A Phase I Study of Single-agent AZD1775 (MK-1775), a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors
Phase: PHASE1
Conditions: Solid Tumors
Sponsor: National Cancer Institute (NCI)

CTEP # 9350 
Clinical Center # 13-C-0032 
 
 
 
 
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TITLE:  A Phase I Study of Single-agent AZD1775 (MK-1775), a Wee1 Inhibitor, in 
Patients with Advanced Refractory Solid Tumors 
Abbreviated Title: Ph I study of AZD1775 
 
Coordinating Center: 
Developmental Therapeutics Clinic (NCIDTC) 
 
National Cancer Institute 
 
10 Center Drive 
 
 
 
 
 
 
 
 
 
 
 Bethesda, MD 20892 
 
Principal Investigator: 
Naoko Takebe, MD, PhDA-E 
 
31 Center Drive 
 
Bldg 31 Room 3A44 
 
Bethesda, MD 20892  
 
Phone: (240) 781-3398 
 
Fax: (240) 541-4515 
 
takeben@mail.nih.gov 
NCI Associate Investigators: 
A. P. Chen, MD, DCTDA-E 
 
James H. Doroshow, MD, DCTDA-E 
Richard Piekarz, MD, PhD, DCTDA-E 
Howard Streicher, MD CTEP, DCTDA-E 
Geraldine O’Sullivan Coyne, MD, PhD, CCRA-E  
Sheila Prindiville, MD, MPH, DCTDA-E 
 
Non-NCI Associate Investigators:  Lamin Juwara, CRNP Leidos Biomed, FNLCRA,B,E 
 
Referral Contact: 
Ashley Bruns, RNA,B,E 
 
Bldg 10/Rm 8D53 
 
Phone: (240) 858-3162; Fax: (301) 451-5625 
 
ashley.bruns@nih.gov 
 
Statistician: 
Larry Rubinstein, PhD, BRB/DCTDE 
 
9609 Medical Center Dr. Rm 5W106 
 
Phone: (240) 276-6026 
 
rubinsteinl@mail.nih.gov 
 
 
NCI Supplied Agent:  
 
AZD1775 (MK-1775) (NSC 751084) 
 
IND Number: 
 
116495 
 
NCT Number: 
 
NCT01748825 
 
Version Date: 
September 11, 2020 
 
Roles: Aobtains information by intervening or interacting with living individuals for research 
purposes; Bobtains identifiable private information about living individuals; Cobtains the 
voluntary informed consent of individuals to be subjects; Dmakes decisions about subject 

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eligibility; Estudies, interprets, or analyzes identifiable private information or data/specimens for 
research purposes 
 

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PRÉCIS 
Background: 
• Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of cyclin-
dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest in 
response to DNA damage to allow time for DNA repair.  Recent preclinical data additionally 
implicates Wee1 in maintenance of genomic integrity during S phase.  
• AZD1775 (formerly known as MK-1775) is a selective inhibitor of Wee1 kinase.  Recent 
preclinical model data additionally show single agent anti-tumor activity in multiple cancer 
cell lines and tumor xenografts. 
• Preliminary data show AZD1775 is tolerable at lower doses in combination with 
chemotherapeutic agents.  We propose to demonstrate single-agent activity for AZD1775.  
 
Primary Objective: 
• To establish the safety and tolerability of single-agent AZD1775 in patients with refractory 
solid tumors 
• To determine the pharmacokinetics of AZD1775 in patients with refractory solid tumors 
 
Secondary Objectives: 
• To evaluate the antitumor activity of AZD1775 in patients with refractory solid tumors 
 
Exploratory Objectives: 
• To determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor 
tissue and circulating tumor cells 
• To assess whether sufficient Wee1 inhibition is maintained throughout the therapeutic regimen 
• To identify tumor genomic alterations and gene expression patterns potentially associated with 
AZD1775 antitumor activity 
 
Eligibility: 
• Patients must have histologically confirmed solid tumors for which all standard therapy 
known to prolong survival have failed, or for which standard therapies do not exist. 
• No major surgery, radiation, or chemotherapy within 3 weeks (or 5 half-lives, whichever is 
shorter) prior to entering the study 
• Adequate organ function 
 
Study Design: 
• This study will follow a traditional 3+3 design. 
• In Arm A starting at dose level 1, AZD1775 will be administered orally, BID, for 5 doses (D1-
3) during each cycle.  Starting at dose level 2 and onwards, AZD1775 will be administered 
orally, BID, for 5 doses for the first 2 weeks of each cycle (D1-3 and 8-10).  Each cycle is 21 
days (± 1 day for scheduling). 
• Once MTD is established, 6 additional patients will be enrolled at the MTD to further evaluate 
that dose for PK and PD endpoints. 
• A further expansion arm of 6 additional patients with documented tumors harboring BRCA-1 
or -2 mutations will also be enrolled at the MTD to further explore the safety of the agent and 
obtain preliminary evidence of activity in this patient population. 

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• Based on preliminary evidence of drug activity in an alternative once-daily dosing schedule, 
patients without a documented BRCA mutation will be accrued to a once-daily dosing 
schedule Arm B, with mandatory paired tumor biopsies at the maximum tolerated single daily 
dose, to further evaluate PD endpoints.  AZD1775 will be administered orally once daily for 5 
days (D1-5 and 8-12) during weeks 1 and 2 of each 21-day cycle (± 1 day for scheduling). 
• During the escalation phase, tumor biopsies will be optional and will be evaluated for 
pharmacodynamic (PD) studies for evidence of Wee1 inhibition, DNA damage and repair, and 
apoptosis (γH2AX, pNbs1, Rad51, pTyr15-Cdk, and caspase 3).  During the expansion phase, 
once MTD is reached, mandatory paired tumor biopsies will be pursued in up to 20 additional 
patients enrolled at the MTD to further evaluate PD endpoints.

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a   During the escalation phase, optional paired tumor biopsies will be performed at baseline (pre-
treatment) and 2-5 hours after the 5th dose of AZD1775 on C1D3.  In instances where there is a 
scheduling conflict, biopsies may be performed within + 1 day of the 5th dose of C1D3.  
During the expansion phase, paired tumor biopsies will be mandatory in the six additional 
patients enrolled at the MTD.  Tumor biopsies will be optional in the 6-patient BRCA mutation 
MTD expansion arm.   
 
b  Blood samples for PK analyses will be collected at the following timepoints: 
C1D1: Prior to the initial first dose, and at 1, 2, 4, 6, and 8 hours after the first dose 
C1D2: Prior to the 3rd dose administered on day 2 
C1D3: Prior to the 5th dose, and 1, 2, 4, 6, and 8 hours after the 5th dose administered on day 3 
Additional PK sampling will be optional (but encouraged).  This sampling would occur 24 and 
48 hours after the 5th dose of AZD1775, and will occur on Days 4 and 5, respectively (not 
reflected in Flow Chart). 
 
c  Circulating tumor cells will be obtained at baseline, and 2-5 hours after the 5th dose of 
AZD1775 during cycle 1 and cycle 2 
 
 
Dose Escalation Schedule for Arm A 
Dose Level 
AZD1775 (orally BID) x 5 doses/weeks 
-1 
200 mg BID x 5 doses (days 1-3) for 1 week 
1 
225 mg BID x 5 doses (days 1-3) for 1 week 
2 
225 mg BID x 5 doses (days 1-3 each week) for 2 weeks 
3 
300 mg BID x 5 doses (days 1-3 each week) for 2 weeks 
4 
400 mg BID x 5 doses (days 1-3 each week) for 2 weeks 
5 
550 mg BID x 5 doses (days 1-3 each week) for 2 weeks 
 
 
 

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Dose Escalation Schedule for Arm B 
Dose Level 
AZD1775 (orally once daily) 
-1 
200 mg daily D1-3 each week for 2 weeks 
1 
200 mg daily D1-5 each week for 2 weeks 
2 
225 mg daily D1-5 each week for 2 weeks 
3 
250 mg daily D1-5 each week for 2 weeks 
4 
300 mg daily D1-5 each week for 2 weeks 
5 
400 mg daily D1-5 each week for 2 weeks 
6 
500 mg daily D1-5 each week for 2 weeks 

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TABLE OF CONTENTS 
SUMMARY OF CHANGES ......................................................... Error! Bookmark not defined. 
TITLE:  A Phase I Study of Single-agent AZD1775 (MK-1775), a Wee1 Inhibitor, in 
Patients with Advanced Refractory Solid Tumors ...............................................................1 
PRÉCIS ............................................................................................................................................3 
SCHEMA (Arm A) ..........................................................................................................................5 
SCHEMA (Arm B) ..........................................................................................................................7 
1 
OBJECTIVES ....................................................................................................................11 
1.1 
Primary Objectives .................................................................................................11 
1.2 
Secondary Objective ..............................................................................................11 
1.3 
Exploratory Objectives ..........................................................................................11 
2 
BACKGROUND ...............................................................................................................11 
2.1 
Cell Cycle Regulation ............................................................................................11 
2.2 
AZD1775 ...............................................................................................................12 
2.3 
Rationale ................................................................................................................13 
2.4 
Correlative Studies Background ............................................................................19 
2.5 
Genetic Sequencing Research Ethics .....................................................................22 
3 
PATIENT SELECTION ....................................................................................................23 
3.1 
Eligibility Criteria ..................................................................................................23 
3.2 
Exclusion Criteria ..................................................................................................25 
3.3 
Inclusion of Women and Minorities ......................................................................25 
3.4 
Eligibility Screening ..............................................................................................25 
4 
REGISTRATION PROCEDURES ...................................................................................26 
5 
TREATMENT PLAN ........................................................................................................27 
5.1 
Agent Administration .............................................................................................28 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................30 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................32 
5.4 
Duration of Therapy ...............................................................................................34 
5.5 
Duration of Follow Up ...........................................................................................34 
5.6 
Criteria for Removal from Study ...........................................................................34 
6 
DOSING DELAYS/DOSE MODIFICATIONS................................................................34 
6.1 
Dose Reduction ......................................................................................................35 
6.2 
Definition of Complete Course ..............................................................................35 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................35 
7.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR) ......................36 
7.2 
Adverse Event Characteristics ...............................................................................39 
7.3 
Expedited Adverse Event Reporting ......................................................................40 
7.4 
Routine Adverse Event Reporting .........................................................................45 
7.5 
Secondary Malignancy ...........................................................................................46 
7.6 
Second Malignancy ................................................................................................46 
8 
PHARMACEUTICAL INFORMATION ..........................................................................46 

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8.1 
AZD1775 (NSC 751084) .......................................................................................46 
8.2 
Agent Ordering, Accountability, and Investigator Brochure Availability .............48 
9 
CORRELATIVE/SPECIAL STUDIES .............................................................................49 
9.1 
Pharmacokinetics ...................................................................................................50 
9.2 
Pharmacodynamics ................................................................................................50 
9.3 
Exploratory whole-exome and RNA sequencing ..................................................56 
10 
STUDY CALENDAR .......................................................................................................58 
11 
MEASUREMENT OF EFFECT........................................................................................61 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................61 
11.2 
Guidelines for Evaluation of Measurable Disease .................................................63 
11.3 
Response Criteria ...................................................................................................65 
11.4 
Duration of Response .............................................................................................68 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................68 
12.1 
Data Reporting .......................................................................................................68 
12.2 
CTEP Multicenter Guideline .................................................................................68 
12.3 
Collaborative Agreements Language .....................................................................68 
12.4 
Genomic Data Sharing Plan ...................................................................................70 
13 
STATISTICAL CONSIDERATIONS...............................................................................70 
13.1 
Study Design/Endpoints.........................................................................................70 
13.2 
Study Design ..........................................................................................................71 
13.3 
Sample Size/Accrual Rate ......................................................................................71 
13.4 
Analysis of Exploratory Endpoints ........................................................................72 
13.5 
Reporting and Exclusions ......................................................................................72 
14 
HUMAN SUBJECTS PROTECTIONS ............................................................................73 
14.1 
Justification for Subject Selection .........................................................................73 
14.2 
Evaluation of Benefits and Risks/Discomforts ......................................................73 
14.3 
Consent and Assent Process and Documentation ..................................................74 
14.4 
Procedure for Protecting Against or Minimizing Any Potential Risks ..................74 
14.5 
Patient Advocate ....................................................................................................74 
REFERENCES .............................................................................................................................75 
1. 
APPENDIX A: PERFORMANCE STATUS CRITERIA .................................................77 
2. 
APPENDIX B: AZD1775 (MK-1775) Activity in the NCI-60 Cell Line Screen .............78 
3. 
APPENDIX C: POTENTIAL DRUG INTERACTIONS..................................................79 
4. 
APPENDIX D: PATIENT’S MEDICATION DIARY - AZD1775 ..................................83 
5. 
APPENDIX E: INFORMATION ON POSSIBLE INTERACTIONS WITH 
OTHER AGENTS FOR PATIENTS AND THEIR CAREGIVERS AND NON-
STUDY HEALTH CARE TEAM .....................................................................................89 
6. 
APPENDIX F: PK/PD COLLECTION WORKSHEET ...................................................91 

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1 OBJECTIVES 
1.1 
Primary Objectives 
• To establish the safety and tolerability of single-agent AZD1775 (formerly known as 
MK-1775) in patients with refractory solid tumors. 
• To determine the pharmacokinetics of single-agent AZD1775 in patients with 
refractory solid tumors. 
1.2 
Secondary Objective 
• To evaluate the antitumor activity of AZD1775 in patients with refractory solid 
tumors. 
1.3 
Exploratory Objectives 
• To determine the effect of AZD1775 on markers of DNA damage and apoptosis in 
tumor tissue and circulating tumor cells (CTCs). 
• To assess whether sufficient Wee1 inhibition is maintained throughout the therapeutic 
regimen. 
• To identify tumor genomic alterations and gene expression patterns potentially 
associated with AZD1775 antitumor activity. 
 
