Conditions: Cervical Carcinoma Endometrioid Adenocarcinoma Malignant Female Reproductive System Neoplasm Recurrent Cervical Carcinoma Stage I Uterine Corpus Cancer AJCC v7 Stage I Vaginal Cancer AJCC v6 and v7 Stage IA Uterine Corpus Cancer AJCC v7 Stage IB Cervical Cancer AJCC v6 and v7 Stage IB Uterine Corpus Cancer AJCC v7 Stage IB2 Cervical Cancer AJCC v6 and v7 Stage II Cervical Cancer AJCC v7 Stage II Uterine Corpus Cancer AJCC v7 Stage II Vaginal Cancer AJCC v6 and v7 Stage IIA Cervical Cancer AJCC v7 Stage IIB Cervical Cancer AJCC v6 and v7 Stage III Cervical Cancer AJCC v6 and v7 Stage III Uterine Corpus Cancer AJCC v7 Stage III Vaginal Cancer AJCC v6 and v7 Stage IIIA Cervical Cancer AJCC v6 and v7 Stage IIIA Uterine Corpus Cancer AJCC v7 Stage IIIB Cervical Cancer AJCC v6 and v7 Stage IIIB Uterine Corpus Cancer AJCC v7 Stage IIIC Uterine Corpus Cancer AJCC v7 Vaginal Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of adavosertib when given together with external beam radiation therapy and cisplatin in treating patients with cervical, vaginal, or uterine cancer. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. External beam radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving adavosertib, external beam radiation therapy, and cisplatin may work better in treating patients with cervical, vaginal, or uterine cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the recommended phase II dose (RP2D) and safety profile of adavosertib (AZD1775) in combination with radiotherapy and concurrent cisplatin in patients with gynecological cancers.

SECONDARY OBJECTIVES:

I. To determine the acute and late toxicity of AZD1775 when administered to patients with gynecological cancer in combination with standard radiotherapy and concurrent cisplatin.

II. To evaluate the pharmacodynamic effects of AZD1775 when administered in combination with radiotherapy and concurrent cisplatin (in particular, for the 15 patients treated in an expansion cohort at the RP2D).

III. To obtain preliminary information about the progression-free survival, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or clinical progression, of AZD1775 in combination with standard radiotherapy and concurrent cisplatin in women with gynecological cancer.

OUTLINE: This is a dose-escalation study of adavosertib.

Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib orally (PO) on days 1, 3, and 5 or once daily (QD) on days 1-5 and cisplatin intravenously (IV) over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then every 4 months for 2 years.

Arms:
arm 1: Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib PO on days 1, 3, and 5 or QD on days 1-5 and cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

Interventions: intervention 1: Adavosertib intervention 2: Cisplatin intervention 3: External Beam Radiation Therapy
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Undergo external beam radiation therapy

Protocol document:
Prot_SAP_000.pdf: 
1 
 
SUMMARY OF CHANGES 
 
NCI Protocol #: 
10132 
Local Protocol #: 
PHL-087 
Version # / Version Date: 
Initial / 11 July 2017 
 
Amendment 1 / 20 February 2018 
 
Amendment 2 / 15 June 2018 
 
Amendment 3 / 28 December 2018 
 
Amendment 4 / 28 June 2019 
 
Amendment 5 / 03 Jun 2020 
 
# 
Section 
Comments 
1. 
All 
Updated the version date in the top left corner. 
2. 
7.1 
Revised AZD1775 CAEPR – Version 2.6, May 14, 2019 to CAEPR version 2.7 
April 27, 2020 
 
• Added New Risk:  
• Also Reported on AZD1775 Trials But With Insufficient 
Evidence for Attribution: Apnea; Blood and lymphatic system 
disorders - Other (right leg deep vein thrombosis); Depressed 
level of consciousness 
 
• Increase in Risk Attribution:  
• Changed to Less Likely from Also Reported on AZD1775 Trials 
But With Insufficient Evidence for Attribution: Muscle cramp; 
Weight loss 
 
Rationale: Updated CAEPR list as per Rapid Request for Amendment (RRA) 
from CTEP dated 21May2020. 
 
 
 


2 
 
NCI Protocol #: 
10132 
Local Protocol #: 
PHL-087 
Version # / Version Date: 
Initial / 11 July 2017 
 
 
 
 
Amendment 1 / 20 February 2018 
 
 
 
 
Amendment 2 / 15 June 2018 
 
 
 
 
Amendment 3 / 28 December 2018 
 
 
 
 
Amendment 4 / 28 June 2019 
 
 
 
 
Amendment 5 / 03 Jun 2020 
 
TITLE: A Phase I Study of the Wee 1 kinase (Wee 1) inhibitor AZD1775 in combination with 
Radiotherapy and Cisplatin in Cervical, Upper Vaginal and Uterine Cancers (10041848, 
10008224, 10008238, 10046888, 10014735) 
 
Corresponding Organization: LAO-11030 / University Health Network Princess Margaret 
Cancer Center LAO 
 
Senior Scientific Investigator: 
Dr. Amit Oza 
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 
 
Principal Investigator: 
Dr. Stephanie Lheureux 
Princess Margaret Cancer Centre  
Department of Medical Oncology 
610 University Avenue, 5-700  
Toronto, Ontario, CANADA M5G 2M9 
Tel: 416-946-2415 
Fax: 416-946-2016 
stephanie.lheureux@uhn.ca 
 
Co-Investigators: 
Dr. Michael Milosevic 
Princess Margaret Cancer Centre  
Radiation Medicine Program  
610 University Avenue 
Toronto, Ontario, CANADA M5G 2M9 
Tel: 416-946-2932 
Fax: 416-946-2777 
mike.milosevic@rmp.uhn.on.ca 
 
 


3 
 
ETCTN Participating Organizations  
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO  
 
 
Statistician:  
 
 
 
Central Office Coordinator: 
Lisa Wang 
 
 
 
 
Natalie Harris 
Princess Margaret Cancer Centre 
 
Princess Margaret Cancer Centre  
610 University Avenue, Toronto 
 
700 University Avenue, Toronto  
Ontario, CANADA M5G 2M 
 
Ontario, CANADA M5G 1X6 
Tel: 416-946-4501 ext. 4883  
 
Tel: 416-946-4501 ext. 5618 
Fax: 416-946-2154  
 
 
Fax: 416-946-2016 
lisawang@uhnresearch.ca 
 
 
natalie.harris@uhn.ca 
 
Responsible Data Manager: 
Chantale Blattler 
Princess Margaret Cancer Centre  
700 University Avenue, Toronto  
Ontario, CANADA M5G 1X6 
Tel: 416-946-4501 ext. 3692 
Fax: 416-946-2154 
chantale.blattler@uhn.ca 
 
 
 
 
NCI Supplied Agent: AZD1775 (previously named MK-1775, NSC#751084, IND#116495) 
Commercial Agent: Cisplatin (NSC#119875) 
 
IND #: 116495 
IND Sponsor: DCTD, NCI 
 
 


4
SCHEMA


5 
 
STUDY SUMMARY 
 
This will be a multi-institution, open-label, dose escalation phase I evaluating different 
schedules of AZD1775 administration in combination with cisplatin-based chemoradiation. 
Eligible patients will have one of the following biopsy-proven gynecological cancers, and a 
decision to treat radically with pelvic radiotherapy (total dose ≥45Gy) and concurrent cisplatin 
chemotherapy (RT-CT): 
 
• Newly diagnosed epithelial carcinoma of the cervix, cT1B-3B, N0/1, M0/1**  
• Newly diagnosed epithelial carcinoma of the upper 1/3 vagina, T1-3, N0/1, M0/1** 
• Newly diagnosed endometrioid adenocarcinoma of the uterus, cT1-3, N0/1, M0 
unsuitable for primary surgery because of the extent of local disease. These patients are 
eligible if a prior decision has been made to treat radically with neoadjuvant 
chemoradiation followed by surgery or further radiotherapy (including brachytherapy) 
depending on response  
• Central pelvis or sidewall recurrence of epithelial carcinoma of the cervix or 
endometrioid adenocarcinoma of the uterus after previous surgery without previous 
pelvic radiotherapy 
**Patient may have small volume metastatic disease in para-aortic or supraclavicular lymph 
nodes or at other metastatic sites as long as, in the best judgment of the treatment team, a radical 
course of pelvic radiotherapy is warranted to assure local disease control 
 
Study design 
 
This phase I dose-escalation study will determine the provisional recommended phase II dose. 
Once the recommended phase II dose is determined, a dose expansion will be performed. 
 
Dose Escalation 
 
A cohort of 3 patients per dose level are planned:  
• The starting dose will be dose level (DL) 1, AZD1775 will be administered daily on Day 
1, 3, and 5 of the week 
• If AZD1775 is tolerable at DL1 with no DLT experienced, 3 patients enter DL2.  
• If AZD1775 is tolerable at DL2 with no DLT experienced, 3 patients enter DL3. 
• If AZD1775 is tolerable at DL3 with no DLT experienced, 3 patients enter DL4 of which 
AZD1775 will be administered Day 1-5 of the week. 
 
If the first 2 patients enrolled in a starting dose level (DL1) experience DLT, further enrollment 
to that dose level will stop and a lower dose level will be explored. If the first 2 patients enrolled 
in the lower dose level (DL-1) experience DLT, further enrollment to that dose level will stop. 
The Principal Investigator will discuss with the sponsors regarding the appropriate next step. 
 
If 1/3 patients encounter a dose-limiting toxicity (DLT), then the cohort will be expanded to 
6 patients. If ≥2/6 of patients encounter DLT, then that dose level will be declared excessively 
toxic. A total of 6 patients will be entered into the previous dose level.  
 


6 
 
The recommended phase II dose (RPTD; also called the MTD) is defined as the dose level with 
< 1/6 patients with DLT. 
 
Dose Expansion 
 
If no patient experiences a DLT at each dose level, dose level 4 will be declared as the 
provisional RPTD. Then 12 additional patients will be enrolled (make up to a total of 15 
patients). 
 
• If 1/3 patients encountered DLT, then the cohort will be expanded to 6 patients.  
• If <1/6 patients encountered DLT, that dose level is declared as the RPTD, and 9 
additional patients will be enrolled (make up to a total of 15 patients). 
• If ≥2/6 of patients encounter DLT, then that dose level will be declared excessively toxic. 
Additional 3 patients will be entered into the lower dose level. If <1/6 patients at the 
lower dose level had DLT, then that level will be declared as the RPTD, and 9 additional 
patients will be enrolled (make up to a total of 15 patients).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


7 
 
TABLE OF CONTENTS 
STUDY SUMMARY.......................................................................................................................5 
1. 
OBJECTIVES ...................................................................................................9 
1.1 
Primary Objectives ...................................................................................................9 
1.2 
Secondary Objectives ...............................................................................................9 
2. 
BACKGROUND ...............................................................................................9 
2.1 
Gynecological Cancer ..............................................................................................9 
2.2 
Target information: AZD1775 ...............................................................................10 
2.3 
Radiotherapy and concurrent cisplatin chemotherapy for the treatment of 
locally advanced cervical cancer ...........................................................................12 
2.4 
Rationale ................................................................................................................13 
2.5 
Correlative Studies Background ............................................................................16 
3. 
PATIENT SELECTION .................................................................................17 
3.1 
Eligibility Criteria ..................................................................................................17 
3.2 
Exclusion Criteria ..................................................................................................19 
3.3 
Inclusion of Women and Minorities ......................................................................20 
4. 
REGISTRATION PROCEDURES .................................................................21 
4.1 
Investigator and Research Associate Registration with CTEP ..............................21 
4.2 
Site Registration .....................................................................................................23 
4.3 
Patient Registration ................................................................................................25 
4.4 
General Guidelines .................................................................................................27 
5. 
TREATMENT PLAN .....................................................................................27 
5.1 
Agent Administration .............................................................................................27 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................36 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................37 
5.4 
Duration of therapy ................................................................................................38 
5.5 
Duration of follow up.............................................................................................38 
5.6 
Criteria for removal from study .............................................................................38 
6. 
DOSING DELAYS/DOSE MODIFICATIONS .............................................38 
6.1 
Dose delays/interruptions.......................................................................................38 
6.2 
Dose modifications ................................................................................................39 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ..........45 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............45 
7.2 
Adverse Event Characteristics ...............................................................................49 
7.3 
Expedited Adverse Event Reporting ......................................................................50 
7.4 
Routine Adverse Event Reporting .........................................................................53 
7.5 
Secondary Malignancy ...........................................................................................53 
7.6 
Second Malignancy ................................................................................................53 
8. 
PHARMACEUTICAL INFORMATION .......................................................53 


8 
 
8.1 
CTEP IND Agent ...................................................................................................53 
8.2 
Cisplatin (NSC #119875) .......................................................................................56 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ......................56 
9.1 
Biomarker Studies Archival tissue .........................................................................56 
9.2 
Pre- and on-Treatment Fresh Tumor Tissues.........................................................57 
10. 
STUDY CALENDAR .....................................................................................60 
11. 
MEASUREMENT OF EFFECT .....................................................................62 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................62 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY   
REQUIREMENTS ..........................................................................................67 
12.1 
Study Oversight .....................................................................................................67 
12.2 
Data Reporting .......................................................................................................67 
12.3 
Collaborative Agreements Language .....................................................................69 
13. 
STATISTICAL CONSIDERATIONS ............................................................71 
13.1 
Study Design/Endpoints.........................................................................................71 
13.2 
Sample Size/Accrual Rate ......................................................................................72 
13.3 
Analysis of Secondary Endpoints ..........................................................................72 
14. 
REFERENCES ................................................................................................73 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ........................................................77 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD ...78 
APPENDIX C 
DATA MANAGEMENT GUIDELINES .......................................................80 
APPENDIX D 
PATIENT DIARY TEMPLATE .....................................................................82 
APPENDIX E  
HI5 PANEL .....................................................................................................91 
APPENDIX F  
TABLE OF DRUGS WITH A KNOWN RISK OF QT PROLONGATION/ 
TORSADES DE POINTES ............................................................................93 
APPENDIX G  
DOSIMETRIC PARAMETERS FOR RADIOTHERAPY POST END OF 
TREATMENT FOR PATIENTS WHO HAD BRACHYTHERAPY AND 
PELVIC BOOST .............................................................................................94 
  
 
 


NCI 10132 / PHL-087  
03Jun2020 
 
9 
 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
• To determine the recommended phase II dose (RP2D) and safety profile of AZD1775 in 
combination with radiotherapy and concurrent cisplatin in patients with gynecological 
cancers. 
 
