Conditions: Adenocarcinoma of the Pancreas
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
The investigators' long-term goal is to improve the survival of patients with pancreatic cancer by enhancing the efficacy of gemcitabine-radiation by adding the Wee1 inhibitor MK-1775.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: MK-1775 intervention 2: Gemcitabine intervention 3: Radiation Therapy
Intervention descriptions: intervention 1: MK-1775 will be given as an oral capsule on days 1 and 2, and on days 8 and 9 of every 3-week cycle . intervention 2: Gemcitabine 1000mg/m2 will be infused over 30 minutes on days 1 and 8 of a 3 -week treatment cycle. intervention 3: 52.5Gy in 25 fractions (2.1Gy/fraction), using intensity modulated radiation therapy (IMRT). Radiation therapy will be administered after chemotherapy.

Protocol document:
Prot_SAP_000.pdf: 
Dose escalation trial of Wee1 inhibitor 
1
A DOSE ESCALATION TRIAL OF THE Wee1 INHIBITOR AZD-1775, IN 
COMBINATION WITH GEMCITABINE (+RADIATION) FOR PATIENTS WITH 
UNRESECTABLE ADENOCARCINOMA OF THE PANCREAS  
Principal Investigator 
Theodore S. Lawrence, MD, PhD1 
Co-Investigators 
Kyle Cuneo, MD1
Mahmoud Al-Hawary, MD2 
John Krauss, MD3 
Jon Maybaum, PhD4 
Meredith Morgan PhD1 
Oxana Rusher, MD3 
Vaibhav Sahai, MBBS3 
Matt Schipper, PhD1 
Mark Zalupski, MD3 
1 Department of Radiation Oncology, University of Michigan 
2Department of Radiology, University of Michigan 
3Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan 
4 Department of Pharmacology, University of Michigan 
Version 8   April 07, 2017
NCT02037230


Dose escalation trial of Wee1 inhibitor 
 
 
 
2
 
 
 
 
 
Table of Contents 
 
Section 
 
 
 
                       Pg 
 
Synopsis 
 
 
 
 
 
3 
1.0 
Background 
 
 
 
 
 
7 
2.0 
Objectives 
 
 
 
 
 
9 
3.0 
Eligibility Criteria 
 
 
 
 
10 
4.0 
Pretreatment Evaluation 
 
 
 
10 
5.0 
Registration Procedures 
 
 
 
11 
6.0 
Treatment Plan 
 
 
 
 
11 
7.0 
Drug Information 
 
 
 
 
13 
8.0 
Dosage Modifications  
 
 
 
15 
9.0 
Patient Assessments and Data Collection 
 
16 
10.0 
Study Monitoring 
 
 
 
 
18 
11.0 
Correlative studies 
 
 
 
 
23 
12.0 
Statistical Considerations 
 
 
 
23 
13.0 
References 
 
 
 
 
 
29 


Dose escalation trial of Wee1 inhibitor 
 
 
 
3
SYNOPSIS 
TITLE 
A Dose Escalation Trial of AZD-1775 (a Wee1 inhibitor) and Gemcitabine-Radiation in 
Locally Advanced Pancreatic Cancer 
 
PROTOCOL NUMBER 
UMCC 2013.094 
CLINICAL PHASE 
Phase I/II 
RATIONALE 
We have developed the use of the combination of gemcitabine and radiation in the 
treatment of locally advanced pancreatic cancer.  These agents cause DNA damage to 
cancer cells leading to tumor response.  However, the disease often progresses after 
treatment.  Our preclinical studies at the University of Michigan have shown that normal 
cells have both a functional G1 and G2 checkpoint that permits them to repair DNA 
damage before undergoing DNA synthesis and mitosis, respectively, thereby avoiding 
cells death.  In contrast, pancreatic cancer cells lack a G1 checkpoint after DNA damage 
due either to mutations in p53 or in the p53 pathway.  Our preclinical work has 
demonstrated that inhibition of Wee1 kinase by AZD-1775 abrogates the G2 checkpoint, 
the only functional checkpoint in pancreatic cancer cells, which causes the pancreatic 
cancer cells, but not normal cells, to progress into mitosis before repairing the DNA 
damage, leading to pancreatic cancer cell death.  Pancreatic cancer cells are selectively 
killed compared to normal cells, which retain a functional G1 checkpoint.  AZD-1775 
causes a selective increase in pancreatic cancer cell death both from radiation and from 
gemcitabine, suggesting that this strategy will improve the outcome of treatment of both 
local and (occult) systemic disease. 
 
OBJECTIVES 
The objectives of this study are: 
Primary 
 
Determine the maximum tolerated dose of AZD-1775 in combination with 
gemcitabine and radiation in patients with locally advanced pancreatic cancer. 
 
Secondary 
1. 
To estimate the efficacy of this regimen (combined with standard 
systemic therapy) at the target dose, as determined by progression-free 
survival and overall survival at one year. 
2. 
To determine if Wee1 is inhibited by AZD-1775 at or below its target dose 
in surrogate tissues. 
 


Dose escalation trial of Wee1 inhibitor 
 
 
 
4
STUDY DESIGN 
Protocol therapy will consist of administration of both AZD-1775 and gemcitabine (with 
and without radiation) at assigned dose levels in accordance with a Time-to-Event 
Continual Reassessment Method (TITE-CRM).  
 
1. 
Cycle 1:  AZD-1775 will be given orally (day 1,2 and 8,9 of a 21-day 
cycle) with gemcitabine given intravenously over 30 minutes on day 1 and 
day 8.   
2. 
Cycles 2 and 3:  The same 21-day cycle of AZD-1775 and gemcitabine 
will be administered as in Cycle 1 but with concurrent radiation therapy.  
Two cycles will be given with 25 radiation treatments. 
3. 
Cycle 3 is followed by a 3 week break in treatment. 
4. 
Cycle 4:  AZD-1775-gemcitabine as described in cycle 1. 
 
The maximum tolerated dose (MTD) will be determined based on the development of 
dose-limiting toxicities within the first 105 days of therapy.  
 
NUMBER OF PATIENTS 
Approximately 36 patients will be accrued to this study. 
TARGET POPULATION 
Patients must have pathologically confirmed locally advanced pancreatic carcinoma.  
 
ESTIMATED LENGTH OF PATIENT PARTICIPATION 
Patients may continue to receive treatment until the development of unacceptable 
toxicities or progressive disease. It is estimated that patients who discontinue treatment 
because of toxicity or progressive disease will participate an average of 3 months with 
one additional month of follow-up. Patients who experience a response or stable disease 
are expected to participate an average of 6 months plus an additional 6-12 months for 
follow-up. 
ESTIMATED STUDY DATES 
December 2013 (first study screening visit) to December 2018 (last study follow-up visit) 
INVESTIGATIONAL REGIMEN DOSE/ ROUTE/ DURATION 
AZD-1775 will be administered at assigned dose and taken orally on days 1 and 2 and 
on days 8 and 9 until the development of unacceptable toxicity, progression of disease, 
or patient decision to discontinue therapy. 
COMBINATION TREATMENT(S) 
Gemcitabine and radiation therapy 


Dose escalation trial of Wee1 inhibitor 
 
 
 
5
SAFETY ASSESSMENTS 
Safety assessments will be conducted every weekly on the day of chemotherapy 
administration and weekly during the course of radiation therapy and include clinical 
evaluation, assessment of adverse events and laboratory evaluation. 
Adverse event seriousness, severity grade, and relationship to study treatment will be 
assessed by the investigator. Severity grade will be defined by the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 
(to permit comparison to prior studies of AZD-1775). 
TUMOR ASSESSMENTS 
Tumor evaluation using CT or MRI will be performed within 4 weeks of registration and 
prior to beginning cycle 4 of treatment (1 month after chemoradiation) and approximately 
every 3 months afterwards.  Response will be evaluated using Response Evaluation 
Criteria in Solid Tumors (RECIST) v.1.1. 
OTHER ASSESSMENTS 
During the first or second cycle of treatment, patients will be asked to undergo 2 punch 
biopsies of the skin: one will occur approximately 3 h after treatment with gemcitabine (but 
before AZD-1775) on day 1 of a cycle and the second will occur on day 2 of a cycle 
approximately 3-5 hours after AZD-1775.  Utilizing immunohistochemistry, we will assess 
Wee1 signaling in response to AZD-1775 in combination with gemcitabine. Using a punch 
biopsy of the skin to evaluate replicating cells in hair follicles, we anticipate that AZD-1775 
plus gemcitabine will reduce Cdk1 (Y15) phosphorylation relative to gemcitabine alone, 
confirming Wee1 inhibition. To confirm Wee1 pathway inhibition, we will assess the mitotic 
marker pHistoneH3, and anticipate that it will be increased in response to AZD-1775 plus 
gemcitabine relative to gemcitabine alone.  Other potential biomarkers of Wee1 inhibition 
will also be assessed. 
 