2 BACKGROUND 
2.1 
Cell Cycle Regulation 
Cell cycle regulation depends on a delicate balance between cyclins, cyclin-dependent 
 kinases (Cdks) that allow for progression through the cell cycle, and Cdk inhibitors that 
halt progression in the setting of DNA damage.  DNA replication during S phase 
generates intermediate DNA structures that are vulnerable to genotoxic insults.  In 
addition, oncogenes can induce lesions at replication forks, further exacerbating genomic 
instability.  In response to DNA damage, surveillance protein complexes such as 
Mre11/Rad50-Nbs1 complex and Rad9/Rad1/Hus1 complex recruit repair proteins and 
halts cell cycle progression, allowing time for DNA repair.  Ataxia-telangectasia mutated 
(ATM) protein kinase and ataxia-telangectasia-related (ATR) protein kinase, two 
 members of the phosphatidyl inositol 3-kinase-like kinase (PIKK) family, are central to 
the DNA damage repair process.  Depending on the type of genotoxic stress, either ATM 
 or ATR is preferentially activated1.  ATM is primarily activated in response to double-
 stranded DNA breaks, while ATR is activated by a broader spectrum of genotoxic stimuli 
and primarily activated in response to single-strand DNA breaks.  
 
ATM/ATR kinases regulates cell cycle checkpoints by phosphorylation of multiple 
downstream proteins, including proteins associated with the recognition of double-
stranded DNA breaks such histone H2AX, proteins involved in the assembly of protein 
complexes at the site of DNA damage, and effector kinases such as checkpoint kinase 1/2 

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(Chk1) and (Chk2).  In contrast to Chk2, Chk1 can be activated by both ATM and ATR, 
and activation can occur during normal cell cycle progression or in response to replicative 
stress2.  Activated Chk1 in turn concomitantly phosphorylates Wee1 and Cdc25C, 
thereby activating Wee1 kinase activity and inactivating Cdc25C phosphatase activity.  
Wee1 is a tyrosine kinase implicated in the inhibitory phosphorylation of CDK1/CDC2-
bound cyclin B complex responsible for G2 arrest3.  Originally identified in fission 
yeast4, wee 1 deficiency resulted in premature mitotic entry and replication of smaller-
sized yeast.  Wee1 belongs to a family of protein kinases involved in the terminal 
phosphorylation and inactivation of (CDK1/CDC2)-bound cyclin B via phosphorylation 
of its Tyr15 residue near the ATP-binding pocket (pTyr15-Cdk), resulting in G2 cell 
cycle arrest in response to DNA damage.  Wee1 overexpression has been demonstrated in 
hepatocellular carcinoma5, luminal and HER-2 positive breast cancers6, colon, lung 
carcinoma, and seminoma tumor samples7. 
2.2 
AZD1775 
Mechanism of Action 
AZD1775, is a selective, adenosine-triphosphate (ATP) competitive, small molecule 
inhibitor of Wee1 kinase (IC50 = 5.18nM), that directly inhibits phosphorylation of CDC2 
at Tyr15.  A comprehensive review of AZD1775 can be found in the AZD1775 
Investigator's Brochure (2017). 
 
AZD1775 has been shown to inhibit phosphorylated CDC2 in p53 mutant WiDr colon 
and lung carcinoma cells, as measured by colorimetric ELISA in a dose-dependent 
manner [Figure 1A].  Reduction of pY15-Cdk levels was recently demonstrated in the 
A673 Ewing sarcoma xenograft model (included as Figure 7).  Additionally, premature 
mitotic entry was demonstrated by concomitant increase in the percentage of cells 
expressing phosphorylated histone H3 at the same doses [Figure 1 B].  AZD1775 has 
demonstrated activity in multiple cancers based on in vitro activity in NCI 60 cell lines 
[Appendix B]. 
 
  
 
 
 
Figure 1A 
 
 
 
 
Figure 1B 

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2.4 
Correlative Studies Background 
During the escalation phase, tumor biopsies will be optional and will be evaluated in 
pharmacodynamic (PD) studies for evidence of Wee1 inhibition, DNA damage and repair, 
and apoptosis (γH2AX, pNbs1, Rad51, pTyr15-Cdk, and caspase 3).  During the expansion 
phase, once MTD is reached, mandatory paired tumor biopsies will be pursued in the 6 
additional patients enrolled at the MTD to further evaluate PD endpoints and to assess 
epithelial-mesenchymal transition and immunopharmacodynamics.  In Arm B, with a once-
daily dosing schedule, tumor biopsies will also be optional during the escalation phase and 
mandatory during the expansion phase.  Paired tumor biopsies will be pursued in up to 20 
additional patients enrolled at the maximum tolerated daily dose to further evaluate PD 
endpoints.  Data generated from the tumor biopsies will be essential in establishing drug 
effect and will be used to inform future sequencing of combination therapies. 
Fresh tissue biopsies will be evaluated for pTyr15-Cdk and γH2AX.  Further evaluation of 
markers of DNA damage response will be performed based on tissue availability: 
2.4.1 Assessing DNA damage response  
Dr. R. Kinders' laboratory, DCTD, has developed a DNA damage response 
immunofluorescence multiplex assay which includes Rad51, pNbs1, and γH2AX 
measurements as markers of DNA damage-repair.  We additionally plan to measure 
cleaved caspase 3 as a marker of apoptosis.  pTyr15-Cdk expression by 
immunofluorescence will be evaluated for evidence of target effect. 
Histone H2AX is one of the H2A histones present in nucleosomes from normal tissues as 
well as cancer tissues.  H2AX is phosphorylated at its C-terminus (serine 139) within 
minutes following DNA double-strand breaks.  Phosphorylated H2AX, referred to as 
γH2AX, can be selectively detected using antibodies by Western blots or 
immunofluorescence.  The levels of γH2AX are directly correlated to the amounts of 
double-strand breaks per cell, and can be used as a dosimeter and biomarker for DNA 
double-strand breaks. 
Nbs1 is an adapter protein, linking Mre11 and Rad50 to form the MRN complex involved 
in recognition of DNA damage and initiation of the signaling cascade in response to 
DNA double-strand breaks. 
Rad51 is a DNA repair protein involved in homologous recombination, where it 
facilitates recognition of homologous DNA sequences and catalyzes strand exchange. 
Although the effect of AZD1775 as a single agent on the observable amount of DNA 
repair is not expected to be great, the collected data will be extremely important in 
evaluating future trials of AZD1775 plus DNA damaging agents.  Additionally, γH2AX 
at longer periods post-dose (>12 hrs) is also a reporter of apoptosis. 

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Caspase-3 is a key protease activated during early stages of apoptosis via cleavage of its 
pro-enzyme form into a heterodimer of 17- and 12-kDa subunits.  Immunofluorescence 
assays have been developed and validated by Dr. Kinders' laboratory, and will be 
performed on biopsy samples as a measure of apoptosis. 
CTCs will be collected at baseline and then throughout the study to evaluate whether we 
can measure changes in the number and phenotype of CTCs in patients over time to 
explore any correlation with response to treatment or disease progression.  This analysis 
will be performed in Dr. Kinders’ lab with the ApoStream instrument, which uses 
antibody-independent CTC isolation technology that can isolate viable CTCs from 
epithelial and non-epithelial cancers.  The enriched cells are then stained with a panel of 
antibodies targeting MUC1 (tumor marker) and CEA (tumor marker), CK (epithelial 
marker), EpCAM (epithelial marker) and β-cat (CTNNB1; epithelial-mesenchymal 
transition marker) and CD45 (PTPRC; leukocyte marker), as an exclusion marker.   
 
2.4.2 Evaluation of WEE-1 Inhibition with Cancer Immunotherapy 
A recent in vitro study demonstrated that WEE-1 inhibition enhances immune mediated 
lysis of human cancer cells19.  This was identified when examining the molecular 
mechanism by which brachyury, a T-box transcription factor that drives the epithelial-
mesenchymal transition (EMT) in human carcinoma, imparts resistance to tumor cells.  
Tumor cells with high levels of brachyury displayed reduced susceptibility to lysis by 
immune cells, due to inefficient caspase-dependent apoptosis, manifested as inefficient 
nuclear lamin degradation in the presence of activated effector caspases.  This 
phenomenon correlated with a loss of cell cycle kinase CDK1, which mediates lamin 
phosphorylation, and pre-treatment of tumor cells with a negative regulator kinase of 
CDK1, using the WEE-1 inhibitor AZD1775 (MK-1775), countered the defective 
apoptosis and sensitized resistant tumor cells to immune mediated lysis.   
 
Based on the finding that WEE-1 inhibition enhances immune mediated lysis, we are 
collaborating with CCR’s Laboratory of Tumor Immunology to evaluate the combination 
of WEE-1 inhibition with cancer immunotherapy, specifically, the effect of AZD1775 on 
immune peripheral blood mononuclear cells (PBMCs).  Peripheral immune cells will be 
evaluated pre- and post-treatment (baseline and day 8) in both Arm A and Arm B using 
27 markers in 4 panels to assess 123 immune subsets (Table 1).  These panels identify 
9 standard immune cell subsets and 114 markers related to the maturation/function of 
these cells.  The results of this study will determine whether WEE-1 inhibition is immune 
inert, immune suppressive, or immune stimulatory, and will provide critical information 
regarding the potential timing and scheduling of combining the AZD1775 with cancer 
immunotherapy (e.g., therapeutic vaccines or checkpoint inhibitors).  Serum will also be 
collected for analysis of cytokines and chemokines as well as immune activation markers 
such as CD40L and CD27, and tumor-associated antigens.    
 
 
 
 

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Table 1: Planned flow-cytometry analysis of PBMC immune subsets 
1. CD4: Helper T lymphocytes (33 subsets) 
2. CD8: Cytotoxic T lymphocytes (30 subsets) 
3. T-regs: Regulatory T-lymphocytes (CD4+ CD25+ FoxP3+ CD127-) (7 subsets) 
4. B lymphocytes: CD19+ (3 subsets) 
5. NK: Natural killer cells (CD56+ CD3-) (20 subsets) 
6. NK-T: CD56+ CD3+ (4 subsets) 
7. cDCs (Conventional DCs): CD3-CD56-HLADR+CD1c+CD303- (5 subsets) 
8. pDCs (plasmacytoid DCs ): CD3-CD56-HLADR+CD1c-CD303+ (5 subsets) 
9. MDSCs: Myeloid-derived suppressor cells (CD11b+ HLA-DRlow/- CD33+) (16 subsets) 
 
2.4.3 Tumor Immunoscore  
The host immune system has been shown to play a role in impeding cancer progression20.  
Therefore, as a pilot correlative study, we will correlate the response to treatment of each 
patient with colorectal cancer and adenocarcinoma with immunological biomarker 
expression in tumor biopsy samples by determining the Immunoscore21.  It is hoped that 
this information will supplement traditional tumor staging (AJCC-UICC-TNM) which 
serves to predict patient prognosis by evaluating histopathological characteristics of tumor 
biopsy samples22.   
 
Immune cells can infiltrate tumors; their number, type, and location (i.e., immune context) 
has been associated with disease-free survival and overall survival in large human cancer 
studies23-25.  An Immunoscore is determined from the enumeration of a set of these 
immune cells, for example, cytotoxic (CD3+ and CD8+) and memory (CD45RO+) T-cells 
in the core of the tumor (CT) and the invasive margin (IM).   
 