1.2 
Secondary Objectives 
 
• To determine the acute and late toxicity of AZD1775 when administered to patients 
with gynecological cancer in combination with standard radiotherapy and concurrent 
cisplatin. 
• To evaluate the pharmacodynamic effects of AZD1775 when administered in 
combination with radiotherapy and concurrent cisplatin (in particular, for the 15 
patients treated in an expansion cohort at the RP2D). Pharmacodynamic biomarkers 
will include: pCDC2, Ki67, γH2AX, pH3, and CC3. 
• To obtain preliminary information about the progression–free survival, as defined by 
RECIST 1.1 or clinical progression, of AZD1775 in combination with standard 
radiotherapy and concurrent cisplatin in women with gynecological cancer. 
 
2. BACKGROUND 
 
2.1 
Gynecological Cancer 
 
2.1.1 Cervical Cancer (code 10041848, 10008224, and 10008238) 
 
Cervix cancer is the fourth most common malignant neoplasm in women worldwide. Routine 
screening has greatly decreased the incidence and mortality of cervical carcinoma.1 Despite 
these advances, the lifetime risk of developing cervical cancer remains significant at 1 in 
150 women. A subset of patients with small localized tumors (FIGO stage IA-IBI) have an 
excellent prognosis with either surgery or radiotherapy and achieve 5-year survival rates in 
excess of 90%. Unfortunately most patients present at a more advanced stage of disease where 
despite aggressive management, 5-year survival rates are disappointingly low (50-75%).2 
Most patients with cervix cancer are candidates for potentially curative treatment using 
primary radiotherapy and concurrent cisplatin chemotherapy, based on the results of several 
phase III studies.3-7 Despite delivery of adequate doses of chemotherapy and radiation, over 
25% of patients with stage IB2 or II disease will have recurrence of disease and this number 
rises to more than 50% in patients with stage III and IVa disease.8 In those patients whose 
disease recurs after failure of chemo-radiation and is not amenable to further loco-regional 
therapy, outlook is generally poor with a median overall survival of about one year.9 As such, 
there is an urgent need to identify new treatment options to increase cure rates with primary 
treatment for patients with localized disease and to improve prognosis of  those patients in whom 
primary therapy fails. 
 


NCI 10132 / PHL-087  
03Jun2020 
 
10 
 
2.1.2 Vaginal Cancer (10046888) 
 
Primary cancer of the vagina is rare and comprises three percent of all malignant neoplasms of 
the female genital tract. The most common histologic subtype is squamous cell carcinoma and 
are likely mediated by human papillomavirus (HPV) infection, as with cervical cancer.10,11 Most 
women are initially diagnosed at an advanced stage and therefore carry a poor prognosis; rates of 
5-year survival according to disease stage as per FIGO stage II-IV, range from 12.9-52%.12 
 
2.1.3 Uterine cancer (10014735) 
 
Uterine carcinoma is the highest incidence gynecologic malignancy and remains the 4th most 
common cancer diagnosis in North American women less frequent only to diagnoses of breast, 
lung and colorectal carcinoma. In 2015, approximately 6300 more women will be diagnosed 
with, and 1000 will die of this disease in Canada.13 US statistics parallel those of Canada with an 
approximately 10-fold difference.14 
 
The majority of women are diagnosed with early stage endometrial carcinoma and have a 
relatively good prognosis, with 5-year disease-free survivals of greater than 77%.15 In the 
contrary, women with advanced disease (Stage III) at presentation have a poor prognosis, with 
survival less than 57%15.  Factors like age > 60, depth of invasion, involvement of lower uterine 
segment, non-endometrioid histology and the presence of lymphovascular invasion or 
aneuploidy, have demonstrated importance in identifying those at a particularly high risk of 
failing primary therapy.16,17 
 
One large retrospective analysis examining the use of intensity-modulated radiation therapy 
(IMRT) for patients with isolated nodal recurrence was feasible, with a median OS of 46 months 
18. Interestingly, patients who received concurrent chemoradiation (given as weekly cisplatin) 
had significantly longer median survival as compared to IMRT alone. 
 
2.2 
Target information: AZD1775 
 
AZD1775 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 checkpoint19,20. 
Cell cycle checkpoints are critical in the DNA damage response, and inhibition of Wee-1 is 
expected to release a tumor cell from chemotherapeutically induced arrest of cell replication. 
In vitro experiments demonstrate that AZD1775 has synergistic anti-tumor effects when 
administered in combination with various DNA damaging agents that have divergent 
mechanisms of action. 
 
The tumor suppressor protein p53 regulates the G1 checkpoint. As the majority of human 
cancers harbor abnormalities in this pathway they become more dependent on S- and G2-phase 
checkpoints21. Thus, S- and G2-checkpoint abrogation caused by inhibition of WEE1 may 
selectively sensitize p53-deficient cells to anti-cancer agents 
 


NCI 10132 / PHL-087  
03Jun2020 
 
11 
 
2.2.1 Non-clinical studies 
 
AZD1775 increases cytotoxicity when used in combination with DNA damaging agents, 
such as gemcitabine, cisplatin, carboplatin and topotecan, in p53- deficient cell lines. In 
xenograft models AZD1775 enhanced the anti- tumor effect of cisplatin, carboplatin, 
gemcitabine, 5-Fluoruracil, and radiotherapy. 
 
The preclinical pharmacokinetic studies of AZD1775 revealed a short terminal half-life (1.6 
and 1.1 h in rats and dogs respectively). The oral bioavailability was 59.7% in rats and 33.6% in 
dogs. 
 
AZD1775 was moderately bound to plasma proteins. Metabolism was the major route of 
elimination of AZD1775 in rat and dog. 
 
In preclinical toxicological studies the major organs affected were proliferation dependent 
organs such as lymphoid and hematopoietic organs and gastrointestinal tract. In preclinical 
toxicity models AZD1775 was observed to marginally prolonged QTc. AZD1775 was 
negative in the Microbial Mutagenesis Assay but positive in vitro Chromosomal 
Aberrations Assays and in vivo Micronucleus Assay. These positive results in the 
chromosomal aberration assay were not unexpected based on the mechanism of action of 
AZD1775. 
 
2.2.2 Metabolism 
 
The in vitro studies suggest that the major pathways of the metabolism of AZD1775 in 
humans involve CYP3A4, although FMO3 and FMO5 may be involved to same extent. In 
addition, AZD1775 was a time-dependent inhibitor of CYP3A4 in vitro in human liver 
microsomes. Therefore, there is a potential for drug-drug interactions when AZD1775 is co-
administered with drugs that are known to be moderate or potent CYP3A4 inhibitors or 
inducers, and when it is co-administered with substrates of CYP3A4. 
 
2.2.3 Clinical experience 
 
As of 11 November 2017, a total of approximately 713 patients have been exposed to AZD1775 
in AstraZeneca-sponsored or Merck-sponsored clinical studies.  In addition, approximately 559 
patients have also received AZD1775 as part of externally-sponsored scientific research.  These 
patients include those who have received single doses as high as 1300 mg of AZD1775 as 
monotherapy, 325 mg of AZD1775 in a single-dose in combination with chemotherapy, and 325 
mg twice a day (BID) in a multiple-dose regimen in combination with chemotherapy. 
 
Adverse drug reactions to AZD1775 monotherapy include: anemia, neutropenia, 
thrombocytopenia, QTc prolongation, gastrointestinal events such as dyspepsia, diarrhea, nausea 
and vomiting (with or without dehydration or serum electrolyte decreases), as well as decreased 
appetite. Adverse drug reactions to AZD1775 in combination with cytotoxic chemotherapy 
include febrile neutropenia, leukopenia, stomatitis, asthenia, fatigue, and myalgia. 
 


NCI 10132 / PHL-087  
03Jun2020 
 
12 
 
Based on information emerging during the clinical development program of AZD1775, potential 
risks with AZD1775 monotherapy are transaminases, asthenia/fatigue, 
lymphopenia/lymphocytes count decreased, leukopenia/WBC count decreased, stomatitis, 
myalgia, gastrointestinal hemorrhage, sepsis, febrile neutropenia.  Potential risks for AZD1775 
in combination with cytotoxic chemotherapy are tachycardia and pancytopenia.  
 
Based on the preliminary comparison of the results of AZD1775 PK parameters at the 225 mg 
dose, PK estimates in Asian patients were higher than in Western patients. After single dose 
administration on Cycle 0 Day 1 (monotherapy), Cmax and AUC at the 225 mg dose were 45% 
and 35% higher, respectively, in the Asian population as compared to the Western population 
(Study PN011). At steady state (Cycle 3 Day 1), a similar trend of higher exposure in Asian 
patients was observed. Additional analysis/investigation will be conducted based on the 
emerging data to understand the exposure differences between the populations. 
 
In Study PN00122, of 176 evaluable patients who received AZD1775 (either single or multiple 
doses) as monotherapy or in combination with gemcitabine, cisplatin, or carboplatin, a partial 
response (PR) (confirmed and unconfirmed) was observed in 17 (9.7%) patients, and stable 
disease (SD) was observed in 94 (53.4%) patients. No complete or PRs were observed in either 
of Studies PN005 or PN008 at the time that they were terminated. 
 
In the phase I clinical trial evaluating AZD1775 as single agent and in combination with 
cisplatin, gemcitabine and carboplatin (Study PN001), the MTD of AZD1775 was determined to 
be 200mg in single-dose combination with cisplatin (75mg/m2) every 21 days; and 200mg BID 
x 2.5 days during week 1 with cisplatin (75mg/m2) every 21 days. The DLT experienced were 
Grade 3 diarrhea, fatigue, nausea and vomiting. As limited data is available for AZD1775 in 
combination with chemoradiation in patients, the initial dose selected for the current protocol 
is 100mg every alternate days (Day 1, 3, 5) weekly for five weeks. 
 
2.3 
Radiotherapy and concurrent cisplatin chemotherapy for the treatment of locally 
advanced cervical cancer  
 
Cisplatin-based chemoradiation has been considered the standard treatment in patients with 
cervical cancer, since 1999 when five randomized clinical trials comparing cisplatin-based 
chemoradiation with radiotherapy alone3,6,22 or hydroxyurea-based chemoradiation4,23 were 
published, showing an improved outcome in the cisplatin-based group. 
The most recently published metanalysis24 has shown an increased overall survival, disease 
free survival, locoregional free survival and distant metastasis free survival. There was a 6% 
absolute 5-year survival improvement (hazard ratio [HR] = 0.81, P ≤.001) from 60% to 66%. 
Among the cisplatin based regimens, weekly cisplatin (dose 40mg/m2) shows a better toxicity 
profile in comparison to the other regimens. The main toxicities observed are gastrointestinal 
and hematological toxicities. 
 
 
 
 
 


NCI 10132 / PHL-087  
03Jun2020 
 
13 
 
Table 2-1: Main toxicities in clinical trials of radiotherapy and concurrent cisplatin 40mg/m2 
 
G1-G2 toxicities (%) 
G3-G4 toxicities (%) 
Keys3 
1999 
Rose4 
1999 
Pearcey5 
2002 
Lanciano7 
2005 
Keys3 
1999 
Rose4 
1999 
Pearcey5 
2002 
Lanciano7 
2005 
Hematological 
55.74 57.95 
- 
- 
21.31 22.73 
4.72 
33.00 
Gastrointestinal 57.92 34.09 
- 
- 
14.21 
6.82 
12.60 
25.00 
Genitourinary 
31.15 
9.66 
- 
- 
1.64 
2.84 
2.36 
- 
Cutaneous 
13.66 
7.39 
- 
- 
0.00 
1.14 
2.36 
- 
Neurologic 
7.65 
7.95 
- 
- 
1.09 
0.57 
1.57 
- 
Other 
18.58 19.89 
- 
- 
6.56 
3.98 
7.87 
- 
- 
Data not available 
 
Several approaches have been evaluated to increase the outcome of patients with cervical 
cancer undergoing chemoradiation treatment, such the addition of a second chemotherapeutic 
agent or the addition of a targeted agent. The addition of gemcitabine concurrently with 
cisplatin-based chemoradiation and as part of an adjuvant regimen has been evaluated recently 
in a clinical trial.25 In this clinical trial, the experimental arm showed an increased disease free 
survival and overall survival, with a significant increase in toxicity. Regarding targeted agents, 
the anti-EGFR agents erlotinib26 and cetuximab,27 and the anti-angiogenic multi-tyrosine 
kinase inhibitor sorafenib28 has been evaluated in phase I clinical trials. The early results 
from two phase II clinical trials evaluating erlotinib and cetuximab respectively have been 
recently communicated.27,29 
 
Given the rarity of vaginal cancer, treatment paradigms are mostly extrapolation of studies from 
cervical cancer due to the fact that they shared similar etiology. Benefit of chemoradiation in 
vaginal carcinoma has been demonstrated in small studies involving women who had 
unresectable disease.12,30  
 
2.4 
Rationale 
 
2.4.1 Wee 1 inhibition and p53 
 
The cell cycle is regulated by a number of cyclin dependent kinases. Wee1, a tyrosine 
kinase, blocks activity of CDK1 (also called CDC2) and CDK2 through its phosphorylation of 
tyrosine residue 15. The ability of Wee1 to negatively regulate CDK  activity  is  critical  to  
the  G2-M  cell  cycle  arrest  in  response  to  DNA damage.19,20,31 More recently, Wee1's 
regulation of CDK activity was also shown to be essential in preventing DNA double strand 
breaks during DNA replication.32 Therefore, inhibition of Wee1 kinase activity can override 
a G2 cell cycle arrest and/or result in DNA damage by disrupting replication of the genome. 
 
The tumor suppressor protein p53 is a key regulator of the G1 checkpoint, and is the most 
frequently mutated gene in human cancers.32 Tumor cells with a defective G1 checkpoint due 
to loss of p53 are more dependent on the S and G2 checkpoints to repair DNA damage 
caused by cytotoxic agents or radiotherapy.33 Therefore, p53-deficient tumor cells treated with 


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14 
 
inhibitors of Wee1 are expected to be particularly susceptible to DNA damage induction due 
to genetic and pharmacologic loss of both the G1 and G2 checkpoints, respectively.31,34 The 
G2 checkpoint escape induced by inhibition of Wee1 forces the DNA-damaged tumor cells 
into the cell cycle causing mitotic catastrophe; however, normal cells, retaining an intact G1 
checkpoint, are less affected by Wee1 inhibition, a form of synthetic lethality. 
 
