy 
will be allowed. Patients requiring >2 dose reductions of these drugs will be discontinued from 
the study drug and chemotherapy. 
 
Brief treatment or visit delays (±7 days) for public holidays or weather conditions do not 
constitute a protocol violation but should be recorded in the electronic case report form (eCRF). 
 
Any patient requiring a toxicity-related dose delay of more than 28 days from the intended day 
of the next scheduled dose must be discontinued from the study unless there is approval from 
the Study PI for the patient to continue. 
 
The AZD1775 and chemotherapy dose level reductions are presented in Table 2. 
The hematologic and non-hematologic Dose modifications and guidelines are as presented in 
Tables 3-5. 
 
Table 2. AZD1775, Carboplatin and Paclitaxel Dose Level Reductions for Toxicity 
 
Agent 
Starting Dose Level 
(DL) 
DL-1 
DL-2 
AZD1775 
225 mg BID 
(5 doses over 2.5 days) 
175mg BID 
(5 doses over 2.5 days) 
125 mg BID 
(5 doses over 2.5 days) 
Paclitaxel 
175 mg/m2 
150 mg/m2 
125mg/m2 
Carboplatin AUC 5 
AUC 4 
AUC 3.5 
 
 
Dose modification due to hematological toxicity 
Complete blood counts (CBC) will be obtained for all patients at the beginning of each 
treatment cycle (Day 1). If hematologic toxicity occurs (see Table 3), treatment should be held 
and ANC and platelets should be monitored weekly until recovery. However, if the investigator 
determines that the hematologic toxicity was due to one study drug and not the other, treatment 
with the remaining study drug may continue as clinically appropriate or dose reductions can be 
done solely for the agent that is felt to be the cause of the AE. This should be clearly 
documented in the EMR. 
 
 
 
Table 3. Day 1 Hematologic Dose Modifications and Management 
 
Treatment Day Blood Counts and Toxicity 
ANC 
Platelets 
Action 
≥1500/μL 
And 
≥75,000/μL 
No dose modification or interruption 
<1500/μL 
Or 
<75,000/μL 
Delay by 1 week intervals until recoverya 


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Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
a If hematologic parameters do not recover within 28 days, the patient should be removed from 
the study treatment. 
 
Table 4. Neutropenia, Infection, Febrile Neutropenia Dose Modifications and 
Management 
 
Grade 3 neutropenic fever (ANC <1000/μL 
+Temperature 
≥101°F 
[38.5°C]) 
or 
neutropenic Infection 
Documented infection with Grade 3 
neutropenia (ANC <1000/μL) 
Grade 4 neutropenia 
(ANC <500/μL >7 days 
Grade 4 thrombocytopenia (platelet count 
<25,000/μL >7 days) 
Hold doseb until recovery. 
Then, 
upon 
resuming 
dosing, 
reduce 
paclitaxel or carboplatin, and AZD1775 to 
the next lower dose levela. 
Grade 4 febrile neutropenia or Grade 4 
infection with neutropenia (both defined as 
septic shock) 
Thrombocytopenic haemorrhage (gross 
occult bleeding) associated with a platelet 
count<50,000/μL 
Discontinue treatment and follow for disease 
progression. 
a No more than two dose reductions will be allowed for any patients. Patients requiring additional dose 
modifications due to toxicity will discontinue study treatment. 
b 
Hold chemotherapy dose until hematologic parameters recover to adequate levels (i.e., ANC 
≥1000/μL platelets ≥75,000/μL). If hematologic parameters have not recovered within 28 days, the 
patient will be removed from the study treatment. 
 
 
Non-hematologic toxicity dose modifications 
Dose modifications for non-hematologic toxicities should be based on toxicities occurring 
during the previous cycle. For toxicities that lead to a dose reduction, the dose will not be 
reescalated during subsequent cycles. Any patient who develops a Grade 3 or 4 
nonhematologic toxicity, that does not resolve to ≤ Grade 1 within 28 days should be removed 
from the study treatment. However, if the investigator determines that the nonhematologic 
toxicity was due to one study drug and not the other, treatment with the remaining study drug 
may continue as clinically appropriate or dose reductions can be done solely for the agent that 
is felt to be the cause of the AE. This should be clearly documented in the EMR. 
Based upon the maximum non-hematologic toxicities experienced during the previous cycle, 
dose adjustments for subsequent cycles are to be made according to the criteria defined in 
Table 5 (unless specified per unique toxicities as noted below): 
 
Table 5. Non-Hematologic Toxicity Dose Modification and Management 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
 
CTCAE v4.03 
Paclitaxel 
Carboplatin 
AZD1775 
Grade 0 - 2 
No dose 
modification 
No dose 
modification 
No dose 
modification 
Grade 3 b,c,d 
Holda 
Holda 
Holda 
Grade 4b 
Hold until toxicity 
resolves to Grade 
≤1. Resume with 
1 dose level 
reduction 
Hold until toxicity 
resolves to Grade 
≤1. Resume with 
1 dose level 
reduction 
Hold until toxicity 
resolves to 
Grade 
≤1. Resume with 
1 dose level 
reduction 
Second repeat 
incidence of 
Grade 3 or 4 
toxicity 
(except nausea, 
vomiting, fatigue, 
malaise, lethargy, 
anorexia, 
alopecia) 
Discontinue 
treatment 
Discontinue 
treatment 
Discontinue 
treatment 
Hepatic 
Grade 1-2 
No dose 
modification 
No dose 
modification 
No dose 
modification 
Grade 3 or 4 
(manifested as 
elevations in 
ALT, AST, ALP 
or bilirubin) 
Hold until 
resolves to Grade 
≤1 or baseline, 
then resume 
paclitaxel with a 1 
level dose 
reduction. If not 
resolved within 28 
days discontinue 
paclitaxel. 
Hold until 
resolves to Grade 
≤1 or baseline, 
then resume 
carboplatin with a 
1 level dose 
reduction. If not 
resolved within 28 
days discontinue 
carboplatin. 
Hold until 
resolves to 
Grade 
≤1 or baseline, 
then resume 
study 
drug with a 1 
level dose 
reduction. If not 
resolved within 
28 days 
discontinue 
study 
drug. 
Diarrhea or Mucositis 
Grade 3 or 4 (or 
requiring 
hospitalization) 
Holda 
Holda 
Holda 
Renal 
Grade ≥ 2 
Hold until resolves 
to Grade 
≤1 or baseline, 
then resume 
Hold until 
resolves to Grade 
≤1 or baseline, 
then resume 
Holda 


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Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
 
paclitaxel with a 1 
level dose 
reduction. If not 
resolved within 28 
days discontinue 
paclitaxel or 
reduce 1 dose 
level. 
If AE reoccurs 
after 1 dose level 
reduction, reduce 
a second dose 
level once AE 
recovers to Grade 
≤1. 
carboplatin with a 
1 level dose 
reduction. If not 
resolved within 28 
days discontinue 
carboplatin. 
Neurotoxicity 
Grade 1 
No dose 
modification 
No dose 
modification 
No dose 
modification 
Grade 2 
Hold until toxicity 
resolves to Grade 
≤1. Resume with 
1 dose level 
reduction. 
Hold until toxicity 
resolves to Grade 
≤1. Resume with 
1 dose level 
reduction. 
No dose 
modification 
Grade 3 or 4 
Discontinue 
treatment 
Discontinue 
treatment 
Discontinue 
treatment 
a Hold until toxicity resolves to ≤ Grade 1, and then resumed at the same dose with no modification. 
b Dose reduction for nausea and vomiting should be made only if Grade 3 or Grade 4 toxicity occurs in 
spite of maximum anti-emetics. 
c For a Grade 3 pulmonary embolism, the dose should be held but the subsequent doses do not have 
to be reduced 1 dose level, at the Investigator’s discretion. 
d Grade 3 electrolyte value(s) (i.e., hypokalaemia), do not require a dose reduction once the electrolyte 
is ≤ Grade 1. 
 