STATISTICAL METHODS_________________________________________________ 
The trial will be monitored using a modification of the Continual Reassessment Method, 
called TITE-CRM.  The TITE-CRM method assumes a model for the time to occurrence 
of toxic response as a function of dose, and allows information from all patients enrolled 
in the trial to be employed when allocating a new patient to a dose level. Because this 
method is very flexible in terms of the number of patients treated at each dose, patients 
may be continuously recruited throughout the trial, without recruitment pauses, as long 
as patients are treated at a dose consistent with the current safety profile.  
 
The acute observation period for toxicity is defined as the first 4 cycles of treatment (with 
a 3 week break between cycle 3 and cycle 4), for a total of 105 days in length. 
 
The target rate DLT is 30%. The target rate will define the MTD of AZD-1775) given 
concurrently with gemcitabine (and radiation therapy for 2 cycles) for locally advanced 
pancreatic cancer. 
 
Expected rates of acute toxicity have been estimated based upon our previous treatment 
experience with gemcitabine-radiation plus cisplatin or oxaliplatin and from gemcitabine-
AZD-1775 in advanced pancreatic cancer patients and clinically acceptable maximal 


Dose escalation trial of Wee1 inhibitor 
 
 
 
6
levels of toxicity. These rates will be re-estimated throughout the conduct of this trial as 
treatment experience is accrued. 
 
Sample Size   
This study will enroll 36 patients for the estimation of the dose-toxicity function. We 
expect to accrue 1-2 patients per month from the multidisciplinary pancreatic cancer 
clinic at the University of Michigan Comprehensive Cancer Center, therefore completing 
accrual to this trial in approximately 3 years. 
 
Cohort size 
Patients will be recruited as available and allocated to treatment according to the 
estimated toxicity rates. No formal cohort size is required; however, a total over one or 
more subjects, of at least 200 days of observation at Dose j must have been completed 
before a subject can be treated at Dose j+1 


Dose escalation trial of Wee1 inhibitor 
 
 
 
7
1.0 
BACKGROUND 
 
1.1 Treatment of Unresectable Pancreatic Cancer 
Pancreatic cancer remains mostly incurable with an overall 5-year survival of less than 
5% (1). Resection is the only therapy with potential for cure, but most patients present with 
metastatic or unresectable disease.  In the case of unresectable pancreatic cancer, the 
standard therapy developed in the 1980’s was the combination of fluorouracil (5FU) and 
radiation.  In the 1990’s gemcitabine was shown to be superior to 5FU in patients with 
advanced pancreas cancer (2).  Therefore, we decided to explore combining radiation 
therapy with gemcitabine.  We were the first to show that gemcitabine is a potent 
radiosensitizer of human tumor cells (3) and of pancreas cancer cells (4).  These initial 
studies and those of other investigators established that radiosensitization occurred under 
conditions of simultaneous dATP pool depletion and redistribution of cells into S phase (3, 
5). In addition, radiosensitization depended on homologous recombination (6) and, in 
other studies, on mismatch repair (7). Importantly, studies in animal models showed that 
the combination of gemcitabine and radiation could improve the therapeutic index (8, 9).  
 
Based on these reports, investigators began incorporating gemcitabine into the treatment 
of unresectable disease. Our group at the University of Michigan was the first to conduct 
prospective clinical trials investigating the combination of full-dose gemcitabine and 
radiotherapy for locally advanced unresectable cancer as well as in the adjuvant post-
operative setting (10, 11). The objective of these trials was to design a regimen that would 
use the most effective drug, gemcitabine, at its full systemic intensity, and at the same 
time, take advantage of its radiosensitizing properties (4). The key conclusion from this 
and our subsequent preclinical (12, 13) and clinical studies adding cisplatin (14) or 
oxaliplatin (15) to gemcitabine in patients with locally advanced disease is that conformal 
radiation permits the use of full systemic doses of chemotherapy, which is important 
support for testing the hypotheses proposed in this clinical trial. 
 
Although pancreatic cancer has a tendency to metastasize, recent evidence confirms that 
radiation therapy improves survival in patients who do not have gross metastatic disease. 
A recent phase III trial for patients with unresectable disease has shown that the 
combination of gemcitabine and radiation produced a statistically significant improvement 
in survival compared to gemcitabine alone, demonstrating that local therapy can improve 
survival (16).  This is consistent with an autopsy study that found that 1/3 of patients who 
die of pancreatic cancer died due to complications of local disease progression (17).  
 
Our data also support the hypothesis that intensification of local therapy, while maintaining 
full dose system therapy, can improve survival.  We recently completed a radiation dose 
escalation study (using 1000 mg/m2 of gemcitabine 2 weeks on one week off) for patients 
with the same eligibility criteria proposed for the current trial (18).  The radiation dose level 
was assigned using TITE-CRM with a DLT target rate set to 0.25. Fifty patients were 
accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or 
dehydration (7); duodenal bleed (3); duodenal perforation (1). The probability of DLT at 55 
Gy (0.24) was closest to the target. The 2-year FFLP was 59% (95% CI: 32-79). Median 
and 2- year overall survival were 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-
45). Twelve patients with initially unresectable disease underwent resection (10 R0, 2 R1) 
and survived a median of 32 months.  This study showed that high dose radiotherapy with 
concurrent gemcitabine can be delivered safely and can produce results that are 
comparable to the best survival reported for patients with unresectable disease. 
 


Dose escalation trial of Wee1 inhibitor 
 
 
 
8
To summarize this section, full dose gemcitabine (alone or with oxaliplatin or cisplatin) can 
be administered safely with full dose radiation if conformal radiation techniques are used.  
Although some progress has been made by the introduction of FOLFIRINOX (19)and 
gemcitabine-nab paclitaxel (20) in the treatment of metastatic disease, these new 
combinations have not yet been demonstrated to improve survival for patients with locally 
advanced disease nor when combined with radiation therapy.  Thus, new systemic agents, 
particularly those that can be combined effectively with radiation, are urgently needed. 
 
1.2 The Potential of Wee1 Inhibitors for the Treatment of Pancreatic Cancer 
In recent years, it has become clear that most tumor cells exhibit abnormalities in one or 
more aspects of cell cycle regulation (i.e., "checkpoints"), and that these abnormalities 
present an attractive target for therapeutic intervention. The overall concept is that defects 
in the cell cycle regulation systems of tumor cells may render them more vulnerable to 
drug treatments than normal cells, due to failure of checkpoints to prevent inappropriate 
DNA replication or mitotic entry.  In particular, we have focused on Wee1 inhibitors, which 
can both abrogate the G2 checkpoint and inhibit homologous recombination repair. The 
great majority of pancreatic cancers express either mutant or non-functioning p53, and, 
therefore, lack a G1 checkpoint.   Tumors must, therefore, depend on the G2 checkpoint 
to protect themselves from DNA damaging agents.  Thus, a Wee1 inhibitor would be 
predicted to potentiate the activity of drugs, such as gemcitabine, and radiation, against 
tumor cells.  In fact, we and others have demonstrated that a highly selective inhibitor of 
Wee1, AZD-1775, can sensitize to radiation and to gemcitabine (21-26). AZD-1775 is a 
highly selective, ATP competitive, small-molecule inhibitor of the Wee1 kinase that 
sensitizes tumor cells to cytotoxic agents and is being developed for the treatment of 
advanced solid tumors and p53 pathway deficient malignancies.  
 
AZD-1775 alone or in combination with chemotherapy (especially gemcitabine) has been 


Dose escalation trial of Wee1 inhibitor 
 
 
 
9
assessed in Phase I clinical trials in over 200 patients. Preliminary analysis of mean 
plasma concentration profiles suggests that the overall trend of AZD-1775 exposure is 
approximately dose proportional at the tested dose levels. Initial studies used AZD-1775 
as monotherapy. In this portion of the study, a single dose of AZD-1775 up to 1300 mg as 
monotherapy was generally well tolerated without DLTs. Phase I studies of a single dose 
of AZD-1775 in combination with cisplatin, gemcitabine, and several other agents have 
been completed, and a MTD has been determined in single and multiple dose combination 
therapy studies. A completed clinical trial of 67 patients showed that the maximum 
tolerated dose of AZD-1775 (given days 1 and 2) combined with Gemcitabine (1000 
mg/m2 on Day 1) is 175 mg, which was, therefore, set as the maximum dose for this trial. 
The most common AEs observed in studies of combination of AZD-1775 with 
chemotherapy include blood and lymphatic disorders, (i.e., thrombocytopenia, 
neutropenia, leukopenia, anemia, febrile neutropenia), gastrointestinal disorders (i.e., 
diarrhea, vomiting, nausea, abdominal pain, and constipation), and investigations 
(hematology and serum chemistries).   
 