AZD1775 is a potent, highly selective, ATP-competitive, small- molecule inhibitor of Wee1. 
AZD1775 was shown in vitro and in vivo to preferentially sensitize tumor cells, relative to 
normal cells, to various DNA- damaging anticancer agents while sparing normal tissues 
from radiotherapy and chemotherapy-induced toxicity. 
 
In pre-clinical models AZD1775 significantly enhanced antitumor activity of a number of 
cytotoxic agents including carboplatin and cisplatin in a dose- dependent manner. In xenograft 
models AZD1775 enhances the anti-tumor growth effect of radiotherapy preferentially in p53 
mutant xenograft tumors. 34 
 
2.4.2 Wee 1 inhibition in cervical cancer 
 
Characteristic of cervical cancer is the presence of high risk (HR) human papillomavirus 
(HPV) DNA in more than 99% of tumors. When the HR HPV genome integrates into the host 
genome, oncogenic E6 and E7 proteins become constitutively expressed. E7 plays an important 
role in the early stage of carcinogenesis by stimulating proliferation. HR HPV E6-induced 
proteasomal degradation of p53 hampers p53 functionality in cell cycle arrest and apoptosis. 
The interaction of HPV- E6  with  p53  is  known  to  be  the  most  important  event  in  
HPV-associated carcinogenesis.35,36 Only a small percentage of cases of cervical cancer have 
a p53 mutation; most cervical cancer cells have a wild-type p53, which is not detectable by 
immunohistochemical analysis due to its short half-life.37 Accumulation of p53 protein is 
associated with aggressive behavior and recurrence of various cancers, including cervical 
cancer.38,39. 
 
In a recent series from Moon et al, 31 of 80 (38.8%)40 samples of squamous cell carcinoma 
of the cervix were immunohistochemically positive for p53. p53 expression was 
significantly related to advanced T stage (p = 0.001), larger than 4 cm in the greatest dimension 
of the tumor (p = 0.002) and more than 1/2 stromal invasion of the cervix (p = 0.005). In this 
series the rate of expression varied from 27.6% from T stage 1 and 68.2% from T stage 2 
cancers.41 This compares to earlier series where expression varied from 39.1% p53 expression 
from stage I cancer and 80.9% expression from stage II–IV cancer.42 Seven percent p53 
expression was seen in carcinoma in situ compared to 62% p53 expression in invasive SCC, 
with no staining of p53 observed in cervical dysplasia, condyloma, or normal cervix was 
observed in another series.40 Dysfunctional p53 is therefore a key feature of cervical cancer. 
 
By using RNA interference (RNAi) approach, Lorns et al. showed that the WEE1 gene is 
over-expressed in cervical cancer cell lines (HeLa), probably as a result of an increase in the 
gene copy number.43 Furthermore, WEE1 was also over-expressed at the protein level in HeLa 
and could be silenced by small interfering RNAs (siRNA) with higher sensitivity than cell lines 
that did not overexpress WEE1. Knockdown of WEE1 in cervical cancer cells, but not in normal 
epithelial cells, in combination with adryamicin treatment, induces G2-abrogation and results in 


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15 
 
apoptosis.44 In vivo, AZD1775 combined with carboplatin in cervical HeLa-luc xenografts 
resulted in significant reduction of tumor growth45. Furthermore, AZD1775 enhanced the 
growth inhibitory effects of cisplatin and topotecan in human 
papilloma virus 
(HPV)+/genetically p53 wild-type (HeLa, SiHa, CaSki, and ME-180) as well as HPV-/p53 
mutant (C-33A and HT-3) cervical cancer cells, suggesting that HPV infection, and not only 
mutation or loss of the p53 loci, renders cervical cancer cells susceptible to chemosensitization 
by AZD1775.46 
 
2.4.3 Rationale for combining AZD1775 with radiotherapy and concurrent cisplatin for cervical 
cancer 
 
AZD1775 is a highly promising agent particularly for tumors with loss of functional p53. Loss 
of functional p53 plays a key role in cervical cancer biology. The following table summarized 
some loss of function p53 mutations according to the IARC TP53 database 47: 
Examples of loss of function p53 mutations: 
 
R175H 
V272M 
V216M 
C277F 
P177L 
R249T 
R248Q 
R280T 
C275Y 
P250L 
R110L 
Y234H 
R273H 
I195T 
G266R 
G279E 
R283P 
P278A 
R248W 
R158L 
V173M 
N239D 
D259Y 
S215R 
R273C 
C141Y 
R280K 
R249G 
D281N 
H179Q 
R282W 
C176Y 
K132N 
V272L 
N239S 
L194F 
G245S 
P151S 
G244S 
R249W 
S241C 
R249K 
R249S 
H193R 
G244D 
D281E 
V143M 
F134L 
Y220C 
E286K 
L194R 
R282G 
C242S 
R280S 
V157F 
C135Y 
R249M 
M246I 
I195F 
Y163H 
M237I 
C242F 
E258K 
C238F 
A138P 
C277Y 
E285K 
G245C 
G154V 
R156P 
P152S 
F270C 
 
H179R 
G266E 
H193L 
P278R 
P278T 
I251S 
Y163C 
V173L 
K132R 
R280G 
R267W 
R280I 
G245D 
P278S 
C135F 
H193Y 
V274F 
S215I 
R273L 
Y236C 
G266V 
D281H 
C176S 
K132E 
Y234C 
C238Y 
M246V 
I255F 
C238S 
K164E 
R248L 
P152L 
G244C 
R213L 
F270L 
R248G 
Y205C 
G245V 
C242Y 
P151H 
S127F 
Y163N 
S241F 
P278L 
A159V 
R213Q 
T155N 
G244V 
R158H 
H214R 
C275F 
R273P 
A159P 
R175G 
Note: this list includes some of the most frequent loss of function mutations, but it is not a restrictive list. Many 
other loss of function mutations are described in the IARC TP53 database. 
 
HPV interaction with p53 may in fact be another mechanism for synthetic lethality with 
AZD1775 in this patient population, and this study will assess this hypothesis. Pre-clinical 


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16 
 
studies suggest AZD1775 may enhance the activity of both cisplatin and radiotherapy. 
 
Cervical cancer is an accessible tumor particularly attractive for studies combining biological 
agents with chemoradiation as the availability of serial tumor biopsies allows “proof of 
principle” correlative studies. In this study we wanted to explore two schedules as AZD1775 is 
thought to enhance both the effect of cisplatin chemotherapy and the effect of radiotherapy. 
By scheduling AZD1775 doses around the time of cisplatin administration, we will explore 
both the effect of the drug on the combination of radiotherapy and concurrent cisplatin 
chemotherapy.   
 
Figure 2-1: Abrogation of the G2 checkpoint by AZD1775. BxPC-3 pancreatic cancer cells 
show a striking increase in the G2 peak following ionizing radiation (IR), whereas 
irradiated cells exposed  to  AZD1775  continue  on  into  mitosis. 
(Findings from D. Hedley laboratory, Princess Margaret Cancer Centre) 
 
 
 
2.5 
Correlative Studies Background 
 
2.5.1 Wee1 and the G2/M checkpoint 
 
The checkpoint kinases which include ATR, CHK1 and Wee1 are important regulators of 
DNA damage surveillance pathways. Their normal functioning at the various transition 
points (G1/S, G2/M) of the cell cycle is critical in order for proliferating cells to repair DNA 
damage accumulated to that point from either endogenous or exogenous sources. Wee1 exerts 
inhibitory phosphorylation of CDC2 at Tyr14 and Tyr15 which in turn stalls cells at G2/M 
preventing entry into mitosis. Inhibition of wee1 therefore releases this inhibition and the 
decreased levels of p-cdc2 allow cells to proceed through mitosis. Cells previously exposed to 
DNA damaging agents and now under the pressure of wee1 inhibition would be expected to 
undergo mitotic catastrophe and apoptosis as a consequence of the accumulation of cytotoxic- 
induced DNA damage. From a molecular standpoint, effective wee1 inhibition with decreased 
p-CDC2 levels would be expected to result in increased p-H3 (phospho- histone 3, 
demonstrating entry into mitosis) and CC3 (cleaved caspase 3 indicative of apoptosis). 
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 


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17 
 
action, inhibition of checkpoint kinases active at G2/M (such as wee1) is 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.45,51,52 
 
2.5.2 Wee1 activity during S-phase 
 
This latter finding may be consistent with the recent description of a critical role for wee1 
(acting through CDK2) during S-phase in protecting against replication stress associated 
DNA breakage.32,53 Specific inhibition of wee1 activity during S-phase results in increased 
cdk2 activity with increased origin firing and slowed replication fork speed with an 
accumulation of dsDNA breaks (indicated by H2AX) and stalling of cells in S-phase (with 
decreased proliferation rates indicated by ki-67). 
 
2.5.3 Other factors potentially influencing AZD1775 activity 
 
This study will include the analysis in archival tissue of p21, Rb and p16. Some p53 mutations 
induce a partial loss of function allele. These mutations failed to activate apoptotic genes, but 
are able to induce p21 transcription.55 In cancers harboring these mutations, we expect to 
observe p21 staining. We hypothesize that in cancers expressing p21, there would be no 
impairment of the G1 checkpoint, thus AZD1775 could be less effective than in tumors with loss 
of function p53 mutations. 
 
The Retinoblastoma (Rb) pathway is also essential regulating the G1 checkpoint. p16 blocks 
Rb protein phosphorylation, favoring Rb suppressor activity. Loss of Rb or dysfunction of 
the Rb pathway leads to chromosome instability.56 In cervical cancer, Rb dysfunction is an 
expected event: HPV E7 oncoprotein disrupts the pRB/E2F transcriptional repressor 
complex, blocking the suppressor effect of Rb protein and releasing E2F transcription 
factor.57 This E7 oncoprotein-induced loss of Rb function in cervical carcinomas, results in 
overexpression of p16.58-60 The underlying mechanism for this p16 overexpression is that 
E2F positively regulates the transcription of p16.61,62 It is still unknown whether changes 
in Rb pathway can influence the activity of AZD1775. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 Patients must have one of the following biopsy proven gynecological cancer and a 
decision to treat with radiotherapy and concurrent cisplatin chemotherapy (RT-CT) 
• Newly diagnosed epithelial carcinoma of the cervix, cT1B-3B, N0/1, M0/1** 
• Newly diagnosed epithelial carcinoma of the upper 1/3 vagina, T1-3, N0/1, 
M0/1** 
• Newly diagnosed endometrioid adenocarcinoma of the uterus, cT1-3, N0/1, M0 
unsuitable for primary surgery because of the extent of local disease. These 
patients are eligible if a prior decision has been made to treat radically with 
neoadjuvant chemoradiation followed by surgery or further radiotherapy 
(including brachytherapy) depending on response 


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18 
 
• Central pelvis or sidewall recurrence of epithelial carcinoma of the cervix of 
endometrioid adenocarcinoma of the uterus after previous surgery without 
previous pelvic radiotherapy 
**Patient may have small volume metastatic disease in para-aortic or supraclavicular 
lymph nodes or at other metastatic sites as long as, in the best judgment of the 
treatment team, a radical course of pelvic radiotherapy is warranted to assure local 
disease control. 
 
3.1.2 Patients must be planned to receive whole pelvic radiotherapy to a total dose of 45Gy or 
greater. 
 
3.1.3 Patients must be able to receive weekly cisplatin. 
 
3.1.4 Patients must be 18 years of age on day of signing informed consent 
• 
Because no dosing or adverse event data are currently available on the use of 
AZD1775 in combination with cisplatin-based chemoradiation in patients <18 
years of age, children are excluded from this study, but will be eligible for future 
pediatric trials. 
3.1.5 ECOG performance status 0 or 1 (Karnofsky ≥60%, see Appendix A). 
 
3.1.6 Life expectancy of greater than 3 months 
 
3.1.7 Patients must have normal organ and marrow function as defined below: 
• 
leukocytes 
≥3,000/mcL 
• 
absolute neutrophil count  ≥1,500/mcL 
• 
platelets 
≥100,000/mcL 
• 
hemoglobin 
≥9 g/dL1 
• 
PT/PTT/INR 
≤ 1.5 ULN 
• 
total bilirubin 
Serum bilirubin within normal limits (WNL) or ≤1.5 
x ULN in patients with liver metastases; or total 
bilirubin ≤3.0 x ULN with direct bilirubin WNL in 
patients with documented Gilbert’s Syndrome  
• 
AST(SGOT)/ALT(SGPT) 
Alanine aminotransferase (ALT) and aspartate  
 
 
 
 
aminotransferase (AST) ≤3 x upper limit of normal  
 
 
 
 
(ULN) or ≤5 x ULN if known hepatic metastases  
• 
Creatinine clearance (CrCl) ≥60 mL/min as calculated by the Cockcroft-Gault 
method  
 
1: Blood transfusions are allowed at any time during the screening, treatment or follow-up period, 
according to the center recommendations. 
2: Cockcroft-Gault formula: 𝐶𝑟𝐶𝑙 = 
(140−𝑎𝑔𝑒)×𝑤𝑒𝑖𝑔ℎ𝑡 (𝑖𝑛 𝑘𝑔) 
72 ×𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝑖𝑛𝑚𝑔
𝑑𝐿) × 𝐹 ;where F=0.85 for females 
 


NCI 10132 / PHL-087  
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19 
 
3.1.8 Patients must be able to swallow whole capsules. 
 
3.1.9 The effects of AZD1775 on the developing human fetus are unknown. The preclinical 
Chromosomal Aberrations Assays have shown potential to induce chromosomal 
aberrations. In addition, cisplatin and radiotherapy are known to be teratogenic. For this 
reason, women of child-bearing potential must agree to use two birth control methods 
(two barrier methods or a barrier method plus a hormonal method) or abstinence prior to 
study entry, for the duration of study participation prior to study entry, for the duration of 
study participation, and for 4 months after coming off study.  Should a woman become 
pregnant or suspect she is pregnant while she is participating in this study, she should 
inform her treating physician immediately. 
 
3.1.10 Females with child-bearing potential must have had a negative serum pregnancy test 
result ≤ 28 days prior to the first dose of study treatment. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have received any radiotherapy or chemotherapy for their current 
gynecological cancer. 
 