Sections from FFPE-tumor tissue blocks will be evaluated for high immune cell infiltration 
and whether or not they include the CT and IM.  Enumeration of lymphocyte populations 
will be performed by Definiens by immunohistochemistry; clinical validation of the 
methods is currently being completed.    
 
2.4.4 Epithelial-mesenchymal transition (EMT) 
EMT is a dynamic process that leads to increases in the migratory and invasive properties 
of tumor cells (1).  Histologically, these changes involve the loss of epithelial marker E-
cadherin (E) and gain of the mesenchymal marker intermediate filament vimentin (V); loss 
of E-cadherin is linked to poor prognosis, tumor progression, and metastasis26,27.  
 
Recent data from DCTD confirm the existence of “transitional” cells that co-express both 
E-cadherin and vimentin at the cellular level in FFPE clinical biopsies.  Quantitative 
analysis of various histologies using an immunofluorescence assay developed and 
validated by DCTD revealed all possible phenotypes from very epithelial (E+V- colorectal 
carcinoma), mesenchymal (E-V+ sarcomas), heterogeneous mixtures of E+V- and E-V+ 
subpopulations, and EMT.   

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The potential clinical utility of this assay has been demonstrated: treatment with the 
multikinase inhibitor pazopanib resulted in a significant shift towards the mesenchymal 
phenotype in drug-sensitive but not insensitive human xenograft models (manuscript in 
preparation).  The EMT immunoassay will be used as to elucidate “baseline” EMT status 
in study patients—differences observed to date suggest inter-patient phenotypic variation 
to be as significant a factor as histological differences within carcinomas—as well as to 
characterize drug response. 
 
2.4.5 Potential predictive molecular biomarkers of AZD1775 antitumor activity 
Tumors containing molecular alterations that enhance replicative stress may be particularly 
susceptible to Wee1 inhibition by AZD1775, with the heightened cell cycle stress in the 
presence of both factors representing a synthetic lethal interaction.  Several genomic 
alterations that induce replicative stress have been shown to potentially enhance AZD1775 
antitumor activity in preclinical and/or clinical studies; these alterations include loss of 
function mutations in BRCA1/216,28,29 and SETD230 and amplification of CCNE1 or MYC29.  
For active Expansion Arm B patients enrolled at the time of Amendment P (11/2/17) 
approval or thereafter, tumor biopsy cores remaining after completion of PD biomarker 
analyses will be used for whole-exome and RNA sequencing to identify these and other 
mutations or gene expression patterns in patient tumor tissue and to examine potential 
associations between such molecular alterations and AZD1775 antitumor activity. 
 
 
 
2.5 
Genetic Sequencing Research Ethics 
This trial will collect genetic data from active Expansion Arm B patients, enrolled at the time 
of Amendment P (11/2/17) approval or thereafter, for exploratory studies to examine 
potential associations between genomic and RNA expression alterations and AZD1775 
antitumor activity.  Tissue specimens used for sequencing analyses will be de-identified, with 
only limited clinical annotation (e.g., response to AZD1775) maintained for each specimen.  
Designing the study poses challenging questions about informed consent, the privacy of the 
patient and the patient’s family, the researchers’ obligation to disclose genetic information to 
the patient, and the use and storage of research data31-33.  In the vast majority of cases, we do 
not know the medical significance of genetic variants34,35.  These challenges will continue to 
be evaluated to maintain the rigor and integrity of the study and the wellbeing of our patients.  
A Certificate of Confidentiality has been obtained from the NIH to help protect the privacy 
of all study participants.   
 
The protocol includes a separate informed consent form for active Expansion Arm B patients 
enrolled at the time of Amendment P (11/2/17) approval or thereafter; this consent form 
contains language pertaining to genetic sequencing studies.  Active Expansion Arm B 
patients already enrolled at the time of Amendment P approval will be re-consented to the 

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new, “genetic analysis” consent form prior to use of their specimens for exploratory 
sequencing analyses. 
 
Whole-exome sequencing (performed for research purposes but non-CLIA) of tumor and 
blood can detect non-ambiguous germline variants, which may raise health and privacy 
implications for the patient and his or her family.  WES will not be validated for clinical use, 
and no clinical decisions can be made based on its results.  Furthermore, no genetic data will 
be shared with the patient. 
 
This study does not meet the criteria specified by the NIH Genomic Data Sharing (GDS) 
Policy (see Section 12.4), and therefore, a GDS plan has not been included in this protocol. 
 
3 PATIENT SELECTION 
3.1 
Eligibility Criteria 
3.1.1 Patients must have histologically confirmed solid tumors for which all standard 
therapy known to prolong survival have failed or for which standard therapies do 
not exist. 
3.1.2 Patients must have measurable disease or evaluable disease for the escalation 
phase; for the 6 additional patients enrolled at MTD for further evaluation of PK 
and PD endpoints (Expansion Arm A).  For the 6-patient BRCA-mutation 
expansion arm, patients must have measurable disease; however, tumor biopsies 
are optional.  For Expansion Arm B, patients must have tumor amenable to biopsy 
(excisional or incision biopsies of skin or H & N lesions under visualization) and 
willingness to undergo a tumor biopsy or patient will be undergoing a procedure 
due to medical necessity during which the tissue may be collected, or tumor 
biopsy tissue from a previous research study or medical care is available for 
submission at registration.  Criteria for the submission of tissue are: 
  •   Tissue must have been collected within 3 months prior to registration 
  •   Patient has not received any intervening therapy for their cancer since the  
      collection of the tumor sample 
  •   Tumor tissue must meet the minimum requirements outlined in Section 9.    
3.1.3 Patients must have completed any chemotherapy, radiation therapy, surgery, or 
biologic therapy ≥ 3 weeks (or ≥ 5 half-lives, whichever is shorter) prior to 
entering the study.  Patients must be ≥ 2 weeks since any prior administration of a 
study drug in an exploratory IND/Phase 0 study or ≥ 1 week from palliative 
radiation therapy.  Patients must have recovered to eligibility levels from prior 
toxicity or adverse events. 
3.1.4 Age >18 years of age. 
3.1.5 ECOG performance status <1 (Karnofsky >60%, see Appendix A). 
3.1.6 Life expectancy of greater than 3 months. 

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3.1.7 Patients must have normal organ and marrow function as defined below: 
 
− leukocytes  
 
 
 
 
>3,000/mcL 
− absolute neutrophil count 
 
>1,500/mcL 
− platelets  
 
 
 
 
 
>100,000/mcL 
− hemoglobin  
 
 
 
 
>9 g/dL 
− total bilirubin 
 
 
 
 
<1.5 X institutional upper limit of normal 
− AST(SGOT)/ 
− ALT(SGPT)  
 
 
 
 
<3 X institutional upper limit of normal 
− creatinine 
 
 
 
 
 
<1.5X institutional upper limit of normal 
 
OR 
 
− creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
3.1.8 The effects of AZD1775 on the developing human fetus are unknown.  For this 
reason and because molecular inhibitors of Wee1 kinase are known to be 
teratogenic, women of child-bearing potential (WoCBP) may be included only if 
acceptable contraception is in place for two weeks before study entry, for the 
duration of the treatment with the study drug, and for 2 months after the last dose 
of AZD1775.  Male patients who are involved in the study must agree to avoid 
procreative and unprotected sex (i.e., by using acceptable forms of contraception) 
and must not donate sperm during the study and for 3 months after the last dose of 
AZD1775.  Where the female partner is pregnant or not using effective birth 
control, men should be advised to abstain while in the study and for 3 months 
after the last dose of AZD1775.  Female partners, who are of child-bearing 
potential, of men participating in clinical studies of AZD1775 will also be 
required to use effective contraceptive measures while their partner is on study 
drug and for 3 months thereafter.  Male patients will be advised to arrange for the 
freezing of sperm samples prior to the start of the study should they wish to father 
children while on AZD1775 or during the 3 months after stopping AZD1775. 
3.1.9 Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with the study drugs, breastfeeding 
should be discontinued prior to the first of study drug and women should refrain 
from nursing throughout the treatment period and for 14 days following the last 
dose of study drug. 
3.1.10 Patients must be able to swallow whole tablets or capsules.  Nasogastric or G-tube 
administration is not allowed.  Any gastrointestinal disease which would impair 
ability to swallow, retain, or absorb drug is not allowed. 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
document. 

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26 
required from each participant to confirm diagnosis.  For the BRCA-mutation 
expansion arm, confirmation of BRCA-1 or -2 mutations will be required prior to 
enrollment; pathology reports from outside institutions will be accepted.  
3.4.2 History and physical examination: Complete history and physical examination 
(including height, weight, vital signs, and performance score) will be conducted 
within 8 days prior to enrollment.  
3.4.3 Imaging Studies (Eligibility screening): Every participant should have an 
evaluation of known sites of disease as part of the eligibility screening.  All 
patients will be required to undergo a CT scan of the chest/abdomen/pelvis to 
evaluate sites of disease within 28 days prior to enrollment.  MRI evaluation of 
site of disease may be performed in lieu of CT evaluation at the discretion of the 
principal investigator if it is the opinion of the investigator that this modality 
would provide a more accurate assessment of disease than a CT would, for a 
given site. 
3.4.4 Laboratory Evaluation: Eligibility screening laboratory data are to be obtained 
within 8 days prior to enrollment: 
• Hematological Profile: CBC with differential. 
• Biochemical Profile: albumin, total bilirubin, BUN, calcium, creatinine, 
phosphorus, SGOT[AST], SGPT[ALT], alkaline phosphatase, chloride, 
magnesium, potassium, and sodium. 
• Coagulation Profile: PT, PTT, INR as clinically indicated prior to tumor 
biopsy. 
• Serum or urine pregnancy test for female participants of childbearing 
potential. 
3.4.5 Cardiac Evaluation: Baseline electrocardiogram will be obtained within 8 days 
prior to enrollment.  Additionally, patients must have electrocardiogram 
evaluation as clinically indicated.   
4 REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office 
(CRO) within 24 hours of signing consent.  A registration Eligibility Checklist from the Web 
site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent 
via encrypted email to: NCI Central Registration Office (HOIS) (ncicentralregistration-
l@mail.nih.gov).   
 
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy 
to advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents.  Verification of Registration will be forwarded electronically via e-
mail.  Please note that it is very important for all registrars to acquire encrypted e-mail from 
NIH Help Desk, since the verification of registration includes patient’s information.  A 
recorder is available during non-working hours. 
 

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Off Protocol Therapy and Off-Study Procedure: Authorized staff must notify the Central 
Registration Office (CRO) when a patient is taken off protocol therapy and when a patient is 
taken off-study.  A Participant Status Updates Form from the website (http:// 
home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and sent 
via encrypted email to:  NCI Central Registration Office (HOIS) (ncicentralregistration-
l@mail.nih.gov). 
 
5 TREATMENT PLAN 
This is an open-label Phase I trial evaluating safety and tolerability of single-agent AZD1775 
(MK-1775), an oral inhibitor of Wee1, in patients with refractory advanced solid tumors.  
Reported adverse events and potential risks for AZD1775 are described in Section 7.  
Appropriate dose modifications for AZD1775 are described in Section 6.  
 
Patient evaluations will be performed throughout the study as described below.  Baseline 
history, physical examination, laboratory evaluations, and ECG must be conducted within 8 
days prior to start of protocol therapy.  If protocol therapy is started within 8 days of the 
eligibility screening evaluations (see Section 3.4), the results from these screening 
evaluations may be used as baseline measurements.  If >8 days have passed since the 
screening evaluations, the medical history, physical examination, laboratory evaluations, and 
ECG must be repeated prior to starting protocol therapy.  Baseline tumor imaging must be 
performed within 28 days prior to start of protocol therapy.  If protocol therapy is started 
within 28 days of the eligibility screening tumor imaging, the screening evaluation imaging 
results may be used as baseline measurements; if >28 days have passed since the screening 
evaluation tumor imaging, the imaging must be repeated prior to starting protocol therapy. 
 
For dose level 1 of the original dosing schema (Arm A), AZD1775 will be administered 
orally for 5 doses each cycle, with doses administered approximately 12 hours apart starting 
with the first dose for that week (for example, if the patient takes the first dose at 9 am on 
Monday then the next dose will be administered at 9 pm that evening).  Starting at dose level 
2 and onwards in this arm, AZD1775 will be administered orally for 5 doses for the first 2 
weeks of each cycle, with doses administered approximately 12 hours apart starting with the 
first dose for that week (as explained above except it will occur over the first two weeks of 
the cycle).  Each cycle is 21 days (± 1 day for scheduling).  Patients will be asked to maintain 
a Study Medication Diary (Appendix D) and record each dose of medication.  Patients will 
be given instructions for completing the medication diary and will be asked to return it to the 
clinic staff at the end of each cycle. 
 