To date, AZD-1775 has been sufficiently well tolerated to permit further evaluations, 
including evaluations of other dosing regimens, and evaluations of regimens combining 
the compound with standard doses of two chemotherapeutic agents.  Our proposed study 
will be the first that uses AZD-1775 with radiation in pancreatic cancer.  (Other radiation 
trials are ongoing for patients with high grade glioma and cervix cancer.)  
 
1.3 Summary 
Our long-term goal is to improve the survival of patients with pancreatic cancer by 
enhancing the efficacy of gemcitabine-radiation by adding the Wee1 inhibitor AZD-1775. 
In the current trial we will determine the maximum tolerated dose (which we will call the 
“target dose” (see statistical section below)) and toxicity profile of AZD-1775 when 
administered concurrently with gemcitabine-radiation. We will also carry out a correlative 
study to determine if Wee1 is being inhibited in patients who have received AZD-1775 at 
or below the target dose.  
 
2.0 
OBJECTIVES 
2.1 Primary objective 
2.1.1  To determine the target dose and toxicity profile of AZD-1775 when 
administered concurrently with gemcitabine and gemcitabine-radiation in 
patients with unresectable pancreas adenocarcinoma. 
 
2.2 
Secondary objectives 
2.2.1 Secondary Objective 1: To estimate the efficacy of this regimen 
(combined with standard systemic therapy) at the target dose, as 
determined by progression-free survival and overall survival at one year. 
2.2.2 Secondary Objective 2: To determine if Wee1 is inhibited by AZD-
1775 at or below its target dose (with gemcitabine or gemcitabine-radiation) 
in surrogate tissues. 
 
 
 
3.0 
ELIGIBILITY CRITERIA 
3.1 
Inclusion Criteria 
3.1.1 Patients must have pathologically confirmed adenocarcinoma of 
the pancreas. 


Dose escalation trial of Wee1 inhibitor 
 
 
 
10
3.1.2 Patients will have unresectable disease, defined radiographically as 
>180 degrees involvement of the superior mesenteric artery or celiac trunk 
or SMV/portal vein impingement that cannot be surgically reconstructed, in 
the absence of distant metastasis.  
3.1.3 Patients must have a Zubrod performance status of < 2. 
3.1.4 Patients must have adequate organ function defined as follows: 
absolute neutrophil count of ≥ 1500/mm3, platelets ≥ 100,000/mm3, Hgb ≥ 
9, serum creatinine ≤ 2 mg/dl, total bilirubin ≤ 3, (with relief of biliary 
obstruction if present (PTC tube or endobiliary stent)) and AST and Alkaline 
phosphatase < 5 times the upper limit of normal. 
3.1.5 Patients of reproductive potential must agree to use an effective 
contraceptive method during participation in this trial and for 6 months after 
the trial.  Patients must not be breastfeeding. 
3.1.6 Patients must be aware of the investigational nature of the therapy 
and provide written informed consent. 
3.1.7 Patients must be at least 18 years old. 
 
3.2 
Exclusion Criteria 
3.2.1 Other serious uncontrolled concomitant systemic disorders or 
psychiatric condition that would interfere with the safe delivery of protocol 
therapy. 
3.2.2 A history of previous chemotherapy for pancreatic cancer or 
abdominal radiation therapy. 
3.2.3 The use of any investigational agent in the month before enrollment 
into the study. 
3.2.4 Inability to discontinue a prescription or non-prescription drugs or 
other products known to be metabolized by CYP3A4, or to inhibit or induce 
CYP3A4 prior to Day 1 of dosing and to withhold throughout the study until 
2 weeks after the last dose of study medication.  Medications of particular 
concern are the following inhibitors of CYP3A4: azole antifungals 
(ketoconazole itraconazole, fluconazole and voriconazole), macrolide 
antibiotics (erythromycin, clarithromycin), cimetidine, aprepitant, HIV 
protease inhibitors, nefazodone and the following inducers of CYP3A4: 
phenytoin, barbiturates and rifampicin. Substrates of CYP3A4 include 
statins (lovastatin, simvastatin, atorvastatin), midazolam, terfenadine, 
astemizole, and cisapride.  Refer to Appendix A for a list of commonly 
used moderate and potent CYP3A4 modifiers.  For other concomitant 
medications not on this list and known to significantly influence CYP3A4, 
the Investigator and Astra Zeneca will determine if it should be 
discontinued. 
3.2.5 Pregnant women are not eligible to participate in this study.  
3.2.6 Cardiac Disease ongoing or in the past 6 months (e.g. congestive 
heart failure, acute myocardial infarction, significant uncontrolled 
arrhythmias).   
 
 
4.0 
PRETREATMENT EVALUATION (Screening) 
 
4.1 
Complete history and physical examination including weight, Zubrod 
performance status, and review of current medications to be completed 
within 2 weeks of registration. 


Dose escalation trial of Wee1 inhibitor 
 
 
 
11
4.2 
Diagnostic CT of the chest, abdomen and pelvis to rule out distant 
metastases and to establish unresectable disease should be performed 
within 4 weeks of registration. 
4.3 
CBC with differential, platelets, serum chemistry panel and CA 19-9 within 
2 weeks of treatment start. 
4.4 
A serum pregnancy test for women of child-bearing potential 
4.5 
12 lead ECG to rule out cardiac disease. 
 
 
5.0 REGISTRATION PROCEDURES 
After informed consent is obtained and PRIOR to the initiation of protocol therapy all 
patients satisfying the inclusion/exclusion criteria must have eligibility confirmed by the GI 
SPORE Clinical Trials Team.  The patient will not be considered registered and enrolled 
in the study until all information is confirmed by the GI SPORE Clinical Trials Data 
Manager.  
 
6.0 TREATMENT PLAN 
AZD-1775 will be given on days 1 and 2, and on days 8 and 9 of every 3-week cycle 
according to the protocol established by phase I trials of gemcitabine-AZD-1775 (AZD-
1775 Investigator’s Brochure and personal communication). Protocol therapy will consist 
of an initial cycle of gemcitabine-AZD-1775, followed by the combination of gemcitabine, 
AZD-1775, and radiation, followed by additional gemcitabine-AZD-1775 as diagrammed 
in the figure. The dose of AZD-1775 will be escalated according to the TITE-CRM design 
(see Section 12.0 Statistical Considerations). Radiotherapy will be delivered beginning 
with the second cycle of systemic therapy. 
 
SCHEMA 
 
*RT: 
52.5Gy in 25 fractions (2.1Gy/fraction), using intensity modulated 
radiation therapy (IMRT). Radiation therapy will be administered after 
chemotherapy. 
 
**Gemcitabine: 800-1000 mg/m2, 30 minute, d1 and d8 of a 21-day cycle 
 
***AZD-1775: 125 to 175 mg (flat dosing), d1,2 and d8,9 of a 21-day cycle. The 
starting dose will be Level 0 (125 mg). The recommended maximum 
tolerated dose (MTD) when administered on days 1 and 2 with 
concurrent gemcitabine is estimated to be 175 mg.  AZD-1775 will be 
administered orally 3-4 hours and 24 hours after completion of the 
gemcitabine infusion. 
 
+Skin Biopsies: Two biopsies will occur on day 1 and day 2 with cycle 1 or cycle 2.   
 
Registration 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9-11 
Wk12 -14 
(1 cycle) 
Wk 
15 
Wk 
15-26 
to 18 
months 
RT* 
 
 
 
X 
X 
X 
X 
X 
Break 
 
DLT evaluation 
Optional 
additional 
cycles 
F/U 
Gemcitabine** 
X 
X 
 
X 
X 
 
X 
X 
X  
AZD-1775*** 
X 
X 
 
X 
X 
 
X 
X 
X 
Skin biopsies+ 
X 
 
 
X 
 
 
 
 
 


Dose escalation trial of Wee1 inhibitor 
 
 
 
12
 
This is a dose-escalation trial to determine the maximum tolerated dose of AZD-1775 
when administered with gemcitabine and radiation, in patients with unresectable 
pancreatic cancer. Dose-escalation will be managed by the TITE-CRM algorithm (see 
below), with the goal of establishing the target dose, as per the table below. Astra Zeneca  
has established that AZD-1775 at 175 mg QD x 2 doses with gemcitabine (1000 mg/m2). 
is the MTD. Therefore, our goal would be to reach 175 mg (day 1, 2 and 8,9) with full dose 
gemcitabine, although we would anticipate pCDC2 inhibition might be achieved at lower 
doses (see Sections 10 and 11 for biomarker assessment). 
 