3.2.2 Patients who received prior pelvic radiotherapy for any indication. 
 
3.2.3 Patients who have a mean resting correct QTc interval using the Fridericia formula 
(QTcF) >470 msec (as calculated per institutional standards) obtained from 3 
electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT 
syndrome. AZD1775 should not be given to patients who have a history of Torsades de 
pointes unless all risk factors contributed to Torsades have been corrected. AZD1775 has 
not been studied in patients with ventricular arrhythmias or recent myocardial infarction. 
 
3.2.4 Patients requiring para-aortic radiotherapy. 
 
3.2.5 Patients who are receiving any other investigational agents or anticancer therapy 
concurrently or within 4 weeks (ie 28 days) 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to AZD1775 or cisplatin. 
 
 
 


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20 
 
3.2.7 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. 
 
3.2.8 Pregnant women are excluded from this study because AZD1775 and chemoradiation are 
agents with the potential for teratogenic or abortifacient effects. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with AZD1775 and cisplatin, breastfeeding must be discontinued if the 
mother is treated with AZD1775 and cisplatin.  These potential risks may also apply to 
other agents used in this study. 
 
3.2.9 Patients with another uncontrolled malignancy. Patients with a previous malignancy, 
treated curatively and without evidence of disease relapse are eligible. 
 
3.2.10 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with AZD1775.  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. 
 
3.2.11 History of active clinically significant bleeding. 
 
3.2.12 History of bowel obstruction or malabsorption syndromes (within the last 3 months) 
which might limit the absorption of the study drug. 
 
3.3 
Inclusion of Women and Minorities 
 
Due to the nature of the disease site, men are ineligible for this study; while women of all races 
and ethnic groups are eligible.  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: 
 
 






NCI 10132 / PHL-087  
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23 
 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm. 
 
For questions about Associate Registration or CTEP-IAM Account Creation, please contact the 
CTEP Associate Registration Help Desk by email at ctepreghelp@ctep.nci.nih.gov. 
 
4.2 
Site Registration  
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to: an active Federal Wide 
Assurance (FWA) number, an active roster affiliation with the Lead Network or a participating 
organization, a valid IRB approval, and compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 10132 protocol page located on the CTSU 
Web site.  Permission to view and download this protocol is restricted and is based on person and 
site roster data housed in the CTSU RSS.  To participate, Investigators and Associates must be 
associated with the Corresponding or Participating protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 


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24 
 
• Click on the Protocols tab in the upper left of your screen. 
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-11030, and 
protocol #10132. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements for 10132 Site Registration: 
 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted) 
• IROC Online Facility Questionnaire 
NOTE:  Per NCI policy all institutions that participate on protocols with a 
radiation therapy component must participate in the Image and Radiation 
Oncology Core (IROC) monitoring program.  If this form has been 
previously submitted to CTSU it does not need to be resubmitted unless 
updates have occurred at the RT facility. 
 
4.2.3 Submitting Regulatory Documents 
 
NCI CIRB Institutions: Submit completed forms along with a copy of your IRB Approval and 
Model Informed Consent to the CTSU Regulatory Office, where they will be entered and tracked 
in the CTSU RSS. Sites will submit their IRB-approved local ICs and all future amended ICs to 
the CTSU Regulatory Office for tracking in RSS. The CTSU Regulatory Office will forward the 
IRB initial approval and accompanying local informed consent(s) to the Central Office (central 
office coordinator on protocol face page) for documentation purposes. This also applies to future 
amendment approvals. 
 
Non-CIRB US Institutions: Submit model informed consent to the Central Office (central 
office coordinator on protocol face page) for pre-approval prior to submitting to your local 
IRB/REB. Once pre-approval is obtained, submit to your local IRB. Sites will submit their 
IRB/REB initial approval (accompanied by local IC); all future amendment approvals 
(accompanied by updated local IC if applicable); and continuing review approvals to the CTSU 
Regulatory Office for tracking in RSS. The CTSU Regulatory Office will forward the IRB initial 
approval and accompanying local informed consent to the Central Office (central office 
coordinator on protocol face page) for documentation purposes. This also applies to future 
amendment approvals. 
  
Canadian Institutions: Submit model informed consent to the Central Office (central office 
coordinator on protocol face page) for pre-approval prior to submitting to your local IRB/REB. 
Once pre-approval is obtained, submit to your local IRB. Sites will submit their IRB/REB initial 
approval (accompanied by local IC); all future amendment approvals (accompanied by updated 


NCI 10132 / PHL-087  
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25 
 
local IC if applicable); and continuing review approvals to the PMP1C Central Office. The 
Central Office will submit copies of IRB approval documentation, ICs (and QIU and CTSI for 
Canadian sites) to the CTSU Regulatory Office for tracking in the RSS. This also applies to 
future amendment approvals.  
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
4.2.4 Checking Site Registration Status 
You can verify your site registration status on the members’ section of the CTSU website.   
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available to users on a 24/7 basis.  It is integrated with 
the CTSU Enterprise System for regulatory and roster data interchange and with the Theradex 
Interactive Web Response System (IWRS) for retrieval of patient registration/randomization 
assignment.  Patient enrollment data entered by Registrars in OPEN / IWRS will automatically 
transfer to the NCI’s clinical data management system, Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment initiation 


NCI 10132 / PHL-087  
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26 
 
to check slot availability.  Registration staff should ensure that a slot is available and secured for 
the patient before completing an enrollment. 
 
• Site staff with the appropriate roles will reserve slots using IWRS (https://open.ctsu.org/). 
• Central Office will receive notification via the IWRS when a slot has been reserved. An 
email will be sent from the Central Office to the site requesting further information such 
as: the patient initials, tumor type and potential start date. The spot will show as ‘pending 
approval’ in the system until the site sends a REGISTRATION CHECKLIST and a copy 
of the signed consent to the Central Office for review and confirmation of eligibility. 
• Once the Registration has been reviewed, the Central Office will either approve or 
disapprove the request depending on confirmation of patient eligibility. If approved, the 
Central Office will update the spot to ‘reserved’ in IWRS.  
• The site can now enroll the patient into the study in OPEN 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN / IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  
• If applicable, all patients have signed an appropriate consent form, and HIPAA 
authorization form. 
 
4.3.3 OPEN / IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk: 
609-619-7802 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 


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27 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
5. TREATMENT PLAN 
 
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. The patient will be requested to 
maintain a medication diary of each dose of medication. The medication diary will be 
returned to clinic staff at the end of each course. 
 
5.1.1 AZD1775 administration 
 
AZD1775 is an oral drug that should be ingested 2 hours before a meal or 2 hours after a 
meal. 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. 
 
The study will have a dose escalation phase to determine the provisional recommended 
phase II dose. Once the recommended phase II dose is determined, a dose expansion will be 
performed. AZD1775 will be administered only during the first five weeks of treatment 
concurrently with external beam whole pelvis radiotherapy and concurrent cisplatin. It will not 
be continued beyond five weeks during brachytherapy or the delivery of additional external 
beam radiotherapy. 
 
Dose Escalation 
 
A cohort of 3 patients per dose level are planned:  
• The starting dose will be dose level (DL) 1, AZD1775 will be administered on Day 
1, 3, and 5 of each week 
• If AZD1775 is tolerable at DL1 with no DLT experienced, 3 patients enter DL2.  
• If AZD1775 is tolerable at DL2 with no DLT experienced, 3 patients enter DL3. 
• If AZD1775 is tolerable at DL3 with no DLT experienced, 3 patients enter DL4 of 
which AZD1775 will be administered Day 1-5 of the week. 
 
If the first 2 patients enrolled in a starting dose level (DL1) experience DLT, further enrollment 


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28 
 
to that dose level will stop and a lower dose level will be explored. If the first 2 patients enrolled 
in the lower dose level (DL-1) experience DLT, further enrollment to that dose level will stop. 
The Principal Investigator will discuss with the sponsors regarding the appropriate next step. 
 
If 1/3 patients encounters a dose-limiting toxicity (DLT), then the cohort will be expanded to 
6 patients. If ≥2/6 of patients encounter DLT, then that dose level will be declared 
excessively toxic. A total of 6 patients will be entered into the previous dose level.  
 
The recommended phase II dose (RPTD; also called the MTD) is defined as the dose level with 
< 1/6 patients with DLT. 
 
Dose Expansion 
 
If excessive toxicity is not observed after exploring all dose levels, dose level 4 will be declared 
as the provisional RPTD. Then 12 additional patients will be enrolled (make up to a total of 15 
patients). 
 
If 1/3 patients encountered DLT, then the cohort will be expanded to 6 patients.  
 
If <1/6 patients encountered DLT, that dose level is declared as the RPTD, and 9 additional 
patients will be enrolled (make up to a total of 15 patients). 
 
If ≥2/6 of patients encounter DLT, then that dose level will be declared excessively toxic. 
Additional 3 patients will be entered into the lower dose level. If <1/6 patients at the lower dose 
level had DLT, then that level will be declared as the RPTD, and 9 additional patients will be 
enrolled (make up to a total of 15 patients). 
 


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29 
 
Table 5-1: Dose Escalation Schedule  
 
Dose Escalation Schedule  
Dose Level 
Dose* 
Radiationa 
(fractions) 
Cisplatinb 
(weekly)  
AZD1775 c  
Week 1-5 
Level -1 
25 days 
40 mg/m2 
100 mg, oral, QD day 3 and 5 of each week 
Level 1 
25 days 
40 mg/m2 
100 mg, oral, QD day 1, 3, 5 of each week 
Level 2 
25 days 
40 mg/m2 
150 mg, oral, QD day 1, 3, 5 of each week 
Level 3 
25 days 
40 mg/m2 
200 mg, oral, QD day 1, 3, 5 of each week 
Level 4 
25 days 
40 mg/m2 
200 mg, oral, QD day 1, 2, 3, 4, 5 of each week 
a Radiation: External beam radiation (45-50 Gy) will be administered five days a week for five weeks. 
b Cisplatin can be administered either on Monday or Wednesday once commenced on external beam radiation every 
week. 
cAZD1775 will be administered on Monday, Wednesday and Friday of each week once commenced on external beam 
radiation every week. 
 
5.1.2 Cisplatin 
 
Cisplatin will be administered as an intravenous infusion at a dose of 40 mg/m2 week. The time 
of infusion will be 1 hour ± 15min. The weekly dose should not exceed 70 mg. Five doses of 
cisplatin will be administered concomitantly with the external beam whole pelvis 
radiotherapy. Cisplatin will not be continued beyond five weeks during brachytherapy or the 
delivery of additional external beam pelvic radiotherapy. 
 
5.1.3 Radiotherapy 
 
All patients will receive whole pelvis external beam radiotherapy (EBRT) with concurrent 
cisplatin and AZD1775 for five consecutive weeks. Further radiotherapy may be delivered after 
five weeks, tailored to the specific disease site, without cisplatin or AZD1775. 
 
Radiotherapy will adhere to the following general guidelines: 
• Whole pelvis EBRT will be delivered in a uniform manner during the first five weeks of 
treatment using conformal, field-based techniques (four coplanar, orthogonal fields), 
intensity modulated radiation treatment (IMRT) or volumetric modulated arc treatment 
(VMAT).  
• Patient management after the initial five weeks of EBRT/cisplatin/AZD1775 will vary 
depending on the patient cohort (cervix, upper vagina, uterus, recurrent disease) and 
treatment response, and may include surgery, brachytherapy, further external beam 
radiotherapy for residual pelvic disease, or no further treatment. To aid in interpreting 


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30 
 
toxicity in this phase I study, detailed reporting of normal tissue radiation dosimetry will 
be required for the initial course of whole pelvis EBRT and for all subsequent 
radiotherapy courses (brachytherapy or further external beam radiotherapy) beyond five 
weeks. Radiotherapy after the initial five weeks will be delivered alone without 
concurrent cisplatin or AZD1775. 
• Patient with newly diagnosed cervical cancer (cT1B-3B, N0/1, M0/1) or upper vaginal 
cancer (T1-3, N0/1, M0/1) will receive brachytherapy after whole pelvis 
EBRT/cisplatin/AZD1775 unless otherwise contraindicated. 
• Patients with newly diagnosed, unresectable endometrial cancer should be re-evaluated 
for surgery after whole pelvis EBRT/cisplatin/AZD1775. If surgery is contraindicated, 
these patients should be considered for brachytherapy unless otherwise contraindicated. 
• Patients with pelvic recurrences of cervical or endometrial cancer after previous surgery 
should be considered for brachytherapy (central pelvic recurrences), further external 
beam radiotherapy (pelvic sidewall recurrences) or both. 
 
5.1.4 Whole Pelvis External Beam Radiotherapy 
 
Whole pelvis EBRT will be delivered in a uniform manner during the first five weeks of 
treatment using conformal, field-based techniques (four coplanar, orthogonal fields), intensity 
modulated radiation treatment (IMRT) or volumetric modulated arc treatment (VMAT). 
Regardless of the treatment technique, the clinical target volume (CTV) and planning target 
volume (PTV) should be adequate to ensure coverage of clinical and subclinical primary tumor 
and lymph node disease extension accounting for inter- and intra-fractional target motion. 
 
