A Randomized Placebo-Controlled Phase II Trial Comparing Gemcitabine Monotherapy to Gemcitabine in Combination With AZD 1775 (MK 1775) in Women With Recurrent, Platinum Resistant Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers
Phase: PHASE2
Conditions: Ovarian Brenner Tumor, Ovarian Clear Cell Cystadenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Malignant Mixed Mesodermal (Mullerian) Tumor, Ovarian Mucinous Cystadenocarcinoma, Ovarian Seromucinous Carcinoma, Ovarian Serous Cystadenocarcinoma, Ovarian Serous Surface Papillary Adenocarcinoma, Ovarian Undifferentiated Carcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma
Sponsor: National Cancer Institute (NCI)

NCI 9568 / PHL-093 
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i 
 
List of Changes 
 
NCI Protocol #: 
9568 
Local Protocol #: 
PHL-093 
Protocol Version / Version Date:   Initial / 17 Mar 2014 
                                                          A1 / 06Jun2014 
                                                          A2 / 15Jul2014 
 
    A3 / 10Jul2015 
 
    A4 / 29Sep2016 
 
    A5 / 14Dec2016 
 
    A6 / 18Apr2017 
 
    A7 / 31Jan2018 
 
    A8 / 11Jun2018 
 
    A9 / 03Jan2019 
 
This amendment is in response to an RA dated 10Dec2018 due to a revision in the CAEPR V 
2.5 (18Apr2018).  It did not result in any changes to the protocol. 
 
 

NCI 9568 / PHL-093 
03Jan2019 
 
1 
 
NCI Protocol #: 
9568 
Local Protocol #: 
PHL-093 
Protocol Version / Version Date:  Initial / 17 Mar 2014 
 
                                                         A1 / 06Jun2014 
                                                         A2 / 15Jul2014 
                                                         A3 / 10Jul2015 
                                                         A4 / 29Sep2016 
                                                         A5 / 14Dec2016 
                                                         A6 / 18Apr2017 
 
   A7 / 31Jan2018 
 
   A8 / 11Jun2018 
 
    A9 / 03Jan2019 
 
TITLE:  A Randomized Placebo-Controlled Phase II Trial Comparing Gemcitabine 
Monotherapy to Gemcitabine in Combination with AZD 1775 (MK 1775) in Women with 
Recurrent, Platinum Resistant Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancers 
 
Coordinating Center: 
 
 
Princess Margaret Phase II Consortium  
Principal Investigator: 
Dr. Amit Oza 
 
Princess Margaret Phase II Consortium 
 
Department of Medical Oncology 
 
610 University Avenue, 5-700  
 
Toronto, Ontario, CANADA 
 
M5G 2M9  
 
Tel: 416-946-2818 
 
Fax: 416-946-2082 
 
amit.oza@uhn.ca  
 
Participating Center: 
 
 
London Regional Cancer Program 
Co-Investigators: 
Dr. Steve Welch  
 
790 Commissioners Road East 
London, Ontario, CANADA 
N6A 4L6 
Phone: (519) 685-8640 
Fax: (519) 685-8624 
stephen.welch@lhsc.on.ca  
 
 
BC Cancer Agency 
 
Dr. Paul Hoskins 
 
600 West Tenth Avenue 
 
Vancouver, British Columbia, CANADA 
 
V5Z 4E6 
 
Phone: (604) 877-6000 
 
Fax: (604) 877-6179 
 
phoskins@bccancer.bc.ca  
 

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BC Cancer Agency - Centre for the Southern Interior 
Dr. Susan Ellard 
399 Royal Avenue 
Kelowna, British Colombia, V1Y 5L3 
Phone: (250) 712-3996 
SEllard@bccancer.bc.ca 
 
 
Ottawa Regional Cancer Centre 
 
Dr. Johanne Weberpals 
501 Smyth Road 
K1H 8L6 
 
Ottawa, Ontario, CANADA 
 
Phone: (613) 737-8899 x76462 
 
Fax: (613) 737-8828 
 
jweberpals@Ottawahospital.on.ca  
 
 
Fox Chase Cancer Center 
 
Dr. Gina Mantia-Smaldone 
 
333 Cottman Ave, CRU 2nd Floor 
 
Philadelphia, Pennsylvania, USA  
 
19111-2497 
 
Phone: (215)728-3175 
 
gina.mantia-smaldone@fccc.edu  
 
Participating Institutions: 
Mayo Clinic Rochester 1 
Dr. Andrea Wahner-Hendrickson 
200 1st Street SW 
Rochester, Minnesota, USA 
55905 
Phone: (507)285-2411 
WahnerHendrickson.Andrea@mayo.edu 
 
 
City of Hope National Medical Center 
 
Dr. Mihaela Cristea 
 
1500 E. Duarte Rd. 
 
Duarte, California, USA 
 
91010 
 
Phone: (626) 359-8111 
 
Fax: (626) 301-8973 
 
mcristea@coh.org 
 
 
 
 
 
1 Dr. Andrea Wahner Hendrickson from Mayo Clinic has participated in the design and 
development of the current protocol. 

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University of Pittsburgh 
 
Dr. Alexander Olawaiye 
 
300 Halket Street 
 
Pittsburgh, Pennsylvania, USA 
 
15213 
 
Phone: (412)641-1153 
 
Fax: (412)641-5417 
 
olawaiyea@upmc.edu 
 
 
University of Chicago Medical Center 
Dr. Gini Fleming 
5841 South Maryland Ave., MC 2115 
Chicago, IL 60637 
Phone: (773) 702-6712 
Fax: (773) 702-0963 
gfleming@medicine.bsd.uchicago.edu 
 
Indiana University Simon Cancer Center 
Dr. Bert O’Neil 
535 Barnhill Drive, Suite 130D 
Indianapolis, IN  46202-5289  
 
 
 
 
Email:  bhoneil@iu.edu   
 
 
Phone:  (317) 278-0320  
 
 
            
Fax:  (317) 274-8022 
 
Decatur Memorial Hospital 
Dr. James L Wade 
2300 N. Edward Street 
Decatur, Il 62526 
Tel: (217) 876 6600 
Fax: (217) 876 4757 
JLWADE3@sbcgloabal.net 
 
 
 
Statistician: 
 
Study Coordinator: 
Lisa Wang 
Karen Chang  
Princess Margaret Cancer Centre 
Princess Margaret Cancer Centre 
610 University Avenue, Toronto  
 
700 University Avenue, Toronto 
M5G 2M9, Ontario, CANADA 
M5G 1X6, Ontario, CANADA 
Phone: 416-946-4501 ext. 4883  
 
 
Phone: 416-946-4501 x3035 
Fax: 416-946-2154 
Fax: 416-946-2016 
 
lisawang@uhnresearch.ca 
Karen.chang@uhn.ca 
 
 
 

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Responsible Manager: 
Chantale Blattler 
Princess Margaret Cancer Centre 
 
610 University Avenue, Toronto 
M5G 2M9, Ontario, CANADA 
Tel: 416-946-4501 ext. 3692 
Fax: 416-946-2154 
 
chantale.blattler@uhn.ca 
 
 
Correlative Science Investigator Dr. James Brenton 
 
Cambridge 
 
NCI-Supplied Agent:  AZD 1775 (MK 1775), NSC#751084; 
Commercially Available Agent: Gemcitabine 
 
 
 

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SCHEMA

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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................5 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives ...................................................................................................8 
1.2 
Secondary Objectives ...............................................................................................8 
1.3 
Exploratory Objectives ............................................................................................8 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Epithelial Ovarian, Primary Peritoneal and Fallopian Tube Carcinoma 
(10033159, 10026669, and 10016180) ....................................................................9 
2.2 
AZD 1775 (MK 1775) .............................................................................................9 
2.3 
Gemcitabine as Treatment for Platinum-resistant or Platinum-refractory 
Epithelial Ovarian, Primary Peritoneal and Fallopian Tube Carcinoma ...............10 
2.4 
Rationale ................................................................................................................10 
2.5 
Correlative Studies Background ............................................................................11 
2.6 
Patient Reported Outcomes....................................................................................14 
3. 
PATIENT SELECTION ....................................................................................................14 
3.1 
Eligibility Criteria ..................................................................................................15 
3.2 
Exclusion Criteria ................................................................................................163 
3.3 
Inclusion of Women and Minorities ......................................................................17 
4. 
REGISTRATION PROCEDURES ...................................................................................18 
4.1 
General Guidelines .................................................................................................18 
4.2 
Registration Process ...............................................................................................19 
5. 
TREATMENT PLAN ........................................................................................................19 
5.1 
Agent Administration .............................................................................................20 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................21 
5.3 
Duration of Therapy ...............................................................................................21 
5.4 
Duration of Follow Up ...........................................................................................21 
5.5 
Criteria for Removal from Study ...........................................................................22 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................22 
6.1 
General Guidelines .................................................................................................22 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................27 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................27 
7.2 
Adverse Event Characteristics ...............................................................................31 
7.3 
Expedited Adverse Event Reporting ......................................................................32 
7.4 
Routine Adverse Event Reporting .........................................................................34 
7.5 
Follow Up of AEs and SAEs .................................................................................34 
7.6 
Secondary Malignancy ...........................................................................................35 
7.7 
Second Malignancy ................................................................................................35 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................35 

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8.1 
AZD 1775 (MK 1775) (NSC 751084) ...................................................................35 
8.2 
Gemcitabine ...........................................................................................................40 
9. 
BIOMARKER, CORRELATIVE AND SPECIAL STUDIES .........................................41 
9.1 
Biomarker Studies ..................................................................................................42 
9.2 
Laboratory Correlative Studies ..............................................................................46 
10. 
STUDY CALENDAR .......................................................................................................49 
11. 
MEASUREMENT OF EFFECT........................................................................................50 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................50 
11.2 
Other Response Parameters – CA125 Response by GCIG Criteria ......................55 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................56 
12.1 
Data Reporting .......................................................................................................56 
12.2 
CTEP Multicenter Guidelines ................................................................................56 
12.3 
Collaborative Agreements Language .....................................................................57 
13. 
STATISTICAL CONSIDERATIONS...............................................................................58 
13.1 
Study Design/Endpoints.........................................................................................58 
13.2 
Sample Size/Accrual Rate ......................................................................................59 
13.3 
Stratification Factors ..............................................................................................61 
13.4 
Analysis of Secondary Endpoints ..........................................................................61 
13.5 
Reporting and Exclusions ......................................................................................61 
14. 
References ..........................................................................................................................63 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................65 
APPENDIX B 
CTEP MULTICENTER GUIDELINES ....................................................66 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................68 
APPENDIX D 
DIARY CARD ...........................................................................................71 
APPENDIX E 
DATA MANAGEMENT GUIDELINES ..................................................72 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To evaluate the progression free survival (PFS) of subjects with recurrent platinum-resistant 
ovarian, fallopian tube or primary peritoneal cancer receiving gemcitabine in combination with 
AZD 1775 (MK 1775) compared to subjects receiving gemcitabine in combination with placebo.  
 
1.2 
Secondary Objectives 
 
1. To evaluate the objective response by RECIST 1.1 of patients receiving 
gemcitabine combined with AZD 1775 (MK 1775) compared to patients receiving 
gemcitabine in combination with placebo. 
2. To evaluate the GCIG CA125 response rate of patients receiving gemcitabine 
combined with AZD 1775 (MK 1775) compared to patients receiving gemcitabine 
in combination with placebo. 
3. To evaluate the overall survival of patients (max 1-yr follow-up) receiving 
gemcitabine combined with AZD 1775 (MK 1775) compared to patients receiving 
gemcitabine in combination with placebo. 
4. To evaluate the safety and tolerability of the combination of gemcitabine combined 
with AZD 1775 (MK 1775) in patients with recurrent, platinum-resistant ovarian, 
fallopian tube or primary peritoneal cancer. 
5. To evaluate TP53 mutations (presence of mutation and type of mutation) as 
potential predictive factors of benefit (defined as response or PFS prolongation) to 
AZD 1775 (MK 1775) and gemcitabine treatment. 
6. To evaluate p53 protein expression by immunohistochemistry as potential 
predictive factors of benefit (defined as response or PFS prolongation) to AZD 
1775 (MK 1775) and gemcitabine treatment. 
 
1.3 
Exploratory Objectives 
 
1. To evaluate patient reported outcomes using PRO-CTCAE 
2. To evaluate the concordance of TP53 mutations in the tumor specimen and TP53 
mutations determined by tagged-amplicon deep sequencing (TAm-Seq) in 
circulating tumor DNA. 
3. To correlate the levels circulating DNA TP53 mutations by TAm-Seq with 
response 
4. Validation of pCDC2 and gamma-H2AX in skin and tumour tissue as a 
pharmacodynamic marker of therapy 
5. To correlate changes in pCDC2 and gamma-H2AX with survival outcomes and 
response rate. 
 
 

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2. BACKGROUND 
 
2.1 
Epithelial Ovarian, Primary Peritoneal and Fallopian Tube Carcinoma (10033159, 
10026669, and 10016180) 
 
Ovarian cancer is the second most common gynecological malignancy and the leading cause 
of death from gynecologic malignancy in Canada 1 and US 2, with approximately 20,000 deaths 
per year. The majority of these cases are (70%) are high-grade serous subtype. Based on their 
similar histological features and behavior, high grade serous ovarian cancer is closely related 
to fallopian tube and peritoneal serous carcinoma. 
 
Current initial treatment consists of debulking surgery followed by combination 
platinum/taxane chemotherapy. In spite of initial response rates as high as 80%, most women 
relapse. Treatment of recurrent epithelial ovarian cancer depends on the treatment-free interval 
after primary chemotherapy with a platinum-taxane combination, with evidence of clinical or 
radiologic disease recurrence. Patients are classified as platinum-sensitive if the disease has 
recurred at least 6 months after the last platinum containing treatment. Platinum-resistant 
patients are characterized by a platinum-free interval of less than 6 months; platinum refractory 
as patients who progress during primary therapy. Platinum-sensitive patients may be re-
challenged with platinum based therapy; these patients will ultimately become platinum 
resistant. For women with platinum resistant disease, preferred therapy is generally single non-
platinum agent therapy, such as liposomal doxorubicin, topotecan, taxanes or gemcitabine. The 
activity of these agents is similar and modest, with an approximate 6 month progression free 
survival of about 15-25%.3,4 Novel therapies which act synergistically with conventional 
chemotherapies are needed to improve response rates and outcomes. 
 
2.2 
AZD 1775 (MK 1775) 
 
AZD 1775 (MK 1775) is a selective, small molecule inhibitor of Wee1-Like Protein Kinase. 
In vitro kinase assays have identified this molecule as a potent inhibitor of Wee1-Like Protein 
Kinase demonstrating an IC50 value of 5.2nmol/L.5 Cell-based assays measuring the levels of 
phosphorylation of CDC2 at tyrosine residue 15 (Tyr 15) confirmed that Wee1-Like Protein 
Kinase inhibition correlated with inhibited phosphorylation of CDC2. 
 
Cell-based assays in colorectal cell lines demonstrated inhibitory effects of AZD 1775 (MK 
1775) in cells pre-treated with several chemotherapy agents namely; gemcitabine, carboplatin 
and cisplatin, strengthening the hypothesis that Wee1-Like Protein Kinase inhibition abrogates 
the G2 checkpoint more effectively in combination with chemotherapy.  
 
In the clinical setting, AZD 1775 (MK 1775) has been evaluated in a phase I as single agent 
and in combination with carboplatin, cisplatin and gemcitabine6. In the first 156 patients 
treated, AZD 1775 (MK 1775) demonstrated acceptable adverse effects to both monotherapy 
and combination therapy. The most common adverse events were cytopenias, nausea/vomiting, 
and fatigue. When used in combination with gemcitabine, the maximum tolerated dose (MTD) 
was 175 mg once daily on days 1, 2, 8, 9, 15, and 16. 