 
Non-hematologic toxicity management guidelines 
5.5.1 Diarrhea 
Patients should be instructed to notify the Investigator or research staff for the occurrence of 
blood or black stools, symptoms of dehydration, fever, inability to take liquids by mouth, and 
inability to control diarrhea within 24 hours of using loperamide or other prescribed antidiarrheal 
medications. 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are recommended: 
hydration and anti-diarrheals.  If diarrhea is severe  (i.e., requiring IV rehydration)  and/or 
associated with fever or severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must 
be prescribed. Patient with severe diarrhea or any diarrhea associated with severe nausea or 
vomiting should be hospitalized for IV hydration and correction of electrolyte imbalances. 
 
5.5.2 Nausea and vomiting Anti-emetic therapy (excluding aprepitant [Emend] or 
fosaprepitant) may be used in accordance with standard practice and/or the discretion of the 
investigator. 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
 
5.5.3 Febrile neutropenia 
Patients experiencing febrile neutropenia with significant symptoms should be managed in a 
hospital setting according to standard procedures, with the urgent initiation of IV antibiotic 
therapy. Patients with febrile neutropenia without symptoms should be managed according to 
standard guidelines. 
 
5.5.4 Motor neuropathy or muscle weakness 
Any onset of > Grade 2 motor neuropathy or > Grade 2 muscle weakness should be evaluated 
by an electromyogram to rule out the possibility of chronic inflammatory demyelinating 
polyneuropathy (CIDP). With a diagnosis of CIDP the patient should be discontinued from study 
treatment. 
5.5.5 Dose modifications for infusion reactions 
Infusion reactions (e.g. rash, urticaria, erythema, pruritus, bronchospasm, and hypotension) 
can occur with the agents used in this study. There is increased risk of a reaction with 
carboplatin and paclitaxel. Carboplatin must be discontinued in patients experiencing a Grade 
3 or 4 infusion reaction during treatment. 
To identify the grade of a reaction, refer to the list below adapted for the General Disorders and 
Administration Site Conditions section of the NCI CTCAE v4.03: 
 
• 
Grade 1: Mild transient reaction; infusion interruption not indicated; intervention not 
indicated. 
• 
Grade 2: Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (e.g., antihistamines, NSAIDs, narcotics, IV fluids indicated for 
≤24 hours). 
• 
Grade 3: Prolonged (e.g., not rapidly responsive to symptomatic mediation and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae. Note: any infusion that is interrupted 
and not resumed within the visit will be considered a Grade 3 reaction. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
 
5.6 
Treatment compliance 
Patients participating  in  this  study  will  be  expected  to  be  compliant  with  the 
medications and study schedule. 
 
5.6.1 
Accountability 
Patient compliance will be monitored by pill diaries. 
 
5.7 
Discontinuation of investigational 
product 
In the absence of treatment delays due to adverse event(s), treatment may continue for 
the time described above or until one of the following criteria applies: 
 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 


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Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
5.8 
Withdrawal from study 
Patients can withdraw from the study or from further treatments at any time. 
Clarifications should be made with the patient whether they wish to withdraw from 
the study or from further treatment. The reason for study or treatment withdrawal 
and the date the patient was removed must be documented in the Case Report 
Form. 
 
 
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
Research data are kept in a secure database with limited access and through OnCore (a Web- 
based, password-protected database), with privacy protected to the full extent of the law. 
Authorized research investigators, the Department of Health and Human Services, and the 
Institutional Review Board may inspect the records. Final approvals have been obtained from 
the IRB. Additional protection is provided through the data safety and monitoring plan described 
below. 
 
6.2 
Data collection at enrollment and 
follow-up 
6.2.1 
Enrollment procedures 
Informed consent must be obtained before any testing to determine a patient’s eligibility. Once 
a patient is enrolled in the study, he/she will be assigned a simple 2 or 3 digit number, with the 
first patient assigned to 01 and so on. A separate spreadsheet with password protection will 
be maintained that contains the patient’s study number along with personally identifiable 
information. Password protection will be maintained in order to keep patient information strictly 
confidential. Upon signing the informed consent form, the patient will be assigned a subject 
number by the investigator or his/her designee. Once assigned to a patient, a subject number 
will not be reused. If the patient fails to be started on treatment for any reason, the reason for 
not being started on treatment will be entered on the Screening Log CRF, and his/her 
demographic information will be captured in the OnCore system. All laboratory, radiologic, and 
pathologic data collected on trial participants will be assigned the unique treatment number 
and stored in a separate database (OnCore). 
 
For external sites only 


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Date: April 8, 2020  
 
 
All subjects must be registered with the External Site Coordination (ESC) office to be able to 
participate in a trial. The participating site must fax or email the completed study specific 
eligibility checklist and registration forms, supporting documents and signed informed 
consent to the Coordinating Center. Unsigned or incomplete  forms  will  be  returned  to 
the site. Once documents are received, the ESC Research Coordinator will review them to 
confirm eligibility and to complete the registration process. If eligibility cannot be confirmed, 
the research coordinator will query the site for clarification or additional documents as 
needed. Subjects failing to meet all study eligibility requirements will not be registered 
and will be unable to participate in the trial. 
 
 
Upon completion of registration, the ESC Research Coordinator will provide the participating 
site with the study sequence number and randomization information, if indicated. Within 24- 
48 hours after registration, it is the site’s responsibility to: 
• 
Enter the  demographic  and  on-study  patient  information  into the Oncore 
database 
• 
Order investigational agent(s) if indicated per protocol 
 
It is the responsibility of the participating Investigator or designee to inform the subject of 
the research treatment plan and to conduct the study in compliance with the protocol as 
agreed upon with Moffitt Cancer Center and approved by the site’s IRB. 
To register a patient send the completed signed eligibility checklist along with the patient 
registration 
form 
and 
supporting 
documentation 
to 
the 
ESC 
via 
email 
at 
affiliate.research@moffitt.org or via fax at 813-745-5666, Monday through Friday between 
8:00AM and 5:00PM (EST). 
 
 
6.2.2 Follow-up procedures 
Patients will be followed for 30 days after removal from study or until death, whichever occurs 
first. Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
6.2.3 Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed in Section 4.3 applies. The 
reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
 
 
6.3 
Efficacy 
In addition to a baseline scan, confirmatory scans should also be obtained 4-6 weeks following 
initial documentation of objective response. Response and progression will be evaluated in this 
study using the new international criteria proposed by the revised Response Evaluation Criteria 
in Solid  Tumors  (RECIST)  guideline  (version  1.1)14.    Changes in  the  largest  diameter 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used 15. 
 