• Patients will undergo CT simulation for radiation treatment planning. 
• Gross target volume (GTV) delineation: The GTV will encompass the gross primary 
tumor volume (GTVp), and any grossly enlarged pelvic lymph nodes (GTVn). 
• Clinical target volume (CTV) delineation: The CTV will include the CTVp and the 
CTVn. 
– The CTVp will include the GTV, entire cervix, uterus, parametria and at least the upper 
half of the vagina, The lower third of the vagina should be included in the CTVp in 
patients with involvement of the upper vagina, at the discretion of the responsible 
radiation oncologist.  
– The CTVn will include the internal, external and distal common iliac lymph nodes, the 
upper pre-sacral lymph nodes anterior to the S1/2 vertebral bodies (CTVn) and the para-
aortic lymph nodes (if clinically warranted, at the discretion of the responsible radiation 
oncologist). Refer to the RTOG GYN postoperative contouring atlas for lymph node 
delineation. The CTVn will be obtained by applying a 7 mm margin around the iliac 
vessels, plus extensions to include any adjacent visible lymph nodes. The presacral 
nodes will be contoured until the superior border of the S3 vertebral body is reached; 
below this point the nodal volume will be separated into two structures. The external 
iliac nodes will be contoured to the superior aspect of the femoral heads. The CTVn 
will be modified to exclude bone, muscle, and bowel. 
• Organs at risk (OAR) delineation: The rectum, sigmoid, small bowel and bladder will be 


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31 
 
delineated in all patients. Refer to the RTOG contouring atlas for normal female pelvic 
anatomy for OAR delineation. 
– Rectum: The outer rectal wall will be contoured from the anus to the level of the 
sigmoid flexure. 
– Sigmoid: The outer sigmoid wall will be contoured from where the rectum ends to the 
point of connection to the ascending colon laterally. Any sigmoid adjacent or above 
the uterus should be contoured. 
– Small bowel: The peritoneal cavity will be contoured from the axial CT/MR slice 1 
cm superior to the upper field border, and will continue to its most inferior extent in 
the pelvis. Individual loops of bowel should not be contoured separately. Rectum 
should be contoured separately from bowel. 
– Bladder: The outer bladder wall in its entirety will be contoured. 
• The external beam pelvic dose will be 45-50 Gy in 25 daily fractions of 1.8-2 Gy. 
Megavoltage radiotherapy (10 MV or greater) will be used. Treatment will be 
delivered daily, five fractions per week. The dose will be prescribed to an ICRU 
reference point in accordance with ICRU 62. All fields will be treated daily. 
• Treatment verification using cone-beam CT imaging of soft tissue and bone anatomy 
will be performed daily on the treatment unit to ensure adequate target coverage and day-
to-day reproducibility. 
• EBRT dose reporting requirements: The absolute rectum, sigmoid, small bowel and 
bladder volumes (cm3), and the percentages of the total delineated organ volumes, 
receiving ≥50% of the prescribed dose and ≥90% of the prescribed dose. 
 
5.1.5 Brachytherapy 
• Patient with newly diagnosed cervical cancer (cT1B-3B, N0/1, M0/1) or upper 
vaginal cancer (T1-3, N0/1, M0/1) will receive brachytherapy after whole pelvis 
EBRT/cisplatin/AZD1775, unless otherwise contraindicated. Patients with newly 
diagnosed, unresectable endometrial cancer may be considered for brachytherapy after 
whole pelvis EBRT/cisplatin/AZD1775 if the disease remains unresectable, unless 
otherwise contraindicated. Patients with central pelvic recurrences of cervical or 
endometrial cancer after previous surgery may be considered for brachytherapy after 
pelvic EBRT/cisplatin/AZD1775, unless otherwise contraindicated. 
• Brachytherapy will begin after completion of whole pelvis EBRT/cisplatin/AZD1775 and 
will be delivered according to the usual practice at the treating institution.  However, CT 
or MR imaging of the pelvis after placement of the brachytherapy applicator(s) with 
delineation of OARs and reporting of OAR doses must be done to aid in interpreting 
acute and late toxicity in this phase I study.  
• For patients with newly diagnosed cervical, upper vaginal or endometrial cancer, 
brachytherapy typically will be delivered using an intrauterine applicator with a vaginal 
ring or ovoids. An intrauterine applicator with a vaginal cylinder may be necessary to 
encompass vaginal disease. Soft tissue imaging (trans-abdominal ultrasound, CT or MR) 
will be performed with each insertion to confirm correct positioning of the intrauterine 
applicator. Treatment planning (including estimation of doses to OARs) will be based on 


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pelvic CT and/or MR obtained after placement of the applicator. A conventional 2D dose 
prescription (ICRU 38 Point A) or optimized 3D volumetric planning (GEC-ESTRO 
recommendations or equivalent) will be allowed. The use of interstitial needles, in 
addition to an intrauterine/intra-vaginal applicator, is encouraged when required to 
assure optimal target coverage and dosimetric sparing of OARs. Treatment may be 
delivered using either a pulsed dose rate (PDR) or high dose rate (HDR) techniques. 
• Organs at risk (OAR) delineation for brachytherapy: The rectum, sigmoid, small bowel 
and bladder will be delineated in all patients using axial CT and/or MR images acquired 
after each brachytherapy applicator insertion. OAR delineation will conform to GEC-
ESTRO (or equivalent) recommendations. 
– Rectum: The outer rectal wall will be contoured from the anus to the level of the 
sigmoid flexure. 
– Sigmoid: The outer sigmoid wall will be contoured from where the rectum ends to the 
point of connection to the ascending colon laterally. Any sigmoid adjacent or above 
the uterus should be contoured. 
– Small bowel: The outer wall of individual small bowel loops within 3-4cm of the 
uterus or applicator will be contoured. 
– Bladder: The outer bladder wall in its entirety will be contoured. 
• Brachytherapy reporting requirements: The following brachytherapy technique and 
dosimetric parameters will be reported:  
– Brachytherapy technique (PDR, HDR) 
– Total brachytherapy dose and total number of fractions 
– The ICRU 38 rectal and bladder reference point doses for each treatment fraction 
– The absolute brachytherapy dose to the maximally irradiated 2 cm3 of rectum, 
sigmoid, bladder and small bowel (D2cm3) for each treatment fraction 
 
5.1.6 External Beam Pelvic Boost Radiotherapy for Residual Disease 
Further external beam radiotherapy may be used at the discretion of the responsible radiation 
oncologist to treat residual pelvic disease not amenable to brachytherapy after the initial five 
weeks of whole pelvis EBRT/cisplatin/AZD1775. This may include persistently enlarged pelvic 
lymph nodes in patients with newly diagnosed cervical, upper vaginal or endometrial cancer, or 
persistent central pelvic or pelvic sidewall disease in patients with recurrence of cervical or 
endometrial cancer. Highly conformal IMRT or VMAT plans are encouraged to minimize the 
dose to adjacent OARs and potential for acute and late toxicity. The planning target volume 
(PTV) should be adequate to account for inter- and intra-fractional target motion. 
• Organs at risk (OAR) delineation for external beam pelvic boost radiotherapy: OAR 
delineation for pelvic boost radiotherapy will adhere to the same guidelines as for whole 
pelvis EBRT: 
– Rectum: The outer rectal wall will be contoured from the anus to the level of the 
sigmoid flexure. 
– Sigmoid: The outer sigmoid wall will be contoured from where the rectum ends to the 
point of connection to the ascending colon laterally. Any sigmoid adjacent or above 
the uterus should be contoured. 
– Small bowel: The peritoneal cavity will be contoured from the axial CT/MR slice 1 


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33 
 
cm superior to the upper field border, and will continue to its most inferior extent in 
the pelvis. Individual loops of bowel should not be contoured separately. Rectum 
should be contoured separately from bowel. 
– Bladder: The outer bladder wall in its entirety will be contoured. 
• External beam pelvic boost radiotherapy dose reporting requirements:  
– External beam pelvic boost total dose and total number of fractions 
– The absolute rectum, sigmoid, small bowel and bladder volumes (cm3), and the 
percentages of the total delineated organ volumes, receiving ≥50% of the prescribed 
dose and ≥90% of the prescribed dose






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5.2 
Definition of Dose-Limiting Toxicity 
 
The dose limiting toxicity period will be considered from week 1 until the end of week 5 +7 
days upon completing the chemo-radiation portion of the treatment. All patients evaluable for 
toxicity will be assessed for DLT. The following treatment related toxicities will be considered 
Dose-Limiting Toxicities (DLTs)1 
 
5.2.1 Hematologic DLT 
 
• Grade 4 thrombocytopenia (platelet count <25 x 109/L) 
• Grade 3 thrombocytopenia (platelet count 25-49 x 109/L) with bleeding 
• Grade 3 Febrile neutropenia (ANC <1.0 x 109/L with a single temperature of >38.3º C 
or ANC <1.0 x 109/L with a sustained temperature of ≥38 ºC for more than one 
hour). 
 
5.2.2 Non-hematologic DLT 
 
• Grade 4 vomiting, or grade 3 vomiting if persistent for longer than 48 hours 
despite treatment with granisetron, ondansetron or an equivalent medication. 
• Grade 4 diarrhea, or grade 3 diarrhea if persistent for longer than 48 hours despite 
treatment with loperamide, diphenoxylate/atropine or an equivalent medication. 
• Grade 3 or 4 rash 
• Other grade 3 or 4 radiotherapy associated acute toxicity 
• Interruption of whole pelvis radiotherapy for more than 3 days due to acute treatment 
toxicity 
• Inability to receive at least 3 of the 5 planned doses of cisplatin 
• If the patient requires an omission longer than 1 week in the administration of 
AZD1775 and/or cisplatin 
• Any grade 3 or 4 non-hematological toxicity with the specific exception of: 
o Nausea, vomiting, diarrhea, or dehydration (all Grade 3) not optimally treated 
and/or lasts less than 48 hours. 
o Alopecia (of any grade) 
o Inadequately treated hypersensitivity reactions 
o Clinically non-significant, treatable or reversible lab abnormalities including, but 
not limited to liver function tests, uric acid, hypokalemia or hypomagnesemia. 
[Note: reversible G3 and G4 electrolyte disturbances will be considered those that 
improve, at least to G2, within 48h when optimally treated] 
 
 
1 An adverse event or any delay not related to the study medication will not be considered DLT 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. Dose escalation will proceed within each cohort according to Table 5-3.  Dose-
limiting toxicity (DLT) is defined above in Section 5.2. 
 
 


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Table 5-3: Dose escalation schema 
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose. Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. 
Once the provisional recommended phase 2 dose is 
found, 9-12* patients will be enrolled in the expansion 
cohort to confirm the safety of this dose. 
*The final number of patients evaluated at the 
recommended phase 2 dose will be 15: 
• If 3 patients have been previously enrolled during the 
dose escalation phase, 12 additional patients will be 
evaluated in the dose expansion phase 
• If 6 patients have been previously enrolled during the 
dose escalation phase, 9 additional patients will be 
enrolled in the dose escalation 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients will be followed jointly during treatment by medical and radiation oncologists. 
General supportive care will be provided in accordance with local institutional practice. Anti-
emetic and anti-diarrheal medications will be prescribed as clinically required. CBC, 
electrolytes, renal function studies and liver function studies will be done weekly prior to 
administration of cisplatin, as per routine practice. The Principal Investigator should be alerted 
if the patient is taking any agent known to affect QTcF prolongation. Appendix F presents 
guidelines for identifying medications/substances that could potentially interact with the study 
agent(s). 


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5.4 
Duration of therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue to 
completion of chemoradiation treatment or until one of the following criteria applies: 
• Disease progression (clinical or radiological) 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Dose limiting toxicity (see Section 5.2) 
• Patient decides to withdraw from the study, or 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
5.5 
Duration of follow up 
 
Once the treatment with AZD1775 is completed, patients will have an end of treatment visit 28 
days ± 7 days after their last dose of AZD1775. After that, they will be followed to evaluate 
toxicity or disease relapse every 4 months (± 2 weeks) for 2 years, until any of the criteria 
mentioned in section 5.6 apply. Patients removed from protocol therapy for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 
5.6 
Criteria for removal from study 
 
Patient will be removed from the study when any of the following criteria listed below applies: 
• Disease progression (clinical or radiological) 
• Patient death 
• Patient withdraws consent 
• 2-year follow up complete 
• Termination of study by Principal Investigator, Sponsor, or Regulatory Authorities 
 
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 
 
Doses of cisplatin and AZD1775 will be reduced for hematological and non-hematological 
toxicities. The NCI Clinical Trials Common Terminology Criteria for Adverse Events (CTCAE) 
will be used to grade toxicity (http://ctep.info.nih.gov/). 
 
6.1 
Dose delays/interruptions 
 
• No more than two AZD1775 or one cisplatin dose reduction for toxicity will be 
permitted. If the toxicity persists despite the reductions, the patient will be removed 
from the trial. 
• Patients will be removed from the protocol therapy for: 
• Any acute toxicity that persists despite two AZD1775 or one cisplatin dose reduction 


39 
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• Any acute toxicity requiring a delay in cisplatin, AZD1775 and/or radiotherapy > 2 weeks, 
unless approved by the Principal Investigator or Senior Protocol Investigator. 
• Any acute Grade 4 non-hematological toxicity 
• For electrolyte disturbances, patients will be discontinued if the electrolyte abnormality 
persists more than 48 hours despite optimal treatment 
• Patients removed from the trial because of acute toxicity will continue treatment for 
cervix cancer with either radiotherapy alone or RT-CT, at the discretion of the 
responsible medical and radiation oncologists. 
• RT is the primary therapeutic modality in this treatment regimen. There will be no 
delays or modifications to the planned course of radiotherapy except in exceptional 
circumstances, at the discretion of the treating radiation oncologist, where acute toxicity 
persists after appropriate cisplatin and/or AZD1775 dose reductions. For toxicity dose 
modifications, or delays, AZD1775 will be modified first, followed by cisplatin. 
Radiation will be maintained on schedule if possible. If a situation arises where dose 
modification or delay is necessary and not captured by the dose adjustment criteria, 
the decision on dose adjustment will be made by the Senior Scientific Investigator and 
Principal Investigator and documented. 
• In case of grade 3 non-hematological DLTs or any hematological DLTs, treatment 
could be resumed if the toxicity is resolved to: 
o Grade 2 if the DLT was radiotherapy-induced dermatitis. 
o Tolerable grade 2 (in areas not included in the radiotherapy volume) 
o Grade 1 or baseline for the remaining DLT toxicities 
The treatment will be resumed with appropriate dose reduction(s) of the study drugs as 
described in section 6.2 
• An exception would be made for the following grade 4 non-hematological toxicities, 
classically associated to cisplatin treatment after which cisplatin will be permanently 
discontinued, but AZD1775 could be resumed following the criteria in Table 6-9. 
o Grade 4 tinnitus 
o Grade 3 and 4 hearing loss 
o Grade 3 and 4 neurotoxicity 
• In case of hematological toxicities that do not fulfill DLT criteria, but require a delay 
on cisplatin treatment according to our administration guidelines (grade 3 neutropenia, 
grade 4 neutropenia less than 7 days, grade 1 or 2 thrombocytopenia or grade 3 
thrombocytopenia without bleeding), treatment with AZD1775 will be withheld. 
Treatment will be resumed if platelets are ≥100 x10e9/L and absolute neutrophil count is 
≥1.0 x10e9/L. 
• If a patient experiences several toxicities and there are conflicting recommendations, 
please use the recommended dose adjustment that reduces the dose to the lowest level. 
 