Dose escalation schema 
 
 
6.1 Gemcitabine 
6.1.1 Gemcitabine 1000mg/m2 will be infused over 30 minutes on days 1 and 8 
of a 3 -week treatment cycle. 
6.1.2 A cycle of treatment may begin when ANC ≥ 1,000/mm3, platelets ≥ 75,000/ 
mm3 and all other treatment related toxicity has resolved to ≤ grade 2  
6.1.3 Dose adjustments for chemotherapy during a cycle and for subsequent 
cycles can be found in section 8.0. 
 
6.2 AZD-1775 
6.2.1 AZD-1775 will be administered, with the assistance of the University of 
Michigan Investigational Drug Services Pharmacy, as an oral capsule 3-4 
hours and 24 hours after completion of the gemcitabine infusion. 
6.2.2 The dose of AZD-1775 will be escalated according to the TITE-CRM design 
(see section 12.0) 
 
6.3 Radiation Therapy 
6.3.1 Treatment Planning 
6.3.1.1 Planning will be performed based on a helical CT obtained within 4 weeks 
of the initiation of radiation therapy. The CT scan will be obtained in the 
treatment position following administration of both oral and intravenous 
contrast. Helical scans will be obtained with a large (48 cm or greater) field 
of view, using an aperture of 3.5 mm or smaller, and a pitch of 2. The CT 
data will be transferred to a treatment planning system for contouring of 
critical structures.  Active Breathing Control will be used to reduce/eliminate 
breathing motion.  If a patient cannot tolerate ABC, a 4D CT will used to 
generate an internal target volume (ITV).  
6.3.1.2 The gross tumor volume (GTV) is defined as the gross tumor including 
enlarged regional lymph nodes.  The clinical target volume (CTV) will be 
the GTV, plus a margin of 0.5 cm to account for occult invasion.  An ITV 
will be generated as described above.  The planning target volume (PTV) 
 
Radiotherapy dose 
Gemcitabine (mg/ m2) 
AZD-1775 dose (mg) 
Level -2 
52.5 
800 
100 
Level -1 
52.5 
1000 
100 
Level 0 
52.5 
1000 
125 
Level 1 
52.5 
1000 
150 
Level 2 
52.5 
1000 
175 


Dose escalation trial of Wee1 inhibitor 
 
 
 
13
will be the ITV plus 0.5 cm for daily patient set-up variation. Note that 
radiographically uninvolved lymph nodes will not be included in the target. 
6.3.1.3 Treatment planning will be performed using IMRT as described previously 
(28), with the isocenter calculated at 100% and the 95% line encompassing 
99.5% or greater of the PTV.  Normal tissue tolerances will be respected 
as described below.  Doses of > 5% above the prescribed dose will not be 
allowed unless they occur within the GTV. 
6.3.1.4 Use of greater than or equal to 10 MV photons is required. 
6.3.1.5 Normal Tissue Tolerances:  The spinal cord and kidneys will be contoured 
into the treatment planning system, using the digital CT data. The spinal 
cord shall not receive greater than 45 Gy. No more than 50% of the 
combined functional renal volume (e.g. 20% of one kidney and 80% of the 
other) will receive >20 Gy. Dose to the small bowel, stomach, or colon will 
be limited to less than the prescription dose (i.e. no “hot spots” permitted) 
as described above. 
6.3.2 Radiation Therapy 
6.3.2.1 Radiation therapy will typically be given during cycle 2 and 3 of 
chemotherapy.  Radiation therapy will be given daily, five times weekly, 
starting on the first day of the first cycle of chemotherapy. Treatment will 
generally begin on a Monday or Tuesday.  
6.3.2.2 All fields will be treated daily. 
6.3.2.3 Patients will be treated in a supine position, generally with their arms up. 
Use of immobilization devices is required. 
6.3.2.4 The total dose will be 52.5 Gy in twenty-five fractions of 2.1 Gy each.  This 
radiation dose is one dose level below the radiation dose established as 
the MTD for high dose radiation combined with gemcitabine. 
6.3.2.5 Cone Beam CT (CBCT) and/or KV imaging for patients with implanted 
fiducial markers will be used for image guidance and will be assessed on a 
daily basis.  These images will be made available for review if required. 
 
 
7.0 
DRUG INFORMATION 
7.1.Gemcitabine 
7.1.1   Description – Gemcitabine hydrochloride (2’, 2’-difluoro-2’deoxycytidine) is 
a deoxycytidine analog with structural and metabolic similarities to 
cytarabine. Gemcitabine is metabolized intracellularly by deoxynucleoside 
kinases to active di- and triphosphate nucleosides.  The active nucleosides 
interfere with ribonucleotide reductase and compete with dCTP for 
incorporation into DNA, respectively, resulting in inhibition of DNA 
synthesis. Gemcitabine pharmacokinetics are linear and are described by 
a two compartment model.  Half-life varies with age, gender, and infusion 
length; for a short infusion it is generally less than 70 minutes.  Nearly all 
of an administered dose is recovered in the urine as active drug (<10%) or 
inactive uracil metabolite.  The maximum plasma concentrations of the 
inactive metabolite are achieved 30 minutes after discontinuation of the 
infusions, and the metabolite is excreted in the urine without undergoing 
further biotransformation.  The metabolite does not accumulate with weekly 
dosing, but its elimination is dependent on renal excretion, and could 
accumulate with decreased renal function. 
7.1.2 Human Toxicity - Myelosuppression is the principal dose-limiting factor with 
gemcitabine therapy including leukopenia, thrombocytopenia and anemia.  


Dose escalation trial of Wee1 inhibitor 
 
 
 
14
Non-hematologic toxicities include reversible hepatic enzyme elevations, 
gastrointestinal toxicity (nausea, vomiting, diarrhea, and stomatitis), fever 
in the absence of infection, flu-like syndrome, rash, and peripheral edema.  
Rarely hemolytic-uremic syndrome, drug-induced pneumonitis and sepsis 
have been reported. 
7.1.3 Pharmaceutical Data – Gemcitabine is supplied as a lyophilized powder in 
sterile vials containing 200 mg or 1 g of gemcitabine as the hydrochloride 
salt, with mannitol and sodium acetate.  Gemcitabine is reconstituted with 
0.9% sodium chloride without preservatives and used within 24 hours. 
7.1.4 Administration – Intravenous infusion over 30 minutes (see treatment plan). 
7.1.5 Storage and Stability – Store at controlled room temperature. 
7.1.6 Supplier – Gemcitabine is commercially available for purchase by third 
party from Eli Lilly and Company. 
 
7.2 AZD-1775 
7.2.1 Description - The chemical name for AZD-1775 is 2-allyl-1-[6-(1-hydroxy-
1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-
1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin- 3-one. The clinical formulation of 
AZD-1775 contains the active ingredient in a DFC, in 10 mg, 25 mg, and 
100 mg strengths (RC-DFC; PMF). AZD-1775 is the only active ingredient 
in the clinical formulation. AZD-1775 is a highly selective, adenosine-
triphosphate (ATP) competitive, small- molecule inhibitor of Wee1 kinase.  
The maximum concentration of AZD-1775 is reached from 1 to 4 hours 
after oral dosing and the ½ life is 9-11 hours. 
7.2.2 Human toxicity – In phase I trials of AZD-1775 combined with gemcitabine, 
the chief toxicity has been hematologic (including both neutropenia and 
thrombocytopenia).  Fatigue and elevated transaminases (AST and ALT) 
have also been noted. Updated information for AZD-1775 includes new 
risks for complications of existing cardiac disease and potential for serious 
GI hemorrhage while taking AZD-1775. A rare, but serious side effect of 
sepsis has been reported while taking AZD-1775. 
7.2.3 Pharmaceutical Data - AZD-1775 is a crystalline, non-hygroscopic, 
monohydrate of the neutral drug. It dehydrates upon heating leading to 
formation of a crystalline anhydrate. AZD-1775 is available for clinical trials 
as a roller-compacted granule of AZD-1775 and excipients (RC-DFC). The 
RC-DFC consists of a roller compacted granule of AZD-1775, lactose, 
microcrystalline cellulose, croscarmellose sodium and intragranular 
magnesium stearate. The granule is lubricated with a further quantity of 
extragranular magnesium stearate prior to encapsulation of the granule. 
The active potencies for the RC-DFCs are 25 mg and 100 mg in size 2 
gelatin capsules. 
7.2.4 Administration – AZD-1775 is administered as an oral capsule (see 
treatment plan)  
7.2.5 Storage and Stability - The capsules are packaged in high-density 
polyethylene (HDPE) bottles fitted with induction seals. Clinical supplies 
should be stored at not more than 30°C.  
7.2.6 Supplier – AZD-1775 is supplied by Astra Zeneca, Inc. 
 
