A Phase 2 Study of WEE1 Inhibition With AZD1775 Alone or Combined With Cytarabine in Patients With Advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome
Phase: PHASE2
Conditions: Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome With Isolated Del(5q), Myelodysplastic/Myeloproliferative Neoplasm, Previously Treated Myelodysplastic Syndrome, Recurrent Adult Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia
Sponsor: Mayo Clinic

 
1  
MC1488 
 
 
 
Mayo Clinic Cancer Center 
 
 
MC1488: A Phase 2 study of WEE1 Inhibition with AZD1775 alone or combined with Cytarabine 
in Patients with advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome 
 
 
 
Study Chair: 
Lisa Sproat, M.D. 
 
 
Mayo Clinic  
 
 
5777 E. Mayo Blvd. 
 
 
Phoenix, AZ 85054 
 
 
480/301-8000 
 
 
IND Holder: 
 
 
 
 
 
Study Co-Chairs: 
  
 
 
 
 
 
 
 
Statistician:
 
 
 
 
 
 
 
 
 
Drug Availability  
Supplied Investigational Agents:  AZD1775 
Commercial Agents:  Cytarabine (cytosine arabinoside or AraC) 
 
 
 Study contributor(s) not responsible for patient care. 
 
 
 
Document History 
(Effective Date) 
Activation 
May 5, 2017 
MCCC Addendum #1  
May 5, 2017 
MCCC Amendment #2 
February 12, 2017 
 
 
 
 

 
3  
AZD1775 in AML and MDS 
 
 
Addendum #1 
 
Index 
 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Grouping and Stratification Factors 
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care/Concomitant Medications 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations 
18.0 
Records and Data Collection Procedures 
19.0 
Budget Considerations 
20.0 
References 
 
Appendix I - ECOG Performance Status Scale 
Appendix II –Medication Diary 
Appendix III - New York Heart Association Classification of Cardiac Disease 
Appendix IV - Revised International Prognostic Scoring System (IPSS-R) for MDS 
Appendix V – Risk Status Based on Validated Cytogenetics and Molecular Abnormalities 
Appendix VI - List of prohibited concomitant medications and concomitant medications requiring caution 
Appendix VII - Patient Information Sheet 
Appendix VIII – EORTC QLQ-C30 & Myeloproliferative Neoplasm Symptom Assessment Form Total 
Symptom Score (MPN-SAF TSS) 
Appendix IX – Childbearing Potential & Contraception

 
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1.0 
Background 
 
1.1 
Acute Myeloid Leukemias (AML) and Myelodysplastic Syndrome (MDS)  
 
Despite progress in the treatment of AML and MDS, most adult patients with AML and 
advanced/progressive MDS still do very poorly with current therapy and many die from 
their disease (Abe et al. 2008). Patients with primary refractory or relapsed AML have a 
particularly poor outcome, as well as MDS patients who are refractory, progress on or 
relapse after hypomethylating agents (HMA) based therapies (Duong et al. 2013, Prébet  
et al. 2011,  Jabbour et al. 2010).  
 
Acute myeloid leukemia patients who fail to achieve a complete remission (CR) with first 
induction therapy have a dismal outcome and only a small percentage of patients are alive 
at 1 year (Bai et al 2008). Current therapy is also inadequate for relapsed leukemias with 
a true long-term cure rate of less than 10% (Bai et al. 2008). Recently, comparable 
clinical activity and outcomes between HMAs and cytotoxic chemotherapy has been 
demonstrated in secondary, elderly and unfavorable cytogenetics AML in first line 
therapy (Quantas-Cardama et al. 2012 and Fenaux et al. 2010). Thus, many experts feel 
that these patients are candidates for lower intensity treatment as first line intervention.  
 
The outcome of patients with advanced myelodysplastic syndrome (MDS) in the 
intermediate and IPSS intermediate-2, and especially high-risk category is almost as poor 
as for patients with acute leukemia. Median survival in this group is 4-5 months (Schanz 
et al. 2012 and Greenberg et al. 1997). The two approved HMAs Azacytidine (AZA) and 
Decitabine (DAC) have activity, however CR rates are less than <10-18% and overall 
responses (CR, PR and clinical benefit such as hematological improvements) approach at 
a maximum 40-50% in the first line treatment setting in MDS (Fenaux et al 2009 and 
Lubbert et al 2011).  
 
Responses and survival in MDS patients having failed or progressed on or after HMA 
treatment is very poor with a median survival of 4.3-5.8 months and a 1-year survival of 
17-29% in the largest three studies to date (Duong et al. 2013, Prébet et al. 2011,  Jabbour 
et al. 2010). Accordingly HMA failure MDS represents one of the largest patient groups 
in need for novel agents and investigational therapies. In fact, apart from allogeneic 
transplant for which most patients do not qualify, investigational regimens were as good 
and better than cytotoxic chemotherapy after HMA failure (Prébet et al. 2011). 
 