Once the MTD is established, 6 additional patients will be enrolled at the MTD to further 
evaluate that dose for PK and PD endpoints (Expansion Arm A).  An additional expansion 
arm of 6 patients with documented tumors harboring BRCA-1 or -2 mutations will also be 
enrolled at the MTD to further explore the safety of AZD1775 and obtain preliminary 
evidence of activity in this patient population.  This information may inform patient selection 
for further development of this agent.  Patients in this BRCA-mutant expansion arm must 
have measurable disease; tumor biopsies will be optional. 
 

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Based on preclinical data with once daily AZD1775 dosing, Arm B, starting at 200 mg once 
daily for 5 doses each week, for two consecutive weeks will be established to evaluate PD 
and PK endpoints.  Patients will be accrued in arms of 3, based on a 3+3 design, for up to 
two dose levels.  The cycle length will remain at 21 days (+ 1 day for scheduling).    Once the 
maximum tolerated single daily dosing is established, up to 20 additional patients will be 
enrolled on Expansion Arm B with mandatory biopsies to further evaluate PD endpoints.   
 
History and physical examination will be done at baseline (within 8 days prior to the start of 
protocol therapy) and before the start of each new cycle thereafter (up to 3 days before the 
start of a new cycle).  Patients will be examined on D1 and D8 at the clinical center during 
the first cycle and prior to every new cycle.  
 
As of Amendment G (dated 07/17/2014), the MTD for Arm A was established at 225 mg 
twice daily for 5 doses each week, for two consecutive weeks.  As of Amendment M 
(dated 11/20/16), the Arm B MTD was established at 300 mg once daily on days 1-5 
each week, for two consecutive weeks. 
 
Labs (CBC with differential; serum chemistries) will be performed at baseline (within 8 days 
prior to the start of protocol therapy), D8, and D15 of cycle 1 (±1 day due to scheduling 
conflicts), then at the start of each cycle (up to 3 days before start of a new cycle). 
 
CT scans will be performed at baseline (within 8 days prior to the start of protocol therapy), 
and repeat imaging scans will be performed every 2 cycles (3 or 4 cycles for patients on 
study for more than one or three years, respectively).  MRI evaluation of site of disease may 
be performed in lieu of CT evaluation at the discretion of the principal investigator if it is the 
opinion of the investigator that this modality would provide a more accurate assessment of 
disease than a CT would for a given site. 
5.1 
Agent Administration 
After cycle 2, a cycle will be considered completed if 90% of the prescribed AZD1775 
doses are administered. 
5.1.1 Dose Escalation Phase (Arm A) 
The primary objective of the trial is to establish the safety, tolerability, and 
maximum tolerated dose of single-agent AZD1775.   
 
For dose level 1, AZD1775 will be administered orally for 5 doses each cycle, 
with doses administered approximately 12 hours apart starting with the first dose 
for that week (for example, if the patient takes the first dose at 9AM on Monday 
then the next dose will be administered at 9 pm that evening).  Starting at dose 
level 2 and onwards, AZD1775 will be administered orally for 5 doses for the first 
2 weeks of each cycle, with doses administered approximately 12 hours apart 
starting with the first dose for that week (as explained above except it will occur 
over the first two weeks of the cycle).  The duration of a cycle will be 21 days 

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(± 1 day for scheduling).  Dose escalation will proceed in arms of 3 patients each 
(3+3 design) as outlined below (Table 1): 
 
Table 1. Arm A Dose Escalation Scheme 
 
Dose Escalation Schedule for Arm A 
Dose 
Level 
AZD1775 (orally BID) x 5 doses/weeks 
-1 
200 mg BID x 5 doses (days 1-3) for 1 week 
1 
225 mg BID x 5 doses (days 1-3) for 1 week 
2 
225 mg BID x 5 doses (days 1-3 each week) for 2 weeks 
3 
300 mg BID x 5 doses (days 1-3 each week) for 2 weeks 
4 
400 mg BID x 5 doses (days 1-3 each week) for 2 weeks 
5 
550 mg BID x 5 doses (days 1-3 each week) for 2 weeks 
 
Optional paired tumor biopsies will be obtained in patients who have disease 
amenable to biopsy during the escalation phase; mandatory paired tumor biopsies 
will be pursued in patients during the expansion phase in the 6 additional patients 
enrolled at the MTD (Expansion Arm A).  For the 6-patient BRCA-mutant 
expansion arm at the MTD, disease must be measurable; however, tumor biopsies 
will be optional.   
 
The trial will follow a standard 3+3 dose escalation study wherein 3 patients 
should have completed at least one cycle of therapy prior to considering dose 
escalation in the next arm of patients.  Dose escalation will proceed until dose-
limiting toxicity is observed.  DLT is defined in Section 5.2.  Determination of 
DLT will be based on toxicities observed in the first cycle of therapy.  Patients are 
considered evaluable for toxicity for the purpose of arm dose escalation decisions 
if they either 1) experienced DLT or 2) have received 90% of treatment doses for 
cycle one of therapy and have been followed for one full cycle without DLT.  All 
toxicities will be reported for all patients who receive any amount of study drug 
on this study.  Evaluation of toxicity will begin with study drug administration on 
cycle 1 day 1. 
 
Intra-patient dose escalation will be permitted if: a) there is no toxicity > Grade 1 
that is related (possibly, probably, or definitely) to the study drug at the initial 
dose level experienced by that patient, b) higher doses have been evaluated and 
completed without DLT, and c) the patient’s disease has not progressed.  Doses 
may be escalated, provided conditions a–c are met, up to the last evaluated dose 
level NOT associated with DLT. 
 

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5.1.2 Dose Escalation Phase (Arm B) 
For Arm B, AZD1775 will be administered once daily for 5 doses each week, for 
two consecutive weeks.  The duration of a cycle will be 21 days (+1 day for 
scheduling).  Dose escalation will proceed in arms of 3 patients each (3+3 design) 
as outlined in Table 2: 
 
Table 2. Arm B Escalation Scheme 
Dose Escalation Schedule for Arm B 
Dose Level 
AZD1775 (orally once daily)  
-1 
200 mg daily D1-3 each week for 2 weeks 
1 
200 mg daily x D1-5 each week for 2 weeks 
2 
225 mg daily x D1-5 each week for 2 weeks 
3 
250 mg daily D1-5 each week for 2 weeks 
4 
300 mg daily D1-5 each week for 2 weeks 
5 
400 mg daily D1-5 each week for 2 weeks 
6 
500 mg daily D1-5 each week for 2 weeks 
 
5.2 
Definition of Dose-Limiting Toxicity 
Determination of dose-limiting toxicity will be based on toxicities observed in the first 
cycle of therapy.  Dose escalation will proceed within each arm according to the 
following scheme.  Dose-limiting toxicity (DLT) is defined below.   

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Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be entered 
at the next lowest dose level if only 3 patients were treated 
previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
<1 out of 6 at highest dose level below 
the maximally administered dose 
This is generally the recommended phase 2 dose.  At least 6 
patients must be entered at the recommended phase 2 dose. 
 
Dose limiting toxicity (DLT) is defined as an adverse event that is related (possibly, 
probably, or definitely) to administration of AZD1775 and fulfills one of the following 
criteria: 
5.2.1 Grade ≥ 3 Non-Hematological Toxicity 
 
 
Grade ≥ 3 non-hematological toxicity felt to be related to study  
 
 
 
 
medications will be considered dose-limiting with the following  
 
 
 
 
clarifications: 

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and fosaprepitant are not permitted due to known drug interactions with 
AZD1775.  In addition, if a patient develops nausea and/or vomiting that is Grade 
2 or greater, antiemetics may be instituted prophylactically at the discretion of the 
investigator.  Nausea and vomiting will be considered refractory if it does not 
resolve to≤ Grade 1 with treatment with a combination of at least 2 of the 
antiemetics within 24 hours.  Patients should be strongly encouraged to maintain 
liberal oral fluid intake. 
5.3.2 Diarrhea 
If diarrhea develops and does not have an identifiable cause other than study drug 
administration, anti-diarrheals such as Lomotil (diphenoxylate HCl 2.5 mg + 
atropine sulfate 0.025 mg/tablet) dosed according to package insert or loperamide 
4 mg po after the first unformed stool with 2 mg po with every 2 hours as long as 
unformed stools continue (4 mg every 4 hours while asleep).  No more than 16 
mg of loperamide should be taken during a 24-hour period.  This regimen can be 
repeated for each diarrheal episode.  Diarrhea will be considered refractory if it 
does not resolve within 24 hours ≤ to Grade 2 with the above regimen (maximum 
of 16 mg of loperamide in a 24-hour period).  If the patient develops blood or 
mucus in the stool, dehydration, or hemodynamic instability, or fever along with 
the diarrhea, anti-diarrheals will be discontinued and the patient will be treated 
with IV fluids and antibiotics as medically indicated. 
5.3.3 Neutropenia 
To reduce the risk of severe myelosuppression events, a complete blood count 
(CBC) should be performed weekly during cycle 1, and at the start of each 
subsequent cycle (up to 3 days before start of new cycle) in the dose escalation 
phase.  In the expansion phase, CBC will be performed on D1 and D8 of cycle 1, 
then at the start of each cycle (up to 3 days before start of new cycle).  Febrile 
neutropenia is a life-threatening complication requiring hospitalization and urgent 
broad spectrum antibiotics, as well as an aggressive search for the source and 
microbial cause of the episode.  Growth factors to prevent neutropenia will not be 
administered prophylactically.  If necessary, they may be administered according 
to accepted American Society of Clinical Oncology (ASCO) guidelines to allow 
re-treatment. 
5.3.4 Anemia 
Symptomatic anemia should be treated with red blood cell transfusion and is 
recommended if the hemoglobin falls below 8 g/dL.  The initiation of 
erythropoietic therapy for the management of chemotherapy-induced anemia 
follows the American Society of Hematology/ASCO clinical practice guidelines 
(http://www.asco.org). 
5.3.5 Thrombocytopenia 
Thrombocytopenia will be treated conservatively.  In the absence of bleeding, or a 
necessary invasive procedure, platelet transfusions should be given for a platelet 

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34 
count ≤10,000/mm3.  If invasive procedure(s) is (are) planned, or the patient 
develops bleeding, platelet transfusions should be administered in accordance with 
the standard of practice, usually maintaining a platelet count above 50,000/mm3. 
5.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies: 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Significant toxicity occurs despite 2 dose reductions as described in Section 6 or no 
lower dose level exists 
• Pregnancy 
• 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 
5.5 
Duration of Follow Up 
Patients will be followed for 30 days after the last dose is administered or until one of the 
following occurs: patient enrolls on another protocol, patient receives standard of  care, or 
death, whichever comes first.  The follow-up will consist of a phone call between Days 
27-30 after the last dose to evaluate adverse events that were ongoing and any new events 
that might be deemed related to the therapy.  Toxicities felt to be possibly, probably, or 
definitely related to the study drugs that have not resolved or stabilized by Day 30 post-
treatment will be followed until stabilization or resolution via phone calls as clinically 
indicated.  An optional biopsy from patients who have progressed may be requested if the 
patient has not yet received any new treatment to assess whether progression correlates 
with a change in study pharmacodynamic marker; separate consent will be obtained.   
5.6 
Criteria for Removal from Study 
Patients will be removed from study for one of the following reasons: completed 30-day 
follow up period or toxicities are unresolved but stabilized, patient enrolls on another 
protocol, or patient receives standard of care.  The reason for study removal and the date 
the patient was removed must be documented in the medical record and communicated to 
Central Registration per Section 4. 
 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
Toxicities should have resolved to < Grade 2 prior to starting the next cycle.  Treatment may 
be delayed for a maximum of 2 weeks beyond the actual cycle length of 21 days for toxicities 
that develop and do not resolve as defined above.  Beyond two weeks, the patient will not 
receive further therapy on this protocol and will be followed for resolution of toxicities.   
Treatments may be delayed up to 7 days past the end of the previous cycle of 21 days for 
scheduling conflicts at the discretion of the investigator.  