 
 
 


Dose escalation trial of Wee1 inhibitor 
 
 
 
15
 
8.0     DOSAGE MODIFICATIONS 
8.1 Dose modifications For Chemotherapy (Gemcitabine and AZD-1775) 
Within in a Cycle (day 8 treatment) 
8.1.1 Hematologic toxicity - dose adjustments of gemcitabine and AZD-1775 will 
be made based on the absolute neutrophil count (ANC) and platelet count 
taken on the day of therapy. 
8.1.2 For ANC ≥ 1,000 /mm3 and platelets ≥ 75,000/mm3, full dose will be given. 
8.1.3 For ANC of 500- 999/mm3 and/or platelets of 50,000 to 74,999/mm3, 50% 
of the gemcitabine dose due will be given and AZD-1775 will be given only 
on day 9 (instead of both days 8 and 9). 
8.1.4 For ANC < 500/mm3 or platelets < 50,000/mm3, the treatment will be held. 
If this toxicity occurs during radiation therapy (cycle 2 or 3), radiation 
therapy will also be held, with combined modality treatment resuming upon 
recovery to values permitting chemotherapy. Combined modality treatment 
will resume (cycles 2 and 3) when ANC > 500 and platelets > 50,000/mm3 
with gemcitabine given at 50% dose reduction. If this hematologic toxicity 
occurs beyond cycle 3, the dose of gemcitabine (and AZD-1775) will be 
dropped and not made up.   
8.1.5 Non-hematological toxicity- Dose adjustments of chemotherapy will be 
made following assessment of non-hematological toxicity on the day of 
therapy. Chemotherapy will be held for ≥ Grade 3 toxicity in any organ 
system.  If gemcitabine and AZD-1775 are held during cycle 2 or 3, 
radiation therapy will also be held while appropriate physical, laboratory, 
radiological assessments are undertaken to define cause and direct 
supportive therapy. Treatment will be resumed upon recovery to toxicity < 
grade 1. If non-hematological toxicity ≥ grade 3 occurs in any cycle beyond 
cycle 3, the chemotherapy dose will be omitted and treatment resumed 
when toxicity resolves to < grade 1 beginning a new cycle with a 25% dose 
reduction of gemcitabine. 
8.1.6 If a day 8 dose of chemotherapy is delayed or omitted because of toxicity, 
all subsequent gemcitabine and AZD-1775 doses will be given at 75% 
previous dose.   
 
8.2 Chemotherapy Dose Modifications for Subsequent Cycles 
8.2.1 A cycle of therapy may begin when ANC ≥ 1,000 /mm3, platelet count is ≥ 
75,000/mm3, and all other treatment related toxicity has resolved to ≤ grade 
2. 
8.2.2 If a chemotherapy treatment is not given the day it is due for toxicity per 
section 7.1, all subsequent gemcitabine and AZD-1775 doses will be given 
at 75% of the previous dose. Once reduced for toxicity requiring 
delay/omission, chemotherapy doses will not be re-escalated. 
8.2.3 If therapy is not given for treatment related toxicity and recovery allowing 
for treatment does not occur within four weeks of the date treatment was 
due, the patient is off protocol. 
 
8.3 Radiation Therapy Modifications:  Radiation will be held for up to one week 
when     chemotherapy is held.  Radiation will restart the second week even if 
chemotherapy does not restart.  Otherwise, there will be no adjustments of the 
radiation therapy dose. 
 


Dose escalation trial of Wee1 inhibitor 
 
 
 
16
 
Dose Modifications 
Gemcitabine (mg/m2) 
AZD-1775 (mg) 
Starting Dose 
Modified Dose 
Starting Dose 
Modified Dose 
1000 
800 
175 
150 on Day 1, 8 
125 on Day 2, 9 
650 
100 
500 
75 
375 
50 
Off treatment 
Off treatment 
800 
650 
150 
100 
500 
75 
375 
50 
Off treatment 
50 on Day 1, 8 
25 on Day 2, 9 
 
 
Off treatment 
 
 
125 
100 
 
 
75 
 
 
50 
 
 
50 on Day 1, 8 
25 on Day 2, 9 
 
 
100 
Off treatment 
 
 
75 
 
 
50 
 
 
50 on Day 1, 8 
25 on Day 2, 9 
 
 
Off treatment 
 
 
 


Dose escalation trial of Wee1 inhibitor 
 
 
 
17
9.0 PATIENT ASSESSMENTS AND DATA COLLECTION 
9.1 Study Calendar 
Staging CT scan will be performed within 28 days of registration. All other 
pre-treatment evaluations will be within 14 days of registration.  
 
  
Pre-
treatment  
(Screening) 
Cycle 1 
 
Cycle 2-
3 
Cycle 4-
8 
Follow-
up 
Visits9 
 
 
 
 
 
 
History/Physical/confirm 
medications 
X 
 
X5 
X 
X 
Performance Status 
X 
 
X5 
X 
X 
CBC,diff,plts 
X 
X2 
X 
X 
X 
Serum Chemistry 
X1 
X5 
X5 
X 
X 
Serum Pregnancy Test 
X 
 
 
 
 
CA 19-9 
X 
 
 
X8 
X 
12 lead ECG 
X 
 
 
 
 
Liver function tests 
 
X10 
X10 
X10 
 
Toxicity Notation 
 
X2 
X6 
X5 
X 
CT 
chest/abdomen/pelvis 
X 
 
 
X8 
X 
Gemcitabine 
 
X3 
X 
X 
 
AZD-1775 
 
X4 
X 
X 
 
Radiation Therapy  
 
 
X7 
 
 
Assess for adverse 
events 
X 
X 
X 
X 
X 
Skin Biopsies 
 
X11 
X11 
 
 
1 Serum chemistry panel will include albumin, alkaline phosphatase, ALT, AST, 
glucose, total bilirubin, creatinine and electrolytes. 
2 Weekly on the day chemotherapy is given  
3 Gemcitabine by 30 minute IV infusion given days 1 and 8 (section 6.1) 
4 AZD-1775 orally days 1, 2 and 8, 9 (section 6.2) 
5 On day 1 of each chemotherapy cycle, except on day 1 of cycle 1 when pre-
treatment values can be used. 
6 Weekly during radiation therapy 
7 Daily treatment M-F for 5 weeks (section 6.3) 
8 Prior to cycle 4 and after last cycle.   
9 Approximately every 3 months for 18 months, then every 4 months +/- 2 months 
for another 18 months. 
10Obtained every other week (alone or as part of chemistry panel (see footnote 1)), 
and includes bilirubin, AST, ALT, and alkaline phosphatase 
11Skin biopsies before and after AZD-1775 administration, day one and day two of 
cycle 1 or cycle 2.   
 
9.2 Follow up Schedule 
With completion of treatment, patients will be seen in follow-up 
approximately every 3 months for 18 months, then every 4 months +/- 2 
months for another 18 months. 
 
 


Dose escalation trial of Wee1 inhibitor 
 
 
 
18
9.3 Toxicity Assessment 
Toxicity will be assessed using the Common Terminology Criteria for 
Adverse Events (CTCAE) version 3.0. Toxicity will be assessed on each 
chemotherapy visit, weekly during radiation therapy and at each follow-up 
visit. Dose-limiting hematologic and non-hematologic toxicities will be 
defined differently, and will be based on events occurring up to 2 months 
after the completion of chemoradiation (approximately 105 days after the 
first day of treatment). In order to be declared a dose-limiting toxicity, an 
adverse experience must be at least possibly related (i.e. definitely, 
probably, or possibly) to study therapy 
9.4 Dose Limiting Toxicity (DLT) 
9.4.1 Grade 4-5 hematological toxicity with the exception of Grade 4 anemia, 
Grade 4 leukopenia, Grade 4 neutropenia lasting for <7 days and Grade 4 
thrombocytopenia lasting for <4 days, EXCEPT if a platelet transfusion is 
required (in other words, Grade 4 thrombocytopenia that requires a platelet 
transfusions considered a DLT).; 
9.4.2 Grade 3 or Grade 4 neutropenia with fever >38.5°C and/or infection 
requiring antibiotic or anti-fungal treatment 
9.4.3 Grade ≥3 non-hematological toxicity, except: 
9.4.3.1 nausea, vomiting, or diarrhea that in the opinion of the investigator occurs 
in the setting of inadequate compliance with supportive care measures and 
lasts for less than 48 hours  
9.4.3.2 hyperbilirubinemia/cholangitis secondary to biliary obstruction 
9.4.3.3 any grade of alopecia; 
9.4.3.4 inadequately treated hypersensitivity reactions 
9.4.3.5 clinically non-significant, treatable or reversible lab abnormalities including 
such as glucose, uric acid, etc. 
9.4.4 Missed doses:  if a patient misses 50% of the scheduled dose of AZD-1775 
during the observation period (4 cycles/ 8 doses), it will be considered a 
DLT (except if due to poor patient compliance in the absence of treatment-
related toxicity).  For example, if a patient is assigned 125 mg x 8 doses, 
then without missing or reducing dose patient would take 1000 mg. If the 
patient was able to receive < 500 mg, it would be considered a DLT. 
9.4.5 A delay of >2 weeks in the scheduled administration of radiation, 
gemcitabine, and AZD-1775 due to drug-related toxicities which do not 
qualify as a DLT per the guidelines above (except if the delay is due to a 
cause unrelated to the disease or treatment under study (e.g. family 
emergency or auto accident) will be scored as a DLT.   
 