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2.3 
Gemcitabine as Treatment for Platinum-resistant or Platinum-refractory Epithelial 
Ovarian, Primary Peritoneal and Fallopian Tube Carcinoma 
 
Gemcitabine is a pyrimidine antimetabolite which is phosphorylated into two active drug forms 
both of which contribute to its antiproliferative effects via the inhibition of ribonucleotide 
reductase and the incorporation of pyrimidine analogues into DNA thereby causing chain 
termination7. In the platinum-resistant setting, the response rate of gemcitabine (1,000 mg/m2 
on days 1, 8, and 15 every 28 days) in phase II and III studies ranges from 12% to 29% .3,4,8-10 
Gemcitabine is one of the recommended treatments in patients with platinum-resistant or 
refractory epithelial ovarian, primary peritoneal or fallopian tube carcinoma according to the 
NCCN guidelines. This recommendation is based on the results of two phase III clinical trial 
in which gemcitabine achieved similar overall survival, progression-free survival and response 
rate than pegylated-lyposomal doxorubicin.3,4 
 
2.4 
Rationale 
 
The checkpoint kinases, which include ATR, CHK1 and Wee1-Like Protein Kinase, are 
important regulators of DNA damage surveillance pathways. Their roles at the various 
transition points (G1/S, G2/M) of the cell cycle are critical in order for proliferating cells to 
repair DNA damage accumulated from either endogenous or exogenous sources 11. Wee1-Like 
Protein Kinase exerts inhibitory phosphorylation of CDC2 at Tyr14 and Tyr15 which in turn 
stalls cells at G2/M preventing entry into mitosis. Inhibition of Wee1-Like Protein Kinase 
releases the inhibition and the decreased levels of pCDC2 allow cells to proceed through 
mitosis. Cells previously exposed to DNA damaging agents and now under the pressure of 
Wee1-Like Protein Kinase inhibition would be expected to undergo mitotic catastrophe and 
apoptosis as a consequence of the accumulation of cytotoxic-induced DNA damage. Malignant 
cells with ineffective regulation of G1/S transition are therefore heavily reliant on the G2/M 
checkpoint to allow for repair of critical DNA damage which would otherwise promote mitotic 
catastrophe, triggering cells to undergo apoptosis. Given this mechanism of action, inhibition 
of checkpoint kinases active at G2/M (such as Wee1-Like Protein Kinase) are theorized to have 
synergistic activity with DNA damaging cytotoxics. Preclinical work in a variety of tumor 
models has been consistent with this hypothesis although the true relevance of functional p53 
status is unclear 5,12,13.  
 
Synergy between gemcitabine chemotherapy and AZD 1775 (MK 1775) has been 
demonstrated in vivo by the sequential treatment of tumour cells with gemcitabine followed by 
AZD 1775 (MK 1775). The antigrowth effects of gemcitabine, as demonstrated by the IC50 
value in cell viability assays and induced cell death were significantly augmented by the 
sequential administration of AZD 1775 (MK 1775).14  
 
Preclinically, the addition of AZD 1775 (MK 1775) to gemcitabine has shown increased 
activity in platinum resistant ovarian cancer cell lines, as well as in xenografts derived from 
those cell lines. Considerable synergy between AZD 1775 (MK 1775) and gemcitabine was 
also seen in gemcitabine resistant and sensitive cell lines [Internal data provided by Merck - 
Shumway]. 

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In the clinical setting, confirmed partial responses to AZD 1775 (MK 1775) in combination 
with chemotherapy have been demonstrated in a number of different disease entities in the 
phase I setting6. AZD 1775 (MK 1775) is currently being investigated in patients with relapsed 
platinum-sensitive ovarian cancer in combination with carboplatin and paclitaxel 
[NCT01357161]. In the phase I portion of the study with 15 patients, a response rate of 79% 
has been observed. In an investigator-initiated study investigating AZD 1775 (MK 1775) in 
combination with carboplatin in patients with refractory or platinum-resistant ovarian cancer, 
6 among the 17 evaluable patients achieved a partial response. 
 
2.4.1 Rationale for the exploratory cohort 
In the current study, only patients with high grade serous ovarian cancer will be considered for 
the statistical analysis in order to evaluate a more homogenous population in which TP53 
alterations are common. However, there is little preclinical and clinical information available 
regarding activity of AZD 1775 (MK1775) in combination with chemotherapy in other ovarian 
cancer histologies. AZD 1775 (MK1775) may sensitize other non-high grade serous ovarian 
cancer to gemcitabine as these tumors may have TP53 mutations or other alterations in the cell 
cycle regulation. Patients with non-high grade serous histologies could be enrolled in an 
exploratory cohort which would not be included in the statistical analysis of the study. Patients 
enrolled in the exploratory cohort will receive open-label AZD 1775 (MK-1775). 
 
2.5 
Correlative Studies Background 
 
2.5.1 Determination of TP53 mutations on archival tissue 
 
TP53 mutations appear to be present in early stage tumours suggesting that they are a critical 
early event in the tumourigenesis of high-grade serous ovarian cancer.15 TP53 is mutated in 
approximately 97% of high-grade serous ovarian cancer (HGSOC) based on the sequencing of 
DNA from 145 patients with pathologically confirmed cases. 16 This has recently been 
confirmed by the results from the Cancer Genome Atlas researchers (TCGA) who found TP53 
mutations in 96% of 489 HGSOC samples tested. 17 The high frequency of TP53 mutations 
makes HGSOC an ideal target for strategic therapies that selectively enhance chemotherapy 
effects in p53-deficient cells. 
 
Preclinical evidence suggests that the activity of AZD 1775 (MK 1775) in combination with a 
DNA damaging agent, such us chemotherapy or radiotherapy, is enhanced in cells with 
deficient G1. One of the most common alterations inducing G1 checkpoint deficiency is the 
loss of p53 function. In pancreatic cancer xenografts, a synergistic effect was observed when 
combining gemcitibine and AZD 1775 (MK 1775). This effect was limited to p53 deficient 
models.13 
 
In the ovarian cancer cell line TOV21G, which has wild-type TP53, abolishing TP53 function 
by introducing siRNA sensitizes the cell lines to the combination of AZD 1775 (MK 1775) and 
chemotherapy (internal data from Merck).  
 

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This study will evaluate the presence of TP53 mutations in archival tissue by two techniques: 
Sanger Sequencing, which would be considered as our reference “gold” standard, and TAm-
Seq. The functional implications of these mutations will be assessed case-by-case in the IARC 
TP53 database:  http://p53.iarc.fr/ 
 
Missense, substitution mutations in TP53 are curated by the IARC according to median level 
of transcriptional activity derived from 8 independent promoter-specific assays. These assays 
were conducted by using endogenous mutants, or by transfecting/over-expressing mutant 
proteins in human or yeast cell systems. Classifiers the IARC database uses include: 
• Nonfunctional (< 20% wild-type transcriptional activity) 
• Partially functional (20-75% wild-type transcriptional activity) 
• Functional (75-140% wild-type transcriptional activity) 
• Gain-of-function (“supertrans”) (> 140% wild-type transcriptional activity) 
 
Transcriptional Activity Data 
“Nonfunctional” mutations 
Nonfunctional 
Partially functional mutations 
Partially functional 
No change in function mutations 
Functional 
“Gain-of-function” mutations 
Supertrans 
 
For statistical purposes, tumors with “TP53 null” status will be defined as those tumors with 
TP53 mutations classified as “Nonfunctional” based on the “Transcriptional Activity Data” 
according to the IARC TP53 database.  
  
2.5.2 Determination of p53 protein expression by immunohistochemistry 
 
The most common type of TP53 mutation found in HGSO are missense mutations, occurring 
in about 50% of cases, with null mutations (including nonsense, frame-shift and splice site 
mutations) accounting for about 30%. 16 The presence of a null mutation, suggested by negative 
immunostaining, may be a poor prognostic factor with increased risk of recurrence (HR 0.71, 
95% CI 0.51–0.99). 18,19 Null mutations might cause loss of p53 function and might be 
associated to increased activity of AZD 1775 (MK 1775) in combination with gemcitabine. 
Some missense mutations induce loss of p53 function (complete or partial), while others cause 
gain of function. As part of the integrated biomarkers in this study, we will evaluate p53 protein 
expression by immunohistochemistry to correlate with the mutational status of TP53 and the 
clinical activity of AZD 1775 (MK 1775) in combination with gemcitabine. Previously 
described methodology will be used to determine p53 protein expression 20. 
 
2.5.3 Determination of TP53 mutations in circulating tumor DNA (ctDNA) 
 
In a recent publication, TP53 mutations have been identified in both circulating tumor DNA 
and tumor specimens from group of patients with ovarian cancers by using TAm-Seq. 
Prospectively, the variation of the levels of TP53 mutations in circulating tumor DNA in two 
patients with ovarian cancer reflected the clinical course of the disease. In the current study, 
we have established collaboration with Dr. James Brenton to perform the determination of 
TP53 mutations in circulating tumor DNA. As part of the research biomarker studies, the 

NCI 9568 / PHL-093 
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mutational status of TP53 found in circulating DNA will be correlated with the TP53 
mutational status in archival tissue. This correlation would provide evidence whether the 
determination of circulating tumor DNA would be a feasible non-invasive technique to 
evaluate the tumor mutational status in the future. 
 
2.5.4  Pharmacodynamic assessment of AZD 1775 (MK 1775) activity in tumor tissue: pCDC2, 
Antigen KI-67, gamma-H2AX, phospho-Histone H3, and cleaved-Caspase-3 
 
From a molecular standpoint, effective Wee1-Like Protein Kinase inhibition with decreased 
pCDC2 levels would be expected to result in increased phospho-Histone H3, (demonstrating 
entry into mitosis) and cleaved-Caspase-3 (indicative of apoptosis). In preclinical models, 
Wee1-Like Protein Kinase inhibition is associated with decreased pCDC2 levels, increased 
gamma-H2AX (DNA damage marker), phospho-Histone H3 and cleaved-Caspase-3.21 Tumors 
treated with AZD 1775 (MK 1775) or AZD 1775 (MK 1775) combined with gemcitabine 
expressed higher levels of Antigen KI-67 (proliferation marker) in comparison to the 
gemcitabine arm. 
In the clinical setting, AZD 1775 (MK 1775)-induced pCDC2 inhibition in skin has been 
described. Paired tumor biopsies have been collected in some ongoing clinical trials for 
pharmacodynamic evaluation in other tumor types, and preliminary results showed target 
modulation in paired tumor biopsies.24 
 
2.5.5 Other potential baseline predictors of response to AZD 1775 (MK 1775): Wee1-Like 
Protein Kinase, p21, p16, and Rb 
 
According to the data from The Cancer Genome Atlas, 10% of the analyzed serous ovarian 
cancers had up-regulation of the WEE1 mRNA. It is still unknown whether the baseline 
expression of Wee1-Like Protein Kinase influences the activity of AZD 1775 (MK 1775); 
hence, there is a rationale to evaluate the role of Wee1-Like Protein Kinase expression in a 
large prospective cohort of patients treated with AZD 1775 (MK 1775) in combination with a 
DNA damaging agent. 
 
Some partial loss-of-function TP53 mutations are able to induce p21 expression, which could 
be detected by immunohistochemistry. We hypothesize that p21 expression might be a sign of 
G1 checkpoint activity and in tumors expressing p21 might be less effective in comparison to 
those tumors lacking p21 expression. 
 
According to The Cancer Genome Atlas analysis, 67% of the high grade ovarian cancers had 
an alteration in the Rb pathway17. This could be another mechanism impairing the activity of 
the G1 checkpoint. Rb and p16 protein expression will be assessed to evaluate the activity of 
the Rb pathway. 
 
2.5.6 BRCA mutation status 
 
There is substantial evidence that high grade serous ovarian cancer patients with BRCA1 or 
BRCA2 germline mutations have better short term survival than non-carriers25. This is now a 
well described prognostic factor. Given the implications for clinical care, identifying genetic 

NCI 9568 / PHL-093 
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14 
 
mutations in BRCA1/2 is now a priority. Data on patient BRCA mutation status will be collected 
from patients for whom it is known in order to see if there is any difference in response based on 
BRCA status. 
 
2.6 
Patient Reported Outcomes 
 
This protocol will evaluate patient reported outcomes using methodology that has been 
developed in conjunction with NCI CTEP, with direct patient assessment of toxicity using paper 
forms or electronic forms through an internet based application.  
 
2.6.1 Exploratory Study Aims: 
 
• Characterize the profile of symptomatic adverse effects associated  with treatment with 
Gemcitabine+MK-1775 vs. Gemcitabine+ placebo across the first three cycles of 
treatment, using PRO-CTCAE 
• Explore the psychometric properties of PRO-CTCAE, with particular attention to its 
responsiveness to change and interpretations of the minimally important clinical 
difference in change over time 
• Using a shadow design, simulate the effects on clinical decision making at the patient and 
trial level as a consequence of one or more provisional/proposed schemas for mapping 
PRO-CTCAE responses into CTCAE clinical grades 
 
Study Design: 
Participating sites (Princess Margaret Cancer Centre, Juravinski Cancer Centre, London 
Regional Cancer Centre) will approach patients who are also able to read and write in English to 
complete PRO-CTCAE measures (see symptoms for inclusion below) at time points specified on 
the study calendar (D1 and D15 of each cycle).  
 
Patients who discontinue treatment for toxicity or at their own request will be asked to complete 
PRO-CTCAE at discontinuation.    
 
Measures:   
The following 9 PRO-CTCAE symptomatic toxicities will be evaluated:  
Bloating [S] 
Anorexia [S,I] 
Abdominal pain [S,I] 
Diarrhea [S] 
Difficulty Swallowing [S] 
Mucositis [S,I] 
Nausea [S] 
Vomiting [F] 
Fatigue [S,I] 
 
PRO-CTCAE Symptom Dimensions: Present/Absent (P); Frequency (F); Severity (S); 
Interference (I) 
 
In addition, patients will be asked to list any other symptoms that they may be experiencing.  
Completion of the 12 PRO-CTCAE items should take approximately 2-3 minutes. 
 
3. PATIENT SELECTION 
 

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15 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed epithelial ovarian, primary 
peritoneal or fallopian tube carcinoma.  All histologic subtypes of epithelial ovarian 
cancer are eligible, but only patients with high grade serous ovarian cancer will be 
considered for the statistical analysis. Non-High Grade Serous Cancers will be allowed in 
an exploratory cohort. 
 
3.1.2 Patients must be platinum-resistant (platinum-free interval < 6 months) or have platinum-
refractory disease as per GCIC criteria. Disease progression has to be radiologic or 
clinical. Biomarker progression with CA125 after a platinum based regimen would not be 
sufficient evidence of disease progression; the patients must have had radiological 
progression to that regimen. 
 
3.1.3 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as >10 mm with CT scan, MRI, or calipers 
by clinical exam.  See Section 11 for the evaluation of measurable disease. 
 
3.1.4 There is no limitation in the number of prior lines of therapy 
 
3.1.5 Patients must have completed any prior chemotherapy, radiotherapy or major surgery at 
least 4 weeks before receiving study treatment.  Ongoing toxicities related to treatment 
must be < grade 1 and patients with grade 2 alopecia or peripheral neuropathy can also be 
included.  Palliative radiation to <10% of bone marrow is permissible if completed within 
one week of commencing study treatment as long as the toxicities secondary to palliative 
radiotherapy are limited to grade 1. The lesions that have received radiation treatment 
immediately before will be excluded as target lesions. Previously irradiated lesions can 
be considered as targeted lesions, as long as there is prove of radiological progression. 
 