 
 
6.3.1 
Disease Parameters 
 
• 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded for non-nodal lesions 
and short axis for nodal lesions) as >20 mm by chest x-ray, as >10 mm with CT scan, or 
>10 mm with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). Note:  Tumor lesions that are situated in 
a previously irradiated area might or might not be considered measurable. If the investigator 
thinks it is appropriate to include them, only lesions that have clearly shown disease 
progression since prior irradiation will be considered or allowed. 
• 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
• 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. “Cystic lesions” thought to represent cystic metastases 
can be considered as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
• 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline. Target lesions should be selected on the basis 
of their size (lesions with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement, in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
• 
Non-target lesions. All other lesions (or disease sites) including any measurable lesions 
over the 5 target lesions, should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout 
follow-up. 


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Drug Substance AZD1775 
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Edition Number 6  
Date: April 8, 2020  
 
 
 
 
 
 
6.3.2 
Methods for Evaluation of Measurable 
Disease 
 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
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. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
• 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
• 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). Use 
of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI that 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of 
the type and site of disease. Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on 
the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image acquisition protocol should 
be followed as closely as possible to prior scans. Body scans should be performed with 
breath-hold scanning techniques, if possible. 
 
 
6.3.3 
Response Criteria 
 
6.3.3.1 
Evaluation of Target Lesions 
 
• 
Complete Response (CR): 
Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 


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Drug Substance AZD1775 
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Edition Number 6  
Date: April 8, 2020  
 
 
• 
Partial Response (PR): At least a 30% decrease in the  sum  of  the diameters 
of target lesions, taking as reference the baseline sum diameters. 
• 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions). 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study. 
 
 
6.3.3.2 
Evaluation of Non-Target Lesions 
 
 
• 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological 
in size (<10 mm short axis). Note: If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete 
clinical response. 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
• 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal 
progression 
of 
existing 
non-target 
lesions. 
Unequivocal 
progression should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase. 
• 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
 
6.3.3.3 
Evaluation of Best Overall Response 
 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
Table 2. For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 


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Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
 
Table 3. For Patients with Non-Measurable Disease (i.e., Non-Target 
Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
6.3.4 
Progression-Free Survival 
 
Progression free survival (PFS) is defined as the time from start of treatment (Cycle 1, Day 1) 
until the date of objective disease progression or death (by any cause in the absence of 
progression) regardless of whether the patient withdraws from therapy or receives another anti- 
cancer therapy before progression. Clinical deterioration in the absence of radiographic 
evidence is not considered progression for purposes of determining PFS. Subjects who die 
without a reported prior progression will be considered to have progressed on the date of their 
death. Subjects who did not progress or die will be censored on the date of their last evaluable 
tumor assessment. Subjects who did not have any on study tumor assessments and did not 
die will be censored on the date they were first treated. Subjects who started any palliative 
local therapy or subsequent anti-cancer therapy without a prior reported progression will be 
censored at the last evaluable tumor assessment prior to initiation of the palliative local therapy 
or subsequent anti-cancer therapy, whichever procedure occurred first. 
 
 
The PFS time will always be derived based on scan/assessment dates not visit dates. 
 
RECIST version 1.1 assessments/scans contributing towards a particular visit may be 
performed on different dates. The following rules will be applied: 
 
• 
Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression 
 
• 
When censoring a patient for PFS the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
 
6.3.5 
Duration of Response 
• 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is objectively 
documented. If a patient does not progress following a response, then their duration of 
response will use the PFS censoring time. 
• 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements. 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
 
 
6.3.6 
Objective Response Rate 
ORR is defined as the number of subjects whose best confirmed objective response (BOR) is 
a CR or PR, divided by the number of subjects who received at least one dose. BOR is defined 
as the best response designation, as determined by the RECIST v1.1, recorded between 
baseline and the date of objectively documented progression per RECIST 1.1 or the date of 
initiation of palliative local therapy or the date of initiation of subsequent anticancer therapy, 
whichever occurs first. For subjects without documented progression or palliative local therapy 
or subsequent anti-cancer therapy, all available response designations will contribute to the 
BOR determination. The final analysis of ORR will take place at the time of PFS analysis. 
 
 
 
6.3.7 
Overall Survival 
OS is defined as the duration of time from the date for first treatment (Cycle 1 Day 1) to the 
date of death. A subject who has not died will be censored at last known date alive. 
 
 
 
6.3.8 
Missing Assessments and Not Evaluable 
Designation 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements can be made at an 
assessment, the case is also considered NE at that time point, unless a convincing argument 
can be made that the contribution of the individual missing lesion(s) would not have changed 
the assigned time-point response. 
 
 
 
6.4 
Safety 
 
 
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 following or during 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. 
 
The term AE is used to include both serious and non-serious AEs. SAE collection will initiate 
at time of consent while AE collection will initiate on C1D1. 


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Clinical Study Protocol 
Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
Death as a result of disease progression is only to be assessed as efficacy measures and not 
as AEs or SAEs. 
Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events 
(CTCAE) version 4.0. CTCAE v4.0 can be accessed on the NIH/NCI website at 
http://ctep.cancer.gov/forms/CTCAEv4.pdfhttp://ctep.cancer.gov/forms/CTCAEv4.pdf. 
CTCAE grade 5 (death) will not be used in this study; rather, this information will be collected 
in the End of Treatment or Survival Information CRF page. Adverse event monitoring should 
be continued for at least 4 weeks following the last dose of study treatment. 
Adverse events (but not serious adverse events) occurring before starting study treatment but 
after signing the informed consent form are recorded on the Medical History/Current Medical 
Conditions Electronic Case Report Form (OnCore). Abnormal Lab values, vital signs or test 
results that do not induce clinical signs/symptoms or require therapy will not be considered 
clinically significant and will not be reported as Adverse Events. In addition, isolated abnormal 
laboratory values that are considered clinically significant (e.g., cause study discontinuation or 
constitutes in and of itself a Serious Adverse Event) should be recorded on the Adverse Events 
CRF. SAEs occurring after initiation of treatment are recorded on the Adverse Event CRF. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE grade 1-4) 
2. Its relationship to AZD1775 (suspected/not suspected) 
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 
medication taken; non-drug therapy given; hospitalization/prolonged hospitalization) 
Information about common side effects already known about the investigational drug can be 
found in the Investigator’s Brochure or will be communicated between IB updates in the form 
of Investigator Notifications. This information will be included in the patient informed consent 
and should be discussed with the patient during the study as needed. 
 
 
6.4.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfills 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 a congenital abnormality or birth defect 


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Edition Number 6  
Date: April 8, 2020  
 
 
• 
Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to AstraZeneca. 
 
6.4.3 
Recording of adverse events 
 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
AE is serious due to 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to Study procedure(s) 
• 
Causality assessment in relation to Other medication 
 
Description of AE 
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. 
 
Adverse Events based on signs and symptoms 
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 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. 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 or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
 
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. 
 
 
Procedure for serious adverse event reporting 
 
The conduct of the study will comply with all FDA, sponsor and IRB safety reporting 
requirements. 
 
All serious adverse experience reports must include the patient number, age, sex, weight, 
severity of reaction (mild, moderate, severe), relationship to study drug (definitely related, 
probably related, possibly related, unlikely related, unrelated), date of administration of test 
medications and all concomitant medications, and medical treatment provided. A MedWatch 
Form 3500A will be used. The reports will include the appropriate HLMCC PMC, IRB, and FDA 
IND protocol reference numbers. 
 
The Principal Investigator is responsible for evaluating all adverse events to determine whether 
criteria for “serious” and “unexpected” as defined above are present. All Serious Adverse 
Events regardless of cause will be entered into the H. Lee Moffitt Cancer Center & Research 
Institute research database (OnCore) and will be reported to the Moffitt Protocol Monitoring 
Committee (PMC). 
 