6.2 
Dose modifications 
 
6.2.1 AZD1775 dose levels 
 
 
 
 


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Table 6-1: AZD1775 dose levels  
Dose Level 
Dose* 
AZD1775   Week 1-5 (mg) 
Level -1 
100 mg, oral, QD day 3 and 5 of the week 
Level 1 
100 mg, oral, QD day 1, 3, 5 of the week 
Level 2 
150 mg, oral, QD day 1, 3, 5 of the week 
Level 3 
200 mg, oral, QD day 1, 3, 5 of the week 
Level 4 
200 mg, oral, QD day 1,2,3,4,5 of the week 
 
6.2.2 Cisplatin dose levels 
 
Table 6-2: Cisplatin dose levels 
 
Dose Level 
Cisplatin Dose 
Reduced dose 
30 mg/m2 
Standard dose 
40 mg/m2 
Note: the “Reduced dose” is one dose level below the “standard dose” 
 
6.2.3 Dose modifications for hematological toxicities 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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. 


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6.2.4 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
nagement 


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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. 
 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 
hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the 
GASTROINTESTINAL DISORDERS SOC. 
 
3Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
4Rash may include rash, erythema, eczema, and rash maculo-papular. 
 
5Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory neuropathy. 
 
6Acute kidney injury includes renal impairment and acute renal insufficiency. 
 
 
Adverse events reported on AZD1775 (adavosertib) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that AZD1775 (adavosertib) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (pancytopenia); Blood and lymphatic system disorders - Other (thrombocytosis); Blood and 
lymphatic system disorders - Other (right leg deep vein thrombosis); 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; Colonic obstruction; Dry mouth; Duodenal ulcer; Dysphagia; 
Enterocolitis; Flatulence; Gastric ulcer; Gastritis; Hemorrhoids; Oral pain; 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; GGT increased; Investigations - Other (blood urea 
increased); Lymphocyte count increased 




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Nausea, vomiting (100%) (early and delayed) 
I E 
Diarrhea 
E 
Hematological 
Hemolysis (Coombs positive) 
E 
Myelosupression +/- infection, bleeding (30%) 
E 
Thrombotic microangiopathy 
E 
Hemolytic uremic syndrome 
E 
Liver/Pancreas 
Increased amylase 
E 
Increased LFTs (transient, rare) 
E 
Metabolic/Endocrine 
Abnormal electrolytes 
(diminished K, Na, Ca, Mg, PO4) 
E 
Increased antidiuretic hormone 
E 
Hyperuricemia (36%) 
I E 
Musculoskeletal 
Muscle cramps 
E 
Neoplastic 
Leukemia (secondary) 
L 
Nervous System 
Dysgeusia 
E 
Neurotoxicity (peripheral, autonomic) 
D 
Other (dorsal column myelopathy-rare) 
D 
Seizure (rare) 
D 
Encephalopathy (rare) 
E D 
Ophthalmic 
Optic neuritis 
D 
Renal 
Nephrotoxicity (36%) 
I E 
Reproductive 
Infertility 
L 
Respiratory 
Hiccups 
E 
Vascular 
Peripheral ischemia (Raynaud’s syndrome-rare) 
D 
Vasculitis (cerebral arteritis-rare) 
E 
Hypersensitivity 
Hypersensitivity 
I 
Injection site 
Injection site reaction (rare) 
I 
I: Immediate; E: early; D: delayed; L: late From CCO monograph 
 
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. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined 


50 
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in section 7.1. 
 
• 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. 
 
7.3 
Expedited Adverse Event Reporting 
 
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 7.3.1). 
 
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. 
 
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.  Each site will submit the electronic version of the CTEP-AERS report to the 
PMH Consortium Central Office. Once review by the lead group coordinator has taken place the 
report will be forwarded to NCI.  CTEP-AERS provides a copy feature for other e-mail 
recipients. 
 
7.3.1 Expedited Reporting Guidelines  
 
Note: A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below. Attribution to treatment or other cause must be 
provided.  Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and administration site 
conditions. Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted. 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
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 Central Office within 3 working days 
from the date the event was known to the investigator. 


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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 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 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 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. 
 
 




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7.4 
Routine Adverse Event Reporting 
 
All Treatment Emergent Adverse Events (TEAEs) must be reported in routine study data 
submissions.  TEAEs reported through CTEP-AERS must also be reported in routine study data 
submissions. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiotherapy or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event: 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agent administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent 
 
8.1.1 AZD1775  
 
Chemical Name: 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[4-(4-methylpiperazin-1-
yl)anilino]pyrazolo[3,4-d]pyrimidin-3-one hemihydrate 
 
Other Names: MK-1775, Adavosertib 
 
Classification: inhibitor of Wee1-kinase 
 
CAS: 1277170-60-1 
 
Molecular Formula:    C27H32N8O2·0.5H2O M.W.: 500.6 


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Mode of Action: AZD1775 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, AZD1775 
selectively enhanced chemotherapy-induced death of cells deficient in p53 signaling. 
 
Description:  AZD1775 is a crystalline, hemihydrate form of the drug substance. 
 
How Supplied: AZD1775 is supplied by AstraZeneca and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI as capsules available in 25 mg (yellow color, size 2 
gelatin capsule) and 100 mg (orange color, size 2 gelatin capsule) strengths. 
 
 
 
 
 
The pharmaceutical collaborator does not have stability data to support repackaging AZD1775 
capsules in any container other than what is provided. 
 
Storage:  Store at 2 to 30˚C (36 to 86˚F).  Do not freeze. 
If a storage temperature excursion is identified, promptly return AZD1775 to between 2-30°C and 
quarantine the supplies.  Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability. 
 
Stability: Shelf life studies of AZD1775 are on-going. 
 
Route of Administration: Oral administration. Take AZD1775 two hours before a meal or two 
hours after a meal. Capsules should not be opened. 
 
Potential Drug Interactions: AZD1775 is primarily metabolized by CYP3A4 and is a weak, 
time-dependent inhibitor of CYP3A4. Avoid concomitant CYP3A4 moderate or strong 
inhibitors/inducers, and sensitive substrates with a narrow therapeutic index. AZD1775 is also 
a weak inhibitor of CYP2C19. Caution should be exercised with concomitant administration 
of sensitive substrates or substrates with a narrow therapeutic index. 
 
In vitro transporter studies have shown that AZD1775 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 could be altered if 
AZD1775 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 


55 
NCI 10132 / PHL-087  
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coadministered with AZD1775 and the use of atorvastatin is therefore prohibited. 
 
Contraindications: Treatment with AZD1775 is contraindicated in subjects with 
hypersensitivity to any component of the drug. Developmental and reproductive toxicity studies 
of AZD1775 have not been performed. AZD1775 is not to be given to women who are pregnant 
or breast feeding. Women of child-bearing potential participating in clinical studies of AZD1775 
must use appropriate contraception throughout the study including abstinence and double barrier 
methods throughout treatment. Refer to the specific protocol for more details about appropriate 
contraceptive methods and duration of use. 
 
Availability: AZD1775 is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI.  AZD1775 is provided to the NCI under a 
Collaborative Agreement between the Pharmaceutical Collaborator and the DCTD, NCI (see 
Section 12.2). 
 
8.1.2 Agent Ordering, Accountability, and Investigator Brochure Availability 
 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF). If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead investigator at that institution. 
In general, sites may order initial agent supplies when a subject is being screened for enrollment 
onto the study. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status and a “current” 
password.  For questions about drug orders, transfers, returns, or accountability, call or email 
PMB any time.  Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
Agent Inventory Records - The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final disposition of 
agent received from the PMB using the NCI Investigational Agent (Drug) Accountability Record 
Form (DARF) for Oral Agents available on the CTEP forms page.  Store and maintain separate 
NCI Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 


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Investigator Brochure Availability - The current versions of the IBs for the agents will be 
accessible to site investigators and research staff through the PMB Online Agent Order 
Processing (OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity 
and Access Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registration status.  Questions about IB access may be 
directed to the PMB IB coordinator via email. 
 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/ 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• IB Coordinator: IBCoordinator@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
8.2 
Cisplatin (NSC #119875) 
 
Cisplatin is an antineoplastic agent. Please refer to the product monograph for the information 
regarding possible side effects and instructions, regarding formulation, preparation, handling, 
dosing, shelf life and storage. It will be administered at a dose of 40 mg/m2 intravenously in 500 
mL of NS. The weekly dose should not exceed 70 mg. 
 
Product description: Commercially available supplies of cisplatin injection, 1 mg/mL. 
 
Solution preparation: Dilute in 500 mL Normal Saline. Also see product monograph. 
 
Route of administration:  Intravenous infusion over 1 hour. Give 500 mL NS hydration post- 
each weekly cisplatin 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
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. An exploratory analysis of WEE1 expression by immunohistochemistry (IHC) will 
be performed in the archival specimens of all patients. An exploratory evaluation of the 


57 
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following potential baseline predictors of response will be performed in the archival tissue if 
available: 
 
• Immunohistochemistry: p53, p21, p16, Rb 
• Molecular profiling using the Hi5 Panel (555 gene, including TP53 – CLIA lab Dr. 
Suzanne Kamel Reid) which includes the most relevant genes involved in the 
pathogenesis of these types of cancer (Appendix F) 
• PCR–RFLP for detection and typing of HPV DNA 
 
Please note that if blocks are provided, they will be returned to the sender at the end of the study. 
 
If no tissue is available for this analysis, the baseline biopsy (optional) will be used for the 
evaluation of these biomarkers (see priority of determination in Table 9-1 at the end of this 
section) 
 
9.2 
Pre- and on-Treatment Fresh Tumor Tissues 
 
Fresh tumor tissues will be collected on 2 occasions only if there is no medical 
contraindication: 
 
• Within 2 weeks prior to day 1 (Biopsy # 1)  
• On day 2-5 post first dose of AZD1775 administered in week 1 or 2 (Biopsy # 2)  
 
Fresh tumor biopsies are optional. Inability to obtain fresh tumor biopsies will not render the 
patient ineligible to participate in the study. 
 
Tru-cut biopsy or 14-gauge (or institutional standard) core biopsy should be performed using 
standard surgical techniques.  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 is as follows: 
 
1. One to two core specimen(s) should be immediately immersed in formalin for 
fixation and then paraffin-embedded. The following evaluations will be 
performed at the STTARR Spatio Temporal Targeting Lab. 
a) 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 Definitens 
Tissue Studio 3.5 semi-automatic 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. 


58 
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Note: Stability of analytes in FFPE 
Protocols for histological staining of all of the proposed markers (apart from 
WEE1 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. 
 
The following exploratory biomarkers will be assessed, but not limited to: 
• WEE1 expression (baseline sample) 
• pCDC2 to evaluate target engagement (baseline and on-treatment sample) 
• Ki67 to investigate changes in proliferation (baseline and on-
treatment sample) 
• γH2AX to evaluate ds DNA damage (baseline and on-treatment sample) 
• phospho-histone H3 (pH3) to delineate specific activity in S-phase vs 
at G2/M1 checkpoint (baseline and on-treatment biopsy) 
• Cleaved caspase-3 (CC3) to evaluate apoptosis (baseline and on-
treatment biopsy) 
b) 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 if patient agrees for biopsy and tissue 
is available. 
 
2. 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, the 
following evaluations will be performed in these samples: 
• PCR–RFLP for detection and typing of HPV DNA (baseline) 
 
3. In the expansion cohort one core 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 AZD1775 levels in the fresh biopsy on 
treatment will be performed. Based on the availability of tissue, the biomarker 
evaluation will be performed according to the priority established in Table 9-1: 
 
Table 9-1: Priority for correlative studies based on tissue availability 
Priority 
Assay 
Sample 
1 
WEE1, pCDC2 and γH2AX expression 
FFPE (paired) 
2 
Hi5 Panel molecular profiling 
FFPE (archival)* 
3 
pH3 and CC3 expression 
FFPE (paired) 
4 
p53, p21, p16 and Rb expression 
FFPE (archival)* 


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5 
HPV DNA determination 
FFPE archival* 
*If no tissue available in the archival tissue, the analysis will be performed on the baseline 
biopsy: p53, p21, p16, and Rb on FFPE and p53 sequencing on fresh frozen. 
 
9.2.1 Sample Shipment 
 
Archival samples, paraffin-embedded samples and fresh frozen biopsy for biomarker 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 and paraffin-embedded samples should be sent at ambient temperature. Both 
kinds of specimens should be shipped to the Princess Margaret Cancer Centre Consortium at 
the Princess Margaret Cancer Centre (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 and fresh tumor specimens should be shipped to:  
Vanessa Speers 
Correlative Studies Program  
Princess Margaret Cancer Centre 
610 University Avenue, Rm 7-420  
Toronto, Ontario M5G 2M9  
Tel: (416) 946-4501 ext 5047 
Fax: (416) 946-4431 
Email:  Vanessa.Speers@uhn.ca 


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10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 21 days prior to day 1, unless otherwise 
indicated.  Scans and x-rays must be done <28 days prior to the start of therapy (day1).  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. All assessments can be performed 
up to 2 days in advance of the calendar specified timepoint. 
 