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Patients will be allowed up to 2 dose reductions.  If more than 2 dose reductions are required, 
the patient will be removed from the study. 
6.1 
Dose Reduction 
Dose modifications are defined below: 
6.1.1 Grade 2 Drug-related toxicity: No changes will be made to the dose of 
AZD1775 for Grade 2 toxicities.  Therapy will not be interrupted for Grade 2 
hematologic toxicities. 
6.1.2 Grade 3-4 Drug-related non-hematologic toxicities: Doses of AZD1775 will be 
held until toxicities recover to < Grade 2 or baseline prior to re-initiating 
treatment at the next lower dose level.  Electrolyte abnormalities will not require 
dose reduction if resolution to Grade 2 or less is documented within 72 hours.  
Dose modifications for nausea, vomiting, and diarrhea will be made only if they 
are refractory to treatment (See Section 5.3).  
6.1.3 Grade 3 Drug-related hematologic toxicities: Dose of AZD1775 will be held 
until hematologic toxicities, except anemia, lymphopenia, or leukopenia in the 
absence of neutropenia, have resolved to < Grade 2 prior to re-initiating treatment 
at the same dose level. 
6.1.4 Grade 4 Drug-related Hematologic Toxicities: Dose of AZD1775 will be held 
until hematologic toxicities, except anemia, lymphopenia, or leukopenia in the 
absence of neutropenia, have resolved to < Grade 2 prior to re-initiating treatment 
at the next lower dose level. 
6.2 
Definition of Complete Course 
 
A cycle is defined as 21 days, with D1 starting the first day of AZD1775 administration.  
If a patient receives 90% of scheduled treatments of AZD1775 and remains in the study 
until D21, the patient will be considered to have completed a cycle of therapy.  Patients 
who do not complete a cycle of therapy for reasons other than toxicity will be replaced.  
Patients who do not complete one cycle of therapy due to toxicity will not be replaced.  
All patients should have completed one cycle of therapy (unless removed from the study 
due to toxicity), at which point they will be evaluable. 
 
 
7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) 
will determine whether the event requires expedited reporting (via CTEP-AERS) in addition 
to routine reporting.   

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NERVOUS SYSTEM DISORDERS - Central nervous system necrosis; Cognitive disturbance; 
Dysesthesia; Dysgeusia; Encephalopathy; Lethargy; Nervous system disorders - Other (hemiparesis); 
Paresthesia; Peripheral neuropathy5; Presyncope; Somnolence; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression 
RENAL AND URINARY DISORDERS - Acute kidney injury6; Hematuria; Urinary frequency; 
Urinary incontinence; Urinary retention; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema; Reproductive system 
and breast disorders - Other (female genital tract fistula) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Bronchopulmonary hemorrhage; Epistaxis; Hiccups; Nasal congestion; Pleural effusion; 
Pneumonitis; Pulmonary hypertension; Respiratory, thoracic and mediastinal disorders - Other 
(diaphragmalgia); Voice alteration; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Bullous dermatitis; Dry skin; 
Hyperhidrosis; Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Purpura; Rash 
acneiform; Skin ulceration; Urticaria 
VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypertension; Hypotension; 
Thromboembolic event 
 
Note: AZD1775 (adavosertib) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
 
7.2 
Adverse Event Characteristics  
• CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting until March 31, 2018.  
CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 2018.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
• ‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for 
expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and 
italicized in the CAEPR (Section 7.1). 
 
• Attribution of the AE: 
 
1. Definite – The AE is clearly related to the study treatment. 
 
2. Probable – The AE is likely related to the study treatment. 
 
3. Possible – The AE may be related to the study treatment. 
 
4. Unlikely – The AE is doubtfully related to the study treatment. 
 
5. Unrelated – The AE is clearly NOT related to the study treatment. 
 

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7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
Event Reporting System), accessed via the CTEP Web site 
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented in 
the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements for 
DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly 
outlined in the tables below (Section 7.3.3). 
7.3.2 In the rare occurrence when Internet connectivity is lost, a 24-hour notification is 
to be made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is 
restored, the 24-hour notification phoned in must be entered electronically into 
CTEP-AERS by the original submitter at the site. 
7.3.3 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below.  Attribution to treatment or 
other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease 
Progression” in the system organ class (SOC) “General disorders and 
administration site conditions.”  Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.  
Phase I and Early Phase I Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the  
Last Administration of the Investigational Agent/Intervention 1, 2
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 

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7.3.5 Pregnancy, Fetal Death, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy 
loss”, or “Neonatal loss”, the Pregnancy Information Form should be completed 
for patients who became pregnant on study, and faxed along with any additional 
medical information to (301) 230-0159.  The potential risk of exposure of the 
fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section of the CTEP-AERS report. 
 
7.3.5.1 Pregnancy 
• Because patients who become pregnant on study risk intrauterine exposure 
of the fetus to agents which may be teratogenic DCTD/DCP is requesting 
that pregnancy should be reported in an expedited manner via CTEP-
AERS as Grade 3 “Pregnancy, puerperium and perinatal conditions - 
Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
• The pregnancy outcome for patients on study should be reported via 
CTEP-AERS at the time the outcome becomes known, accompanied by 
the same Pregnancy Report Form used for the initial report. 
 
7.3.5.2 Pregnancy loss 
 
• Pregnancy loss is defined in CTCAE as “Death in utero.” 
• Any pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
• A pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a patient death. 
 
7.3.5.3 Death Neonatal 
 
• Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. 
• A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the General disorders and administration SOC. 
• Neonatal death should NOT be reported as Grade 5 “Death neonatal” 
under the General disorders and administration SOC.  If reported as such, 
the CTEP-AERS interprets this as a death of the patient being treated. 
 

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7.3.6 NIH IRB Expedited Reporting of Adverse Events, Unanticipated Problems, and 
Deaths 
7.3.6.1 Definitions 
Adverse event 
An adverse event is defined as any reaction, side effect, or untoward event that 
occurs  during the course of the clinical trial associated with the use of a drug in 
humans, whether or not the event is considered related to the treatment or 
clinically significant.   For this study, AEs will include events reported by the 
patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation.  A new illness, symptom, sign or clinically 
significant laboratory abnormality or worsening of a pre-existing condition or 
abnormality is considered an AE.  All AEs must be recorded on the AE case 
report form unless otherwise noted in Section 7.3.4. 
 
All AEs, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until satisfactory resolution.  
AEs should be reported up to 30 days following the last dose of study drug.  An 
abnormal laboratory value will be considered an AE if the laboratory abnormality 
is characterized by any of the following: 
 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms 
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including 
hospitalization 
• Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the 
investigator will provide details about the action taken with respect to the 
test drug and about the patient’s outcome. 
 
Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  For the purposes of 
IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the adverse event.  A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug. 
 
Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, 
is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application.  “Unexpected” also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator 

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brochure as occurring  with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
 
Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the 
definition of a Serious Adverse Event or if it compromises the safety, welfare or 
rights of subjects or others. 
 
Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the 
view of the investigator or the sponsor, it results in any of the following: 
• Death, 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in this definition. 
 
Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
 
Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, 
in the view of the investigator or sponsor, at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction that had it occurred in a 
more severe form, might have caused death. 
 
Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB approved research protocol. 
 
Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program 
(HRPP) policies, IRB requirements, or regulatory requirements for the protection 
of human research subjects 
 
Unanticipated Problem 
Any incident, experience, or outcome that: 
 
• Is unexpected in terms of nature, severity, or frequency in relation to 

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(a) the research risks that are described in the IRB-approved  
 
 
research protocol and informed consent document; Investigator’s   
 
Brochure or other study documents, and 
 
(b) the characteristics of the subject population being studied; AND 
 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized.  
 
7.3.6.2 NIH IRB and Clinical Director Reporting Requirements 
 
The Protocol PI will report in the NIH Problem Form to the NIH-IRB and 
NCI Clinical Director: 
• All deaths, except deaths due to progressive disease 
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
 
Reports must be received within 7 days of PI awareness via iRIS. 
 
7.3.6.3 NIH IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition an unanticipated 
problem will need to be reported to the NIH IRB. 
7.4 
Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
through CTEP-AERS must also be reported in routine study data submissions. 
 
7.4.1 NIH IRB Requirements for PI Reporting at Continuing Review 
Please use the following table for reporting adverse event at time of CR: 
 
System 
Organ Class 
CTCAE 
Term 
Grade 
# of events 
since last CR 
Total # of 
events 
Attribution to 
Research 
Serious? 
Unexpected? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The protocol PI will report to the NIH IRB: 
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
 
• All Grade 2 unexpected events that are possibly, probably or definitely 
related  to the research; 

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• All Grade 3 and 4 events that are possibly, probably or definitely related to 
the research; 
• All Grade 5 events regardless of attribution; 
• All Serious Events regardless of attribution. 
 
 
 
NOTE: Grade 1 events are not required to be reported. 
7.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy).  A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS.  Three options are available to 
describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
7.6 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified.  
 
 
8 PHARMACEUTICAL INFORMATION  
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
8.1 
AZD1775 (NSC 751084) 
Chemical Name: 
2-allyl-1-[6-(1-hydroxy-1-methylethyl) pyridin-2-yl]-6-{[4-(4-
methylpiperazin-1-yl) phenyl]amino}-1,2-dihydro-3H-
pyrazolo[3,4-d]pyrimidin-3-one hemihydrate 
Other Names: 
MK-1775, Adavosertib 
Classification: 
(CAS): 
Inhibitor of Wee1-kinase  
(1277170-60-1) 
Molecular Formula: 
C27H32N8O2·0.5H2O  

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Agent Inventory Records - The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of agent received from the PMB using the NCI Investigational Agent (Drug) 
Accountability Record Form (DARF) for Oral Agents available on the CTEP forms page.  
Store and maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation and ordering investigator on this protocol. 
 
Investigator Brochure Availability - The current versions of the IBs for the agents will be 
accessible to site investigators and research staff through the PMB Online Agent Order 
Processing (OAOP) application.  Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  Questions about IB access may be directed to 
the PMB IB coordinator via email. 
 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm  
• PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
9 CORRELATIVE/SPECIAL STUDIES 
We plan to evaluate the in vivo molecular effects of AZD1775 using pre- and post-treatment 
tumor biopsy specimens and CTCs; blood will additionally be collected for PK analysis.  
Samples will be collected during cycle 1 at baseline and 2-5 hours after the 5th dose of 
AZD1775 or, as of Amendment M (11/20/16), prior to the 6th dose of AZD1775 on day 8 
during cycle 1 only.  In addition, an optional “restaging follow-up biopsy” may be performed 
on day 1 (± 2 days) of the cycle following any restaging at which a 10-20% increase in tumor 
volume is observed (according to RECIST criteria) if the patient has been on study for at 
least 4 cycles, or at time of disease progression.  Patients have the option to undergo paired 
tumor biopsies as part of participation in this study during the escalation phase; paired tumor 
biopsies will be required during the expansion phase at the MTD (Expansion Arm A).  
Tumor biopsies will be optional in the expansion arm of BRCA patients.  For Arm B on a 
once-daily dosing schedule, mandatory paired tumor biopsies will be pursued in up to 20 
patients enrolled at the maximum tolerated daily dose to further evaluate PD endpoints.  

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Biopsy tissue quality will be monitored and accrual will stop once we have obtained 10 
usable paired samples.  Tumor biopsies will be collected for evaluation of levels of DNA-
damage repair and apoptosis after the 5th dose of AZD1775 during cycle 1. 
 
9.1 
Pharmacokinetics 
AZD1775 will be assayed in plasma from all patients.  Blood samples for PK analyses 
will be collected during cycle 1 only.  Blood samples (6 mL) will be collected in 
lavender-top (EDTA) tubes and will be stored at -20°C until all time points (see 
Section 9.1.1) have been collected for that cycle.  Samples will be shipped to Covance 
(See Section 9.1.2).  
9.1.1 Blood Samples 
Blood samples for PK analyses on Arm A will be collected at the following time 
points: 
Cycle 1, Day 1: prior to treatment and at 1, 2, 4, 6, and 8 hours after the first dose 
Cycle 1, Day 2: prior to the 3rd dose 
Cycle 1, Day 3: prior to the 5th dose, and at 1, 2, 4, 6, and 8 hours after the 5th 
dose. 
Additional PK sampling will be optional (but encouraged).  This sampling would 
occur 24 and 48 hours after the 5th dose of AZD1775, and will occur on Days 4 
and 5, respectively. 
 
Blood samples for PK analyses on Arm B will be collected at the following time 
points: 
Cycle 1, Day 1: prior to treatment and at 2 and 4 hours after the first dose  
Cycle 1, Day 8: prior to the eighth dose 
 
9.1.2 Laboratory Contact 
PK plasma samples will be shipped in 10 kg of dry ice to: 
Covance Central Laboratory Services 
Attn:  Phyllis Sellars – Special Handling 
8211 SciCor Drive 
Indianapolis, Indiana 46214 
Phone:  317-271-1200 
 
9.2 
Pharmacodynamics 
Evaluation of drug effect on DNA damage response will be performed by 
immunofluorescence assays for measurement of DNA damage-repair markers, such as 
Rad51, pNbs1, and γH2AX.  Evaluation of caspase-3 by immunofluorescence assays will 
be performed on biopsy specimens as a marker of drug effect on apoptosis.  Evaluation of 
Wee1 kinase inhibition will be performed by an immunofluorescence assay for pY15-

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Cdk. 
 