All SAEs will be reported to HLMCC PMC, IRB, and FDA as per their requirements. 
 
 
 
6.5 
Instructions for Rapid Notification of 
Serious Adverse Events 
Information about all adverse events, whether volunteered by the subject, discovered by the 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. An adverse event is any 
undesirable sign, symptom or medical condition occurring after starting study drug (or therapy) 
even if the event is not considered to be related to study drug (or therapy). Study drug (or 
therapy) includes the drug (or therapy) under evaluation, and any reference or placebo drug 
(or therapy) given during any phase of the trial. 
 
• 
If it is unclear what study treatment includes, list all drug(s), other therapies, changes to 
existing therapy, diagnostic procedure, etc. that are specified by the protocol 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment (any procedures specified in the 
protocol). Adverse events occurring starting after study treatment are recorded. Abnormal 
laboratory values or test results constitute adverse events only if they induce clinical signs or 
symptoms or require therapy and are recorded. 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
Information about all serious adverse events will be collected and recorded on the FDA 
MedWatch 3500a form. To ensure patient safety, each serious adverse event must also be 
reported to AstraZeneca within 24 hours of learning of its occurrence. A serious adverse event 
is an undesirable sign, symptom, or medical condition that: 
 
1. is fatal or life-threatening 
2. required or prolonged hospitalization 
3. results in persistent or significant disability/incapacity 
4. constitutes a congenital anomaly or a birth defect 
5. is medically significant, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Events not considered to be serious adverse events are hospitalizations for the: 
 
• 
routine treatment  or  monitoring  of  the  studied  indication,  not  associated  with  
any deterioration in condition. 
• 
treatment, which was elective or pre-planned, for a pre-existing condition that did not 
worsen 
• 
treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions 
of serious given above and not resulting in hospital admission. 
Pregnancy, although not itself a serious adverse event, should also be reported on a serious 
adverse event form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any birth 
defects or congenital abnormalities. 
 
Any serious adverse event occurring after the patient has provided informed consent, has 
started taking the study medication, and until 4 weeks after the patient has stopped study 
participation must be reported. This includes the period in which the study protocol interferes 
with the standard medical treatment given to a patient (e.g., treatment withdrawal during 
washout period, change in treatment to a fixed dose of concomitant medication). The period 
after discontinuing study drug may be extended if there is a strong suspicion that the drug has 
not yet been eliminated. 
 
6.5.1 
Instructions for rapid notification of 
serious adverse events 
 
Reporting responsibility 
 
The principal investigator has the obligation to report all serious adverse events to the FDA, 
IRB, and AstraZeneca. 
 
Reporting of serious adverse events 
For External Sites 
Information about all serious adverse events will be collected and recorded. To ensure 
patient safety, each serious adverse event must be reported to the PI and to the sponsor 


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Drug Substance AZD1775 
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Edition Number 6  
Date: April 8, 2020  
 
 
expeditiously. Moffitt Cancer Center and all participating sites will report SAEs by completing 
an SAE report in OnCore, the electronic data capture system. The SAE must be reported by 
email (affiliate.research@moffitt.org) to the External Site Coordination (ESC) office within 2 
working days. If applicable, the site should also follow protocol guidelines for additional 
reporting to government agencies. See Below. 
All Sites Safety Reporting 
 
Investigators and other site personnel must inform the FDA, via a MedWatch/AdEERs form, of 
any serious or unexpected adverse events that occur in accordance with the reporting 
obligations of 21 CFR 312.32, and will concurrently forward all such reports to AstraZeneca. A 
copy of the MedWatch/AdEERs report must be faxed or emailed to AstraZeneca via the 
AstraZeneca database at the time the event is reported to the FDA. It is the responsibility of 
the investigator to compile all necessary information and ensure that the FDA receives a report 
according to the FDA reporting requirement timelines and to ensure that these reports are also 
submitted to AstraZeneca at the same time. 
 
When reporting to AstraZeneca, a cover page should accompany the MedWatch/AdEERs form 
indicating the following: 
 
• 
Investigator Sponsored Study (ISS) 
 
• 
The investigator IND number assigned by the FDA 
 
• 
The investigator’s name and address 
 
• 
The trial name/title and AstraZeneca ISS reference number 
 
Investigative site must also indicate, either in the SAE report or the cover page, the causality 
of events in relation to all study medications and if the SAE is related to disease progression, 
as determined by the principal investigator. 
 
Send SAE report and accompanying cover page by way of Email to 
AEMailboxClinicalTrialTCS@astrazeneca.com or by fax to AstraZeneca’s  
designated fax line: US: 302-886-4114, ex-US +46 31 776 37 34 
 
 
 
Serious adverse events that do not require expedited reporting to the FDA need to be reported 
to AstraZeneca preferably using the MedDRA coding language for serious adverse events. 
 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to 
the investigational product. All SAEs will be documented. The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 


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Date: April 8, 2020  
 
 
7. 
DATA SAFETY MONITORING PLAN 
7.1 
Data Monitoring Board 
7.1.1 
Risk to Subjects 
 
7.1.1.1 
Human Subject Involvement and Characteristics 
 
 
Human subjects who have the diagnosis of advanced SQCLC are eligible to participate in the 
clinical trial described in this proposal. The risk to subjects will be outlined clearly and in detail 
in the informed consent. Women who are pregnant are not eligible. 
 
7.1.2 
Adequacy of Protection Against Risk 
 
7.1.2.1 
Recruitment and Informed Consent 
Patients who present to the Thoracic Oncology Program at the Moffitt Cancer Center who have 
advanced SQCLC are offered participation in the clinical trial described in this proposal. The 
trial is explained in detail to the patients by one of the physician co-investigators on the trial, 
the patients are given the opportunity to read the informed consent document, they are given 
a chance to ask questions, and finally they sign the informed consent document in the presence 
of a witness. The physician who participates in the informed consent process also documents, 
in a clinic note, the nature of the consent process that occurred. 
 
7.1.2.2 
Protection Against Risk 
To protect participants from excess risk, the above-mentioned study procedures and dose- 
escalation scheme were instituted. Additional protection is provided through the data safety 
and monitoring plan described below. The complete care of each patient, including the clinical 
management of all toxicities, are provided to the patient by physicians at the Moffitt Cancer 
Center. The clinical data are kept in the patient's individual Moffitt Cancer Center hospital 
record. Research data are kept in a locked room with limited access and through OnCore (a 
Web-based, password-protected database), with privacy protected to the full extent of the law. 
Authorized research investigators, the Department of Health and Human Services, and the 
Institutional Review Board may inspect the records. Final approvals have been obtained from 
the IRB. 
 
Additional protection is provided through the data safety and monitoring plan described below. 
 
 
7.1.3 
Importance of the Knowledge to be Gained 
The development of a well-tolerated and effective regimen in a disease could potentially at 
worst add to the armamentarium of available regimens and at best change standard of care. 
Specific strategies to improve the care of patients relapsing following chemotherapy for lung 
cancer are direly needed. 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
7.1.4 
Data Safety and Monitoring Plan 
 
The Data Safety & Monitoring Plan (DSMP) will ensure that this trial is well designed, 
responsibly managed, appropriately reported, and that it protects the rights and welfare of 
patients. The following internal and external review and monitoring processes provide oversight 
and active monitoring of this trial: 
• 
The Principal Investigators (PI) 
• 
The Clinical Trials Office (CTO) 
• 
The Scientific Review Committee (SRC) 
• 
The Protocol Monitoring Committee (PMC); 
• 
The Research Compliance Division (RCD) of the Cancer Center's Compliance Office; 
• 
Institutional Review Board (IRB). 
 