 
9.5 Definition of Outcome Measures 
9.5.1 Progression Free Survival: Time from date of registration to the date of 
documented progressive disease, other disease related therapy or death. 
9.5.2 Response Rate:  Objective response assessed from the CT scan obtained 
prior to cycle 4 and again at completion of study treatment. 
9.5.3 Freedom from Local Progression: Time from date of registration to the date 
of documented local progressive disease. 
9.5.4 Overall Survival: Time from date of registration to date of death or last 
follow up. 
 
9.6 Criteria for Removal from Study 


Dose escalation trial of Wee1 inhibitor 
 
 
 
19
9.6.1 Evidence of progressive disease. 
9.6.2 Treatment delay of > 4 weeks. 
9.6.3 Patient refusal to continue therapy. 
9.6.4 Toxicity that despite protocol specified delay and dose reduction requires 
treatment cessation. 
 
10.0 
STUDY MONITORING 
10.1 Adverse Event Reporting Guidelines 
10.1.1 Adverse events monitoring and reporting is a routine part of every clinical 
trial and is done to ensure the safety of subjects enrolled in the studies as well 
as those who will enroll in future studies using similar agents.  Data on adverse 
events will be collected from the time of informed consent through 30 days after 
the last study treatment.  Any serious adverse event that occurs more than 30 
days after the last treatment and is considered related to the study treatment 
must also be reported.  Serious Adverse Events (SAEs) will continue to be 
followed until: 
• 
Resolution of the symptoms or signs that constitute the serious adverse event 
return to baseline; 
• 
There is satisfactory explanation other than the study treatment for the 
changes observed; or  
• 
Death. 
The investigator is responsible for the detection, documentation, grading, and 
assignment of attribution of events meeting the criteria and definition of an AE 
or SAE.  The definitions of AEs and SAEs are given below.  It is the 
responsibility of the principal investigator to ensure that all staff involved in the 
trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial 
study treatment is considered to be pre-existing in nature.  Any known pre-
existing conditions that are ongoing at time of study entry should be considered 
medical history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 
10.1.2, occurring from the time of informed consent through 30 days following 
the last study treatment must be recorded as an adverse event in the patient’s 
source documents and on the CRF regardless of frequency, severity (grade) 
or assessed relationship to the study treatment.  
In addition to new events, any increase in the frequency or severity (i.e., toxicity 
grade) of a pre-existing condition that occurs after the patient begins study 
treatment is also considered an adverse event. 
10.1.2 Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a 
patient receiving study treatment and which does not necessarily 
have a causal relationship with this treatment.  An AE can be any 
unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of 


Dose escalation trial of Wee1 inhibitor 
 
 
 
20
an experimental intervention, whether or not related to the 
intervention.  
 
• 
Diagnostic and therapeutic non-invasive and invasive (i.e., 
surgical) procedures will not be reported as adverse events.  
However, the medical condition for which the procedure was 
performed must be reported if it meets the definition of an 
adverse event unless it is a pre-existing (prior to protocol 
treatment) condition. 
 
• 
Abnormal laboratory values or test results constitute adverse 
events if they induce clinical signs or symptoms or require 
therapy.  They are to be captured under the signs, symptoms or 
diagnoses associated with them. 
 
• 
All AEs will be categorized according to system organ class for 
annual reporting to the FDA.  Only grade 3 and above AEs, 
which are noted in the medical record to be related to the 
study treatment (RT + gemcitabine +AZD-1775) will be 
reported to the IRB.  SAE’s will be reported per 10.1.4. 
• 
During the course of an adverse event, severity and/or causality 
and/or seriousness may change.  For CRF documentation this 
adverse event represents one entity from onset to resolution 
and the worst of the observed categories shall be attributed 
 
• 
When event reoccurs after it disappeared, it should be handled 
as a new AE.  However, AEs that occur intermittently can be 
recorded as one AE 
Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the 
investigator it results in any of the following outcomes: 
  
o Death 
If death results from (progression of) the disease, the disease 
should be reported as event (SAE) itself. 
 
o A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of 
the investigator its occurrence places the patient or subject at 
immediate risk of death.  It does not include an adverse event 
that, had it occurred in a more severe form, might have caused 
death.  
 
o Inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization for > 24 hours. 
 


Dose escalation trial of Wee1 inhibitor 
 
 
 
21
o A persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions 
 
o A congenital anomaly/birth defect 
 
o Important medical event 
Any event that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the 
patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition of “Serious 
Adverse Event”.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that do not result in 
inpatient 
hospitalization 
or 
the 
development 
of 
drug 
dependency or drug abuse. 
 
o Any events or hospitalizations that are unequivocally due to 
progression of disease (with the exception of death) should not 
be reported as a SAE.  The causality of SAEs (i.e., their 
relationship to study treatment) will be assessed by the 
investigators per section 8.2.2 
 
Previously planned (prior to signing the informed consent form) 
surgeries should not be reported as SAEs unless the underlying 
medical condition has worsened during the course of the study.  
Preplanned 
hospitalizations 
or 
procedures 
for 
preexisting 
conditions that are already recorded in the patient’s medical history 
at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a 
precipitating clinical AE (for example, for the administration of study 
therapy or other protocol-required procedure) should not be 
considered SAEs.  However, if the preexisting condition worsened 
during the course of the study, it should be reported as an SAE.  
Hospitalization or emergency room visits secondary to expected 
cancer morbidity, such as admission for palliative care or pain 
management will not constitute a SAE. 
 
Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
• 
For approved and marketed drugs or devices, those 
adverse events are described in the approved Package 
Insert (Label).  
• 
For investigational new drugs or devices, those adverse 
events are described in the FDA Investigator’s Brochure.  
• 
In clinical research studies, information on expected 
adverse events is also summarized in the protocol and in 
the consent document.  See section 9.1 for the list of 
expected adverse events related to the drug under study. 


Dose escalation trial of Wee1 inhibitor 
 
 
 
22
Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not 
described in the Package Insert, Investigator’s Brochure, in 
published medical literature, in the protocol, or in the informed 
consent document. 
 
 
10.1.3 Adverse Event Characteristics 
CTCAE Term 
(AE description) and grade: The descriptions and grading scales 
found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the 
CTCAE version 3.0.  (We recognize that the current CTCAE list 
version is 4.0.  However, all prior studies with AZD-1775 have been 
conducted using version 3.0, and this scoring will greatly facilitate 
comparison to prior studies.) 
Attribution of the AE 
The investigator or co-investigator is responsible for assignment of 
attribution. 
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. 
 
10.1.4 Serious Adverse Event Reporting Guidelines  
The Principal Investigator must be notified within 2 business days 
of study team’s knowledge of any event meeting the criteria and 
definition of a serious adverse event related to study treatment 
occurring during the study or within 30 days of the last 
administration of the study related treatment. 
Only adverse events deemed serious and related will be reported 
to the IRB within 7 days of awareness of the event.  All other events 
will be noted in the patient’s medical record and reported to the IRB 
according to IRB guidelines. 
 
Serious Adverse Event (SAE) Reporting to Astra-Zeneca and FDA:  
Investigator shall forward to Astra_Zeneca all serious adverse 
experiences as detailed in the contract with the sponsor.  
 