Azacitidine (AZA) and Decitabine (DAC) are often used as lower intensity, outpatient 
treatments in elderly AML patients not fit for induction treatment. Responses are 
comparable to somewhat lower than in treating MDS patients with CR/CRi rates ranging 
from 7-18% (Fenaux et al. 2010 and Kantarjian et al. 2012). Thus, there is likewise a 
great demand for improvement of alternative lower intensity, outpatient regimens and 
new combinations for elderly AML patients.  Interestingly, in several earlier studies low-
dose s.c. Cytarabine (AraC) alone or with growth factor support exhibited quite 
encouraging response rates of CR and PR of 18%  and 8% respectively (Aul & Schneider 
1989). Several studies also have been reported on the potential activity of low-dose AraC 
(AraC) in MDS (Visani et al. 2004). However, if the natural history of the disease is 
changed, and there is significant room for improvements in therapeutic options for these 
patients. In summary, available data demonstrates the clinical activity of HMAs and 
AraC specifically in elderly AML and MDS patients, providing additional clinical 

 
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justification, in addition to our pre-clinical data, to combine AZD1775 with AraC as one 
of the treatment arms in this protocol.  
 
In conclusion, improvements in therapy for elderly AML patients, patients with 
relapsed/refractory AML as well as advanced MDS patients, particularly those who failed 
HMA treatments are urgently needed. Investigational therapies are one of the 
recommended therapeutic choices for these patients due to the lack of effective standard 
salvage treatments. Pre-clinically, inhibition of WEE1 kinase is one of the most potent 
sensitizers to AraC, identified in large-scale RNAi screens. Sensitization potential 
between WEE1 inhibtion and AraC was best at lower AraC concentrations as we have 
published (Tibes et al. 2012), and hence lower dose AraC will be used in the combination 
arm as proposed in this protocol. The design of this trial offers relapsed and progressive 
AML and MDS patients novel treatment options in the form of either single agent 
AZD1775 or in combination with AraC, and thereby will investigate for the first time the 
clinical activity of WEE1 inhibition in AML and MDS.  
 
 
1.2 
Overview of the WEE1 pathway and DNA damage and Cell cycle inhibition  
 
 
1.21  
Background on Cytarabine, DNA Damage Repair and Cell Cycle 
Checkpoints 
 
Cytarabine (AraC) has been the most widely used and is still the overall most active drug 
in AML (Rowe 2009). It forms the backbone of most AML and MDS induction and 
consolidation regimens, and has activity at low doses given subcutaneously both in AML 
and MDS (Bolwell et al. 1987, Kantarjian et al 2012). AraC is an S-phase (cell cycle) 
specific agent that undergoes conversion and phosphorylation to a tri-phosphate form 
with subsequent incorporation into DNA of dividing cells. This usually triggers activation 
of the intra-S phase checkpoint a genotoxin-activated signaling pathway that stabilizes 
stalled replication forks and slows cell cycle progression by blocking the firing of late-
acting DNA replication origins (Dimitrova  & Gilbert 2000, Morita 1976, Grant 1998).  
AraC incorporation leads to single stranded DNA damage that later is converted to 
double strand DNA damage ultimately leading to cell cycle arrest and repair of damaged 
DNA (Do et al. 2013). Many of these processes are either directly regulated by WEE1 
kinase, i.e. cell cycle arrest via CDK1/2, as well as WEE1 kinase plays a central role in 
the networks of DNA repair initiation, i.e. via its effect on CHEK1 or PLK1. Thus WEE1 
kinase has a central role in many checkpoint and DNA damage mediated processes 
(Langerak & Russell 2011, Perry & Kornbluth 2007).  
 
Interfering with cell cycle checkpoints and DNA damage repair (DDR) in combination 
with agents that cause DNA single or double strand breaks has been proposed as a 
promising concept in cancer therapy and captures a potential synthetic lethal molecular 
interaction. Advanced leukemias are genomically highly unstable, with cell cycle 
checkpoints and DDR pathways  impaired causing these cells to rely on a fewer number 
of checkpoints, and highly reliant on the later stage in the cycle cycle at the G2/M 
transition  (Cavelier et al. 2009, Didier et al. 2008). Thus, interfering with cell cycle 
checkpoints and DNA damage repair (DDR) in combination with agents that cause DNA 
single or double strand breaks such as AraC has been proposed as a promising concept in 

 
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cancer therapy and captures  a potential synthetic lethal molecular interaction (Tibes et al. 
2012). 
 