The protocol includes a section that specifies the following with respect to Adverse Event 
reporting: what constitutes an adverse event (versus what is a serious adverse event), the 
entities to which adverse events should be reported, the timing of this reporting, and the person 
or persons responsible for reporting. This includes prompt (within one day of knowledge of the 
event) reporting to the IRB for unanticipated risks to subjects and reporting in writing within five 
working days to the IRB and sponsor. 
 
7.2 
Scientific Review Committee (SRC) 
 
The Cancer Center maintains two full board Scientific Review Committees (SRC), meeting 
every other week (the first Wednesday and third Thursday of every month) as well as one 
Behavioral Ad-Hoc SRC. 
Each SRC conducts a formal internal peer review of all clinical protocols and general scientific 
oversight of interventional clinical research. Protocols are reviewed for scientific merit, 
adequate study design, safety, availability of targeted study population, and feasibility of timely 
completion of all proposed research projects to be conducted by its assigned programs at the 
Cancer Center. Each SRC is responsible for evaluating the risk/benefit assessment and 
corresponding data and safety monitoring plan as part of the scientific review and approval 
process. The SRC will refer any potential conflicts of interest identified in the proposed 
research to the Conflict Committee. 
7.3 
PI Responsibility 
 
The PI of each study is ultimately responsible for every aspect of the design, conduct, and 
actions of all members of the research team. This includes the final analysis  of  the protocol. 
The PI is responsible for ensuring that: 
All protocols include a DSMP and procedures for its implementation commensurate with the 
risk and complexity of the study. The DSMP must include a structured adverse event 
determination, monitoring and reporting system, including standardized forms, and procedures 
for referring and/or treating subjects experiencing adverse events. The plan must include data 
and safety-monitoring procedures for subjects enrolled who may be receiving a part of their 
protocol-required treatment at community sites. 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
In all cases, the PI of the study will have primary responsibility for ensuring that the protocol is 
conducted as approved by the SRC and IRB. The PI will ensure that the monitoring plan is 
followed, that all data required for oversight of monitoring are accurately reported to a DSMB 
and/or to the PMC and IRB as required, that all adverse events are reported according to 
protocol guidelines, and that any adverse  actions reflecting patient  safety  concerns  are 
appropriately reported. 
7.4 
Protocol Monitoring Committee (PMC) 
The PMC meets once a month. The PMC reviews and evaluates safety and/or efficacy data 
for all physician authored clinical intervention trials. The PMC ensures the safety of patients 
and the validity and integrity of data. PMC reviews SAEs, deviations, Interim analysis, interim 
and final reports from the external Data Monitoring Committee (DMC) as well as audits both 
internally and externally. The PMC can make the following determinations, Accepted, 
Acceptable with Corrective Action, and Tabled. 
Investigators of studies, which are designated to be reviewed by the PMC for data and safety 
monitoring, shall provide an interim statistical analysis report of the study’s progress and 
summary of adverse events and deviations based on the phase of the study and the associated 
risk of the study or more often if applicable. The external DSMB (if applicable) shall forward its 
report for high-risk studies designated for external review at least annually or more often if 
applicable. 
7.5 
Research Compliance Division (RCD) 
RCD of the Corporate Compliance Office is the coordinating center for internal audits of clinical 
trials conducted at the Cancer Center and its affiliates. The audit procedure is a formal, 
comprehensive, source document review of all clinical trials. External audit reports that meet 
the criteria of the internal audit may be accepted in lieu of an internal audit. 
The (RCD) shall provide a report to the PMC of internal audit findings for PMC action. A 
representative of the RCD will be present to discuss the audits with the PMC. For cause, audits 
will be discussed during an executive session of the PMC. Only members (voting and ex- 
officio) may attend this session. 
 
 
7.6 
The Institutional Review Board (IRB) 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be reviewed routinely by the MCC Clinical Research Monitoring Core for 
accuracy, completeness and source verification of data entry, validation of appropriate 
informed consent process, adherence to study procedures, and reporting of SAEs and protocol 
deviations according to MCC Monitoring Policies. 
 
The trial will not be initiated without approval of the appropriate Institutional Review Board 
(IRB). All administrative requirements of the governing body of the institution will be fully 
complied with. This protocol, consent procedures, and any amendments must be approved by 
the IRB in compliance with current regulations of the Food and Drug Administration. A letter 
of approval will be sent to the institution(s) funding the study prior to initiation of the study and 
when any subsequent modifications are made. The IRB will be kept informed by the 
investigator as to the progress of the study as well as to any serious or unusual adverse events. 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 6  
Date: April 8, 2020  
 
 
7.7 
Suspension/Termination 
The PMC and/or the IRB may vote to suspend or terminate approval of a research study not 
being conducted in accordance with the IRB, the Cancer Center and/or regulatory requirements 
or that has been associated with unexpected problems or serious harm to subjects. The 
PMC/IRB will notify the PI in writing of such suspension or terminations. It is the responsibility 
of the PMC/IRB Chairperson to ensure prompt written notification of any suspensions or 
terminations of PMC/IRB approval to the relevant Federal Agencies, including OHRP, FDA, 
the study sponsor/funding source and if applicable, the Affiliate Program. 
 
7.8 
Trial Discontinuation 
For reasonable cause, the Investigator and/or sponsor may terminate this study prematurely. 
Conditions that may warrant termination include but are not limited to: the discovery of an 
unexpected, significant, or unacceptable risk to the patients enrolled in the study or if the accrual 
goals are met. A written notification of termination will be issued. 
 
7.9 
Monitoring of the Study and Regulatory 
Compliance 
The Principal Investigator and the Clinical Research Coordinator assigned to the case will be 
primarily responsible for maintaining all study-related documents including the clinical research 
forms. ONCORE will serve as the study database of record. All CRF entries will be verified with 
source documentation and will be maintained by the Data Management Specialist and Clinical 
Research Coordinator. The patient case books will be secured in a locked office within each 
institution’s applicable department. The review of medical records will be done in a manner to 
assure that patient confidentiality is maintained. 
 
For External Sites Only: Data Management and Monitoring/Auditing 
 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be monitored internally according to Moffitt Cancer Center Monitoring 
Policies. Monitoring will be performed regularly to verify data is accurate, complete, and 
verifiable from source documents; and the conduct of the trial is in compliance with the currently 
approved protocol/amendments, Good Clinical Practice (GCP), and applicable regulatory 
requirements. 
 
To obtain access to OnCore, the External Site Coordination (ESC) office Coordinator will 
supply forms required to be completed by the site staff. Once the completed forms are received, 
the site coordinator will receive DUO access, logon/password, and information on how to 
access OnCore. The ESC office will provide OnCore training to the site once initial access is 
granted and on an ongoing basis, as needed. 


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Drug Substance AZD1775 
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Edition Number 5 
Date: August 15, 2019 
 
 
7.10 
Protocol Modifications 
No modifications will be made to the protocol without the agreement of the investigators. 
Changes that significantly affect the safety of the patients, the scope of the investigation, or the 
scientific quality of the study will require Institutional Review Board approval prior to 
implementation, except where the modification is necessary to eliminate apparent immediate 
hazard to human subjects. Any departures from the protocol must be fully documented in the 
case report form and the source documentation. 
 