3.1.6 Age ≥18 years on day of consent.  Because no dosing or adverse event data are currently 
available on the use of AZD 1775 (MK 1775) in combination with gemcitabine in 
patients <18 years of age, children are excluded from this study, but will be eligible for 
future pediatric trials. 
 
3.1.7 ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.8 Life expectancy of greater than 3 months 
 
3.1.9 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 

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16 
 
− 
hemoglobin 
≥ 90 g/L2 
− 
PT, PTT & INR 
≤ 1.5 ULN 
− 
total bilirubin 
≤ 1.5 × institutional upper limit of normal; unless due to  
 
 
 
 
Gilbert’s syndrome 
− 
AST(SGOT) & ALT(SGPT) ≤ 3 × institutional upper limit of normal (5x if liver 
metastases) 
− 
creatinine 
≤ 1.5 × institutional upper limit of normal 
OR 
− 
creatinine clearance 
≥40 mL/min/1.73 m2 for patients with creatinine levels 
above 1.5 x institutional limit of normal. 
3.1.10 Patients must be able to tolerate oral medication and not have evidence of active bowel 
obstruction 
Note: patients can have a history of prior bowel obstruction, provided the patient is not 
having symptoms of bowel obstruction at the time of enrolment and the bowel 
obstruction is not anticipated to recur during the participation in the study. 
 
3.1.11 Patients must have disease amenable to biopsy and must be willing to undergo a paired 
biopsy for correlative analyses (the first biopsy within 28 days prior to start of treatment 
and the second biopsy while on treatment). 
 
3.1.12  The effects of AZD 1775 (MK 1775) on the developing human fetus are unknown.  For 
this reason and because gemcitabine is known to be teratogenic, women of child-bearing 
potential must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study participation.  
Should a woman become pregnant or suspect she is pregnant while she is participating in 
this study, she should inform her treating physician immediately.   
 
Women of childbearing potential include women who have experienced menarche and 
who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or are not post-menopausal. Postmenopause is 
defined as amenorrhea ≥12 consecutive months. Note: women who have been 
amenorrheic for 12 or more months are still considered to be of childbearing potential if 
the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression 
or any other reversible reason. 
 
3.1.13 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who previously received gemcitabine for the treatment of recurrent disease. 
 
3.2.2 Patients who are receiving any other investigational agents. 
 
 
2 Blood transfusions are allowed at any time during the screening, treatment or follow-up period, 
according to the center recommendations. 

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17 
 
3.2.3 Patients with clinically or radiologically unstable brain metastases are excluded from this 
clinical trial.   
Note: Patients with stable brain metastases after treatment, for at least 3 months prior to 
enrolling on this trial, could participate in the study. Patients should be off, or on a stable 
dose of steroids. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to AZD 1775 (MK 1775) or gemcitabine.  
 
3.2.5 Patients taking the following prescription or non-prescription drugs or other products (i.e. 
grapefruit juice) are ineligible: sensitive CYP3A4 substrates, CYP3A4 substrates with a 
narrow therapeutic index, moderate to potent inhibitors / inducers of CYP3A4. Patients 
would be eligible if the medications can be discontinued two weeks prior to Day 1 of 
dosing and withheld throughout the study until 2 weeks after the last dose of study 
medication. Specifically excluded substances may be listed in the Appendix C.   
 
3.2.6 Pregnant and breastfeeding women are excluded from this study.  
 
3.2.7 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with AZD 1775 (MK 1775).  In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
 
3.2.8 Uncontrolled intercurrent illness including, but not limited to, myocardial infarction 
within 6 months, congestive heart failure, symptomatic congestive heart failure, unstable 
angina pectoris, active cardiomyopathy, unstable ventricular arrhythmia, uncontrolled 
hypertension, uncontrolled psychotic disorders, serious infections, active peptic ulcer 
disease, active liver disease or cerebrovascular disease with previous stroke, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.3 
Inclusion of Women and Minorities 
 
Women of all races and ethnic groups are eligible for this trial.  This study is designed to include 
minorities as appropriate.  However, the trial is not designed to measure differences in 
intervention effects.  The population of Southern Ontario is ethnically diverse and the proportion 
of different ethnic groups in the community is provided in the table below.  Universal access to 
health care will ensure that there is no discrimination on the basis of race or gender (Guide to 
Canadian Human Rights Act: www.chrc-ccdp.ca/public/guidechra.pdf ). Individual hospital 
registries and databases do not routinely collect racial data, under the direction of the Canadian 
Human Rights Code. 
 
The population demographics and distribution of minorities in Canada is included in the 
following table: 
 

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18 
 
Table: Visible minority population by Consortium Provinces  (2001 Census)  
 
British Columbia Alberta 
Ontario 
Nova Scotia 
Total 
Total population of province 3,868,870 
2,941,150 
11,285,550 
897,570 
18,993,140 
Visible Minorities 
Population % 
Population % 
Population % 
Population % 
Population % 
Black 
25,465 
1% 
31,390 
1% 
411,095 
4% 
19,670 
2% 
487,620 
3% 
Asian 
768,435 
20% 268,660 
9% 
1,513,825 
13% 12,630 
1% 
2,563,550 
13% 
Latin American (Hispanic) 
23,880 
1% 
18,745 
1% 
106,835 
1% 
520 
0% 
149,980 
1% 
Visible minority, not included 
elsewhere 
4,195 
0% 
4,220 
0% 
78,915 
1% 
1,170 
0% 
88,500 
0% 
Multiple visible minority 
14,465 
0% 
6,910 
0% 
42,375 
0% 
535 
0% 
64,285 
0% 
Total Visible minority 
population 
836,440 
22% 329,925 
11% 2,153,045 
19% 34,525 
4% 
3,353,936 
18% 
Source: Statistics Canada, Census of Population.  
 
Data from our consortium has been compiled regarding the representation of minorities on 
previous clinical trials, and the distribution is as follows: 
 
Population Percentage of Minority and Gender of entering PMHC Trials 
 
2010 
2011 
2012 
Visible Minorities 
 
 
 
Black 
0.9 
2.3 
1.2 
Asian 
10.1 
10.9 
11.6 
Hispanic 
10.1 
2.3 
3.5 
Total  
21.1 
15.5 
16.3 
Women 
59.6 
56.6 
44.2 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
The Study Coordinator at the Princess Margaret Consortium Central Office will enter eligible 
patients on study centrally.  All sites should call the Study Coordinator (listed on cover page) to 
verify dose level availabilities.  The required forms (Eligibility Checklist) will be provided upon 
site activation. 
 
Following registration, patients should begin protocol treatment within 7-10 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator (cc the central 
office study coordinator).  If a patient does not receive protocol therapy following registration, 
the patient’s registration on the study may be cancelled.  The Study Coordinator should be 
notified of cancellations as soon as possible. 
 
 

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19 
 
There will be no starter supplies for this study.  Patient-specific supplies will be sent at the time 
of registration and follow-up orders will be placed by the institution PI or Ordering Designee 
through the on-line ordering system (described in the pharmaceutical section provided). 
 
4.2 
Registration Process 
 
Prior to registering a patient, each institution must have submitted all necessary regulatory 
documentation to the PMH Phase II Consortium Central Office.  The eligibility checklist will 
only be sent once this has been received.   
 
No patient can receive protocol treatment until registration with the Central Office has taken 
place.  All eligibility criteria must be met at the time of registration.  There will be no exceptions.  
Any questions should be addressed with the Central Office prior to registration.   
 
To register a patient, the following documents are to be completed by the research nurse or data 
manager and sent / faxed to the Central Office Study Coordinator: 
• 
Signed patient consent form 
• 
Eligibility Checklist CRF signed by the investigator  
 
To complete the registration process, central office will review the checklist and once eligibility 
has been confirmed: 
• 
Assign a patient study number 
• 
Assign the patient a dose 
• 
Register the patient on the study 
• 
Fax or e-mail the confirmation worksheet with the patient study number and dose to the 
participating site 
 
To ensure immediate attention is given to the faxed checklist, each site is advised to also call the 
study coordinator listed on the front sheet. Patient registration will be accepted between the 
hours of 9am to 5pm Monday to Friday, excluding Canadian statutory holidays when the central 
office will be closed. 
 
5. TREATMENT PLAN 
 
This is a randomized, placebo-controlled, phase II clinical trial evaluating AZD 1775 (MK-
1775)/Placebo in combination with gemcitabine. The study is powered to evaluate efficacy in 
patients with high grade serous ovarian cancer, as outlined in the statistical section. 
 
An exploratory cohort of patients (maximum of 15) with non-high grade serous histology 
(including but not limited to clear cell, endometrioid, or adenocarcinoma NOS) will be accrued. 
Response assessment will be by RECIST and > 4/10 objective responses (if available depending 
on accrual) will be considered a signal of activity. 
 
Simultaneously, 75 patients with high-grade serous histology will be randomized to Gemcitabine 
with/without AZD1775 (MK-1775). 
 

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20 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Regimen Description – Open Arm 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
AZD 1775 
(MK 1775)  
No premedication required 
before AZD 1775 (MK 
1775) 
175 mg  
(7x25mg capsules) 
Oral 
Days: 1, 2, 8, 9, 15, 
16 
28 days  
 
 
 
Gemcitabine Dexamethasone 8 mg PO 
Prochlorperazine maleate 
10 mg orally 
1000 mg/m2 
in 250 mL Normal 
Saline 
 
IV in 30 
min 
 
Days 1, 8, 15 
 
 
Regimen Description – Blind Arms 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
AZD 1775 
(MK 1775) 
or Placebo 
No premedication required 
before AZD 1775 (MK 
1775)/Placebo 
175 mg  
(7x25mg capsules) 
Oral 
Days: 1, 2, 8, 9, 15, 
16 
28 days  
 
 
 
Gemcitabine Dexamethasone 8 mg PO 
Prochlorperazine maleate 
10 mg orally 
1000 mg/m2 
in 250 mL Normal 
Saline 
 
IV in 30 
min 
 
Days 1, 8, 15 
 
5.1.1 AZD 1775 (MK 1775)/Placebo 
 
AZD 1775 (MK 1775)/Placebo is an oral drug that should be ingested 1 hour before a meal or 2 
hours after a meal.  The first dose will be taken with the gemcitabine infusion (may be taken 
before, during or immediately after). The second dose should be taken 24 +/- 3 hours after first 
dose. 
 
Capsules should not be broken, crushed or chewed.  Missed doses should not be made up, 
resume dosing with the next scheduled dose.  If vomiting occurs shortly after dosing, the dose 
should not be repeated.  Patients will be instructed to bring all unused capsules and their 
medication diary (refer to Appendix D) to each study visit for assessment of compliance 
 
5.1.2 Gemcitabine 
 
Gemcitabine will be administered as a 30 minute (+/- 5 minutes) intravenous infusion at a dose 
of 1000 mg/m2 on days 1, 8, and 15 of each 28 day cycle. Gemcitabine dose will be recalculated 

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21 
 
if the weight on day 1 (all cycles) has changed by >10% from baseline or the last time the 
gemcitabine dose has been adjusted for weight loss.  Patients will receive dexamethasone 8 mg 
orally and prochlorperazine maleate 10 mg orally prior to the gemcitabine administration.  In 
case of nausea after treatment, the patients will receive prochlorperazine maleate 10 mg every 8 
hours if needed. Additional anti-nausea medication, such as 5HT3 inhibitors (ondansetron, 
granisetron) is allowed. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of AZD 1775 (MK 1775) with other concomitantly 
administered drugs through the CYP3A4, the case report form must capture the concurrent use of 
all other drugs, over-the-counter medications, or alternative therapies.  The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential to affect 
the CYP3A4.   
 
The following medications are prohibited: sensitive CYP3A4 substrates, CYP3A4 substrates 
with a narrow therapeutic index, or moderate to potent inhibitors / inducers of CYP3A4.  
Aprepitant is also prohibited due to interaction with AZD 1775 (MK 1775).  Appendix C 
presents guidelines for identifying medications/substances that could potentially interact with the 
study agent(s). 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• 
Clinical progression 
• 
Patient non-compliance 
• 
Pregnancy 
• 
All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation 
• 
The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
 
5.4 
Duration of Follow Up 
 
 
 
Follow-Up Period 
 
 
Survival Follow-Up 
every 12 weeks (±2 
Follow-up for progression every 
6-8 weeks (after the 30-37 day 
Adverse Event 
Follow Up** 

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22 
 
weeks), up to 1 year 
safety visit), until disease 
progression* or death 
(whichever occurs first), up to 
1year 
Reason Patients removed 
from study: 
Disease progression 
X 
 
X 
Unacceptable adverse 
events (grade 3 or 4 
serious adverse event, 
related to study drug) 
X 
X 
X 
All other patients 
X 
X 
X 
* Can be documented clinically or radiologically 
** Follow for AEs until all other follow-up requirements are met.  Refer to section 7.5 for guidance in the following of ongoing 
or new AEs or SAEs 
 
Once the AEs are resolved the patients will undergo telephonic follow-up, or health records 
search every three months during one year to evaluate overall survival, unless the patients are 
being seen by the study team for other reasons such as receiving conventional treatment.  
Patients discontinued due to unacceptable adverse events or patients discontinued due to other 
reasons different to disease progression would not need telephonic follow-up if they are still 
being assessed every 6-8 weeks until clinical or radiological evidence of disease progression is 
observed. Once disease progression is observed, the patients will have telephonic follow-up or 
health records search every three months, up to one year after the patient’s 30-37 day safety visit. 
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the following criteria apply: 
• Death 
• Withdrawal from study 
• Completion of one year follow-up 
• Termination of the study by sponsor or regulatory authority 
 
The reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
General Guidelines 
 
In addition to the recommendations from the guidelines below, more conservative dose 
reductions will be allowed upon discussion with the sponsor, if there are concerns of toxicity or 
if it is believed to be in the best interest of a subject´s safety. 
 
Table 6.1-1: AZD 1775 (MK 1775)/Placebo Dose modifications 
Dose Level 
AZD 1775 (MK 1775)/Placebo Dose 
1 
175 mg, once daily (on days 1, 2, 8, 9, 15, and 16) 
-1 
150 mg, once daily (on days 1, 2, 8, 9, 15, and 16) 

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23 
 
-2 
100 mg, once daily (on days 1,2, 8, 9, 15, and 16) 
 
Table 6.1-2: Gemcitabine Dose Modifications for Non-Hematological Toxicities and Febrile 
Neutropenia (in any dosing day) and for Neutropenia and Thrombocytopenia Occurring on 
Day 1 of any Cycle. 
Dose Level 
Gemcitabine 
1 
1000 mg/m2 
DL-1 
800 mg/m2 
DL-2 
600 mg/m2 
 
6.1.1 Dose Modifications for Hematological Toxicities 
 
Table 6.1.1-1: Dose Modification for Neutropenia 
Neutropenia 
Management/Next Dose for  
AZD 1775 (MK 1775)/Placebo 
Management/Next Dose for 
Gemcitabine 
Dose Modification for Neutropenia on day 1 of any cycle – Permanent dose modification 
≤ Grade 1 
(<LLN-1.5x 109/L) 
No change in dose 
No change in dose 
Grade 2 
(<1.5-1.0x109 /L) 
No change in dose 
No change in dose 
Grade 3 
(<1.0-0.5x109/L) 
First and second occurrences 
Hold* until ≤ Grade 2. 
 Resume at one dose level lower 
Hold* until ≤ Grade 2 
Resume at one dose level lower, if 
indicated.** 
Grade 4 
(<0.5x109/L) 
First and second occurrences 
Hold* until ≤ Grade 2. 
 Resume at one dose level lower 
Hold* until ≤ Grade 2 
Resume at one dose level lower, if 
indicated.** 
*Patients requiring a delay of >2 weeks should be discussed with PI. Patients may continue therapy if receiving 
benefit otherwise, patient should discontinue the study. 
**Patients requiring more than two dose reductions of AZD 1775 (MK 1775)/Placebo or gemcitabine should be 
discussed with PI. Patients may continue therapy if receiving benefit; otherwise, patient should discontinue the 
study. 
The use of GCSF is allowed in patients according to institutional guidelines 
Dose Modification for Neutropenia on day 8 and 15 of any cycle - Temporary dose modification 
≤ Grade 1 
(<LLN-1.5x 109/L) 
No change in dose 
No change in dose 
Grade 2 
(<1.5-1.0x109/L) 
No change in dose 
No change in dose 
Grade 3 
(<1.0-0.5x109/L) 
No change in dose 
Administer 75% of the dose 
administered on day 1 of that cycle 
Grade 4 
(<0.5x109/L) 
Omit dose for both day 8 and 9, or 
day 15 and 16 as applicable 
Omit dose 
Gemcitabine dose reductions due to neutropenia on day 8 or 15 of each cycle are temporary dose reductions.  
The use of GCSF is allowed in patients according to institutional guidelines. 
 