For the twice-daily dosing schedule (Arm A), CTCs will be obtained in all patients pre-
dose, on C1D3 and C2D3 after the 5th administration of AZD1775, for evaluation of 
γH2AX as a marker of drug effect on apoptosis.  For the once-daily dosing schedule 
(Arm B), CTCs will be obtained in all patients on day 1 (prior to AZD1775 
administration), on day 4 (4 ± 1 hours after AZD1775 administration), on day 8 prior to 
the dose of AZD1775, on day 8 (4 ± 1 hours after AZD1775 administration), and on day 
11 (4 ± 1 hours after AZD1775 administration).  Additional optional CTC samples will 
be obtained at each restaging and at time of disease progression or “restaging follow-up” 
biopsy.  Arm B CTC specimens will be evaluated for γH2AX, pHH3, pNbs1, and pY15-
Cdk. 
  
9.2.1 Laboratory Contact 
At least 24 hours prior to tumor biopsy or blood sample collection, the research 
nurse will contact the NCI Phase I/II PK/PD Support Group in NIH Building 10: 
E-mail (preferred): NCIPK-PDsupportgroup@mail.nih.gov, Pager (preferred): 
102-12798, Phone: 240-858-3963, Fax: 301-480-5871.  For biopsies, tubes pre-
labeled with the information specified in Section 9.2.4, biopsy date, and site of 
tissue biopsy will be provided.  Initial processing and shipping of the samples will 
be completed as described below. 
9.2.2 Blood Collection for CTC Studies (optional)* 
Whole blood will be collected aseptically by venipuncture or from a venous port 
into one 4-mL sodium heparin green glass tube (Arm A) or two 4-mL EDTA 
tubes (Arm B); the collected blood samples should be shipped to PADIS on the 
day of sample collection to avoid excessive CTC cell death prior to specimen 
processing.  Blood samples for CTCs will be collected from patients enrolled on 
Arm A at the following time points: 
 
• Cycle 1 prior to treatment, 
• Cycle 1, day 3: 2-5 hours after the 5th dose 
• Cycle 2, day 3: 2-5 hours after the 5th dose 
 
For patients enrolled on Arm B, on the once daily dosing schedule, blood samples 
for CTCs (two 4-mL EDTA tubes per time point) will be collected from all 
patients at the following time points during each cycle: 
 
• Day 1, prior to treatment, 
• Day 4, 4 ± 1 hours after AZD1775 administration 
• Day 8, prior to treatment 
• Day 8, 4 ± 1 hours after AZD1775 administration 
• Day 11, 4 ± 1 hours after AZD1775 administration 
• Every 2 cycles at restaging (3 or 4 cycles for patients on study more than one 

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or three years, respectively) 
• Optionally, at time of disease progression or “restaging follow-up biopsy,” on 
day 1 (± 2 days) of the cycle following any restaging at which a 10-20% 
increase in tumor volume is observed (according to RECIST criteria) if the 
patient has been on study for at least 4 cycles. 
 
9.2.3 Blood Collection for ImmunoPD Studies (PBMCs and serum; optional) for the 
Laboratory of Tumor Immunology 
For patients enrolled on Arm B once-daily dosing schedule, optional blood 
samples for immunoPD will be collected into one 6-mL sodium heparin tube and 
one 7-mL SST at the following time points:  
• Cycle 1 prior to treatment, 
• Cycle 1, day 8 prior to treatment (+/- 1 day for scheduling) 
 
Sample processing will be performed by the Clinical Services Program (CSP), 
FNLCR; flow cytometry will be performed by LTIB.   
 
Samples should be kept at room temperature prior to processing.  Shipment by 
CSP Courier may be arranged by contacting Jennifer Bangh, FNLCR, Tel.: 301-
846-5893.   
 
9.2.4 Tumor Biopsies 
9.2.4.1 Timing of tumor biopsies 
Biopsies will be optional during the escalation phase and mandatory in the 6 
additional patients enrolled at the MTD during the expansion phase (Expansion 
Arm A).  Tumor biopsies will remain optional in the expansion arm of BRCA 
patients and follow the biopsy collection times as follows.  Biopsies will be 
collected: 
• before drug administration on study (baseline), and 
• on cycle 1, day 3; 2-5 hours after the 5th dose of AZD1775 
 
For the patients enrolled on Arm B, biopsies will remain optional during the 
escalation phase, but will be mandatory in up to 20 patients enrolled at the 
maximum tolerated single daily dosing schedule during the expansion phase.  
Biopsies will be collected: 
• before drug administration on study (baseline), and 
• on cycle 1, day 8; prior to the 6th dose of AZD1775 (+/- 1 day) 
• optionally, at disease progression or on day 1 (± 2 days) of the cycle following 
any restaging at which a 10-20% increase in tumor volume is observed 
(according to RECIST criteria) if the patient has been on study for at least 4 
cycles.  (For example, a biopsy would be performed on cycle 6 day 1 for a 10-
20% tumor volume increase detected at the restaging following cycle 4). 
 

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9.2.4.2 Biopsy Procedure 
Serial tumor biopsies will be obtained by the Interventional Radiology team by a 
percutaneous approach.  It is preferred that up to 5 core biopsies ≥18 gauge in 
diameter and ≥1 cm in length will be obtained during each procedure if 
considered safe and feasible.  It is estimated that there will be between 2 million–
5 million cells from each biopsy.  If a site is deemed appropriate for biopsy with 
minimal risk to the participant by agreement between the investigators and 
Interventional Radiology team, an attempt for biopsy will be made. 
 
The use of imaging to facilitate biopsies will be decided by members of the 
Interventional Radiology team and may include ultrasound, CT scan, or MRI.  
Should a CT scan be needed for biopsy, the number of scans for each procedure 
will be limited to the minimum number needed to safely obtain a biopsy.  Tumor 
biopsies and local anesthesia will be administered only if they are considered to 
be of low risk to the participant, as determined by the investigators and 
Interventional Radiology. 
 
Acceptable biopsy procedures are: percutaneous biopsy with local anesthetic; 
excisional cutaneous biopsy with local anesthetic; other biopsy with local 
anesthetic and/or sedation that has been shown to have a risk of severe 
complications < 2%; biopsy with removal of additional tumor tissue during a 
medically necessary mediastinoscopy, laparoscopy, gastrointestinal endoscopy, 
bronchoscopy, or craniotomy; removal of additional tumor tissue during a 
medically necessary surgical procedure.  No open surgical, laparoscopic 
endoscopic procedure will be performed solely to obtain a biopsy for this 
protocol. 
 
If the participant chooses not to undergo tumor biopsy, he/she will still remain in 
the study and receive study medication, and all the other correlative studies will 
be performed. 
 
Tumor biopsies are optional during the escalation phase and mandatory for the 
additional patients enrolled at the MTD during the BRCA-arm expansion phase.  
Baseline biopsies will be performed following patient enrolling on study.  For 
Arm B, if the patient had a biopsy within the past 3 months and had no treatment 
since that biopsy, an attempt will be made to obtain and process that tissue as 
baseline biopsy.  If the tissue is not of sufficient quality or cannot be used for 
protocol-specified PD studies, a percutaneous biopsy will be performed.  If an 
initial attempt at percutaneous biopsy is unsuccessful, the patient will be given an 
option to proceed with a repeated attempt at percutaneous biopsy.  A separate 
consent form must be signed for each biopsy procedure, so patients may choose 
not to undergo subsequent biopsies.  If the baseline biopsy is unsuccessful or the 
patient refuses to undergo subsequent biopsies, no further biopsies will be 
performed but the patient will remain on study, receive study medication, and 
other correlative studies will be performed.  
 

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9.2.4.3 Solid Tumor Biopsy Processing 
Up to 5 tissue cores will be collected.  Cores will be flash frozen in liquid 
nitrogen and submitted to Dr. Kinders' laboratory for evaluation of DNA damage 
markers, and H&E pathology evaluation.  The frozen biopsy specimens are 
transferred to PADIS, where the core biopsy samples are stored at -80°C and 
subsequently processed within 7-10 days for analysis.  Biopsy samples will be 
analyzed for γH2AX and pTyr15-Cdk.  Additional analyses of markers of DNA 
damage will depend on tissue availability.  One half-core pre-treatment flash 
frozen biopsy will be saved and stored for future analyses: targeted sequencing for 
DNA repair defects and p53 mutational analysis is being discussed with the 
laboratories.  Such studies, if performed, will be conducted following an 
amendment to the current protocol. 
 
Biopsies for PD analysis will be shipped on dry ice to: 
 
Attention: Dan Danner 
NCI-F/FNLCR 
1073 Beasley Street, Building 1073 
Fort Detrick 
Frederick, MD 21701 
Phone: 301-846-5748 
NCI_PD_Support@mail.nih.gov 
 
Blood for CTC analysis will be shipped at room temperature on the day of sample 
collection to: 
Attention: Dan Danner 
NCI-F/FNLCR 
1073 Beasley Street, Building 1073 
Fort Detrick 
Frederick, MD 21701 
Phone: 301-846-5748 
NCI_PD_Support_CellSearch@mail.nih.gov 
 
Shipment should be by CSP Courier and may be arranged by contacting Jennifer 
Bangh, FNLCR, Tel.: 301-846-5893 
 
9.2.5 Sample Collection and Processing 
Biospecimens will be collected and processed using validated SOPs that will 
ensure both specimen quality and patient confidentiality pursuant to informed 
consent provisions.  Information about each specimen (e.g., blood, tumor biopsy, 
circulating tumor cells, per specific protocol) will be recorded on a PK/PD 
collection worksheet included in Appendix F. 
 
Using a computerized inventory system and a backup hardcopy process, all 
specimen collection and processing steps will be documented and the specific 

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location of each specimen will be tracked.  Each new specimen collected will be 
assigned a unique barcode identifier that can be linked to the original specimen 
collected and other relevant information within the inventory system.  To ensure 
patient confidentiality, only containers used for the initial specimen collections 
will be labeled with patient identifiers.   
 
Only the barcode identifier will be applied to all subsequent specimen containers.  
When specimens are processed and aliquoted, no patient information will be 
included on the new containers.  Original specimen containers will be discarded.  
Only barcode-labeled specimens without patient identifiers will be shipped for 
analysis and/or storage.  Specimen labels will indicate: CTEP protocol number, 
unique patient accession number, 3-digit sample number (see list below), 
collection time, and total volume collected, as appropriate.  Samples from sets of 
at least three patients will be grouped for scientific analysis. 
 
Standardized 3-digit sample collection numbers: 
100 series: urine for PK 
200 series: blood for PK 
300 series: blood for PD 
400 series: blood for circulating tumor cells (CTCs) 
500 series: tumor biopsies 
800 series: blood for pharmacogenomics or other research use 
 
The inventory process contains other security provisions sufficient to safeguard 
patient privacy and confidentiality.  Access to the inventory system and associated 
documents will be restricted to appropriate individuals.  Requests to use 
specimens stored in the repository must be approved.  The only patient 
information available in the inventory system will be the patient sex, diagnosis, 
and level of informed consent given.  SOPs ensure that any changes in informed 
consent made by a patient and relayed to the PI will be reflected in the inventory 
system to ensure that specimens are destroyed as appropriate.  All laboratory 
personnel will be trained to adhere to SOPs and will be monitored for high-quality 
performance. 
 
Any pharmacokinetic sample remaining after analysis for AZD1775 may 
be used for exploratory DDI, metabolite, or biomarker analyses.  For example, 
circulating citrulline concentration is emerging as a biomarker candidate for the 
assessment of intestinal function and chemotherapy-induced gastrointestinal 
toxicity, and preclinical studies of AZD1775 found a reasonable correlation 
between villus atrophy and decreases in body weight and plasma citrulline. Thus, 
remaining plasma PK samples may be used to evaluate changes in plasma 
citrulline and its relationship to GI toxicities. 
 
Any new use of these samples will require prospective IRB review and approval.  
Access to these samples will only be granted following IRB approval of an 
additional protocol, granting the rights to use the material. 

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If at any time, a patient withdraws from the study and does not wish for their 
existing samples to be utilized, the individual must provide a written request.  
Following receipt of this request, the samples will be destroyed (or returned to the 
patient, if so requested), and reported as such to the IRB.  Any samples lost (in 
transit or by a researcher) or destroyed due to unknown sample integrity (i.e., 
broken freezer allows for extensive sample thawing, etc.) will be reported as such 
to the IRB. 
 