7.11 
Patient Privacy 
In order to maintain patient confidentiality, all case report forms, study reports, and 
communications relating to the study will identify patients by initials and assigned patient 
numbers. The US Food and Drug Administration (FDA) may also request access to all study 
records, including source documentation for inspection. 
 
7.12 
Records Retention 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to 
the conduct of this study and the distribution of investigational drug, including CRFs, consent 
forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 2 years after marketing application approval. If no application is filed, 
these records must be kept 2 years after the study is discontinued and the U.S. FDA and the 
applicable national and local health authorities are notified. 
 
 
8. 
BIOLOGICAL SAMPLING PROCEDURES 
8.1 
Pharmacodynamics 
 
 
8.1.1 
Collection of pharmacodynamic 
markers 
In summary, archival tumor specimens and optional serial tumor biopsies will be collected. 
These samples will be used to evaluate potentially predictive biomarkers and complete other 
correlative studies. Archival tissue specimens will be collected on all participants. Approximately 
125 μL of tumor sample is required for this purpose. Fresh tumor specimens will be collected by 
image-guided biopsy for those without available archival tissue. In addition optional pre- and 
post-treatment tumor biopsies will be obtained on at least 7-10 total patients during the study. 
The biopsies will be performed under image guidance (including but not limited to CT or 
ultrasound-guided core biopsies) as determined by the location of tumor and risks associated 
with each procedure. Tumor biopsies will be performed pretreatment and at cycle 1, day 15 ± 
7 days. 
 
The tumor collected through these methods will be analyzed to explore whether positive vs. 
negative biomarkers could predict response and resistance to the AZD1775-carboplatin- 


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Drug Substance AZD1775 
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Edition Number 5 
Date: August 15, 2019 
 
 
paclitaxel combination. More specifically for the fresh tumor biopsies, on-site evaluations for 
tissue quality will be performed by the cytotechnologist to ensure viable tissue and for collection 
of adequate tumor sample. Four to 6 core biopsy samples will be collected. At a minimum, 2 
will be placed in neutral-buffered formalin and embedded in paraffin wax and two core needle 
samples will be snap frozen and stored in liquid nitrogen. 
 
Immunohistochemistry will be used to assess the levels of the proposed molecules (WEE1, 
PAXIP 1, p53 in order of priority) in histological tumor collected before and after therapy where 
appropriate. Additional biomarkers may be explored including but not limited to cleaved Parp. 
We will utilize advanced NGS DNA analyses to test and identify the p53 mutation type,. 
Further, exploratory correlative studies may be completed based on the additional data 
obtained from the utilization of an advanced DNA platform for p53 testing. The collection and 
interpretation of additional data has the potential to help address some of the critical barriers 
for effective personalized treatment. 
 
8.1.2 
Molecular Analyses 
After obtaining the results from IHC, the associations between the biomarkers (PAXIP1 and 
WEE1) will be made using Spearman’s correlation coefficient. 
 
We will also test whether p53 mutation status (yes/no as determined by sequencing) is 
associated with patient response (CR+PR) using the unconditional test.16 
 
In addition, univariable analyses (Cox regression analysis) will be performed to see whether 
the markers predict for PFS. The impact of the change in markers on PFS (and overall survival) 
and response will be examined using Cox proportional hazard model and logistic regression, 
respectively. The three biomarkers (WEE1, PAXIP1, and p53) will be tested separately and 
will be considered significant if P < 0.05. The change in both the PAXIP1 and WEE1 marker 
scores will be assessed using the normal scores test. All analyses will be carried out using 
SAS 9.3 statistical software (SAS, Inc, Cary, NC). 
 
Pre- and post-treatment biopsies will be obtained on at least 7-10 total patients from the 
SQCLC study. The biopsies will be performed under image guidance (including but not limited 
to CT or ultrasound-guided core biopsies) as determined by the location of tumor and risks 
associated with each procedure. Tumor biopsies will be performed pretreatment and at cycle 
1, day 15 ± 7 days. Here we will explore the extent to which changes between pre- and post- 
treatment levels correlate with response. This will be done on the percent change from the 
pre-treatment values for the 3 biomarkers using the Wilcoxon signed rank test at α = .05. 
 
 
 
8.2 
Handling, storage and destruction of 
biological samples 
8.2.1 
Handling 
 
The handling of the tissue samples will be per the laboratory manual. 


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8.2.2 
Shipping 
Tissue samples are to be Shipped to Dr Alvaro Monteiro’s laboratory at: 
Alvaro Monteiro’s Laboratory 
12902 Magnolia Drive, MRC-3 West 
Tampa Florida 336122 
813-745-6321/3322 
ALVARO.MONTEIRO@MOFFITT.ORG 
 
 
 
9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
9.1 
Description of analysis sets 
Demographic and other baseline data (including disease characteristics) will be 
summarized descriptively for the ITT, safety and per protocol populations. 
Categorical data will be presented as frequencies and percentages. For 
continuous data, mean, standard deviation, median, minimum, and maximum 
will be presented. 
9.1.1 
Evaluable for response analysis set 
Consists of all patients treated whom have a radiographic assessment for 
evaluation by RECIST v 1.1 following at least 3 days of treatment. 
 
9.1.2 
Safety analysis set 
Consists of all patients who received at least one dose of study drug and had at least 
one post-baseline safety assessment. 
Please note: the statement that a patient had no adverse events (on the Adverse 
Event CRF) constitutes a safety assessment. Patients who have received at least 
one dose of study drug but who have no post-treatment safety data of any kind would 
be excluded from the safety population. 
9.2 
Methods of statistical analyses 
Sample Size Justification. Historical data indicate a median PFS/time to progression of about 
4 months for newly diagnosed, advanced-stage NSCLC patients treated with platinum doublet 
chemotherapy.11-13,17,18 With a one-sided significance level of 0.10, a total of 51 patients will 
provide 91% power (obtained from PASS 13) to assess a median PFS of 4.0 months against 
a median PFS of 6.5 months (HR = 0.615). It is assumed that the accrual time will be 30 
months. We expect to enroll 75 patients to have 51 evaluable subjects. 
 
Statistical Considerations for the Primary Objective. 
PFS. PFS is measured from date first study treatment to death, progression of disease, or the 
last follow-up data, whichever comes first. The final analysis will be undertaken when all 
patients have been followed for at least 6 months. With our assumptions, we anticipate that 


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Date: August 15, 2019 
 
 
roughly 24 patients would have had an event at 6 months, compared to an expectation of 33 
events if AZD1775 wasn’t part of the treatment regimen. The median survival will be estimated 
assuming an exponential distribution,19 with patients not progressing at one year being 
censored at that time (3 times the null hypothesis median PFS). 
 
We will test for the exponentiality of the survival distribution using the RPEXE fit19   with α = 
0.10. The exponential distribution assumption will be considered to hold until the first 
changepoint identified. If no changepoint is identified, exponentiality will be considered to hold 
to the median follow-up time of censored cases. If the exponential distribution is found not to 
hold to at least 8 months (two times the null hypothesis median survival), the lower 80% 
confidence bound of the Kaplan-Meier estimated median survival time (which corresponds to 
a one-sided test at α = 0.10) will be used to assess whether the median survival is greater than 
4.0 months. 
 