The Study Team will coordinate with the Michigan Institute for 
Clinical and Health Research (MICHR) IND/IDE Investigator 
Assistance Program 
(MIAP) office for the reporting of any and all IND safety reports to 
the FDA as per the requirements outlined in 21 CFR 312.32. SAEs 


Dose escalation trial of Wee1 inhibitor 
 
 
 
23
meeting the requirements for expedited reporting (unexpected and 
related) will be submitted to the FDA within 7 calendar days.   
 
10.1.5 Routine Reporting 
Adverse events will no longer be reported if the patient has another 
pancreas-directed therapy 
10.1.6 Reporting of Unanticipated Problems 
Upon becoming aware of any incident, experience, or outcome (not 
related to an adverse event) that may represent an unanticipated 
problem, the investigator should assess whether the incident, 
experience, or outcome represents an unanticipated problem.  The 
incident, experience, or outcome is considered unanticipated if it 
meets all of the following criteria: 
1. 
Unexpected (in terms of nature, severity, or frequency); 
2. 
Related or possibly related to participation in the research; 
and 
3. 
Suggests that the research places subjects or others at a 
greater risk of harm than was previously known or recognized. 
If the investigator determines that the incident, experience, or 
outcome represents an unanticipated problem, the investigator 
must report it to the IRB within 7 calendar days of the study team 
becoming aware of the problem if the problem is serious, and within 
14 calendar days if the problem is non-serious. 
 
 
10.1 Data and Safety Monitoring 
10.2.1 This trial will be monitored in accordance with the NCI approved 
University of Michigan Comprehensive Cancer Center Data and Safety 
Monitoring Plan. 
 
The study specific Data and Safety Monitoring Committee (DSMC), 
consisting of the protocol investigators, data manager or designee and 
other members of the study team involved with the conduct of the trial, 
will meet monthly or more frequently depending on the activity of the 
protocol to provide continuous review of the data and patient safety. The 
discussion will include matters related to the safety of study participants 
(SAE/UaP reporting), validity and integrity of the data, enrollment rate 
relative to expectations, characteristics of participants, retention of 
participants, adherence to the protocol (potential or real protocol 
deviations) and data completeness. 
 
At the regular DSMC meetings, the protocol specific Data and Safety 
Monitoring Report form will be completed. The report will be signed by 
the Principal Investigator or by one of the co-investigators. 
 
Data and Safety Monitoring Reports will be submitted to the University 
of Michigan Comprehensive Cancer Center Data and Safety Monitoring 
Board (DSMB) on a monthly basis for independent review. 


Dose escalation trial of Wee1 inhibitor 
 
 
 
24
 
 
 
11 
DETERMINATION OF THE EFFECT OF AZD-1775 ON WEE1 ACTIVITY 
 
11.2 Biopsies for Surrogate Markers 
During the first or second cycle of treatment, patients will undergo 2 
biopsies: the first will occur 3 h after treatment with gemcitabine (but before 
AZD-1775) on day 1 of cycle 1 or 2, and the second will occur 
approximately 3-5 hours after AZD-1775 administration on day 2 of cycle 1 
or 2.   We will obtain 3mm punch biopsies of the skin to evaluate replicating 
cells in hair follicles.  Patients who refuse skin biopsies are still eligible for 
treatment. 
 
11.3 Biomarkers 
Utilizing immunohistochemistry, we will assess Wee1 signaling in response 
to AZD-1775 in combination with gemcitabine. Using a punch biopsy of the 
skin to evaluate replicating cells in hair follicles, we hypothesize that AZD-
1775 plus gemcitabine will reduce Cdk1 (Y15) phosphorylation relative to 
gemcitabine alone, confirming Wee1 inhibition. To confirm Wee1 pathway 
inhibition, we will assess the mitotic marker pHistoneH3, and anticipate that 
it will be increased in response to AZD-1775 plus gemcitabine relative to 
gemcitabine alone. To confirm the presence of DNA damage in response 
to AZD-1775 we will evaluate γH2AX and pChk1 (S345) (29). We expect 
that AZD-1775 plus gemcitabine will lead to an induction of these surrogate 
markers of DNA damage.  Other potential biomarkers of AZD-1775 activity 
include Capsase-3 cleavage and Rad51 foci.  Eight genes (CLSPN, 
CCNE1, MCM10, MYB, CCNE2, FBX05, EGR1, and HIST1H2BD) have 
been identified as potential candidates for PD markers by microarray 
analysis by other investigators and will also be evaluated.  
 
12 
STATISTICAL CONSIDERATIONS 
This is a phase I dose-escalation trial to determine the maximum tolerated dose of AZD-
1775 when administered with gemcitabine ± radiation, in patients with unresectable 
pancreatic cancer.  Dose-escalation will be managed by the TITE-CRM algorithm, with the 
goal of establishing the target dose (see below) (14, 30-32).  Section 12.1 describes the 
TITE-CRM design in detail and provides operating characteristics under several simulation 
scenarios. Section 12.2 describes the proposed analysis addressing each of the study 
aims. 
 
In mid-2017, after the enrollment of 24 patients, the target rate of DLT was increased from 
25% to 30%.  A rate of 30% is within the normal range of target rates, particularly in this 
patient population receiving Chemo-RT in addition to the investigational agent. Data from 
all previously treated patients will continue to be utilized in estimating posterior 
probabilities of DLT at each dose level. 
 
12.1 
Trial Design 
12.1.1 Number of Patients: 36 subjects evaluable for toxicity will be 
accrued to this trial.  Based on recent recruitment, it is expected that 
15 subjects can be accrued to this trial per year.  The trial will be 
run until either 36 patients evaluable for toxicity have been enrolled 


Dose escalation trial of Wee1 inhibitor 
 
 
 
25
OR the estimated probability of toxicity at the lowest dose level 
exceeds 35%, in which case the trial would be stopped early.  
12.1.2 Dose Assignment: The first patient will be treated at level 0.  Each 
subsequent patient’s dose level will be assigned using the TITE-
CRM algorithm.  When a new subject is enrolled, the probability of 
toxicity at each dose is estimated, based on the toxicity data 
accrued up to that time, using a one-parameter logistic dose-toxicity 
model described below.  The subject is assigned to the highest 
dose with estimated probability of toxicity closest to the target rate 
of 30% but not exceeding 35%, subject to two dose-escalation 
restrictions: (1) the dose of subject i cannot be more than one level 
greater than the dose of subject i-1; (2) a total, over one or more 
subjects, of at least 200 days of observation at Dose j must have 
been completed before a subject can be treated at Dose j+1. 
12.1.3 Target Dose:  The target dose will be that which produces DLT at 
a frequency of 0.30.  That is, the goal of the trial is to treat patients 
at the dose associated with DLT in 30% of patients. 
12.1.4 Initial Estimates of Probability of Toxicity: Before any subjects 
are treated, the estimated probability of toxicity at each dose level 
is given in the following table. The sensitivity of operating 
characteristics of the trial (number of toxicities, quality of estimation 
of target dose) to these estimates is assessed by means of Monte 
Carlo simulations. 
 
 
 
True Probabilities Used in Simulation 
 
Prior Values 
Rescaled Dose (drs) Scenario 1 
Scenario 2 Scenario 3 
Dose Level 
Pd 
 
pd1 
pd2 
pd3 
-2 
0.05 
-5.94 
0.05 
0.05 
0.15 
-1 
0.10 
-5.20 
0.10 
0.10 
0.25 
0 
0.15 
-4.73 
0.15 
0.15 
0.40 
1 
0.20 
-4.39 
0.20 
0.25 
0.55 
2 
0.25 
-4.10 
0.25 
0.40 
0.65 
 
Dose (d), initial estimate of probability of toxicity for dose d (drs), 
rescaled dose values, and true probabilities of toxicities used in 
Monte Carlo simulations (pd1-pd3) of TITE-CRM trials. 
 