 
9.2.5.1 Human Data Sharing Plan 
What data will be shared?  
We will share human data generated in this research for future research as 
follows: 
x De-identified data in an NIH-funded or approved public repository  
x Identified data in BTRIS (automatic for activities in the Clinical Center)  
x De-identified or identified data with approved outside collaborators under 
appropriate agreements  
 
How and where will the data be shared?  
Data will be shared through:  
x An NIH-funded or approved public repository: clinicaltrials.gov 
x BTRIS (automatic for activities in the Clinical Center)  
x Approved outside collaborators under appropriate individual agreements  
x Publication and/or public presentations  
 
When will the data be shared?  
x At the time of publication or shortly thereafter 
 
 
9.3 
Exploratory whole-exome and RNA sequencing 
For active Expansion Arm B patients enrolled at the time of Amendment P (11/2/17) approval or 
thereafter, baseline, cycle 1 day 8, and progression/“restaging follow-up” tumor biopsy tissue 
remaining after completion of PD biomarker analyses will be used for exploratory whole-exome 
sequencing (WES) and RNA sequencing (RNA-seq) as appropriate to identify tumor genomic 
alterations and gene expression patterns potentially associated with AZD1775 antitumor activity, 
including loss of function mutations in SETD230 and amplification or overexpression of CCNE1 
or MYC29.  Baseline and cycle 1 day 8 blood samples will also be collected for sequencing to 
enable comparison of tumor and germline sequences.  Tissue specimens used for sequencing 
analyses will be de-identified, with only limited clinical annotation (e.g., response to AZD1775) 
maintained for each specimen.  Active Expansion Arm B patients already enrolled at the time of 
Amendment P approval will be re-consented to the new, “genetic analysis” consent form prior to 
use of their specimens for exploratory sequencing, and, if both pre- and post- biopsies have 

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already been collected from such patients, a blood sample will be collected at time of re-consent 
for germline DNA analysis, as described below.   
 
Biopsy cores and tissue sections are to be used for exploratory WES or RNA-seq only after PD 
biomarker analyses have been completed.  Tissue availability will be tracked in real time using 
Labmatrix.  Although the MoCha Laboratory is CLIA-certified, these sequencing studies will not 
be done per CLIA specifications as the data are not returned to the patients or used for clinical 
decision making.  WES analysis will be prioritized over RNA-seq (see “Biopsy specimen use 
prioritization” diagram, below).  WES and RNA-seq analysis of both baseline and cycle 1 day 8 
tumor tissue specimens is preferred; however, WES may be performed for a sample from only 
one time point depending on tissue availability.  RNA-seq may be performed for baseline 
specimens only if no cycle 1 day 8 tissue is available. 
 
Biopsy specimen use prioritization 
 
 
 
9.3.1 Tumor samples 
Biopsy tissue suitable for exploratory sequencing analyses includes frozen or FFPE tumor 
biopsy cores (< 1 core per sequencing run) or a series of slide-mounted FFPE tumor tissue 
sections (approximately 20 4 µm-thick tumor sections per sequencing run). 
 
For all patients, frozen (cores) or FFPE (cores or slides) tumor tissue will be submitted for 
genetic analyses to the MoCha Laboratory.  Samples labeled with unique patient IDs only 
will be transferred directly from PADIS to Dr. Mickey Williams’ laboratory.  Do NOT 
include patient identifiers (e.g., medical record number, patient name, or initials) with 
the samples. 
 
MoCha Lab, Frederick National Laboratory for Cancer Research 
Fort Detrick 
Building 433 Room #3/#15 
Frederick, MD 21702 
NCIFrederickMoChaRND@mail.nih.gov 
 

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58 
The biopsy specimen will be extracted for nucleic acids using the Qiagen FFPET All-Prep 
procedure.  DNA and RNA will be assessed for quantity and quality by spectroscopy 
(OD 260/280) and a PCR-based amplification quality assessment test.  All specimens that 
meet necessary quantity and quality criteria will be used for whole-exome and RNA 
sequencing as appropriate. 
 
9.3.2 Blood samples 
Optional whole blood samples will be collected at baseline and cycle 1 day 8 to obtain 
mononuclear cells.  The nucleic acid extracted from the patient’s mononuclear cells will be 
sequenced to compare somatic mutational status to the tumor biopsy specimen.  For active 
Expansion Arm B patients already enrolled at the time of Amendment P approval who are re-
consented to the new, “genetic analysis” consent form after both pre- and post- biopsies have 
already been collected, an optional blood sample will be collected at time of re-consent. 
 
One 7-mL K3 EDTA tube should be collected on the same day as the biopsy (either before or 
after the biopsy procedure) and shipped at ambient temperature.  Samples should be labeled 
with only the unique patient ID.  Do NOT include patient identifiers (e.g., medical record 
number, patient name, or initials) with the samples. 
 
Shipment of blood samples should be by CSP Courier and may be arranged by contacting 
Jenn Bangh, FNLCR, Tel.: 301-846-5893.  Samples should be sent to: 
 
MoCha Lab, Frederick National Laboratory for Cancer Research  
Fort Detrick  
Building 433 Room #3/#15 
Frederick, MD 21702 
NCIFrederickMoChaRND@mail.nih.gov 
 
 
10 STUDY CALENDAR 
Eligibility screening evaluations are to be performed within 8 days prior to enrollment, with 
the exception of tumor imaging scans which must be performed within 28 days prior to 
enrollment (see Section 3.4).  Baseline history, physical examination, laboratory evaluations, 
urinalysis, and ECG are to be conducted within 8 days prior to start of protocol therapy.  If 
protocol therapy is started within 8 days of the screening evaluations, the screening 
evaluations may be used as baseline measurements.  If >8 days have passed since the 
screening evaluations, the medical history, physical examination, laboratory evaluations, 
urinalysis, and ECG must be repeated prior to starting protocol therapy.  Scans/x-rays and 
ECHO must be done within 28 days prior to the start of protocol therapy.  In the event that 
the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of the next cycle of therapy.  Start of next cycle may be delayed for 
up to 1 week to accommodate scheduling conflicts.  For cycle 2 and beyond, history, physical 

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59 
examination, and laboratory evaluations can be performed up to 3 days before the start of the 
next cycle. 

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60 
 
Pre- 
Study 
Eligibility 
Screening 
Baseline 
Clinical 
Evaluation 
C1
W
1 
C1
W
2 
C1
W
3 
C2 
W
1 
C2
W
2 
C2
W
3 
C3 
W
1 
C3
W
2 
C3
W
3 
C4 
W
1 
C4 
W
2 
C4 
W
3 
Off 
Treatmentk 
AZD1775 DL1a 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
AZD1775 DL2 ona 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xl 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
Concurrent meds 
X 
Xl 
X---------------------------------------------------------------X 
 
Physical examb 
X 
Xl 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signs 
X 
Xl 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Height 
X 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
Xl 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Performance status 
X 
Xl 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CBC w/diff, pltsc 
X 
Xl 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Serum chemistryc 
X 
Xl 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
PT, INR, PTTd 
X 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
β-HCGe 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Adverse event 
evaluation 
 
 
X---------------------------------------------------------------X 
X 
Radiologic evaluation 
X 
Xl 
Radiologic measurements should be performed every 2 
cycles (see Section 11.2 for patients on study for more 
than one year).  Documentation (radiologic) must be 
provided for patients removed from study for 
progressive disease. 
X 
Tumor biopsyf 
 
 
Biopsies will be performed as described in Section 
9.2.4. 
 
PK blood samplingg 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Circulating tumor cellsh 
 
 
Blood for circulating tumor cells (optional) will be 
collected at multiple time points as specified in Section 
9.2.2 
 
Immunoblood samplingi 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
ECGj 
X 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: For dose level 1, AZD1775 will be administered orally for 5 doses each cycle, with doses administered 
approximately 12 hours apart starting with the first dose for that week (for example, if the patient takes the first 
dose at 9 AM on Monday then the next dose will be administered at 9 pm that evening).  Starting at dose level 
2 and onwards, AZD1775 will be administered orally for 5 doses for the first 2 weeks of each cycle, with 
doses administered approximately 12 hours apart starting with the first dose for that week (as explained above 
except it will occur over the first two weeks of the cycle).  Each cycle is 21 days (± 1 day for scheduling). 
For Arm B, AZD1775 will be administered orally once daily, for 5 doses each week, for two consecutive 
weeks.  Cycle length will remain 21 days (± 1 day for scheduling). 

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61 
b: Physical examination at the Clinical Center should be performed at the start of each cycle (up to 3 days before 
start of a new cycle) 
c: Serum chemistry (albumin, total bilirubin, calcium, creatinine, phosphorus, magnesium, potassium, sodium, 
SGOT [AST], SGPT [ALT]); CBC w/diff, platelets weekly during cycle 1, then every 3 weeks at the start of 
each subsequent cycle (up to 3 days before start of new cycle).  If clinically indicated, labs may be obtained 
with more frequency with subsequent cycles. 
d. PT/INR, PTT prior to biopsy. 
e: Serum or urine pregnancy test (women of childbearing potential) within 1 week prior to enrollment, prior to 
starting each treatment cycle, and as clinically indicated. 
f. Tumor biopsies will be performed as specified in Section 9.2.4.  Tumor biopsies are optional during the 
escalation phase, but will be mandatory in the 6 patients enrolled at MTD (Expansion Arm A) for evaluation of 
PK and PD endpoints.  Tumor biopsies will be optional in the 6 patients in the BRCA-1 or -2 mutation 
expansion arm.  For patients enrolled on Arm B at once daily dosing, tumor biopsies will remain optional until 
the maximum tolerated daily dosing is established, at which point up to 20 additional patients will be enrolled 
and tumor biopsies will be mandatory.  With Amendment P (11/2/17), on the day of each biopsy procedure 
(either before or after the biopsy procedure), an optional blood sample should be collected into a 7-mL K3 
EDTA tube for exploratory sequencing analyses (see Section 9.3.2). 
g: PK samples for Arm A will be performed at the following time-points: 
C1D1: Pre-dose, at 1, 2, 4, 6, and 8 hours after the first dose 
C1D2: Prior to the 3rd dose 
C1D3: Prior to the 5th dose, and 1, 2, 4, 6, 8 hours after the 5th dose. 
Additional PK sampling will be optional (but encouraged).  This sampling would occur 24 and 48 hours after 
the 5th dose of AZD1775, and will occur on Days 4 and 5, respectively. 
For patients enrolled on Arm B, PK samples will be performed at the following time-points: 
C1D1: Prior to the first dose and at 2 and 4 hr after the first dose, 
C1D8: Prior to the 6th dose 
h:  Circulating tumor cells (optional) will be collected at multiple time points as specified in Section 9.2.2. 
i:  Optional blood and serum for immune PD studies (Gulley Lab) will be collected for Arm B patients prior to 
treatment and prior to dosing on cycle 1 day 8 (+/- 1 day). 
j:  ECG will be performed at baseline for evaluation of QTc and as clinically indicated thereafter. 
k: Off-study evaluation. 
l: Values from eligibility screening tests may be used as baseline evaluation values if the test was performed 
within 8 days of start of protocol therapy (or, for radiologic evaluation and tumor measurement, within 28 
days of start of protocol therapy).  See Section 3.4 and Section 5. 
 
 
11 MEASUREMENT OF EFFECT 
11.1 
Antitumor Effect – Solid Tumors 
Although response is not the primary endpoint of this trial, patients with measurable 
disease will be assessed by standard criteria.  For the purposes of this study, patients 
should be re-evaluated for response every 6 weeks (every 2 cycles; 3 or 4 cycles for 
patients on study more than one or three years, respectively).  In addition to a baseline 
scan, confirmatory scans should also be obtained at least 4 weeks following initial 
documentation of objective response. 
 

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62 
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) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
11.1.1 Definitions 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of 
their first treatment with AZD1775. 
 
Evaluable for objective response:  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response:  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  
11.1.2 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) as 
>20 mm by chest x-ray or as >10 mm with CT scan, MRI, or calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
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. 
 

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63 
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 sites of disease) including any 
measurable lesions over and above 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.  
11.2 
Guidelines 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.  

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64 
 
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).   
 
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. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 

CTEP # 9350 
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65 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
11.3 
Response Criteria 
11.3.1 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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66 
 
Partial Response (PR): 
 At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum of 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 of diameters while on 
study. 
 
11.3.2 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). 

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67 
11.3.3 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. 
 
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* 
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. 
 
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 
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 
 

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68 
11.4 
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. 
 
 
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.  
 