 
Pre- 
Study 
 
D1 
 
D8 
 
D15 
 
D22 
 
D29 
 
D36-43 
(+12d window) 
 
End of Treatment 
(28±7 days after last 
dose of AZD1775) 
 
Follow-up k 
 
 
Off Study 
AZD1775a 
 
X-------------------------------X a 
 
 
 
 
Cisplatin b 
 
X-------------------------------X b 
 
 
 
 
Radiotherapy c 
 
X-------------------------------X c 
X c 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X-------------------------------------------------------------------------------------------X  
 
Physical exam 
X 
X l 
X 
X 
X 
X 
 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
ECOG Performance Status 
X 
X l 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
CBC w/diff, plts d 
X 
X l 
X 
X 
X 
X 
Xn 
X 
X 
X 
Serum chemistry d,e 
X 
X l 
X 
X 
X 
X 
Xn 
X 
X 
X 
Creatinine clearance p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation tests d 
X 
 
 
 
 
 
 
 
 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
Adverse event evaluation d 
 
X-------------------------------------------------------------------------------------------X 
X 
Tumor measurements f 
 
X 
 
 
 
 
 
 
X 
Xh 
 
X 
Chest CT, CT abdomen/pelvis, MR 
pelvis d 
X 
 
 
 
 
 
 
X 
Xh 
X 
Vaginal Examd 
X 
 
 
 
 
 
 
 
 
 
B-HCG i 
X 
 
 
 
 
 
 
 
 
 
Archival tissue collection o 
X 
 
 
 
 
 
 
 
 
 
Optional Tumor biopsy 
Xj 
Xj 
 
 
 
 
 
 
 
Assessment for Disease Progression q 
 
 
 
 
 
 
 
X 
X 


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a: AZD1775: as per dose level and schedule.  Refer to Table 5-1 and Section 5.1.1 
b: Cisplatin: 40 mg/m2 IV administered over 1 hour, starting on Day 1 or 3, then weekly for a total of 5 consecutive weeks during radiotherapy. Refer to 
Table 5-1 and Section 5.1.2 
c: Radiotherapy: 45-50 Gy external beam pelvic radiotherapy in 25 fractions, followed by brachytherapy. Refer to Table 5-1 and Section 5.1.3 
d: Routine investigations for all patients with cervix cancer, uterine cancer and vaginal cancer, regardless of study participation 
e: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium. 
f: RECIST 1.1 measurements to be done using the same imaging modality for all scans at pre-study, end of treatment, 4 months after completion of 
radiation therapy and if patients come off study within 4 months after planned treatment. 
g: To be repeated in the off-study visit in those patients with cardiac history or with clinically significant alterations in the baseline ECG. 
h: Tumor measurements will be performed at radiological assessment 4 months after completion of radiotherapy. Follow-up imaging can be performed 
at other time points at the discretion of local investigator or standard of care at local practice. Documentation (radiologic) must be provided for 
patients removed from study for progressive disease. 
i: Serum pregnancy test (women of childbearing potential). 
j: Optional Tumor biopsy will be performed within 2 weeks prior to day 1 and on week 1 or 2 of treatment. Refer to Section 9.2 and Table 9-1 
k: Follow up assessments: every 4 months ±15 days after the End of Treatment visit, up to 2 years. 
l: If completed within 7 days prior to day 1 it does not need to be repeated on day 1. 
m : Only for patients who do not already have radiologically documented progression. 
n: Safety blood work assessment will be performed before starting brachytherapy. 
o: Collection of primary archival tissue block will be initiated at baseline. 
p: Creatinine clearance will be calculated by the Cockcroft-Gault method. 
q: Can be documented clinically or radiologically as per local investigator discretion.  
 
 
 


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11. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, response rate and progression free 
survival are secondary endpoints. Patients with measurable disease will be assessed by standard 
criteria. For the purposes of this study, patients should be re-evaluated on every 4 months (± 15 
days) of the post-treatment period for 2 years. 
 
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. 
 
11.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with AZD1775, radiotherapy or cisplatin. 
 
Evaluable for objective response. The patients will be assessed for response according to the 
local investigator.   
 
11.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray 
or as ≥10 mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
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 


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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, which can be measured reproducibly should be selected. 
A sum of the diameters (longest for non- nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up. 
 
11.1.3 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. 
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable. 
 
Conventional CT and MRI This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 


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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. 
 
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response. 
 
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 
 
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. 
 


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Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
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). 
 
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 
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 


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Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** 
 As response rate is not the primary endpoint of the study, no 
confirmatory imaging evaluation is required. 
*** 
 In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration.”  Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of response will be assessed in patients with measurable disease. 
 
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 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 


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whichever occurs first. Patients without an event will be censored at the end of 2 year follow-up. 
 
12. STUDY OVERSIGHT AND 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 
Study Oversight 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, the Protocol Principal Investigator will have at least monthly, or more frequently, 
conference calls with the Study Investigators and the CTEP Medical Officer(s) to review accrual, 
progress, and adverse events and unanticipated problems.   
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
12.2.1 Method 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA, Lab Admin, SLA or Site Investigator) on 
either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA 
role or CRA Lab Admin role, the user must hold a minimum of an AP registration type.  To hold 
the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR.  
Associates can hold read-only roles in Rave. 


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Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 799-7580 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 


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from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 
unique study requirements.  The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation.  CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
 
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. 
 


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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 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) 


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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 
 
13.1.1 Primary Objectives 
 
To determine the recommended phase II dose (RP2D) and safety profile of AZD1775 in 
combination with radiotherapy and concurrent cisplatin patients with gynecological cancer 
(phase I). 
 
The proportion of patients who experience DLT will be recorded for all patients in dose 
escalation and dose expansion. Because toxicities can be cumulative, the proportion of patients 
evaluable for toxicity requiring treatment discontinuation or dose reduction/interruption at any 
time through the duration of therapy will also be recorded. 
 
The first dose level will be level 1. If 1/3 patients encounter a dose-limiting toxicity (DLT), 
then a cohort will be expanded to 6 patients. If > 2/3 of patients encounters DLT, then that 
dose level will be declared excessively toxic. A total of 6 patients will be entered into the 
previous dose level. The recommended phase II dose (RPTD; also called the MTD) is defined as 
the dose level with < 1/6 patients with DLT. 
 
13.1.2 Secondary Objectives 
 
• To evaluate the pharmacodynamic effects of AZD1775 drugs when administered in 
combination with radiotherapy and concurrent cisplatin (in particular, for the 15 patients 
treated in an expansion cohort at the RP2D). Pharmacodynamic biomarkers will include: 
pCDC2, Ki67, γH2AX, pH3, and CC3. 
• To obtain preliminary information about the progression–free survival of AZD1775 in 
combination with radiotherapy and concurrent cisplatin in women with locally 
advanced gynecological cancer. 


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• To determine the acute and late toxicity of AZD1775 when administered to patients 
with gynecological cancer in combination with radiotherapy and concurrent cisplatin. 
 
13.2 
Sample Size/Accrual Rate 
 
A minimum of 9 patients and a maximum of 33 will be enrolled in this phase I study. A 
maximum of 24 patients for initial dose finding part and additional 9-12 patients for the 
expansion cohort will be enrolled. We estimate accrual as follows: 1-2 patients for dose finding 
per month and 1-2 patients for expansion cohort per month. Estimated study duration is 20- 
24 months. 
 
13.3 
Analysis of Secondary Endpoints 
 
13.3.1 Clinical Endpoints 
 
Summary statistics, such as the mean, median, counts and proportion, will be used to 
describe patients’ clinical characteristics. Objective response to treatment will be assessed 
according to local investigator. 
 
Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional 
hazards regression and/or generalized estimating equations as appropriate. Potential 
predictors include clinical predictors and molecular correlates. Descriptive statistics and 
plotting of data will also be used to better understand potential relationships. 
 
Frequency and severity of adverse events will be tabulated using counts and proportions 
detailing frequently occurring, serious and severe events of interest. Adverse events will be 
summarized using all adverse events experienced, although a subanalysis may be conducted 
including only those adverse events in which the treating physician deems possibly, 
probably or definitely attributable to one or both study treatments.  
 
All analyses will be considered exploratory and inference will be performed with appropriate 
caution. For all statistical tests, two-sided tests will be performed and no p- value adjustment 
performed due to the exploratory nature of these tests. A p-value of 0.05 or less will be 
considered statistically significant. 
 
 


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cisplatin and definitive radiotherapy in untreated patients with locally advanced squamous cell 
cervical carcinoma--Final report of a phase II trial, ASCO Annual Meeting Proceedings, 2011, 
pp 5033 
 
30. 
Dalrymple JL, Russell AH, Lee SW, et al: Chemoradiation for primary invasive 
squamous carcinoma of the vagina. Int J Gynecol Cancer 14:110-7, 2004 
 
31. 
Wang Y, Li J, Booher RN, et al: Radiosensitization of p53 mutant cells by 
PD0166285, a novel G(2) checkpoint abrogator. Cancer Res 61:8211-7, 2001 
 
32. 
Sorensen CS, Syljuasen RG: Safeguarding genome integrity: the checkpoint 
kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic 
Acids Res 40:477-86, 2012 
 
33. 
Kuerbitz SJ, Plunkett BS, Walsh WV, et al: Wild-type p53 is a cell cycle 
checkpoint determinant following irradiation. Proceedings of the National Academy of Sciences 


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89:7491-7495, 1992 
 
34. 
Bridges KA, Hirai H, Buser CA, et al: MK-1775, a novel Wee1 kinase inhibitor, 
radiosensitizes p53-defective human tumor cells. Clin Cancer Res 17:5638-48, 2011 
 
35. 
Cooper B, Schneider S, Bohl J, et al: Requirement of E6AP and the features of 
human papillomavirus E6 necessary to support degradation of p53. Virology 306:87-99, 2003 
 
36. 
Nuber U, Schwarz SE, Scheffner M: The ubiquitin-protein ligase E6-associated 
protein (E6-AP) serves as its own substrate. Eur J Biochem 254:643-9, 1998 
 
37. 
Milner J, Medcalf EA, Cook AC: Tumor suppressor p53: analysis of wild-type 
and mutant p53 complexes. Mol Cell Biol 11:12-9, 1991 
 
38. 
Baalbergen A, Ewing-Graham PC, Eijkemans MJ, et al: Prognosis of 
adenocarcinoma of the uterine cervix: p53 expression correlates with higher incidence of 
mortality. Int J Cancer 121:106-10, 2007 
 
39. 
Ikuta A, Saito J, Mizokami T, et al: Correlation p53 expression and human 
papilloma virus deoxyribonucleic acid with clinical outcome in early uterine cervical carcinoma. 
Cancer Detect Prev 29:528-36, 2005 
 
40. 
Holm R, Skomedal H, Helland A, et al: Immunohistochemical analysis of p53 
protein overexpression in normal, premalignant, and malignant tissues of the cervix uteri. J 
Pathol 169:21-6, 1993 
 
41. 
Moon A, Won KY, Lee JY, et al: Expression of BDNF, TrkB, and p53 in early-
stage squamous cell carcinoma of the uterine cervix. Pathology 43:453-8, 2011 
 
42. 
Park CS, Joo IS, Song SY, et al: An immunohistochemical analysis of heat shock 
protein 70, p53, and estrogen receptor status in carcinoma of the uterine cervix. Gynecol Oncol 
74:53-60, 1999 
 
43. 
Iorns E, Lord CJ, Grigoriadis A, et al: Integrated functional, gene expression and 
genomic analysis for the identification of cancer targets. PLoS One 4:e5120, 2009 
 
44. 
Wang Y, Decker SJ, Sebolt-Leopold J: Knockdown of Chk1, Wee1 and Myt1 by 
RNA interference abrogates G2 checkpoint and induces apoptosis. Cancer Biol Ther 3:305-13, 
2004 
 
45. 
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 
 
46. 
Pronin SM, Novikova OV, Andreeva JY, et al: Fertility-Sparing Treatment of 
Early Endometrial Cancer and Complex Atypical Hyperplasia in Young Women of Childbearing 
Potential. Int J Gynecol Cancer 25:1010-4, 2015 
 
47. 
Petitjean A, Achatz MI, Borresen-Dale AL, et al: TP53 mutations in human 
cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26:2157-
65, 2007 
 
48. 
Schwarz JK, Siegel BA, Dehdashti F, et al: Association of posttherapy positron 
emission tomography with tumor response and survival in cervical carcinoma. Jama 298:2289-
2295, 2007 
 
49. 
Siva S, Herschtal A, Thomas JM, et al: Impact of post‐therapy positron emission 
tomography on prognostic stratification and surveillance after chemoradiotherapy for cervical 
cancer. Cancer 117:3981-3988, 2011 
 
50. 
Schwarz JK, Siegel BA, Dehdashti F, et al: Metabolic response on post-therapy 
FDG-PET predicts patterns of failure after radiotherapy for cervical cancer. International Journal 
of Radiation Oncology* Biology* Physics 83:185-190, 2012 


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51. 
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 
 
52. 
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 
 
53. 
Domínguez-Kelly R, Martín Y, Koundrioukoff S, et al: Wee1 controls genomic 
stability during replication by regulating the Mus81-Eme1 endonuclease. The Journal of cell 
biology 194:567-579, 2011 
 
54. 
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, 
ASCO Annual Meeting Proceedings, 2011, pp 3068 
 
55. 
Rowan S, Ludwig R, Haupt Y, et al: Specific loss of apoptotic but not cell-cycle 
arrest function in a human tumor derived p53 mutant. The EMBO journal 15:827, 1996 
 
56. 
Manning AL, Dyson NJ: pRB, a tumor suppressor with a stabilizing presence. 
Trends in cell biology 21:433-441, 2011 
 
57. 
Munger K, Basile JR, Duensing S, et al: Biological activities and molecular 
targets of the human papillomavirus E7 oncoprotein. Oncogene 20:7888-7898, 2001 
 
58. 
Lambert APF, Anschau F, Schmitt VM: p16 INK4A expression in cervical 
premalignant and malignant lesions. Experimental and molecular pathology 80:192-196, 2006 
 
59. 
Agoff SN, Lin P, Morihara J, et al: p16INK4a expression correlates with degree 
of cervical neoplasia: a comparison with Ki-67 expression and detection of high-risk HPV types. 
Modern pathology 16:665-673, 2003 
 
60. 
Andersson S, Hansson B, Norman I, et al: Expression of E6/E7 mRNA from'high 
risk'human papillomavirus in relation to CIN grade, viral load and p16INK4a. International 
journal of oncology 29:705-712, 2006 
 
61. 
Masumoto N, Fujii T, Ishikawa M, et al: p16 INK4a overexpression and human 
papillomavirus infection in small cell carcinoma of the uterine cervix. Human pathology 34:778-
783, 2003 
 
62. 
von Knebel Doeberitz M: Searching for new biomarkers for cervical cancer: 
molecular accidents and the interplay of papillomavirus oncogenes and epithelial differentiation-
Part 1. Papillomavirus Report 13:35-41, 2002 
 
63. 
Peiro G, Peiro FM, Ortiz-Martinez F, et al: Association of mammalian target of 
rapamycin with aggressive type II endometrial carcinomas and poor outcome: a potential target 
treatment. Hum Pathol 44:218-25, 2013 
 
64. 
Kong D, Suzuki A, Zou TT, et al: PTEN1 is frequently mutated in primary 
endometrial carcinomas. Nat Genet 17:143-4, 1997 
 
65. 
Minaguchi T, Yoshikawa H, Oda K, et al: PTEN mutation located only outside 
exons 5, 6, and 7 is an independent predictor of favorable survival in endometrial carcinomas. 
Clin Cancer Res 7:2636-42, 2001 
 
66. 
Rash may include rash, erythema, eczema, and rash maculo-papular.,  
 
67. 
Peripheral neuropathy includes both peripheral motor neuropathy and peripheral 
sensory neuropathy.,  


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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 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
 
INFORMATION FOR PATIENTS, THEIR CAREGIVERS AND NON-STUDY 
HEALTHCARE TEAM ON POSSIBLE INTERACTIONS WITH OTHER DRUGS AND 
HERBAL SUPPLEMENTS 
 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to the 
patient at the time of enrollment. Use or modify the text as appropriate for the study agent, so 
that the patient is aware of the risks and can communicate with their regular prescriber(s) 
and pharmacist.  A convenient wallet-sized information card is also included for the patient 
to clip out and retain at all times. If you choose to use them, please note that the information 
sheet and wallet card will require IRB approval before distribution to patients.] 
 