 
 
Statistical Considerations for the Secondary Objectives. 
Overall survival analysis (OS). The median OS of treated stage IV SQCLC patients is ~ 10 
months20. The median OS for patients treated with AZD1775 plus carboplatin/paclitaxel is 
unknown, but hypothesized to be greater than that of patients treated with chemotherapy alone. 
We will be able to estimate whether or not this is true by comparing the median OS of study 
patients with the historical control value of 10 months. The median survival will be estimated 
assuming an exponential distribution 19  with patients not progressing at 2.5 years being 
censored at that time (3 times the null hypothesis median OS). 
 
 
Duration of response analysis. We will also estimate the duration of response using an 
exponential distribution survival model.19 Disease control rates, DCR, ORR, SD, and PR will 
be summarized appropriately. 
 
 
 
 
10. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
10.1 
Overdose 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives within 
one day, i.e., immediately but no later than the end of the next business day of when he or 
she becomes aware of it. 
 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 


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10.2 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca through the same procedure 
as reporting SAE’s described in section 6.5.1. 
 
11. 
ADMINISTRATIVE PROCEDURES 
11.1 
Regulatory and Ethical Compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC and US Code of Federal 
Regulations Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the Investigator and 
IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC/REB must be given to AstraZeneca 
before study initiation. 
 
 
11.3 
Informed Consent 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they should 
not be entered in the study. 
 
 
11.4 
Optional Biopsy Consent 
Studies with an optional biopsy component will have a separate acknowledgement covering 
those studies. This will be adapted for each Study based on a standard template used globally 
for all Studies. The optional biopsy informed consent will be submitted for ethical approval 
together with the Study Protocol and as part of the main informed consent form of the Study. If 


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Drug Substance AZD1775 
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Date: August 15, 2019 
 
 
a subject opts not to participate in the optional biopsy assessments, this in no way affects the 
subject’s ability to participate in the main research Study. 
 
 
11.5 
Amendments to the Protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by AstraZeneca, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol amendments, 
the investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
AstraZeneca should be notified of this action and the IRB/IEC/REB at the study site should be 
informed within 10 working days. 
 
 
 
11.6 
Monitoring 
Data will be captured in OnCore, Moffit’s Clinical Trials Database. Regulatory documents and 
case report forms will be monitored internally according to Moffitt Cancer Center Monitoring 
Policies.  Monitoring will be performed regularly to verify data is accurate, complete, and 
verifiable from source documents; and the conduct of the trial is in compliance with the 
currently approved protocol/amendments, Good Clinical Practice (GCP), and applicable 
regulatory requirements.” 
11.7 
Study Drug Supply and Resupply, 
Storage, and Tracking/Drug 
Accountability 
Study drugs must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, the AZD1775 should be stored according to 
the instructions specified on the drug labels. Clinical supplies are to be dispensed only in 
accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and the medication number but no 
information about the patient. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Patients will be asked to return all unused study drug and 
packaging at the end of the study or at the time of study drug discontinuation. 


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12. 
PROTOCOL ADHERENCE 
12.1 
Investigators ascertain they will apply 
due diligence to avoid protocol 
deviations 
Publication of results: Any formal presentation or publication of data from this trial may be 
published after review and comment by AstraZeneca and prior to any outside submission. 
AstraZeneca must receive copies of any intended communication in advance of publication (at 
least fifteen working days for presentational materials and abstracts and thirty working days for 
manuscripts). These requirements acknowledge AstraZeneca’ responsibility to provide peer 
input regarding the scientific content and conclusions of such publications or presentations. 
Principal Investigation/Institution shall have the final authority to determine the scope and 
content of its publications, provided such authority shall be exercised with reasonable regard 
for the interests of AstraZeneca and, in accord with the trial contract and shall not permit 
disclosure of AstraZeneca confidential or proprietary information. 
12.2 
Disclosure and Confidentiality 
The investigator agrees to keep all information provided by AstraZeneca in strict confidence 
and to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by AstraZeneca (investigators' brochures and other material) will be stored 
appropriately to ensure their confidentiality. The information provided by AstraZeneca to the 
investigator may not be disclosed to others without direct written authorization from 
AstraZeneca, except to the extent necessary to obtain informed consent from patients who 
wish to participate in the trial. 
 
 
13. 
ETHICS AND GOOD CLINICAL PRACTICE 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in AstraZeneca standard operating procedures and: 
1. 
ICH  Harmonized  Tripartite  Guidelines  for  Good  Clinical  Practice  1996.  Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
2. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects). 
The investigator agrees to adhere to the instructions and procedures described in it and thereby 
to adhere to the principles of Good Clinical Practice that it conforms to. 
 
 
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Parker LL, Piwnica-Worms H. Inactivation of the p34cdc2-cyclin B complex by the 
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Drug Substance AZD1775 
Study Number 18304 
Edition Number 5 
Date: August 15, 2019 
 
 
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AACR. 
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Munoz IM, Jowsey PA, Toth R, Rouse J. Phospho-epitope binding by the BRCT 
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Cho EA, Prindle MJ, Dressler GR. BRCT domain-containing protein PTIP is essential 
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Borisy AA, Elliott PJ, Hurst NW, et al. Systematic discovery of multicomponent 
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Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab 
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14. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
15. 
Schwartz LH, Bogaerts J, Ford R, et al. Evaluation of lymph nodes with RECIST 1.1. 
Eur J Cancer 2009;45:261-7. 
16. 
Lydersen S, Fagerland MW, Laake P. Recommended tests for association in 2 x 2 
tables. Stat Med 2009;28:1159-75. 
17. 
Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination 
with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in 
patients with advanced non-small-cell lung cancer: final results of a phase III trial. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2012;30:2055- 
62. 
18. 
Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced- 
stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543-51. 
19. 
Han G, Schell MJ, Kim J. Improved survival modeling in cancer research using a 
reduced piecewise exponential approach. Stat Med 2014;33:59-73. 


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Drug Substance AZD1775 
Study Number 18304 
Edition Number 5 
Date: August 15, 2019 
 
 
20. 
Socinski MA, Okamoto I, Hon JK, et al. Safety and efficacy analysis by histology of 
weekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients with 
advanced non-small-cell lung cancer. Ann Oncol 2013;24:2390-6. 


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Clinical Study Protocol 
Drug Substance 
AZD1775 
Study Code 
Edition Number 
1 
Date 
22 October 2014 
Protocol Dated 
22 October 2014 
Appendix A 
Disallowed Medications 
 
 
 
 
15. 
APPENDIX A: DISALLOWED MEDICATIONS AND 
MEDICATIONS TO BE ADMINISTERED WITH CAUTION 
 
Formal drug-drug interaction studies have not yet been performed with AZD1775, therefore, 
the potential for drug-drug interaction described in this protocol are based on findings from in 
vitro studies and clinical experience. 
 
In vitro data has shown that AZD1775 is metabolized predominantly by CYP3A4, with an FMO3 
and/or FMO5 component. As a result, there is potential for the exposure of AZD1775 to be 
effected by drugs which inhibit or induce the metabolism of CYP3A4. In the clinic, 
coadministration of AZD1775 with the moderate CYP3A4 inhibitor, aprepaitant, resulted in a 
60% increase in the plasma levels of AZD1775. Drugs known to be moderate to strong 
inhibitors/inducers of CYP3A4 are therefore prohibited for use in the current study, including 
aprepitant. 
 