Table 6.1.1-2: Dose Modifications for Febrile Neutropenia 

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24 
 
Febrile Neutropenia 
Management/Next Dose for  
AZD 1775 (MK 1775)/Placebo 
Management/Next Dose for 
Gemcitabine 
Febrile Neutropenia 
First and second occurrences 
Hold* until fever is resolved and 
neutropenia < Grade2 
Resume at one dose level lower, if 
indicated.** 
Hold* until fever is resolved and 
neutropenia < Grade2 
Resume at one dose level lower, if 
indicated.** 
*Patients requiring a delay of >2 weeks should be discussed with PI. Patients may continue therapy if receiving 
benefit otherwise, patient should discontinue the study. 
**Patients requiring more than two dose reductions of AZD 1775 (MK 1775)/Placebo or gemcitabine should be 
discussed with PI. Patients may continue therapy if receiving benefit; otherwise, patient should discontinue the 
study. 
The use of GCSF is allowed in patients according to institutional guidelines 
 
Table 6.1.1-3: Dose Modification for Thrombocytopenia 
Thrombocytopenia 
Management/Next Dose for 
AZD 1775 (MK 1775)/Placebo 
Management/Next Dose for 
Gemcitabine 
Dose Modification for Thrombocytopenia on day 1 of any cycle – Permanent dose modification 
<LLN-100x 109/L 
No change in dose 
No change in dose 
<100x 109/L-50 x 
109/L 
First and second occurrences 
Hold* until platelets ≥100 x109/L 
Resume at one dose level lower, if 
indicated.** 
Hold* until platelets ≥100 x109/L 
Resume at one dose level lower, if 
indicated.** 
<50 x 109/L 
First and second occurrences 
Hold until platelets ≥100 x109/L 
Resume at one dose level lower, if 
indicated.** 
Hold* until platelets ≥100 x109/L  
 Resume at one dose level lower, if 
indicated.** 
*Patients requiring a delay of >2 weeks should be discussed with PI. Patients may continue therapy if receiving 
benefit otherwise, patient should discontinue the study. 
**Patients requiring more than two dose reductions of AZD 1775 (MK 1775)/Placebo or gemcitabine should be 
discussed with PI. Patients may continue therapy if receiving benefit; otherwise, patient should discontinue the 
study. 
Dose Modification for Thrombocytopenia on day 8 or 15 of any cycle – Temporary dose 
modification 
<LLN-100x 109/L 
No change in dose 
No change in dose 
<100x 109/L-50 x 
109/L 
No change in dose 
Administer 75% of the dose 
administered on day 1 of that cycle 
<50 x 109/L 
Omit dose for both day 8 and 9, or 
day 15 and 16 as applicable 
Omit dose 
Gemcitabine dose reductions due to thrombocytopenia on day 8 or 15 of each cycle are temporary dose reductions.  
 
Note: no dose modifications were required for leukopenia, lymphopenia or anemia. 
 
 
 
 
6.1.2 Dose Modifications for Non-Hematological Toxicities 
 

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25 
 
Table 6.1.2-1: Dose Modification for Nausea (despite optimal treatment) 
Nausea 
Management/Next Dose for  
AZD 1775 (MK 1775)/Placebo 
Management/Next Dose for  
Gemcitabine 
Grade 1 or 2 
(after optimal 
management) 
No change in dose 
No change in dose 
Grade 3 
(after optimal 
management) 
First and second occurrences 
 
Hold* until ≤ Grade 2.  
Resume at one dose level lower, if 
indicated.** 
Hold* until ≤ Grade 2 
Resume at one dose level lower, if 
indicated.** 
*Patients requiring a delay of >2 weeks should be discussed with PI. Patients may continue therapy if receiving 
benefit otherwise, patient should discontinue the study. 
**Patients requiring more than two dose reductions of AZD 1775 (MK 1775)/Placebo or gemcitabine should be 
discussed with PI. Patients may continue therapy if receiving benefit; otherwise, patient should discontinue the 
study 
Recommended management:  antiemetics and  intravenous hydration if required 
Note: Optimal treatment include: ondansetron, granisetron or similar agent, dexamethasone and metoclopramide or 
olanzapine (The use of Aprepitant is prohibited due to its interaction with AZD 1775 (MK 1775)) 
 
Table 6.1.2-2: Dose Modification for Vomiting 
Vomiting 
Management/Next Dose for 
AZD 1775 (MK 1775)/Placebo 
Management/Next Dose for  
Gemcitabine 
≤ Grade 1 
(1-2 episodes in 24 h) 
No change in dose 
No change in dose 
Grade 2 
(3-5 episodes in 24 h) 
despite optimal 
treatment 
Hold* until ≤ Grade 1. 
 Resume at same dose level. 
Hold* until ≤ Grade 1. 
 Resume at same dose level 
Grade 3 
(≥6 episodes in 24 hrs; 
tube feeding, TPN or 
Hospitalization 
indicated) 
despite optimal 
treatment 
First and second occurrences 
 
Hold* until ≤ Grade 1.   
Resume at one dose level lower, 
if indicated.** 
Hold* until ≤ Grade 1. 
 Resume at one dose level lower, if 
indicated.** 
Grade 4 
despite optimal 
treatment 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should be discussed with PI. Patients may continue therapy if receiving 
benefit otherwise, patient should discontinue the study. 
**Patients requiring more than two dose reductions of AZD 1775 (MK 1775)/Placebo or gemcitabine should be 
discussed with PI. Patients may continue therapy if receiving benefit; otherwise, patient should discontinue the 
study. 
Recommended management:  antiemetics and intravenous hydration if required 
Note: Optimal treatment include: ondansetron, granisetron or similar agent, dexamethasone and metoclopramide or 
olanzapine (The use of Aprepitant is prohibited due to its interaction with AZD 1775 (MK 1775)) 
 
Table 6.1.2-3: Dose Modification for Diarrhea 
Diarrhea 
Management/Next Dose for  
Management/Next Dose for  

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26 
 
AZD 1775 (MK 1775)/Placebo 
Gemcitabine 
Grade 1 or 2 
(after optimal 
management) 
No change in dose 
No change in dose 
Grade 3 
(after optimal 
management) 
First and second occurrences 
 
Hold* until ≤ Grade 2.  
 Resume at one dose level lower, if 
indicated.** 
Hold* until ≤ Grade 2 
Resume at one dose level lower, if 
indicated.** 
Grade 4 
(after optimal 
management) 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should be discussed with PI. Patients may continue therapy if receiving 
benefit otherwise, patient should discontinue the study. 
**Patients requiring more than two dose reductions of AZD 1775 (MK 1775)/Placebo or gemcitabine should be 
discussed with PI. Patients may continue therapy if receiving benefit; otherwise, patient should discontinue the 
study. 
 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-free for 12 hours 
(maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Table 6.1.2-4: Other Non-Hematological Toxicities: 
Event 
Management/Next Dose for  
AZD 1775 (MK 1775)/Placebo 
Management/Next Dose for  
Gemcitabine 
Grade 1 or 2 
No change in dose 
No change in dose 
 
Grade 3 
First and second occurrences 
 
Hold* until ≤ Grade 2.  
Resume at one dose level lower, if 
indicated.** 
Hold* until ≤ Grade 2 
Resume at one dose level lower, if 
indicated.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should be discussed with PI. Patients may continue therapy if receiving 
benefit otherwise, patient should discontinue the study. 
**Patients requiring more than two dose reductions of AZD 1775 (MK 1775)/Placebo or gemcitabine should be 
discussed with PI. Patients may continue therapy if receiving benefit; otherwise, patient should discontinue the 
study. 
 
This table only applies to non-hematological adverse events considered related to the study medication and 
considered clinically significant as per investigator judgment.  Clinically non-significant, treatable or reversible 
lab abnormalities including, but not limited to alkaline phosphatase or gamma-glutamyl transferase, uric acid, or 
electrolytes abnormalities does not require dose modifications. 
 
 
 

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27 
 
 
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. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification.  
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
NOTE: Many adverse events on this CAEPR are treatment-emergent events that have been 
observed in trials of AZD1775 in combination with chemotherapy including carboplatin, 
cisplatin, gemcitabine, 5-fluorouracil, paclitaxel, or topotecan. There are limited adverse event 
data reported with monotherapy of AZD1775 at this time. 
 
7.1.1 CAEPRs for CTEP IND Agent 
 
7.1.1.1 
CAEPR for AZD 1775 (MK 1775) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 213 patients. Below is the CAEPR for 
AZD1775 (MK-1775). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 

NCI 9568 / PHL-093 
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28 
 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
Version 2.5, April 18, 20181 
 
 Adverse Events with Possible  
 Relationship to AZD1775 (MK-1775) 
 (CTCAE 5.0 Term) 
[n= 213] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Atrial fibrillation 
  
 
 
Supraventricular tachycardia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - Other 
(hepatitis) 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
 Infection2 (Gr 3) 
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased (Gr 3) 
 
Lymphocyte count decreased 
 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 4) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
  
 
Hypokalemia 
 
 Hypokalemia (Gr 2) 
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
 
 
Intracranial hemorrhage 
  
PSYCHIATRIC DISORDERS 
  

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29 
 
 
 Adverse Events with Possible  
 Relationship to AZD1775 (MK-1775) 
 (CTCAE 5.0 Term) 
[n= 213] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Hypoxia 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash3 
 
 Rash3 (Gr 2) 
VASCULAR DISORDERS 
  
 
 
Phlebitis 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included 
in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
3Rash may include rash, erythema, eczema, and rash maculo-papular. 
 
4Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory neuropathy. 
 
5Acute kidney injury includes renal impairment and acute renal insufficiency. 
 
 
Adverse events reported on AZD1775 (MK-1775) trials but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that AZD1775 (MK-1775) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Blood and lymphatic system disorders - Other (thrombocytosis); Febrile neutropenia; Leukocytosis 
CARDIAC DISORDERS - Cardiac disorders - Other (cardiomegaly); Chest pain - cardiac; Myocardial infarction; 
Palpitations; Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain; Hearing impaired; Tinnitus 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (eye swelling); Eye pain; Keratitis; 
Photophobia; Scleral disorder; Vision decreased; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal pain; Ascites; Belching; Bloating; Cheilitis; 
Colitis; Dry mouth; Duodenal ulcer; Dysphagia; Enterocolitis; Flatulence; Gastric ulcer; Gastritis; Hemorrhoids; 
Lower gastrointestinal hemorrhage; Oral pain; Rectal hemorrhage; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema trunk; 
Flu like symptoms; Gait disturbance; General disorders and administration site conditions - Other (catheter site 
pain); Infusion site extravasation; Malaise; Non-cardiac chest pain; Pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (excoriation); Injury, poisoning and procedural complications - Other (ligament sprain) 
INVESTIGATIONS - Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin 
increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations 
- Other (blood urea increased); Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Alkalosis; Hypercalcemia; Hyperglycemia; Hyperkalemia; 
Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hyponatremia; Hypophosphatemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Bone pain; Flank 

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30 
 
pain; Generalized muscle weakness; Muscle cramp; Muscle weakness lower limb; Musculoskeletal and connective 
tissue disorder - Other (groin pain); Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (carcinoid tumor); Tumor pain 
NERVOUS SYSTEM DISORDERS - Central nervous system necrosis; Cognitive disturbance; Dysesthesia; 
Encephalopathy; Lethargy; Nervous system disorders - Other (hemiparesis); Paresthesia; Peripheral neuropathy4; 
Presyncope; Somnolence; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression 
RENAL AND URINARY DISORDERS - Acute kidney injury5; 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 (MK-1775) 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. 
 
 
7.1.2 Adverse Event List for Gemcitabine 
 
ORGAN SITE 
SIDE EFFECT 
(%) 
ONSET 
Cardiovascular 
Arrhythmia 
(rare) 
 
E 
 
 
Arterial thromboembolism 
(rare) 
 
E 
 
Heart failure 
(rare) 
 
E 
 
Hypertension 
(<2%) 
 
E 
 
Dermatological 
Alopecia 
(14%) 
 
E 
 
 
Rash 
(25%)  
(may be severe) 
 
E 
 
Gastrointestinal 
Constipation 
(8%) 
 
E 
 
 
Diarrhea 
(12%) 
 
E 
 
Mucositis 
(8%) 
 
E 
 
Nausea, vomiting 
(64%) 
I 
 
 
General 
Edema 
(20%) 
 
E 
 
 
Fatigue 
 
I 
 
 
Flulike symptoms 
(37%) 
I 
 
 
Other (radiosensitizer) 
 
 
E 
 
Hematological 
Hemolytic uremic syndrome 
(<1%) 
 
E 
 
 
Myelosuppression ± 
infection, bleeding 
(25%)  
(severe) 
 
E 
 
Hepatobiliary 
↑ LFTs 
(68%) 
 
E 
 

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31 
 
(10% severe) 
Hypersensitivity Hypersensitivity 
(rare) 
I 
 
 
 
Infection Infection 
(9%) 
(severe 1%) 
 
E 
 
Injection site Injection site 
reaction 
(4%) 
I 
 
 
Musculoskeletal Musculoskeletal pain 
(16%) 
I 
 
 
Nervous System Headache 
 
 
E 
 
 
Peripheral neuropathy 
(3%) 
 
E 
 
Somnolence 
(9%) 
 
E 
 
Renal 
Creatinine increased 
(7%) 
 
E 
 
 
Proteinuria 
(36%) 
 
E 
 
Respiratory 
Adult respiratory distress 
syndrome (ARDS) 
(rare) 
 
E 
 
 
Dyspnea 
(8%) 
I 
 
 
Pneumonitis  
(rare) 
 
E 
 
Vascular 
Capillary leak syndrome 
(rare) 
 
E 
D 
 
Gangrene 
(rare) 
 
E 
 
Vasculitis 
(rare) 
 
E 
 
"Rare" may refer to events with < 1% incidence 
I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to 
months) 
 
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 until March 31, 2018 for AE reporting. 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 . 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the grade 
is above the grade provided in the SPEER. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
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). 
 
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. 
 
7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  Once the electronic version of the CTEP-AERS report is 
submitted to the PMH Phase II Consortium Central Office it will be reviewed prior to 
being forwarded to NCI.    
 
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 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  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.  
 
In order to ensure the timely fulfillment of both US and Canadian IND regulatory 
reporting requirements, all CTEP-AERS reports must be sent to the PMH Phase II 
Consortium Central Office within 3 working days from the date the event was known to 
the investigator. 
 