 
The patient 
is enrolled on a clinical trial using the 
experimental study drug AZD1775.  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. 
 
THESE ARE THE THINGS THAT YOU AS A PRESCRIBER NEED TO KNOW: 
 
AZD1775 interacts with certain specific enzymes in the liver and certain transport proteins 
that help move drugs in and out of cells. 
 
• The enzymes in question are CYP 3A4 and 2C19. AZD1775 is metabolized by 
CYP3A4 and may be affected by other drugs that inhibit or induce these enzymes. 
AZD1775 is an inhibitor of CYP 3A4 and 2C19 and may affect the metabolism of 
other drugs. 
• The proteins in question are OATP1B1, OATP1B3, MATE1, MATE2K, P-gp, and 
BCRP. AZD1775 is a substrate of P-gp and BCRP and may be affected by other 
drugs that inhibit or induce these transporters.  AZD1775 is an inhibitor of OATP1B1, 
OATP1B3, MATE1, MATE2K, P-gp, and BCRP and may affect transport of other 
drugs in and out of cells. 
 
TO THE PATIENT: TAKE THIS PAPER WITH YOU TO YOUR MEDICAL 
APPOINTMENTS AND KEEP THE ATTACHED INFORMATION CARD IN YOUR 
WALLET. 
 
AZD1775 may interact with other drugs which can cause side effects.  For this reason, it is 
very important to tell your study doctors of any medicines you are taking before you enroll 
onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  
When you talk about your current medications with your doctors, remember the following: 




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APPENDIX C 
DATA MANAGEMENT GUIDELINES 
 
Case Report Form Submission Schedule 
 
Data required for the study will be collected in Case Report Forms provided by the PMH 
Consortium Central Office.  The site will be required to complete a paper Registration 
Checklist 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 2 weeks of on study date 
On Treatment (Cycle) eCRFs 
Within 7 days of each visit 
Off Treatment eCRFs 
Within 2 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 PMH 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 
 
Refer to Section 12.1 of the protocol 
 
 


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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 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 
Central Office. 
• All investigators must have an up-to-date CV (signed within 2 years) on file with 
the 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 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 
Central Office. 
• A completed Site Participant List/Training Log is required and must be submitted 
to the Central Office 
• Continuing approval will be obtained at least yearly until follow-up on patients 
is completed and no further data is being obtained for research purposes. 
 




















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APPENDIX E  
HI5 PANEL 
 
Somatic Mutation Genes (555) 
ABL1 
CCND1 
EPHA5 
GNA11 
LPP 
NOTCH1 
RAD21 
SUZ12 
ABL2 
CCND2 
EPHA7 
GNA13 
LRP1B 
NOTCH2 
RAD50 
SYK 
ACTG1 
CCND3 
EPHB1 
GNAI3 
LTF 
NOTCH4 
RAD51 
SYNE1 
ACVR2A 
CCNE1 
EPHB4 
GNAQ 
LTK 
NPM1 
RAD51C 
SYT1 
ADAMTS20 
CD74 
EPHB6 
GNAS 
MAF 
NRAS 
RAD51D 
TAF1 
AFF1 
CD79A 
ERBB2 
GPR124 
MAFB 
NSD1 
RAF1 
TAF1L 
AFF3 
CD79B 
ERBB3 
GPS2 
MAGEA1 
NTRK1 
RALGDS 
TAL1 
AKAP9 
CDC73 
ERBB4 
GRIN2A 
MAGI1 
NTRK2 
RARA 
TBX22 
AKT1 
CDH1 
ERCC1 
GRM8 
MALT1 
NTRK3 
RB1 
TCF12 
AKT2 
CDH11 
ERCC2 
GSK3B 
MAML2 
NUMA1 
RBM15 
TCF3 
AKT3 
CDH2 
ERCC3 
GUCY1A2 
MAP2K1 
NUP214 
RECQL4 
TCF7L1 
ALK 
CDH20 
ERCC4 
HCAR1 
MAP2K2 
NUP93 
REL 
TCF7L2 
AMER1 
CDH23 
ERCC5 
HGF 
MAP2K4 
NUP98 
RET 
TCL1A 
ANKRD24 
CDH5 
ERG 
HIF1A 
MAP3K1 
PAK3 
RHOH 
TERT 
APC 
CDK12 
ESR1 
HIST1H1E 
MAP3K7 
PALB2 
RICTOR 
TET1 
AR 
CDK4 
ETS1 
HLF 
MAPK1 
PARP1 
RNASEL 
TET2 
ARAF 
CDK6 
ETV1 
HNF1A 
MAPK8 
PAX3 
RNF2 
TFE3 
ARFGAP3 
CDK8 
ETV4 
HNRNPK 
MARK1 
PAX5 
RNF213 
TGFB1 
ARFRP1 
CDKN1B 
ETV5 
HOOK3 
MARK4 
PAX7 
RNF43 
TGFBR2 
ARID1A 
CDKN2A 
ETV6 
HOXB13 
MBD1 
PAX8 
ROS1 
TGM7 
ARID2 
CDKN2B 
EWSR1 
HRAS 
MCL1 
PBRM1 
RPL22 
THBS1 
ARNT 
CDKN2C 
EXT1 
HSP90AA1 
MDM2 
PBX1 
RPN1 
TIMP3 
ASPSCR1 
CEBPA 
EXT2 
HSP90AB1 
MDM4 
PCDHAC2 
RPS6KA2 
TLR2 
ASXL1 
CHEK1 
EZH2 
ICK 
MECOM 
PDE4DIP 
RPTOR 
TLR4 
ATF1 
CHEK2 
EZR 
ID3 
MED12 
PDGFB 
RRM1 
TLX1 
ATM 
CHIC2 
FAM175A 
IDH1 
MEF2B 
PDGFRA 
RUNX1 
TMEM216 
ATR 
CIC 
FAM46C 
IDH2 
MEN1 
PDGFRB 
RUNX1T1 
TMPRSS2 
ATRX 
CKS1B 
FAM5C 
IGF1R 
MET 
PDK1 
SAMD9 
TNFAIP3 
AURKA 
CMPK1 
FANCA 
IGF2 
MITF 
PER1 
SBDS 
TNFRSF14 
AURKB 
COL1A1 
FANCC 
IGF2R 
MKL1 
PGAP3 
SDHA 
TNK2 
AURKC 
CRBN 
FANCD2 
IKBKB 
MLF1 
PHF6 
SDHB 
TOP1 
AXL 
CREB1 
FANCE 
IKBKE 
MLH1 
PHLPP2 
SDHC 
TP53 
B2M 
CREB3L2 
FANCF 
IKZF1 
MLH3 
PHOX2B 
SDHD 
TPM3 
BAI3 
CREBBP 
FANCG 
IL2 
MLLT1 
PIK3C2B 
SEPT9 
TPR 
BAP1 
CRKL 
FANCL 
IL21R 
MLLT10 
PIK3C3 
SETBP1 
TRAF3 
BARD1 
CRLF2 
FAS 
IL3 
MLLT3 
PIK3CA 
SETD2 
TRIM24 
BCL10 
CRTC1 
FBXW7 
IL6ST 
MLLT4 
PIK3CB 
SF3B1 
TRIM33 
BCL11A 
CSF1R 
FGF10 
IL7R 
MMP2 
PIK3CD 
SGK1 
TRIP11 
BCL11B 
CSF3R 
FGF14 
ING4 
MN1 
PIK3CG 
SH2B3 
TRRAP 
BCL2 
CSMD3 
FGF19 
INHBA 
MNX1 
PIK3R1 
SH2D1A 
TSC1 
BCL2L1 
CSNK2B 
FGF23 
INPP4B 
MPL 
PIK3R2 
SMAD2 
TSC2 


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BCL2L2 
CTCF 
FGF3 
IRF4 
MRE11A 
PIM1 
SMAD4 
TSHR 
BCL3 
CTDNEP1 
FGF4 
IRF8 
MSH2 
PKD1L2 
SMARCA4 
TYK2 
BCL6 
CTNNA1 
FGF6 
IRS2 
MSH6 
PKHD1 
SMARCB1 
U2AF1 
BCL9 
CTNNB1 
FGFR1 
ITGA10 
MTOR 
PLAG1 
SMC1A 
UBR5 
BCOR 
CUL3 
FGFR2 
ITGA9 
MTR 
PLCG1 
SMC3 
UGT1A1 
BCORL1 
CYLD 
FGFR3 
ITGB2 
MTRR 
PLCG2 
SMO 
UMODL1 
BCR 
CYP2C19 
FGFR4 
ITGB3 
MUC1 
PLEKHG5 
SMUG1 
USP9X 
BIRC2 
CYP2D6 
FH 
JAK1 
MUTYH 
PML 
SNX31 
VHL 
BIRC3 
DAXX 
FIP1L1 
JAK2 
MYB 
PMS1 
SOCS1 
WAS 
BIRC5 
DCC 
FLCN 
JAK3 
MYC 
PMS2 
SOCS3 
WHSC1 
BLM 
DDB2 
FLI1 
JUN 
MYCL 
POT1 
SOX10 
WISP3 
BLNK 
DDIT3 
FLT1 
KAT6A 
MYCN 
POU5F1 
SOX11 
WRN 
BMPR1A 
DDR2 
FLT3 
KAT6B 
MYD88 
PPARG 
SOX2 
WT1 
BOD1L1 
DDX3X 
FLT4 
KDM5A 
MYH11 
PPP2R1A 
SP140 
XPA 
BRAF 
DEK 
FN1 
KDM5C 
MYH9 
PPP6C 
SPEN 
XPC 
BRCA1 
DICER1 
FOXA1 
KDM6A 
NBN 
PRCC 
SPI1 
XPO1 
BRCA2 
DIS3 
FOXL2 
KDR 
NCOA1 
PRDM1 
SPOP 
XRCC2 
BRD3 
DNAH9 
FOXO1 
KEAP1 
NCOA2 
PRDM16 
SRC 
ZMYM2 
BRIP1 
DNMT3A 
FOXO3 
KIT 
NCOA4 
PREX2 
SRSF2 
ZNF217 
BTK 
DOT1L 
FOXP1 
KLF6 
NCOR2 
PRKAR1A 
SS18L1 
ZNF384 
BUB1B 
DPYD 
FOXP4 
KLHL6 
NF1 
PRKDC 
SSX1 
ZNF521 
C11orf30 
DST 
FUS 
KMT2A 
NF2 
PSIP1 
SSX2 
ZNF703 
CACNA1E 
EGFR 
FZR1 
KMT2C 
NFE2L2 
PTCH1 
SSX4 
ZRSR2 
CALR 
EGR1 
G6PD 
KMT2D 
NFKB1 
PTEN 
STAG2 
ZSWIM4 
CARD11 
EML4 
GATA1 
KRAS 
NFKB2 
PTGS2 
STAT3 
CASC5 
EP300 
GATA2 
LAMP1 
NFKBIA 
PTPN11 
STAT4 
CASP8 
EP400 
GATA3 
LCK 
NIN 
PTPRD 
STK11 
CBFB 
EPCAM 
GDNF 
LIFR 
NKX2-1 
PTPRT 
STK36 
CBL 
EPHA3 
GID4 
LPHN3 
NLRP1 
RAC1 
SUFU 
 
 
Translocation genes (78) 
ABL1 
CCND1 
ETV6 
IL3 
MLLT3 
PBX1 
ROS1 
TFE3 
AFF1 
CD74 
EWSR1 
MAF 
MLLT4 
PDGFB 
RPN1 
TMPRSS2 
ALK 
CHIC2 
EZR 
MALT1 
MNX1 
PDGFRA 
RUNX1 
TPM3 
ASPSCR1 COL1A1 
FGFR1 
MAML2 
MYC 
PDGFRB 
RUNX1T1 WT1 
ATF1 
CREB3L2 FGFR3 
MECOM 
MYH11 
PML 
SS18L1 
ZMYM2 
BCL2 
CRTC1 
FIP1L1 
MKL1 
NPM1 
PPARG 
SSX1 
IGL 
BCL6 
DDIT3 
FLI1 
MLF1 
NUP214 
PRCC 
SSX2 
IGK 
BCR 
DEK 
FOXO1 
MLL 
PAX3 
PRDM16 
SSX4 
IGH 
BIRC3 
EML4 
FUS 
MLLT1 
PAX7 
RARA 
SYT1 
CBFB 
ERG 
HLF 
MLLT10 
PAX8 
RBM15 
TCF3 
 


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APPENDIX F  
TABLE OF DRUGS WITH A KNOWN RISK OF QT 
PROLONGATION/ TORSADES DE POINTES 
 
 
Amiodarone 
Ibutilide 
Anagrelide 
Levofloxacin 
Arsenic trioxide 
Levomepromazine  
Astemizole  
Levomethadyl acetate  
Azithromycin 
Levosulpiride  
Bepridil  
Mesoridazine  
Chloroquine 
Methadone 
Chlorpromazine 
Moxifloxacin 
Cilostazol 
Ondansetron 
Ciprofloxacin 
Oxaliplatin 
Cisapride  
Papaverine HCl (Intra-
coronary) 
Citalopram 
Pentamidine 
Clarithromycin 
Pimozide 
Cocaine 
Probucol  
Disopyramide 
Procainamide 
Dofetilide 
Propofol 
Domperidone 
Quinidine 
Donepezil 
Roxithromycin  
Dronedarone 
Sevoflurane 
Droperidol 
Sotalol 
Erythromycin 
Sparfloxacin  
Escitalopram 
Sulpiride  
Flecainide 
Sultopride  
Fluconazole 
Terfenadine  
Gatifloxacin  
Terlipressin  
Grepafloxacin  
Terodiline  
Halofantrine  
Thioridazine 
Haloperidol 
Vandetanib 
Ibogaine  
 
 
 
NOTE: The table above may not be exhaustive, and investigators should refer to a frequently 
updated medical reference for the most current information. This list was obtained from 
www.crediblemeds.org and accessed on 09Jun2017.