In vitro data suggests that AZD1775 may be a weak reversible inhibitor of CYP2C19 (IC50 12 
uM). Caution should therefore be exercised when AZD1775 is coadministered with agents that 
are sensitive substrates of CYP2C19, or substrates of this enzyme with a narrow therapeutic 
range. 
 
Based on in vitro studies, AZD1775 has been shown to be a weak reversible inhibitor (IC50 14 
µM) and a time-dependent inhibitor of CYP3A4 (Kinact 0.061/min, Ki 6.04 µM). The full impact 
of the time dependent inhibition is currently unknown, however, modeling data has predicted 
an 8-10 fold increase in the exposure of sensitive CYP3A4 substrates when administered with 
AZD1775 (250 mg BID for 5 doses). To date, no significant DDI effects have been reported in 
the clinic that may be related to the TDI finding.  However, sensitive CYP3A4 substrates or 


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substrates of CYP3A4 with a narrow therapeutic window are prohibited. 
 
AZD1775 has been shown to be a weak inducer of CYP1A2 in vitro (39% increase in activity 
of positive control). Given the nature of the AZD1775 dosing schedule, however, the risk of 
induction in the clinic is considered low. No specific precautions are recommended at this time, 
except to be initially vigilant when using substrates of CYP1A2 with a narrow therapeutic range. 
 
Transporter studies (in vitro) have shown that AZD1775 is both a substrate and inhibitor 
(IC50 20 µM) of P-gp. Maximum impact of these finding is likely to occur for drugs 
administered orally at the same time as AZD1775. Caution should therefore be exercised 
when agents that are inhibitors or substrates of P-gp are administered concomitantly with 
AZD1775. 
 
Recent in vitro transporter studies have shown AZD1775 to be an inhibitor of BCRP (IC50 5.1 
µM). This finding is particularly relevant for drugs administered orally where exposure is 
normally limited by BCRP-mediated efflux, in particular some statins.  Modeling has predicted 
a substantial increase in the exposure of Atorvastatin when coadministered with Clinical Study 
Protocol Appendix D Drug Substance AZD1775 Study Code D6011C00003 Edition Number 1 
Date 22 October 2014 
 
AZD1775 and the use of Atoravastatin is therefore prohibited in the current study. Other drugs 
where the disposition is mediated via BCRP should be administered with caution, dose 
modification considered or substituted by an alternative drug. 
 
Use of metformin is prohibited in this study as recent in vitro transporter data have shown 
AZD1775 is an inhibitor of Multidrug and Toxin Extruder 1 (MATE1) and MATE2K. Caution 
should be used when administering drugs that are substrates of these transporters (e.g. 
cimetidine, acyclovir, fexofenadine) as the clinical relevance of AZD1775 inhibition of the MATE 
pathway is not known in these compounds. 
 
Herbal preparations/medications can be substrates, inhibitors and inducers, similar to any 
registered medication. Herbal preparations are therefore not allowed throughout the study. 
These herbal medications include, but are not limited to: St. John’s wort, kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and 
ginseng. 
 
In addition, any other drugs should be avoided at the Investigator’s discretion if, in their 
opinion, the co-administration with AZD1775 may increase the risk of a clinically significant 
drug interaction. 
 
A list of the main CYP3A4 substrates, inhibitors (strong and moderate) and inducers, 
CYP2C19 substrates, P-gp substrates and inhibitors and BCRP substrates are shown 
below. This is not an exhaustive list and further details can be found at Expert Opin. Drug 
Metab. Toxicol. (2013) 9(6):737-751. 


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CYP3A Inhibitors 
Strong 
• 
Clarithromycin 
• 
Telithromycin 
• 
Ketoconazole 
• 
Itraconazole 
• 
Fluvoxamine 
• 
Nefazodone 
• 
Ritonavir 
• 
Indinavir 
• 
Nelfinavir 
• 
Saquinavir 
• 
Atazanavir 
• 
Amprenavir 
 
• 
Conivaptan 
• 
Fosamprenavir 
• 
Grapefruit Juice 
• 
Telaprevir 
• 
Troleandomycin 
 
Moderate 
• 
Aprepitant 
• 
Cimetindine 
• 
Diltiazem 
• 
Erythromycin 
• 
Fluconazole 
• 
Imatinib 
• 
Nifedipine 
• 
Posaconazole 


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• 
Seville oranges 
• 
Star fruit 
• 
Verapamil 
 
 
CYP3A Inducers (strong and moderate) 
• 
Barbutrates 
• 
Bosentan 
• 
Carbamazepine 
• 
Efavirenz 
 
• 
Etavirine 
• 
Nafcillin 
• 
Nevaripine 
• 
Pheonobarbitone 
• 
Phenytoin 
• 
Rifampin 
• 
St. John’s Wort 
 
 
CYP3A4 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 
• 
Alfentanil 
• 
Alfuzosin 
• 
Amiodarone 
• 
Bexaroine 
• 
Bortezomib 
• 
Carbazitaxel 
• 
Cyclophosphamide 
• 
Cyclophosporine 
• 
Dasatinib 
• 
Dihydroergotamine 
• 
Disopyramide 


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• 
Docetaxel 
• 
Dofetilide 
• 
Ebastine 
 
• 
Eletriptan 
• 
Eplerenone 
• 
Ergotamine 
• 
Erlotinib 
• 
Etoposide 
• 
Everolimus 
• 
Fentanyl 
• 
Gefitinib 
• 
Halofantrine 
• 
Ifosfamide 
• 
Ironotecan 
• 
Imatinib 
• 
Ixabepilone 
• 
Lapatinib 
• 
Mosapride 
• 
Nilotinib 
• 
Paclitaxel 
• 
Pazopanib 
• 
Pimozide 
• 
Propafenone 
• 
Propofol 
• 
Quinidine 
• 
Ranolazine 
• 
Romidepsin 


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Clinical Study Protocol Appendix D Drug Substance AZD1775 Study Code D6011C00003 
Edition Number 1 Date 22 October 2014 
• 
Sirolimus 
• 
Sorafenib 
• 
Sunitinib 
• 
Tacrolimus 
• 
Temsirolimus 
• 
Theoophylline 
• 
Thioridazine 
• 
Thiotepa 
• 
Tretinoin 
• 
Vinblastine 
• 
Vincristine 
• 
Vinorelbine 
 
 
CYP2C19 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 
• 
Bortezomib 
• 
Cyclophosphamide 
• 
Phenytoin 
• 
S-mephenytoin 
 
 
CYP1A2 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 
• 
Alosetron 
• 
Duloxetine 
• 
Erlotinib 


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• 
Lidocaine 
• 
Mexilietine 
• 
Propafenone 
• 
Tacrine 
• 
Theophylline 
• 
Tizanidine 
 
 
P-gp Substrates 
Digoxin. 
 
– 
if a patient requires initiation of digoxin during the study, or is already receiving 
treatment with digoxin, monitoring of digoxin levels is recommended according 
to local practice (as the levels of digoxin may increase).  Monitoring of digoxin 
levels is also recommended when the patient has completed dosing with study 
treatment (as the levels of digoxin may then decrease). 
 
 
P-gp Inhibitors (strong) 
• 
Quinidine 
• 
Valspodar 
 
 
BCRP Substrates 
• 
Atorvaststin 
• 
Fluvastatin 
• 
Rosuvastatin 
• 
Simvastatin 
• 
Topotecan