• 
In the unlikely event that an adverse event occurs that does not meet the reporting 
requirements for CTEP-AERS, but does meet the definition of a Serious Adverse 
Event, a CTEP-AERS report must still be completed and sent to the Central Office 

NCI 9568 / PHL-093 
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33 
 
within 3 working days of the event being known to the investigator.  The event must 
be telephoned or e-mailed to Central Office within 1 working day.   
 
• 
The PMH Phase II Consortium Central Office will be responsible for reporting to 
Canadian regulatory authorities all Serious Adverse Events that are both unexpected 
and related to study drug.  The Central Office will notify all Investigators of all 
Serious Adverse Events that are reportable to regulatory authorities in Canada from 
this trial or from other clinical trials as reported to the Central Office by the NCI U.S. 
 
Investigators must notify their local Research Ethics Boards (REB/IRBs), according to 
their guidelines, of all SAE reports from their centre and file the report in their regulatory 
study binder.   In addition, all reports sent out to centres by the PMH Phase II Consortium 
Central Office must be sent to local REB/IRBs, according to their guidelines.  
Documentation from the REB/IRB of receipt of these reportable events must be kept on 
file in each institution's regulatory binder.  
 
Late Phase 2 and Phase 3 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/Intervention1, 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 jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to 
the NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 

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34 
 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are 
found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the 
CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS 
within 24 hours of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 
10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite 
require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
− 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 
radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was 
last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
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. 
 
7.5 
Follow Up of AEs and SAEs 
 
Ongoing SAEs and AEs should be followed until they are resolved (return to normal or baseline 
values), stabilized, improve to < Grade 2, the patient is lost to follow-up and cannot be contacted, 
or the patient has withdrawn consent.  Additional investigations (e.g., laboratory tests, diagnostic 
procedures, or consultation with other healthcare professionals) may be required to completely 
investigate the nature and/or causality of an AE or SAE.  
 
The following table describes the frequency of AE follow up after the 30-37 day safety follow-
up visit: 
End of Treatment Reason 
AE Follow-up Frequency 
Disease progression (radiological or clinical) 
Every 3 months for:  
− 
any ongoing or new Grade 3+ SAEs 

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35 
 
thought to be related to study 
treatment 
− 
any ongoing or new Grade 2 AEs that 
are related to study treatment AND 
result in hospitalization 
Unacceptable adverse event(s) 
Every month for: 
− 
any ongoing or new Grade 3+ SAEs 
thought to be related to study 
treatment 
− 
any ongoing or new Grade 2 AEs that 
are related to study treatment AND 
result in hospitalization 
All other reasons 
Every 3 months for:  
− 
any ongoing or new Grade 3+ SAEs 
thought to be related to study 
treatment 
− 
any ongoing or new Grade 2 AEs that 
are related to study treatment AND 
result in hospitalization 
 
7.6 
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.  
 
7.7 
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 
 
8.1 
AZD 1775 (MK 1775) (NSC 751084) 
 
Chemical Name: 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[4-(4-methylpiperazin-1-

NCI 9568 / PHL-093 
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36 
 
yl)anilino]pyrazolo[3,4-d]pyrimidin-3-one hemihydrate  
 
Other Names:  AZD-1775 (MK 1775) 
 
Classification: inhibitor of Wee1-kinase 
 
CAS: 1277170-60-1 
 
Molecular Formula: C27H32N8O2·0.5H2O  M.W.: 500.6 
 
Approximate Solubility: Aqueous solubility is 0.02 mg/mL   
 
Mode of Action: AZD 1775 (MK 1775) is an inhibitor of the Wee1-kinase. Wee1 is a tyrosine 
kinase upstream of CDC2 thereby involved in regulation of cell cycle checkpoints, particularly the 
G2 checkpoint. As the majority of human cancers harbor abnormalities in the p53 pathway they 
become more dependent on S- and G2-phase checkpoints. In preclinical models, AZD 1775 (MK 
1775) selectively enhanced chemotherapy-induced death of cells deficient in p53 signaling.  
 
Description: AZD 1775 (MK 1775) is a crystalline, non-hygroscopic, hemihydrate of the neutral 
drug. It dehydrates upon heating leading to formation of a crystalline anhydrate. 
 
How Supplied:  AZD 1775 (MK 1775)  (NSC 751084) and matching Placebo will be provided 
free of charge by Merck or Astra Zeneca and distributed by the Pharmaceutical Management 
Branch (PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and 
Diagnosis (DCTD), National Cancer Institute (NCI). 
 
The capsule consists of a roller compacted granule of AZD 1775 (MK 1775), lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. The 
granule is lubricated with a further quantity of magnesium stearate prior to encapsulation of the 
granule. The placebo capsule is identical with the omission of AZD 1775 (MK 1775). 
 
Open label AZD1775 (MK-1775) will be in high density polypropylene (HDPE) bottles of 20 – 25 
mg capsules with a child-resistant cap and tamper evident seal.   
 
 
Blinded AZD 1775 (MK 1775) and matching Placebo will be supplied in bottles containing 45 – 25 
mg capsules of AZD 1775 (MK 1775) or 45 – 0 mg capsules (Placebo for AZD 1775 (MK 1775)) 
with a child-resistant cap and tamper evident seal. 
 
Storage: Store bottles at 2 to 30˚C (36 to 86˚F).  Do not freeze. 
 
Stability:  Shelf life studies of AZD 1775 (MK 1775) are on-going. 
 
Administration:  Take AZD 1775 (MK 1775) /placebo on an empty stomach, 1 hour prior or 2 hours 
after a meal.   
 
Potential Drug Interactions: In human liver microsomes, AZD 1775 (MK 1775) is primarily 

NCI 9568 / PHL-093 
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37 
 
metabolized by CYP450 3A4, so exercise caution in patients taking 3A4 inhibitors and inducers. 
It is also a weak reversible inhibitor of CYP2C8, 2C9, 2C19 and 3A4. Avoid concomitant 
medications with a narrow therapeutic window that are substrates for these isoforms. AZD 1775 
(MK 1775) is a p-glycoprotein substrate. 
 
In vitro transporter studies have shown that AZD1775 (MK-1775) was an inhibitor of OATP1B1, 
OATP1B3, MATE1, MATE2K, P-glycoprotein (P-gp) and breast cancer resistance protein 
(BCRP), and a substrate for P-gp and BCRP.  The PK parameters of AZD1775 (MK-1775) could 
be altered if AZD1775 (MK-1775) is coadministered with P-gp and BCRP inhibitors/inducers, and 
there is potential for drug-drug interactions when coadministered with OATP1B1, OATP1B3, 
MATE1, MATE2K, P-gp and BCRP substrates.  This finding is particularly relevant for drugs 
administered orally where exposure is normally limited by BCRP-mediated efflux, in particular 
some statins.  Modelling has predicted a substantial increase in the exposure of atorvastatin when 
coadministered with AZD1775 (MK-1775) and the use of atorvastatin is therefore prohibited. 
 
 
Contraindications: Treatment with AZD 1775 (MK 1775) is contraindicated in subjects with 
hypersensitivity to any component of the drug. Developmental and reproductive toxicity studies 
of AZD 1775 (MK 1775) have not been performed. AZD 1775 (MK 1775) is not to be given to 
women who are pregnant or breast feeding. Women of child-bearing potential participating in 
clinical studies of AZD 1775 (MK 1775) must use appropriate contraception throughout the study 
including abstinence and double barrier methods throughout treatment. Refer to Section 3.1.12 for 
more details about appropriate contraceptive methods and duration of use. 
 
8.1.1 Agent Ordering: 
 
No blinded or open label starter supplies will be available for this study. Blinded patient-
specific clinical supplies will be sent to the registering investigator at the time of registration and 
should arrive within approximately 7 to 10 days. Patients will be registered by the PMH Phase II 
Consortium Central Office. The assigned patient ID number must be recorded by the registering 
institution at the time of registration for proper clinical supply dispersion. Once a patient has 
been registered, the PMH Phase II Consortium Central Office will electronically transmit a 
clinical drug request for that patient to the PMB. This request will be entered and transmitted by 
the PMH Phase II Consortium Central Office the day the patient is registered and will be 
processed by PMB the next business day and shipped the following business day. Shipments 
within United States will be sent by FedEx Ground (up to five day delivery) and shipments to 
Canada will be sent by FedEx (generally one to two day delivery).  Thus, if a patient is registered 
on Monday, PMH Phase II Consortium Central Office would enter a clinical drug request for that 
patient on Monday and PMB would process that request on Tuesday and ship the drug on 
Wednesday.  United States clinical sites could expect to receive their order approximately 
Monday or Tuesday (depending on the FedEx Ground service) and Canadian clinical sites could 
expect to receive their order either Thursday or Friday.  NOTE: An account number is not 
needed for regular (FedEx Ground) shipments.  
 
Blinded Clinical Supplies 
The initial request will be for 2 bottles of AZD 1775 (MK 1775) or matching placebo, a quantity 

NCI 9568 / PHL-093 
11Jun2018 
 
38 
 
sufficient for 2 cycles of therapy.  Six (6) weeks after the initial electronic request [i.e., two (2) 
weeks before needed], sites may reorder an additional 2 bottles of AZD 1775 (MK 1775) or 
matching placebo by placing an order through the PMB Online Agent Order Processing (OAOP) 
application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires 
the establishment of a CTEP Identity and Access Management (IAM) account (https://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a “current” 
password.  The assigned patient ID number and the patient initials must be entered in the "Patient 
or Special Code" field.  A separate order is required for each patient ID being ordered.  All drug 
orders will be shipped directly to the physician responsible for treating the patient. 
 
Blinded Patient-Specific Bottle Labeling  
Each patient-specific bottle will be labeled with: 
• the protocol number (i.e., “9568”) 
• the bottle number (i.e., “Bottle 1 of 2” and “Bottle 2 of 2”) 
• the number of capsules (i.e., “45 capsules”) 
• the patient ID number (e.g.,"093-XXX", where “XXX” represents a unique patient identifier 
assigned at registration) 
• the patient initials (i.e., Last Initial, First initial, Middle initial [e.g., “LFM”]) 
• the agent identification (i.e., “AZD 1775 (MK 1775)  25 mg or Placebo”) 
• a blank line for the pharmacist to enter the patient’s name  
• administration instructions (i.e., “Take __ capsules daily.”) 
• storage instructions (i.e., “Store at controlled room temperature, not to exceed 30 ºC).” 
• emergency contact instructions 
• a Julian date 
 
The Julian date indicates the day the bottle was labeled and shipped and is composed of the last 
two digits of the calendar year (e.g., 2014 = 14, 2015 = 15) and a day count (e.g., January 1 = 
001, December 31 = 365).  For example, a bottle labeled and shipped on January 1, 2014 would 
have a Julian date of ‘14001’ and a bottle labeled and shipped on December 31, 2014 would have 
a Julian date of ‘14365’.  The Julian date will be used by PMB for recalls.  When a lot expires, 
PMB will determine the last date the expired lot was shipped and will recall all bottles (i.e., both 
AZD 1775 (MK 1775) and Placebo) shipped on or before that date thus eliminating any chance 
of breaking the blind.  The Julian Date / order number should be recorded in the “Lot No.” field 
on the NCI Agent Accountability Form (DARF). 
 
 
Open Label Clinical Supplies 
The initial request will be for 6 bottles of AZD1775 (MK-1775), which provides enough study 
drug for 2 cycles. Six (6) weeks after the initial electronic request [i.e., two (2) weeks before 
needed], sites may reorder an additional 6 bottles of AZD1775 (MK-1775) by placing an order 
through the PMB Online Agent Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and 
the maintenance of an “active” account status and a “current” password.  The assigned patient ID 
number and the patient initials must be entered in the "Patient or Special Code" field.  A separate 
order is required for each patient ID number being ordered.  All drug orders will be shipped 

NCI 9568 / PHL-093 
11Jun2018 
 
39 
 
directly to the physician responsible for treating the patient. 
 
Open-label Patient-Specific Bottle Labeling  
Each patient-specific bottle will be labeled with: 
• the protocol number (i.e., “9568”) 
• the bottle number (i.e., “Bottle 1 of 6” and “Bottle 2 of 6”, etc.) 
• the number of capsules (i.e., “20 capsules”) 
• the patient ID number (e.g.,"093-xxx", where “xxx” represents a unique patient identifier 
assigned at registration) 
• the patient initials (i.e., Last initial, First initial, Middle initial [e.g., “LFM”]) 
• the agent identification (i.e., “AZD1775 (MK-1775) 25 mg”) 
• a blank line for the pharmacist to enter the patient’s name  
• administration instructions (i.e., “Take __ capsules daily.”) 
• storage instructions (i.e., “Store at 2° - 30°C (36° - 86°F).  DO NOT FREEZE.).” 
• emergency contact instructions 
• a Julian date 
 
The Julian date indicates the day the bottle was labeled and shipped and is composed of the last 
two digits of the calendar year (e.g., 2014 = 14, 2015 = 15) and a day count (e.g., January 1 = 
001, December 31 = 365).  For example, a bottle labeled and shipped on January 1, 2015 would 
have a Julian date of ‘15001’ and a bottle labeled and shipped on December 31, 2015 would have 
a Julian date of ‘15365’.  The Julian date will be used by PMB for recalls.  When a lot expires, 
PMB will determine the last date the expired lot was shipped and will recall all bottles (i.e., both 
AZD1775 (MK-1775) and Placebo) shipped on or before that date thus eliminating any chance 
of breaking the blind.  The Julian Date should be recorded in the “Lot No.” field on the Oral NCI 
Agent Accountability Form (DARF). 
 
8.1.2 Agent Inventory Records 
 
 
Agent Accountability:  
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, disposition and return of all drugs received by the PMB using the Drug 
Accountability Record Form for Oral Agents (Oral DARF) available on the NCI home page 
(http://ctep.cancer.gov).    
 
Electronic logs are allowed as long as a print version of the log process is the exact same 
appearance as the current NCI Oral DARF. A separate NCI Drug Accountability Record Form 
for Oral Agents must be maintained for each patient ID number (e.g., “093-XXX”) on this 
protocol.  The combination Julian date / order number in the upper right hand corner of the 
patient-specific bottle label (e.g., 10365-9999) should be recorded as the lot number. 
 
Agent Returns:  
Only undispensed drug supplies (no partial bottles) should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when expired vials are recalled by the 
PMB), investigators should return the study drug to the PMB using the NCI Return Agent Form 
available on the NCI home page (http://ctep.cancer.gov).   

NCI 9568 / PHL-093 
11Jun2018 
 
40 
 
 
Agent Transfers:  
Bottles may NOT be transferred from one patient to another patient or from one protocol to 
another protocol. All other transfers (e.g., a patient moves from one participating clinical site to 
another participating clinical site, the registering investigator for a given patient changes) must 
be approved in advance by the PMB. To obtain an approval for transfer, investigators should 
complete and submit to the PMB (fax number (240) 276-7893) a Transfer Investigational Agent 
Form available on the CTEP home page (http://ctep.cancer.gov).  
 
For questions about drug orders, transfers, returns, or accountability, call (240) 276-6575 
Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
8.1.3 Emergency Un-blinding Procedures 
 
Examples of emergencies include which could result in un-blinding the patient: 
1) A life threatening unexpected adverse event that is at least possibly related to the 
investigational agent and for which un-blinding would influence treatment decisions 
2) A medication error, such as an accidental overdose. 
 
Contact the Approving Physician (Dr. Amit Oza; 416-946-2818; amit.oza@uhn.ca) outlining the 
request for the Emergency Un-blinding.  If an Executive Officer cannot be reached, contact the 
PMH Phase II Consortium Central Office and they will contact the Approving Physician or the 
alternate (Dr. Moore).  Note:  The Central Office cannot give permission for un-blinding; only a 
GROUP Approving Physician can authorize emergency un-blinding. 
 