12.1.5 Dose-toxicity function: A continuous, monotonically increasing 
function relating treatment dose to the probability of toxicity is 
employed to allow subjects’ experience at any dose to contribute to 
the estimation of the probability of toxicity at all doses.  The function 
is an approximation to the true state of nature; the trial estimates 
are robust against misspecification of this function.  This trial will 
use a logistic dose-toxicity model: 
 
p(DLT|d)=exp(3+α•drs)/(1+exp(3+α•drs)), 
 


Dose escalation trial of Wee1 inhibitor 
 
 
 
26
where α, the dose-toxicity parameter, is to be estimated, and td is 
the rescaled dose, calculated from the initial estimate of probability 
of toxicity (pd), assuming α=1. 
12.1.6 Estimation of p(DLT|d): The prior distribution of the dose-toxicity 
parameter, α, is Gaussian, with mean 1 and standard deviation 0.3.  
At any time, the probability of toxicity at each dose is estimated by 
calculating the expected value of alpha, given the prior and the trial 
data up to that time, and entering the expected value of alpha into 
the logistic dose-toxicity function.  At a given point of time, the 
datum of subject i is represented by the triple (di, yi, wi), where di 
denotes the dose the subject received, yi the response (0=no DLT, 
1=DLT) and wi the weight (per section 12.1.7 below) derived from 
the portion of the approximately 105-day observation period the 
subject has completed at the given time, or, if the subject has 
experienced DLT, 1.  The expectation of α can be calculated using 
a straightforward univariate numerical integration, and is 
implemented in a SAS code that has been used in a number of 
trials.  
12.1.7 Observation Period: Observation for DLT (as defined in Section 
9.4) will begin on the first day of treatment, and continue until an 
assessment at a follow-up visit following (~day 21 of) cycle 4 (prior 
to optional cycle 5 and beyond, approximately day 105).  Subjects 
who are rendered unevaluable for DLT during this period for 
reasons unrelated to toxicity of treatment (e.g., disease 
progression) will not be counted towards the accrual goal, but will 
be fractionally counted in the estimation of the probability of toxicity.  
The first cycle will be weighted more than later cycles because 
proportionally more DLT’s are expected during cycle 1.  The 
cumulative weight assigned to a subject who completes each cycle 
without DLT is given below. Subjects who experience DLT have 
weight 1.0 regardless of when the DLT occurred.  
 
 
 
 
 
12.1.8 Operating Characteristics: Operating characteristics, estimated 
by means of Monte Carlo simulation, are presented below.  The 
primary goal of the simulations is to check the design robustness 
against the misspecification of the dose-conditional probability of 
toxicity.  For this presentation, 1000 trials were simulated for each 
of three sets of characteristics (Section 12.1.5), where the true state 
of nature was as specified in the protocol (pd1), more toxic than 
assumed (pd2), and much more toxic than assumed, with a rapid 
increase in toxicity near the target rate (pd3).  Metrics presented 
include the distribution of selected target doses (a measure of 
estimation efficacy), the number of observed toxicities (a measure 
of risk) and the numbers of subjects treated at each dose (indicating 
the number of subjects treated at potentially therapeutic doses).  In 
each of the 3 simulations, the correct dose is the most frequently 
selected dose.  When the priors are correct the highest dose level 
Day 0 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
0 
.5 
.7 
0.9 
1.0. 


Dose escalation trial of Wee1 inhibitor 
 
 
 
27
is selected in greater than 70% of trials.  When the priors are far off, 
as in the case of Simulation 3, the correct dose level is still selected 
in more than half of all trials.  Simulation 3 also represents the 
potentially riskiest state of nature, but even in this case the median 
number of DLT’s is 11 (31% of the total 36 patients).  In all three 
simulations, the average number of subjects treated at the target 
dose or within 1 level, is over 25, allowing for Phase IIa estimates 
of efficacy. It has been previously  demonstrated [30] that, in 
general, the TITE-CRM design is not significantly riskier (in terms 
of number of toxicities/subjects treated) than the ‘traditional’ design, 
while better estimating the target dose, and treating a greater 
number of subjects at potentially therapeutic doses. 
 
 
 
 
 
Cumulative Number of DLTs Per Trial 
Simulation  
10th 
Percentile 
25th 
Percentile 
Median 
75th 
Percentile 
90th 
Percentile 
1 
5 
6 
7 
8 
10 
2 
7 
8 
9 
10 
11 
3 
7 
9 
11 
12 
13 
 
 
 
Average Number of Patients Treated at Each Dose Level 
Simulation  
-2 
-1 
0 
1 
2 
1 
0 
2 
8 
9 
17 
2 
0 
2 
10 
12 
12 
3 
7 
13 
10 
3 
0 
 
Operating characteristics of example TITE-CRM trial: Upper plot shows the 
percent of simulated trials selecting each dose level as the target dose. In the 
table showing the average number of patients treated at each dose level, the 


Dose escalation trial of Wee1 inhibitor 
 
 
 
28
numbers may not sum to 36 due to rounding or to the fact that some trials stop 
early and thus enroll fewer than 36 patients.   
 
12.2 
Data Analysis plan  
 
Primary Objective: To determine the target dose and toxicity profile of AZD-1775 
when administered concurrently with gemcitabine and gemcitabine-radiation in 
patients with unresectable pancreas adenocarcinoma. 
 
At the end of the trial, once all evaluable subjects have completed observation, 
p(DLT|d) will be calculated for each dose using the tite-CRM method (one 
parameter logistic regression model with prior distribution on the parameter alpha). 
The final estimated target dose will be the dose d with estimated p(DLT|d) closest 
to the target rate but not exceeding 35%. To further characterize toxicity as a 
function of dose, we will use maximum likelihood to fit a two parameter logistic 
regression model to the data from this trial. This more flexible model typically 
provides estimates of toxicity very close to the tite-CRM estimates at and near the 
target dose, but better estimates toxicity at doses further from the selected target 
dose.  The numbers of subjects treated at each dose and the numbers 
experiencing DLT will be tabulated.  Toxicities at each dose level will be tabulated, 
categorized by grade and by whether they are not, possibly, probably or definitely 
related to treatment.  Toxicities not considered dose limiting may also be 
summarized in this manner and modeled as a function of dose level.   
 
Secondary Objective 1: To estimate the efficacy of this regimen (combined with 
standard systemic therapy) at the target dose, as determined by progression-free 
survival, overall survival, freedom from local progression and response rates. 
 
Overall survival (OS), progression-free survival (PFS) and freedom from local 
progression (FFLP) will be summarized by Kaplan-Meier curves and characterized 
by descriptive statistics such as median OS and PFS times. For OS, subjects alive 
at the time of last FU will be censored at that time.  Similarly, for PFS and FFLP, 
subjects alive and without progression will be censored at the last date on which 
they were assessed for progression.  Cox proportional hazards regression models 
will be used to estimate OS, PFS and FFLP as a function of dose and possibly 
other covariates such as age or inhibition of Wee1.  Response will be assessed 
per RECIST at 4 months.  The number and proportion of patients with progressive 
disease, stable disease, partial and complete response will be calculated for each 
dose level and overall.  Logistic regression models will be used to model probability 
of any response as a function of dose level.  Exploratory analyses will be 
conducted to assess for any relation between Wee-1 inhibition and efficacy 
outcomes. 
 
Although efficacy is only a secondary aim of this trial and it is not formally powered 
for efficacy, we nevertheless show that the proposed design has reasonable power 
to make early efficacy assessments.  Specifically, we calculate the power of the 
design to compare the observed overall survival at 1 year to that in historical control 
patients.  The estimated overall survival at 1 year in Murphy et al was 46%.  In 
each of the 3 simulation scenarios above, there were at least 25 patients treated 
at the target dose +/- 1.  Based on these numbers and a 1-sided .15 level chi-
square test, the proposed design has at least 77% power to detect an improvement 


Dose escalation trial of Wee1 inhibitor 
 
 
 
29
of 1 year survival to 65%.  In addition to aggregating survival data for patients 
treated at the target dose with those treated one dose level above or below, we 
will look for a dose response relationship using a logistic or Cox regression model.  
Based on this fitted model, we will also compare the model-estimated outcome at 
the target dose level to the historical control data.   
 
Secondary Objective 2: To determine if Wee1 is inhibited by AZD-1775 at or below 
its target dose (with gemcitabine or gemcitabine-radiation) in surrogate tissues. 
 
During the first or second cycle of treatment, patients will undergo 2 biopsies:  3 h 
after treatment with gemcitabine (but before AZD-1775), and on day 2  
approximately 3-5 hours after AZD-1775.  WEE1 signaling will be assessed using 
IHC to measure phosphorylation of various markers including Cdk1 (Y15). 
Inhibition will be quantified as the within subject change in the above markers 
between the two biopsy timepoints. Descriptive statistics of inhibition across 
subjects (for each marker) will be calculated and reported by dose level.  
Regression models of inhibition as a function of AZD-1775 dose will be fit to obtain 
smooth and efficient estimates of mean inhibition at a given dose level. In addition 
to mean inhibition, the proportion of patients with inhibition greater than 0 (i.e. 
positive change) or another fixed level of interest will be estimated via logistic 
regression models.  Since AZD-1775 dose is of primary interest in this aim, 
patients in dose levels -2 and -1 may be lumped together since they receive the 
same AZD-1775 dose and only there dose of gemcitabine differs.  
 
 


Dose escalation trial of Wee1 inhibitor 
 
 
 
30
13 
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Appendix A New PDF of drug interactions is added to the pdf version-
word version is not available from Astra Zeneca.