 
12 DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
12.1 
Data Reporting 
12.1.1 Method 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  
Data will be collected in the Center for Cancer Research C3D database and will 
be transmitted  to CTMS electronically at least once every 2 weeks. 
 
 
Note: All adverse events that have occurred on the study, including those reported 
through CTEP-AERS, must be reported via the monitoring method identified 
above. 
12.1.2 Responsibility for Data Submission 
N/A 
12.2 
CTEP Multicenter Guideline 
N/A 
12.3 
Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI 
Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 

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69 
Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained within the terms of award, apply to the use of the Agent(s) in this study: 
 
 
12.3.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 
clinical study.   Collaborator(s) data for Agent(s) are confidential and proprietary 
to Collaborator(s) and shall be maintained as such by the investigators.  The 
protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI.  If a 
copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement.  
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
12.3.2 For a clinical protocol where there is an investigational Agent used in 
combination with (an)other Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as "Multi-
Party Data”):  
12.3.3 a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
 
clinical trial by any other Collaborator solely to the extent necessary to allow said  
 
other Collaborator to develop, obtain regulatory approval or commercialize its  
 
own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
 
must agree in writing prior to the commencement of the trials that it will use the 
 
Multi-Party Data solely for development, regulatory approval, and 
 
commercialization of its own Agent. 
12.3.4 Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 

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12.3.5 When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
12.3.6 Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
12.3.7 Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least 
three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings.  Press releases and other media 
presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
E-mail: ncicteppubs@mail.nih.gov 
 
 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
12.4 
Genomic Data Sharing Plan 
The NIH Genomic Data Sharing (GDS) Policy does not apply to this protocol as we will 
be performing exploratory genetic analysis of no more than 26 patient samples; therefore, 
this study does not meet GDS criteria, and no GDS plan has been developed. 
13 STATISTICAL CONSIDERATIONS 
13.1 
Study Design/Endpoints 
13.1.1 Primary Endpoints 
The primary objectives are: 
• To establish the safety and tolerability of single agent AZD1775 in patients 
with refractory solid tumors. 
• To determine the pharmacokinetics of AZD1775 in patients with refractory 

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solid tumors. 
13.1.2 Secondary Endpoint 
 
The secondary objective is: 
 
• To evaluate the antitumor activity of AZD1775 in patients with refractory 
solid tumors. 
13.1.3 Exploratory Endpoints 
The exploratory objectives are: 
• To determine the effect of AZD1775 on pharmacodynamic markers of DNA 
damage and apoptosis in tumor tissue and blood. 
• To assess whether sufficient Wee1 inhibition is maintained throughout the 
therapeutic regimen. 
• To identify tumor genomic alterations and gene expression patterns 
potentially associated with AZD1775 antitumor activity. 
 
13.2 
Study Design 
This Phase I study will use a standard 3+ 3 design, and permits intra-patient dose 
modification (defined in Section 5.1).  The MTD or recommended Phase II dose is the 
dose level at which no more than 1 of 6 patients experience DLT during the first cycle of 
treatment, and the dose below that at which at least 2 (of < 6) patients have DLT as a 
result of the drug. 
13.3 
Sample Size/Accrual Rate 
With Amendment E (dated 09/24/2013), an additional expansion arm of 6 patients with 
documented tumors harboring BRCA- 1 or-2 mutations will also be enrolled at the MTD 
to further explore the safety of AZD1775 and obtain preliminary evidence of activity in 
this patient population.  This information may inform patient selection for further 
development of this agent. 
 
With Amendment G (dated 07/17/2014) an additional Arm B will be established to 
further evaluate an alternative once-daily dosing schedule.  Patients will be enrolled 
based on the standard 3+3 design.  Once the maximum tolerated daily dosing is 
established, up to 20 additional patients will be enrolled at this dose to further evaluate 
PD endpoints.  With that number, and a tumor biopsy QA criteria failure rate of 40% with 
respect to paired (pre- and post-dose) biopsies, we have an 87% likelihood of having at 
least 10 usable PD samples, and 94% likelihood of having at least 9 usable samples.  
Biopsy tissue quality will be monitored and accrual will stop once we have obtained 10 
usable paired samples. 
 
The study is a standard design using 3 patients per arm, unless DLT is noted, in which 

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point up to 6 patients may be enrolled in an arm.  Up to 30 patients will be enrolled for 
determination of the MTD.  In addition, an additional 6 patients will be enrolled at the 
MTD to further define the dose and evaluate PD studies at this dose level (Expansion 
Arm A).  To allow for a small number of patients who may not be evaluable, and the 
addition of Arm B, the accrual ceiling for this trial is set at 72 patients.  It is anticipated 
that 2-3 patients per month may be enrolled onto this study.  Depending on the number of 
patients needed to reach MTD, it is expected that 24-48 months will be required to accrue 
the number of patients necessary to complete the trial. 
13.4 
Analysis of Exploratory Endpoints 
We will assess the effect of AZD1775 on DNA damage response based on 
immunofluorescence analysis of markers of DNA damage, Rad51, pNbs1, and γH2AX in 
tumor biopsies, pTyr15-Cdk, and caspase 3 in CTCs as a marker of apoptosis. 
13.5 
Reporting and Exclusions 
13.5.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time of 
their first treatment with study agents. 
13.5.2 Evaluation of response – All patients included in the study will be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible.  Each patient will be assigned one of the following categories: 
1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 7) 
early death because of other cause, or 9) unknown (not assessable, insufficient 
data).  [Note: By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) will be included in the main analysis of 
the response rate.  Patients in response categories 4-9 will be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or 
drug administration does not result in exclusion from the analysis of the response 
rate.  Precise definitions for categories 4-9 will be protocol specific. 
 
All conclusions will be based on all eligible patients.  Sub-analyses may then be 
performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, 
these sub-analyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis will 
be clearly reported.  The 95% confidence intervals will also be provided. 
 
 

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14 HUMAN SUBJECTS PROTECTIONS 
14.1 
Justification for Subject Selection 
This study will be open to all individuals regardless of gender, ethnicity, or race, 
provided that the aforementioned inclusion and exclusion criteria are met.  Patients for 
this study will be recruited through internal referral, our physician referral base, and 
through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-
4Cancer).  To date, there is no information that suggests that differences in drug 
metabolism or effect on tumor would be expected in one ethnic group compared to 
another.  Efforts will be made to extend accrual to each representative population, but a 
balance must be struck between participant safety considerations and limitations on the 
number of individuals exposed to potentially ineffective treatments on the one hand and 
the need to explore racial/ethnic aspects of clinical research on the other hand.  If 
differences in outcome that correlate to ethnic identity are noted, a follow-up study may 
be written to investigate those differences more fully. 
 
Due to lack of knowledge of the effects of AZD1775 on the fetus or infants, as well as 
the possibility of teratogenic effects, pregnant and nursing women will be excluded from 
this trial.  Patients with unstable or serious medical conditions are excluded due to the 
possibility that AZD1775 may worsen their condition and the likelihood that the 
underlying condition may obscure the attribution of adverse events to AZD1775.  HIV-
positive patients on combination antiretroviral therapy are excluded from the study 
because of possible PK interactions with AZD1775. 
14.1.1 Participation of Children 
This study includes patients 18 years of age and older.  Because insufficient 
dosing or adverse event data are currently available on the use of AZD1775 in 
patients <18 years of age, children are excluded from this study, but may be 
eligible for future pediatric trials.  Studies will be performed in patients <18 years 
of age when it is appropriate to do so. 
14.2 
Evaluation of Benefits and Risks/Discomforts 
There may or may not be any clinical benefit to a patient from participation in this trial.  
Their participation will benefit future cancer patients.  Potential risks include the possible 
occurrence of any of a range of side effects that are listed in the consent document.  The 
procedure for protecting against or minimizing risks will be to medically evaluate 
patients as described in Sections 5 and 6.  Although no compensation is available, any 
injury will be fully evaluated and treated in keeping with the benefits or care to which 
participants are entitled under applicable regulations. 
 
All patients > 18 years old will be offered the opportunity to assign a substitute decision 
maker on the “NIH Advance Directive for Health Care and Medical Research 
Participation” form, so that another person can make decisions about their medical care if 
they become incapacitated or cognitively impaired.  The process for determining whether 

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adults who lose capacity to give consent may continue participation in this trial, with its 
heavy reliance on non-therapeutic endpoints and collection of research samples, will be 
on a case-by case basis and will include consultation among the substitute decision 
maker, protocol PI, and patient’s physician regarding the health of the patient and 
likelihood of benefit from continued treatment. 
 
14.3 
Consent and Assent Process and Documentation 
An associate or principal investigator on the trial will inform patients of the purpose, 
alternatives, drug administration plan, research objectives, and follow-up of this trial.  
The patient will be provided an IRB-approved consent for review and signature and 
his/her questions will be answered.  After a decision is made to enroll into the study, a 
signature will be obtained from the patient.  The original signed consent goes to Medical 
Records; a copy will be placed in the research record. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on 
study. 
14.4 
Procedure for Protecting Against or Minimizing Any Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature 
and severity.  This study may involve risks to patients, which are currently unforeseeable.  
All patients will be monitored for side effects from taking study medication.  This 
research represents a greater than minimal risk to participants, but presents the prospect 
of direct benefit to individual subjects. 
 
The research component of this study required to obtain up to 3 CT tumor biopsies 
confers radiation exposure at an effective dose of 2.4 rem.  This dose is below NIH RSC 
guidelines and represents a slightly greater than minimal risk to patients. 
14.5 
Patient Advocate 
The patients’ rights representative is available to patients receiving treatment on this 
protocol at the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical 
Research Center, Room 1-3521, on the Bethesda NIH campus.  Patients will be informed 
that they can contact the study PI or RN at any time with questions about their medical 
care, and that the patients’ rights representative is also available to answer non-medical 
questions about the study. 

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1. APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without 
restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (e.g., light housework, 
office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities.  Up 
and about more than 50% of 
waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 

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2. APPENDIX B: AZD1775 (MK-1775) Activity in the NCI-60 Cell Line Screen 
 
 
 

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4. APPENDIX D: PATIENT’S MEDICATION DIARY - AZD1775 
 
Arm A DL1 and DL-1 of AZD1775 only 
 
 
INSTRUCTIONS 
1. Complete one form for each cycle of treatment. 
2. Swallow each capsule whole with a full glass of water either 2 hours before or 2 hours after a meal.  Do not chew or open the 
capsules.  If capsule is broken and the powder of the capsules gets on skin, wash the exposed area with as much water as necessary.  
Inform investigator or nurse if that occurs. 
3. Record the date and time you took the capsule.  The boxes in gray reflect times when you should not be taking drug. 
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Please bring this form and your bottle of AZD1775 when you return for your Day 21 appointment. 
6. In case of errors, please place a single slash mark through the error and initial it.  Please do not white out any error or scribble it out 
with ink.  Please do not write the correct information directly over the error, but on a separate line next to the error. 
 
 
 
 
 
 
 
 
 

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APPENDIX D - PATIENT’S MEDICATION DIARY - AZD1775 
 
Arm A DL2 of AZD1775 and Higher 
 
 
INSTRUCTIONS 
1. Complete one form for each cycle of treatment. 
2. Swallow each capsule whole with a full glass of water either 2 hours before or 2 hours after a meal.  Do not chew or open the 
capsules.  If capsule is broken and the powder of the capsules gets on skin, wash the exposed area with as much water as necessary.  
Inform investigator or nurse if that occurs. 
3. Record the date and time you took the capsule.  The boxes in gray reflect times when you should not be taking drug. 
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Please bring this form and your bottle of AZD1775 when you return for your Day 21 appointment. 
6. In case of errors, please place a single slash mark through the error and initial it.  Please do not white out any error or scribble it out 
with ink.  Please do not write the correct information directly over the error, but on a separate line next to the error. 

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APPENDIX D - PATIENT’S MEDICATION DIARY - AZD1775 
 
Arm B 
 
 
INSTRUCTIONS 
1. Complete one form for each cycle of treatment. 
2. Swallow each capsule whole with a full glass of water either 2 hours before or 2 hours after a meal.  Do not chew or open the 
capsules.  If capsule is broken and the powder of the capsules gets on skin, wash the exposed area with as much water as necessary.  
Inform investigator or nurse if that occurs. 
3. Record the date and time you took the capsule.  The boxes in gray reflect times when you should not be taking drug. 
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Please bring this form and your bottle of AZD1775 when you return for your Day 21 appointment. 
6. In case of errors, please place a single slash mark through the error and initial it.  Please do not white out any error or scribble it out 
with ink.  Please do not write the correct information directly over the error, but on a separate line next to the error.

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6. APPENDIX F: PK/PD COLLECTION WORKSHEET