The following information will be required when contacting the Approving Physician: 
•   Study number (i.e., “PHL-093”) 
•   Patient ID number (e.g., “093-XXX”) 
•   Patient initials  
•   Institution name 
•   Name and telephone number of treating physician 
•   Name and telephone number of person requesting the un-blinding procedure 
•   Name and telephone number of contact person to inform of treatment assignment 
•   Reason for emergency un-blinding 
 
After authorization by a designated Approving Physician, the treatment assignment will be 
provided to the contact person by the PMH Phase II Consortium Central Office. 
 
Note that once a subject is un-blinded, they are permanently removed from the study. 
 
8.2 
Gemcitabine 
 
Product description: Gemcitabine is a novel deoxycytidine analogue, a pyrimidine 
antimetabolite related to cytarabine.Gemcitabine exhibits cell phase specificity, primarily killing 
cells undergoing DNA synthesis (S phase) and also blocking the progression of cells through the 

NCI 9568 / PHL-093 
11Jun2018 
 
41 
 
G1/Sphase boundary. Gemcitabine is a prodrug and is metabolized intracellularly to the active 
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effects of 
gemcitabine are exerted through dFdCDP inhibition of ribonucleotide reductase and 
incorporation of dFdCTP into DNA, resulting in inhibition of DNA synthesis and induction of 
apoptosis. 
 
Please refer to the product monograph for information regarding possible side effects and 
instructions, formulation, preparation, handling, shelf life and storage. 
 
Route of administration:  To be administered as an intravenous infusion, following dilution in 
250 mL IV Normal Saline.  Care should be taken to avoid contact with the skin or mucous 
membranes. 
 
Agent Ordering:  Gemcitabine is commercially available as 200 mg and 1 gram vials.   
 
9. BIOMARKER, CORRELATIVE AND SPECIAL STUDIES 
 
Table 9-1: Biomarker Summary 
Biomarker 
Tissue Specimen 
Technique 
Integral / Integrated 
/ Research 
TP53 mutation 
Archival tissue 
Sanger sequencing 
Integrated 
TP53 mutation 
Archival tissue 
ctDNA 
TAm-Seq 
Integrated 
p53 protein 
expression 
Archival tissue 
IHC 
Integrated 
Wee1-Like Protein 
Kinase expression 
Archival tissue 
Baseline biopsy 
IHC 
Exploratory 
pCDC2 
Paired biopsies: 
-tumor 
-skin 
Immunofluorescence 
Exploratory 
Antigen KI-67 
Paired tumor biopsies Immunofluorescence 
Exploratory 
gamma-H2AX 
Paired tumor biopsies Immunofluorescence 
Exploratory 
phospho-Histone H3 
Paired tumor biopsies Immunofluorescence 
Exploratory 
cleaved-Caspase-3 
Paired tumor biopsies Immunofluorescence 
Exploratory 
Intratumoral 
pharmacokinetics 
Biopsy # 2 
(on treatment biopsy) 
Pharmacokinetics 
Exploratory 
h
tt
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:/
/
w
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w
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NCI 9568 / PHL-093 
11Jun2018 
 
42 
 
i.
n
l
m
.
n
i
h
.
g
o
v
/
p
m
c
/
a
r
ti
c
l
e
s
/
P
M
C
6
6
4
4
0
6
6
/ 
Plasma 
pharmacokinetics 
Plasma 
Pharmacokinetics 
Exploratory 
 
9.1 
Biomarker Studies 
 
9.1.1 Biomarker Studies Archival tissue 
 
Paraffin embedded archival blocks are preferred. However if blocks cannot be released, 20 
unstained slides 4-5 microns each mounted on positively charged slides are also acceptable.   
If not tissue is available for this analysis, the baseline biopsy will be used for the evaluation of 
these biomarkers according to the priority described in Table 9-1. 

NCI 9568 / PHL-093 
11Jun2018 
 
43 
 
 
 
9.1.1.1 
Determination of TP53 mutations on archival tissue 
 
Hypothesis: Certain TP53 mutation might be associated to deficient G1 checkpoint. Tumors with 
deficient G1 checkpoint might be more sensitive to the combination of gemcitabine + AZD 1775 
(MK 1775).  
 
Rationale for this biomarker analysis has been provided in Section 2.5.1 
 
TP53 mutations will be determined by two different techniques: Sanger sequencing (integrated 
biomarker) and tagged-amplicon deep sequencing methodology (TAm-Seq) (research 
biomarker), to correlate with the mutations found in circulating tumor DNA. Exons 5 to 8 of 
TP53 will be sequence by Sanger direct sequencing; Targeted re-sequencing of exons 2-11 will 
be performed by TAm-Seq. 
 
Sanger sequencing will be performed at Dr. Suzanne Kamel-Reid’s lab (CLIA certified lab) and 
TAm-Seq re-sequencing will be performed at Dr. James Brenton’s lab (Cambridge Research 
Institute, UK).22  This biomarker will be ideally analyzed in all patients to evaluate the role of 
TP53 mutations as predictors of response to the combination of gemcitabine and AZD 1775 (MK 
1775). 
 
9.1.1.2 
Determination of p53 protein expression by immunohistochemistry 
 
Hypothesis: different p53 staining patterns may correlate with the underlying TP53 mutations. 
 
In a recent communication, Kobel M., Brenton J. et al.23 had scored the p53 expression of a 
collection of 224 ovarian cancer samples using a 4-tier system: complete absence, wild type pattern 
(nuclear staining of variable intensity from 1-70%), overexpression (>70% strong nuclear 
staining), and cytoplasmic staining. Aberrant expression combined overexpression, complete 
absence and cytoplasmic expression patterns. Overexpression was scored to indicate missense 
mutation while complete absence or cytoplasmic expression was scored as possible indel, nonsense 
or splicing mutation. Immunohistochemistry for p53 performed on a Leica Bond Max platform 
using DO-7 DAKO monoclonal antibody, correctly predicted the presence of TP53 mutation in 
92% (sensitivity 96%, specificity 82%, positive predictive value 93%, negative predictive value 
88%) and the type of mutation in 94% of cases (sensitivity 98%, specificity 88%, positive 
predictive value 94%, negative predictive value 94%). 
 
The following evaluations/correlations will be performed as part of the current protocol: 
• Retrospectively correlation of the p53 expression by immunohistochemistry and the TP53 
mutational status. 
We will evaluate the compliance of the 3-tier system initially described by Kobel et al18 and 
the new 4-tier system described for Kobel, Brenton et al23. 
• Evaluation of p53 protein expression by immunohistochemistry as potential predictive 
factors of benefit (defined as response or PFS prolongation) to AZD 1775 (MK 1775) and 
gemcitabine treatment. 

NCI 9568 / PHL-093 
11Jun2018 
 
44 
 
 
Immunohistochemistry will be performed at the Drug Development Program Lab (Dr. Ming S. 
Tsao). Dr. Tsao and his group have extensive experience on biomarker evaluation by 
immunohistochemistry. Dr. Tsao has previously evaluated the role of p53 protein expression in 
non-small cell lung cancers.20 Additional information on procedures and analysis are described 
in the standard operating procedures and lab manual. 
 
9.1.1.3 
Other potential baseline predictors of response to AZD 1775 (MK 1775) 
 
As research biomarkers, the expression of Wee1-Like Protein Kinase, p21, Rb, and p16 will be 
evaluated. The rationale for this evaluation has been provided in Section 2.5.  These exploratory 
analyses will be performed at the Drug Development Program Laboratory. 
Wee1-Like Protein Kinase 
• Hypothesis: baseline Wee1-Like Protein Kinase expression (in archival tissue and baseline 
biopsy) might correlate with benefit from the treatment combination. 
p21 
• Hypothesis: p21 expression might be a useful biomarker to identify tumors with TP53 
mutations, but proficient G1 checkpoint. 
Rb and p16 
• Hypothesis: Rb and p16 immuno-staining might identify tumors with deficient G1 
checkpoint by dysfunction of the Rb pathway. 
 
9.1.2 Pre- and on-Treatment Fresh Tumor Tissues 
 
Fresh tumor tissues will be collected on 2 occasions only if there is no medical contraindication: 
• Within 28 days prior to day 1 (Biopsy # 1) after having signed the informed consent 
• On cycle 1 day 2 or 9 post AZD 1775 (MK 1775) (Biopsy # 2); + 24 hours window is 
allowed 
*Screening tumor and skin biopsies can be performed on different days, but should be done within 7days of each 
other. Tumor tissue biopsy to be completed on the same day as skin biopsy for on-treatment timepoint. 
 
Tru-cut biopsy or 14-gauge (or institutional standard size) core biopsy should be performed 
using standard surgical techniques in visible lesions or by CT or ultrasound guidance.  If 
possible, 3-4 cores should be obtained at each biopsy. Labeled screw-cap cryovials, a flask of 
liquid nitrogen, and formalin-filled specimen containers should be brought to the room where 
the core biopsy is to be performed. 
 
The disposition of the 3-4 core specimens are as follows: 
A) One to two core specimens should be immediately immersed in formalin for fixation and 
then paraffin-embedded. The following evaluations will be performed at the Drug 
Development Program Lab.  
• Protein expression by immunohistochemistry: formalin fixed paraffin-embedded (FFPE) 
sections of tumor biopsies will be examined by four-colour immunofluorescence using 
DAPI to outline individual nuclei for cell by cell analysis. Tissue sections will be scanned 
using a multilaser scanning platform. Acquired digital images will be analyzed using 
semi-automated protocols developed in the Definitions Tissue Studio 3.5 semi-automatic 

NCI 9568 / PHL-093 
11Jun2018 
 
45 
 
histology image analysis platform which uses a “learn by example” algorithm to delineate 
and analyze regions of interest (ROI) across a sample set, scoring different parameters to 
allow for elucidation of co-localization relationships. 
• Note: Stability of analytes in FFPE 
Protocols for histological staining of all of the proposed markers (apart from 
Wee1-Like Protein Kinase and pCDC2) have already been optimized and are in 
common use at our institution for research purposes; good staining in FFPE 
samples has been demonstrated. 
B) One to two core specimens should be immediately transferred from the core biopsy needle 
directly into cryovials and embedded in O.C.T. This should then be immediately frozen in 
liquid nitrogen. Samples should be stored in liquid nitrogen or in a -70°C freezer. If not 
enough tissue available in the archival specimen, TP53 determination by sanger sequencing 
(exons 5 to 8) will be performed in this sample 
C) One core from biopsy # 2 will be immediately transferred from the core biopsy needle 
directly into cryovials and embedded in O.C.T. This should then be immediately frozen in 
liquid nitrogen. Samples should be stored in liquid nitrogen or in a -70°C freezer. 
Determination of AZD 1775 (MK1775) levels in the fresh biopsy on treatment will be 
performed. These levels will be compared with serum levels. 
 
9.1.2.1 
Pharmacodynamic assessment of AZD 1775 (MK 1775) activity in tumor tissue 
 
Hypothesis: The following exploratory biomarkers are expected to be modulated by the 
treatment with AZD 1775 (MK 1775) and gemcitabine.  
• pCDC2 to evaluate target engagement (baseline and on-treatment sample) 
• Antigen KI-67 to investigate changes in proliferation (baseline and on-treatment sample) 
• gamma-H2AX to evaluate ds DNA damage (baseline and on-treatment sample) 
• phospho-Histone H3 to delineate specific activity in S-phase vs at G2/M1 checkpoint 
(baseline and on-treatment biopsy) 
• Cleaved-Caspase-3 to evaluate apoptosis (baseline and on-treatment biopsy) 
 
A comparison between baseline and on treatment and between the two treatment arms will be 
performed.  The rationale for these biomarkers determination has been already defined in section 
2.5. 
 
9.1.2.2 
Evaluation of other biomarkers in the baseline biopsy 
 
• Wee1-Like Protein Kinase expression will be evaluated in the baseline biopsy and correlated 
with the activity of the treatment combination. 
• If the available archival tumor is not enough for the determination of p53, p21, p16 and Rb, 
the determination of these biomarkers will be assessed by immunohistochemistry in the 
baseline biopsy. 
 
9.1.2.3 
Evaluation of intratumoral pharmacokinetics 
• AZD 1775 (MK1775) concentration will be evaluated on biopsy #2. The drug levels 
achieved in the tumor tissue will be correlated with the plasma pharmacokinetics. 

NCI 9568 / PHL-093 
11Jun2018 
 
46 
 
• Rationale: to evaluate the correlation between the drug concentrations achieved in plasma 
and tissue. Limited drug distribution can potentially be a limitation on drug activity. 
 
9.1.3 Skin Biopsies 
 
Skin biopsies will be performed at each of the two time-points: 
• Within 28 days prior to day 1 (Biopsy # 1) 
• On cycle 1 day 2 or 9 post AZD 1775 (MK 1775) (Biopsy # 2); + 24 hours window is 
allowed 
* Screening tumor and skin biopsies can be performed on different days, but should be done within 7 days of each 
other. Skin biopsy to be completed on the same day as tumor tissue biopsy for on-treatment timepoint. 
 
A punch biopsy will be performed using standard surgical techniques from an unexposed skin 
area. The specimen should be immediately immersed in formalin for fixation and then paraffin-
embedded. Protein expression analysis will be performed at the Drug Development Program 
Laboratory. The protein expression of pCDC2 will be assessed in both biopsies and correlate 
with the tumor tissue paired biopsies. 
 
9.2 
Laboratory Correlative Studies 
 
9.2.1 Determination of TP53 Mutations in Circulating Tumor DNA (ctDNA) 
 
Blood will be collected in a 9 ml EDTA tube. Sample processing and plasma storage at -80ºC 
will be performed according to the standard operating procedure (refer to Lab Manual for 
details). Frozen samples will first be sent to the Princess Margaret Consortium Correlative 
Studies Laboratory for batching until a patient has completed treatment. At that point, those 
samples will be sent to the Cambridge Research Institute for analysis. The presence of TP53 
mutation in serial plasma samples will be analyzed and correlated with the radiological response 
and the CA125 levels.  
 
9.2.2 Pharmacokinetics Study 
 
Plasma pharmacokinetics will be performed in all the patients participating in study. Plasma 
levels of AZD 1775 (MK 1775) will be correlated with AZD 1775 (MK 1775) in the tumor 
biopsy. 
 
The following table summarizes the time points for pharmacokinetic sample collection:  
 
Table 9.2.2-1: Pharmacokinetic Samples Collection Schedule  
 
Treatment Day 
Timing (from AZD 1775 (MK 1775)/Placebo 
administration) 
Cycle 1 Day 1 
Pre-dose, 1 h, 2 h, 4 h, and 8 h post-dose 
Cycle 1 Day 2 
Pre-dose, 1 h, 2 h, 4 h, and 8 h post-dose 
 
A 10 minute window pre and post the schedule time is allowed for each sample collection 

NCI 9568 / PHL-093 
11Jun2018 
 
47 
 
 
 
9.2.2.1 
Pharmacokinetic Samples Processing 
 
Five (5) mL of venous blood will be collected by venipuncture, through a heparin lock or 
through a central line into a heparinized vacutainer at the time points specified above. Samples 
must be kept in ice bath immediately after collection. Within 30 minutes of collection, each 
blood sample should be centrifuged at 4°C and 3000 rpm for 10 minutes. The plasma portion 
will be transferred in equal portions to duplicate properly labeled polypropylene tubes and frozen 
at -70°C in an upright position within 1 hour of collection. Each tube will be labeled with study 
number, patient initials, patient’s study number, date and time of drug administration, and date 
and time of sample collection. All labels will be affixed to the test tubes properly and prior to 
freezing. A PK sample log will be provided by the Princess Margaret Consortium Correlative 
Studies Laboratory, and completed at the site. 
 
9.2.3 Sample Shipment 
9.2.3.1 
Archival samples, skin samples, paraffin-embedded samples and fresh frozen biopsy 
for biomarker and tissue pharmacokinetic analysis 
For shipment of samples between facilities, fresh tumor biopsy samples that have been frozen 
should be sent in dry ice. Frozen samples should be buried in a large quantity of dry ice in a 
styrofoam container and shipped by overnight FedEx.  The person shipping the samples should 
contact the recipient before the package is sent to ensure that the package will be handled 
appropriately upon arrival, and provide a FedEx tracking number. 
 
Archival samples, skin samples and paraffin-embedded samples should be sent at ambient 
temperature. Both kinds of specimens should be shipped to the Princess Margaret Phase II 
Consortium at the Princess Margaret (see below). Samples should only be shipped on a Monday, 
Tuesday or Wednesday.  Samples and inventory sheet must be shipped by overnight delivery in a 
Styrofoam container and packaged in dry ice to ensure that they remain frozen. Shipment must 
be scheduled for a Monday, Tuesday or Wednesday only. 
 
Archival specimens should be shipped to: 
Correlative Studies Program 
Princess Margaret Cancer Centre 
610 University Avenue 9-718 
Toronto, Ontario M5G 2M9 
Tel: (416) 946-4501 ext 5047 
Fax: (416) 946-4431 
Email: CCRUcorrelativestudies@uhn.ca 
9.2.3.2 
Serum Samples for Pharmacokinetic Analysis 
Serum for pharmacokinetic analysis will be sent to AstraZeneca or recommended CRO for 
analysis. Samples will be pack in dry ice in shipping container. The Specimen Shipping 
Inventory Log (see Lab Manual) should be completed and included in the shipping container. 
 

NCI 9568 / PHL-093 
11Jun2018 
 
48 
 
Please, refer to Lab Manual for additional details on the Notice of Shipment of Biological 
Specimens and shipping process. 
 

NCI 9568 / PHL-093 
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49 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 10 days prior to start of protocol therapy unless 
otherwise stated.  Scans, x-rays and biopsies must be done within 28 days prior to the start of 
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.   For subsequent 
cycles (2+), day 1 and 15 assessments (physical exams, vitals, weight, ECOG, labs, CA125, 
ctDNA collection) can be completed up to 48hrs prior to day 1 and day 15.  A cycle is 28 days 
long.   
 
 
Pre-Study (Screening) 
Cycle 1 
Cycle 2+ 
30-37 day 
Safety Visit 
(after last dose) 
+ Follow Up8 
 
Within 28 
days from 
start 
Within 10 
days from 
start 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
AZD 1775 
(MK1775)/Placebo1 
 
 
X---------------X 
 
X---------------X 
 
Gemcitabine2 
 
 
X---------------X 
 
X---------------X 
 
Informed consent3 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X4 
 
 
 
X 
 
 
X 
Concurrent medications 
X 
X 
X-----------------------------------------------X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital signs (BP, pulse, RR, 
temp) 
X 
X 
X4 
 
X 
 
X 
 
X 
X 
Weight 
X 
X 
X4 
 
X 
 
X 
 
X 
X 
ECOG Performance Status 
X 
X 
X4 
 
X 
 
X 
 
X 
X 
PT/INR and PTT 
X 
X 
 
 
 
 
 
 
 
 
CBC w/diff plts 
X 
X 
X4 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry5 
X 
X 
X4 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
X--------------- as indicated --------------X 
X6 
CA1257 
 
X 
X4 
 
 
 
X 
 
 
X 
Adverse Event Evaluation 
 
 
X------------------------------------------------------------------X 
Radiological Evaluation 
X 
 
Radiological measurements should be 
performed every 8 weeks regardless of any 
delay in treatment. Documentation must be 
provided for patients removed from study 
for progressive disease 
Must be 
provided for 
patients 
removed from 
study due to PD 
Pregnancy test (B-HCG)9 
X 
 
 
 
 
 
 
 
 
 
Tumor + Skin Biopsy 
X11 
 
X11 
 
 
 
 
 
 
 
ctDNA Collection10 
X 
 
X 
 
X 
 
X 
 
X 
X 
Pharmacokinetics 
 
 
X12 
 
 
 
 
 
 
 
PRO-CTCAE13 
X 
 
X 
 
X 
 
X 
 
X 
X 
Archival tissue collection  
X14 
 
 
 
 
 
 
 
 
 
1.  AZD 1775 (MK 1775)/Placebo schedule 175 mg once daily on days 1, 2, 8, 9, 15, and 16 of each cycle 
2.  Gemcitabine 1000 mg/m2 on days 1, 8, and 15 of each cycle. If any changes are made to dosing schedule for logistical 
reasons, prior and subsequent doses are to be at least 6 days apart. 
3.  Completed prior to study related tests 
4.  If completed within 4 days prior to day 1 it does not need to be completed 
5.  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. Coagulations (aPTT, PT/INR) are required at baseline for 
eligibility only. 
6.  To be repeated in the off-study visit in those patients with cardiac history or with clinically significant alterations in the 
baseline ECG 
7.  Every 4 weeks for assessment (Day 1) according to GCIG criteria 
8.  Refer to 5.4 for subsequent follow-up expectations 
9.  Women of childbearing potential 
10.  Refer to Section 9.2 

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50 
 
11.  Refer to section 9.1 for timeline; pre treatment skin and tumor biopsies are to be completed within 7 days of each other; on-
treatment skin and tumor biopsies are to be completed on the same day. Pre-treatment biopsy #1 to be performed up to 28 
days prior to start of therapy. On treatment biopsy #2 to be performed on D2 or D9, ± 24 hours 
12.  Refer to table 9.2.2-1 for Day 1 and Day 2 timeline 
13.  PRO-CTCAE questionnaires will be completed at baseline, on treatment (days 1, and 15 of each cycle), and in the off study 
assessment at select sites only 
14.  Archival tissue is to be sent for analysis before the conclusion of the study. 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
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. 
 
Lesions that have been radiated immediately prior to study therapy will be excluded as target 
lesions. Previously irradiated lesions can be considered as target lesions, as long as there is 
evidence of radiological progression.  The amount of bone marrow radiated during the palliative 
radiation immediately before participating in the clinical trial will be evaluated by the treating 
Radiation Oncologist according to the treatment plans and dosimetry on a case-by-case basis. 
Palliative radiation therapy will be classified as radiating < 10% or ≥ 10% of the bone marrow in 
order to calculate the required wash out period after the radiation treatment. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with AZD 1775 (MK 1775)/Placebo or gemcitabine. 
 
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 ≥10 mm with CT 

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51 
 
scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area may be considered 
measurable if the lesion has progressed prior to registration.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or 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.  
 

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52 
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
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 

NCI 9568 / PHL-093 
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53 
 
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 
[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. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
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. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 

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54 
 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study, including baseline. Response will not change from PR to SD. 
 
11.1.4.2 
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). 
 
11.1.4.3 
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 
 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 

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55 
 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**      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. 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
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.  
 
11.1.6 Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first. 
 
11.2 
Other Response Parameters – CA125 Response by GCIG Criteria 
 
Evaluation of Response according to CA-125 
Patients can be evaluated according to CA-125 only if they have a pretreatment sample that is at 
least twice the upper limit of normal and within 2 weeks prior to starting treatment. 
 
Definition of response: A response according to CA-125 has occurred if there is at least a 50% 
reduction in CA-125 levels from a pretreatment sample. The response must be confirmed and 
maintained for at least 28 days.  
 
To calculate CA-125 responses accurately, the following rules apply: 
• Intervening samples and the 28-day confirmatory sample must be less than or equal to 
(within an assay variability of 10%) the previous sample. 
• Variations within the normal range of CA-125 levels will not interfere with the response 
definition. 
• For each patient, the same assay method must be used and the assay must be tested in a 
quality-control scheme. 

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56 
 
• Patients are not evaluable by CA-125 if they have received mouse antibodies (unless the 
assay used has been shown not to be influenced by HAMA [1, 2]) or if there has been 
medical and/or surgical interference with their peritoneum or pleura during the previous 
28 days. If assessing therapy that includes two treatment modalities for relapse (e.g., 
surgery and chemotherapy), any CA-125 response results from both treatments 
modalities. CA-125 cannot distinguish between the effects of the two treatments. 
 
Patients who have both a CA-125 response and whose CA-125 level falls to within the normal 
range, can be classified as CA-125 complete responders. 
 
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 Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis, either by FTP burst of data or via the CDS web application.  Reports are due 
January 31, April 30, July 31, and October 31.  Instructions for submitting data using the CDUS 
can be found on the CTEP Web site  
(http://ctep.cancer.gov/reporting/cdus.html).    
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above.  If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
 
Study participants are responsible for entering their data into the Medidata Rave system and 
submitting copies of their source notes to the Central Office / Coordinating Centre within 3 
weeks of the end of cycle.  Please refer to Appendix E, Data Management Guidelines, for further 
details regarding data submission requirements. 
 
The PMHC is responsible for compiling and submitting CDUS data to CTEP for all participants 
and for providing the data to the Principal Investigator for review.   
12.2 
CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 

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Coordinator) and the procedures for auditing are presented in Appendix B. 
The Principal Investigator/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports received from CTEP to all participating institutions for submission to 
their individual IRBs for action as required. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
 
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 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: 
 
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. 
 
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”): 
 
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 

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Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. 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. 
 
4. 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. 
 
5. 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. 
 
6. 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: 
 
Email:  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. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
Primary Objectives: 
To evaluate the progression free survival (PFS) of subjects with recurrent platinum-resistant 
ovarian, fallopian tube or primary peritoneal cancer receiving gemcitabine in combination with 

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59 
 
AZD 1775 (MK 1775) compared to subjects receiving gemcitabine in combination with placebo.  
 
Secondary Objectives: 
1. 
To evaluate the objective response by RECIST 1.1 of patients receiving gemcitabine 
combined with AZD 1775 (MK 1775) compared to patients receiving gemcitabine in 
combination with placebo. 
2. 
To evaluate the GCIG CA125 response rate of patients receiving gemcitabine combined 
with AZD 1775 (MK 1775) compared to patients receiving gemcitabine in combination 
with placebo. 
3. 
To evaluate the overall survival (max 1-yr follow-up) of patients receiving gemcitabine 
combined with AZD 1775 (MK 1775) compared to patients receiving gemcitabine in 
combination with placebo. 
4. 
To evaluate the safety and tolerability of the combination of gemcitabine combined with 
AZD 1775 (MK 1775) in patients with recurrent, platinum-resistant ovarian, fallopian tube 
or primary peritoneal cancer. 
5. 
To evaluate TP53 mutations (presence of mutation and type of mutation) as potential 
predictive factors of benefit (defined as response or PFS prolongation) to AZD 1775 (MK 
1775) and gemcitabine treatment. 
6. 
To evaluate p53 protein expression by immunohistochemistry as potential predictive 
factors of benefit (defined as response or PFS prolongation) to AZD 1775 (MK 1775) and 
gemcitabine treatment. 
 
Exploratory Objectives: 
1. 
 To evaluate patient reported outcomes using PRO-CTCAE 
2. 
To evaluate the concordance of TP53 mutations in the tumor specimen and TP53 
mutations determined by TAm-Seq in circulating tumor DNA. 
3. 
To correlate the levels circulating DNA TP53 mutations by TAm-Seq with response 
4. 
Validation of pCDC2 and gamma-H2AX in skin and tumour tissue as a pharmacodynamic 
marker of therapy 
5. 
To correlate changes in pCDC2 and gamma-H2AX with survival outcomes and response 
rate. 
 
Only patients with high-grade serous cancers will be considered for the efficacy endpoint 
analysis.  
 
13.2 
Sample Size/Accrual Rate 
 
A randomized phase 2 design recruiting patients to receive gemcitabine in combination with 
placebo or AZD 1775 (MK 1775) at a ratio of 1:2 will be used to detect a difference between 
placebo and AZD 1775 (MK 1775). 
 
All patients with epithelial ovarian cancer are eligible to participate. As TP53 mutations are most 
prevalent in high grade serous ovarian cancer, the sample size assessments will be based on this 
population. If TP53 mutation/functional mutations seem to be responsible for clinical synergy 
with AZD 1775 (MK1775), the cohort size will be amended to ensure sufficient statistical power 
in women with loss of function TP53 mutations. 

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60 
 
 
An exploratory cohort of patients with non-high grade serous histology (including but not limited 
to clear cell, endometrioid, or adenocarcinoma NOS) will be accrued. Response assessment will 
be by RECIST and > 4/10 objective responses (if available depending on accrual) will be 
considered a signal of activity. 
 
Seventy-five patients with high grade ovarian cancer should be accrued over approximately 
15 months, randomized 2:1 in favor of the experimental (AZD1775(MK175)) arm, and 
followed for PFS for approximately 8 months, until 65 events are observed, yielding 90% 
power to detect a 100% increase in median PFS (7 vs. 3.5 months), at the 1-sided .10 
significance level. 
 
If this comparison is negative, the comparison could be repeated in an expanded TP53 “non-
functional” mutation subpopulation, according to the following design.  
 
Before accrual is re-opened to the TP53 “non-functional” mutation subpopulation, a restricted 
(futility analysis) comparison could be made among the patients with TP53 “non-functional” 
mutations already accrued, at the .35 significance level.  If this comparison is positive, the TP53 
“non-functional” mutation subpopulation could be expanded to a total of 40 patients, with 
approximately 12 months additional accrual, randomized 2:1 in favor of the experimental arm, 
and followed for PFS for approximately 6 months, until 36 events are observed, yielding 90% 
power to detect a 150% increase in median PFS (6.25 vs. 2.5 months), at the 1-sided .10 
significance level.  (The futility analysis would yield 65% likelihood of termination if there is no 
true treatment effect in the restricted population, with 94% likelihood of expansion if the true 
treatment related median PFS increase in the restricted population is the targeted 150%.)  
 
The functional implications of TP53 mutations will be assessed case-by-case in the IARC TP53 
database: 
http://p53.iarc.fr/ 
 
Missense, substitution mutations in TP53 are curated by the IARC according to median level of 
transcriptional activity derived from 8 independent promoter-specific assays. These assays were 
conducted by using endogenous mutants, or by transfecting/over-expressing mutant proteins in 
human or yeast cell systems. Classifiers the IARC database uses include: 
• Nonfunctional (< 20% wild-type transcriptional activity) 
• Partially functional (20-75% wild-type transcriptional activity) 
• Functional (75-140% wild-type transcriptional activity) 
• Gain-of-function (“supertrans”) (> 140% wild-type transcriptional activity) 
 
 
Transcriptional Activity Data 
“Nonfunctional” mutations 
Nonfunctional 
Partially functional mutations 
Partially functional 
No change in function 
mutations 
Functional 
“Gain-of-function” mutations 
Supertrans 
 

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61 
 
For statistical purposes, tumors with “TP53 null” status will be defined as those tumors with 
TP53 mutations classified as “Nonfunctional” based on the “Transcriptional Activity Data” 
according to the IARC TP53 database.  
 
13.3 
Stratification Factors 
 
NA 
 
13.4 
Analysis of Secondary Endpoints 
 
Summary statistics, such as mean, median, counts and proportion, will be used to summarize the 
patients. Survival estimates will be computed using the Kaplan-Meier method. Potential 
association between variables will be measured using Pearson correlation coefficients, chi-square 
tests, one- or two-sample t-tests or logistic regression analyses as appropriate. Non-parametric 
tests such as Spearman correlation coefficients, Fisher’s exact tests and Wilcoxon rank sum test 
may be substituted if necessary.  95% percent confidence intervals will be constructed and 
selected results will be illustrated using figures and plots. 
 
Frequency and severity of adverse events will be tabulated using counts and proportions 
detailing frequently occurring, serious and severe events of interest. 
 
All the analysis results are considered hypothesis generating.  
 
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 AZD 1775 (MK 1775)/PLACEBO or gemcitabine. 
 
13.5.2 Evaluation of Response:  All patients included in the study must 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 8) unknown 
(not assessable, insufficient data).  [Note:  By arbitrary convention, category 8 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) should be included in the main analysis of the response rate.  
Patients in response categories 4-7 should 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 4-7 
will be protocol specific.  
 
All conclusions should 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 

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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 should be clearly reported.  The 95% confidence 
intervals should also be provided.  
 
 

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14. REFERENCES 
 
1.IARC: Globocan, 2008 
2.Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 63:11-30, 2013 
3.Ferrandina G, Ludovisi M, Lorusso D, et al: Phase III Trial of Gemcitabine Compared With 
Pegylated Liposomal Doxorubicin in Progressive or Recurrent Ovarian Cancer. Journal of 
Clinical Oncology 26:890-896, 2008 
4.Mutch DG, Orlando M, Goss T, et al: Randomized Phase III Trial of Gemcitabine Compared 
With Pegylated Liposomal Doxorubicin in Patients With Platinum-Resistant Ovarian Cancer. 
Journal of Clinical Oncology 25:2811-2818, 2007 
5.Hirai H, Iwasawa Y, Okada M, et al: Small-molecule inhibition of Wee1 kinase by MK-1775 
selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther 
8:2992-3000, 2009 
6.Schellens J, Shapiro G, Pavlick A, et al: Update on a phase I pharmacologic and 
pharmacodynamic study of MK-1775, a Wee1 tyrosine kinase inhibitor, in monotherapy and 
combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors., 
Journal of Clinical Oncology 29: 2011 (suppl; abstr 3068) 
7.Plunkett W, Huang P, Searcy CE, et al: Gemcitabine: preclinical pharmacology and 
mechanisms of action. Semin Oncol 23:3-15, 1996 
8.Friedlander M, Millward MJ, Bell D, et al: A phase II study of gemcitabine in platinum pre-
treated patients with advanced epithelial ovarian cancer. Annals of Oncology 9:1343-1345, 1998 
9.Markman M, Webster K, Zanotti K, et al: Phase 2 trial of single-agent gemcitabine in 
platinum-paclitaxel refractory ovarian cancer. Gynecol Oncol 90:593-6, 2003 
10.D'Agostino G, Amant F, Berteloot P, et al: Phase II study of gemcitabine in recurrent 
platinum-and paclitaxel-resistant ovarian cancer. Gynecol Oncol 88:266-9, 2003 
11.Tobey RA: Different drugs arrest cells at a number of distinct stages in G2. Nature 254:245-7, 
1975 
12.Kreahling JM, Gemmer JY, Reed D, et al: MK1775, a selective Wee1 inhibitor, shows single-
agent antitumor activity against sarcoma cells. Mol Cancer Ther 11:174-82, 2012 
13.Rajeshkumar NV, De Oliveira E, Ottenhof N, et al: MK-1775, a potent Wee1 inhibitor, 
synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic 
cancer xenografts. Clin Cancer Res 17:2799-806, 2011 
14.Hirai H, Arai T, Okada M, et al: MK-1775, a small molecule Wee1 inhibitor, enhances anti-
tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther 
9:514-22, 2010 
15.Lee Y, Miron A, Drapkin R, et al: A candidate precursor to serous carcinoma that originates 
in the distal fallopian tube. J Pathol 211:26-35, 2007 
16.Ahmed AA, Etemadmoghadam D, Temple J, et al: Driver mutations in TP53 are ubiquitous in 
high grade serous carcinoma of the ovary. J Pathol 221:49-56, 2010 
17.The Cancer Genome Atlas: Integrated genomic analyses of ovarian carcinoma. Nature 
474:609-15, 2011 
18.Kobel M, Reuss A, Bois A, et al: The biological and clinical value of p53 expression in pelvic 
high-grade serous carcinomas. J Pathol 222:191-8, 2010 
19.Shahin MS, Hughes JH, Sood AK, et al: The prognostic significance of p53 tumor suppressor 
gene alterations in ovarian carcinoma. Cancer 89:2006-17, 2000 
20.Tsao M-S, Aviel-Ronen S, Ding K, et al: Prognostic and Predictive Importance of p53 and 

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RAS for Adjuvant Chemotherapy in Non–Small-Cell Lung Cancer. Journal of Clinical Oncology 
25:5240-5247, 2007 
21.Guertin AD, Li J, Liu Y, et al: Preclinical evaluation of the WEE1 inhibitor MK-1775 as 
single-agent anticancer therapy. Mol Cancer Ther 12:1442-52, 2013 
22.Forshew T, Murtaza M, Parkinson C, et al: Noninvasive identification and monitoring of 
cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 4:136ra68, 2012 
23.Piskorz AM, Kobel M, Liu S, et al: Sensitive immunohistochemistry predicts presence and 
type of TP53 mutation in ovarian carcinomas., ISCO 2014. Malaga, Spain, 2014, pp [submitted] 
24. Do KT, Wilsker D, Balasubramanian P, et al: Phase I trial of AZD 1775 (MK 1775), a wee1 
kinase inhibitor, in patients with refractory solid tumors., ASCO 2014, Abstract 2503. 
25. Jayson GC, Kohn EC, Kitchener HC, Ledermann JA: Ovarian cancer., Lancet 2014 Oct 11; 
384(9951): 1376-88.    
 
 
 

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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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APPENDIX B            CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office 
(PIO).  The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments.  The protocol must not be 
rewritten or modified by anyone other than the Protocol Chair.  There will be only one 
version of the protocol, and each participating institution will use that document.  The 
Protocol Chair is responsible for assuring that all participating institutions are using the 
correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible for 
assuring that each participating institution has an OHRP assurance and must maintain copies 
of IRB approvals from each participating site.  
• Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each participating 
site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for review by 
the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two options 
for AE reporting: (1) participating institutions may report directly to CTEP with a copy to the 
Coordinating Center, or (2) participating institutions report to the Coordinating Center who 
in turn report to CTEP.  The Coordinating Center will submit AE reports to the Protocol 
Chair for timely review. 
• Audits may be accomplished in one of two ways:  (1) source documents and research records 
for selected patients are brought from participating sites to the Coordinating Center for audit, 
or (2) selected patient records may be audited on-site at participating sites.  If the NCI 
chooses to have an audit at the Coordinating Center, then the Coordinating Center is 
responsible for having all source documents, research records, all IRB approval documents, 
NCI Drug Accountability Record forms, patient registration lists, response assessments 
scans, x-rays, etc. available for the audit. 
 

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Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
• The title page must include the name and address of each participating institution and the 
name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
• The Coordinating Center must be designated on the title page. 
• Central registration of patients is required.  The procedures for registration must be stated 
in the protocol. 
• Data collection forms should be of a common format.  Sample forms should be submitted 
with the protocol.  The frequency and timing of data submission forms to the 
Coordinating Center should be stated. 
• Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center. 
• Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be ordered 
by a participating site only after the initial IRB approval for the site has been forwarded by 
the Coordinating Center to the CTEP PIO.  
 
 
 
 
 

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APPENDIX C             INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent AZD 1775 (MK 1775).  This clinical trial is sponsored by the National 
Cancer Institute.  This form is addressed to the patient, but includes important information for 
others who care for this patient.  
 
AZD 1775 (MK 1775) interacts with many drugs that are processed by your liver.  Because of 
this, it is very important to tell your study doctors about all of your medicine before you start this 
study.  It is also very important to tell them if you stop taking any regular medicine, or if you 
start taking a new medicine while you take part in this study.  When you talk about your 
medicine with your study doctor, include medicine you buy without a prescription at the drug 
store (over-the-counter remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
The following medications are specifically prohibited for the duration of the study treatment: 
 
Prohibited CYP3A Inhibitors: 
amprenavir 
 
fluconazole 
nelfinavir 
aprepitant 
fosamprenavir 
posaconazole 
atazanavir 
grapefruit juice 
ritonavir 
boceprevir 
imatinib 
saquinavir 
ciprofloxacin 
indinavir 
telaprevir 
clarithromycin 
itraconazole 
telithromycin 
conivaptan 
ketoconazole 
verapamil 
darunavir/ritonavir 
lopinavir/ritonavir 
voriconazole 
diltiazem 
mibefradil 
 
erythromycin 
nefazodone 
 
 
Prohibited CYP3A Inducers: 
avasimibe 
glucocorticoids  
phenytoin 
bosentan 
modafinil  
rifampin 
carbamazepine  
nafcillin  
St. John’s wort 
efavirenz  
nevirapine 
 
etravirine  
phenobarbital 
 
 
Prohibited CYP3A Substrates: 
alfentanil 
eletriptan 
nisoldipine 
aprepitant 
eplerenone 
pimozide 
astemizole 
ergotamine 
quetiapine 

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budesonide 
everolimus 
quinidine 
buspirone 
felodipine 
saquinavir 
cisapride 
fentanyl 
sildenafil 
conivaptan 
fluticasone 
simvastatin 
cyclosporine 
indinavir 
sirolimus 
darifenacin 
lopinavir 
tacrolimus 
darunavir 
lovastatin 
terfenadine 
dasatinib 
lurasidone 
tipranavir 
dihydroergotamine 
maraviroc 
tolvaptan 
dronedarone 
midazolam 
triazolam 
 
• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to switch 
any medicines that are considered strong inducers/inhibitors or sensitive substrates of 
CYP3A4 or CYP3A4 substrates with a narrow therapeutic range.   
• Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see if 
any medicine they want to prescribe is on a list of drugs to avoid.   
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s usually 
big and catches your eye.  They also have a generic name—it’s usually small and located 
above or below the brand name, and printed in the ingredient list.  Find the generic name and 
determine, with the pharmacist’s help, whether there could be an adverse interaction.   
• Be careful:  
o If you take acetaminophen regularly:  You should not take more than 4 grams a day if 
you are an adult or 2.4 grams a day if you are older than 65 years of age.  Read labels 
carefully!  Acetaminophen is an ingredient in many medicines for pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while you 
are taking AZD 1775 (MK 1775)/PLACEBO. 
 
Other medicines can be a problem with your study drugs.  
• You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.  
• Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.  Your study doctor’s name is 
_____________________ and he or she can be contacted at 
__________________________________ 
 
 

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INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent AZD 
1775 (MK 1775).  This clinical trial is sponsored by the NCI.  AZD 1775 
(MK 1775) interacts with drugs that are processed by your liver.  
Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, or pharmacist) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
AZD 1775 (MK 1775) interacts with a specific liver enzyme called 
CYP3A4 and must be used very carefully with other medicines that 
interact with this enzyme.  
➢ Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP3A4” 
➢ Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

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APPENDIX D            DIARY CARD 
 
Physician’s Office will complete this section: 
The above information has been reviewed with the patient:  
Patient Name: _______________ 
Physician/Nurse Signature __________________________________Date ________________________ 
 
 
INSTRUCTIONS  
1. 
You will take 7 x 25mg AZD 1775 (MK 1775)/Placebo capsules once a day on the designated days 
(1, 2, 8, 9, 15 and 16).  Capsules must be taken on an empty stomach 1 hour before or 2 hours after 
a meal.   The day 2 dose should be taken 24 +/- 3 hours after day 1 dose. 
2. 
Swallow each capsule whole.  Do not crush or chew the capsules. 
3. 
If you miss any of the doses or you vomit one of the capsules do not repeat or replace the dose.  
Resume dosing at the next scheduled dose. 
4. 
Record the date and time that the dose was taken.  
5. 
If you have any comments or notice any side effects, please record them in the comments column.   
6. 
Please bring this form at each clinic visit. 
7. 
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. 
Day 
Date - Time 
AZD 1775 (MK 
1775) OR Placebo 
Dose 
Comments 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 

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APPENDIX E             DATA MANAGEMENT GUIDELINES 
 
Case Report Form Submission Schedule 
 
Data required for the study will be collected in Case Report Forms provided by the PMHC 
Central Office.  The site will be required to complete a paper Eligibility Checklist case report 
form (CRF) at the time of patient registration.  All other data will be collected on electronic case 
report forms (eCRFs) in the Medidata Rave system.  Site staff access to Medidata Rave will be 
initiated at the time of site activation.  The form submission schedule is outlined below. 
 
Case Report Form 
Submission Schedule 
Eligibility Checklist 
At the time of registration 
Baseline eCRFs 
Within 3 weeks of on study date 
On Treatment (Cycle) eCRFs 
Within 3 weeks of the end of each cycle of treatment 
Off Treatment eCRFs 
Within 3 weeks of the patient coming off-study 
Short Follow-up eCRFs 
Within 3 weeks of the patient coming to clinic.   
Final eCRFs 
Within 3 weeks from the follow-up period being complete or of 
the patient's death being known to the investigator unless this 
constitutes a reportable adverse event when it should be reported 
according to CTEP-AERS guidelines 
 
Case Report Form Completion 
 
The paper Eligibility Checklist CRF must be completed using black ink.  Any errors must be 
crossed out so that the original entry is still visible, the correction clearly indicated and then 
initialed and dated by the individual making the correction. 
 
eCRFs will be completed according to the schedule noted above and all relevant supporting 
documentation such as scans, progress notes, nursing notes, blood work, pathology reports, etc., 
will be submitted to the PMHC Phase 2 Consortium Central Office for review.  All patient 
names or other identifying information will be removed prior to being sent to the Central Office 
and the documents labeled with patient initials, study number and the protocol number.   
 
eCRF completion guidelines are available for all sites. 
 
Monitoring 
 
Central data monitoring will take place throughout the trial at the Central Office.  On-site 
monitoring will be performed once a year at participating sites during which a subset of PMHC 
studies will be picked for on-site monitoring.  
 
Data in the Medidata Rave eCRFs will be monitored on a regular basis and quality assurance 
measures will be performed.  Electronic data queries as well as paper query letters may be issued 
to the site prior to the quarterly submission of data to CDUS. 

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Patient Registration 
 
• Refer to Section 4 of the protocol 
 
Data Safety 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the 
data from this research throughout the study to see if there are unexpected or more serious side 
effects than described in the consent. 
 
Regulatory Requirements 
 
 
• Please submit all required documents to the PMHC Central Office. 
• Canadian Principal Investigators must submit a completed Qualified Investigator 
Undertaking. 
• All investigators must have a current NCI investigator number on file with the PMHC 
Central Office. 
• All investigators must have an up-to-date CV (signed within 2 years) on file with the PMH 
Phase 2 Consortium Central Office. 
• Laboratory certification/accreditation and normal ranges are required 
• Confirmation of all investigators having undergone training in the Protection of Human 
Research Subjects is required.  It is preferred that other staff involved in the trial also 
undergoes such training. 
• Investigators and site staff are required to complete Medidata eCRF training modules 
depending on delegated tasks  
• OPRR assurance numbers for each institution are required 
• Consent forms must be reviewed by the Central Office before submission to the local ethics 
regulatory board (REB/IRB) and must include a statement that 1) information will be sent to 
and 2) medical records will be reviewed by the PMHC Central Office. 
• A Membership list of the local ethics board is required. 
• A copy of the initial approval letter from the ethics board must be submitted to the PMHC 
Central Office. 
• A completed Site Participant List/Training Log is required and must be submitted to PMHC 
• Continuing approval will be obtained at least yearly until follow-up on patients is completed