 
 
 
1.22  
Inhibition of WEE1 kinase by AZD1775  
 
WEE1 kinase is an evolutionary conserved kinase regulating late G2/M cell cycle 
checkpoints, directing cells either towards cell cycle arrest allowing time for DNA repair 
or proceeding with progression into mitosis. However, emerging data indicates that 
WEE1 kinase activates the intra S-phase checkpoint as well and interferes with DNA 
damage response through various processes. WEE1 kinase acts through and is the main 
kinase phosphorylating and regulating Cdc2 (CDK1), which in complex with Cyclin B  is 
a master regulator of mitotic entry at G2/M. However, WEE1 is also the main kinase 
phosphorylating CDK2 (assembles with cyclin A) and exerts a prominent function in 
G1/S phase and the intra S-phase checkpoint (Perry & Kornbluth 2007).  
Based on two unbiased RNAi screens and subsequent validation studies, 
inhibition of WEE1 kinase was identified as one of the most potent sensitizers to AraC in 
AML cells (Tibes et al 2012, Porter et al. 2012). We postulate that WEE1 kinase is the 
essential kinase that governs the “escape pathway” in malignant myeloid cells under 
cellular stress with cytotoxic agents, particularly AraC. Therefore inhibition of WEE1 
kinase by AZD1775 with AraC is a rational combination in aggressive myeloid 
malignancies and leukemias. In addition, AZD1775 had single agent activity and its anti-
leukemic activity alone or in combination is independent of p53 mutation and function in 
AML (Van Linden et al. 2013 and Tibes, unpublished observation). 
 
 
1.23 
Rational of combined Cytarabine (AraC) and WEE1 inhibition  
 
AraC is the backbone of therapy for myeloid leukemias. It is used in regimens for 
lymphoid leukemias as well as for patients with advanced MDS. Pre-clinically WEE1 
inhibition sensitized cells to several cytotoxic agents including AraC. In Phase 1 and 2 
ongoing clinical trials in solid tumor patients, the only in class Wee1 inhibitor AZD1775 
is well tolerated with platinum compounds and gemcitabine providing a therapeutic 
window even at full standard doses of cytotoxic chemotherapies.  We have generated 
preliminary data that shows potent sensitization with synergy combining AraC and 
AZD1775 in vitro and ex vivo.  In addition WEE1 is highly expressed in myeloid 
leukemias (Tibes et al. 2012). Based on these data we hypothesize that the combination 
of AraC and WEE1 inhibitor AZD1775 will have strong synergistic clinical activity with 
manageable toxicity (given the already existing clinical data of tolerability in solid 
tumors) in patients with advanced myeloid malignancies. We further postulate that there 
will be single agent anti-leukemic activity of AZD1775 providing a rationale to compare 
AZD1775 single agent vs. in combination with AraC in patients with MDS and AML that 
would otherwise have limited therapeutic options remaining. 
 
 
 
 
1.3  
Overview of AZD1775 
 
 

 
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The following overview of AZD1775 (Section 1.3 and 1.4) is based on the knowledge 
available at the time this protocol was first finalized and is based on Edition 12 of the 
Investigator’s Brochure, Edition 12, dated 18 February 2015, with a data cut-off date of 
11 November 2014.  For more detailed and up-to-date information, please consult the 
current Investigator’s Brochure. 
 
 
AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small-
molecule inhibitor of the WEE1 kinase that sensitizes tumour cells to cytotoxic agents 
and is being developed for the treatment of advanced solid tumours with p53 pathway 
deficient malignancies. Inhibition of the DNA damage checkpoint kinase WEE1 
potentiates genotoxic chemotherapies by abrogating cell-cycle arrest and eliminating the 
opportunity for proper DNA repair to occur. From a therapeutic standpoint, inhibition of 
checkpoint kinases that mediate cell-cycle arrest may force tumour cells to continue cell 
division before chemically induced DNA damage is repaired, eventually causing 
apoptosis or mitotic catastrophe (Medema and Macurek 2012). 
 
The primary objective of the clinical development of AZD1775 is its use as a 
chemosensitizing drug in combination with a cytotoxic agent (or combination of agents) 
for treatment of advanced tumors. In vitro experiments demonstrate that AZD1775 has 
synergistic cytotoxic effects when administered in combination with various DNA 
damaging agents that have divergent mechanisms of action. In studies with matched 
ovarian cell lines (p53 WT and shRNA p53 knockdown), AZD1775 enhanced cell death 
induction by gemcitabine in p53-deficient but not in p53 positive control cells. AZD1775 
also demonstrates synergistic effects on cell death induction when used in combination 
with cisplatin and carboplatin in a p53-dependent manner. Cervical cancer cells with 
HPV induced inactivation of p53 demonstrated chemosensitization to cisplatin and 
topotecan by AZD1775. 
 
The ability of AZD1775 to affect tumour growth as monotherapy or to enhance the 
antitumor effects of gemcitabine, carboplatin, cisplatin, capecitabine, 5-fluorouracil, and 
gamma irradiation was evaluated in immunocompromised host animals bearing human 
xenograft tumors. 
 
The anti-tumor effect of AZD1775 dosed as monotherapy was investigated in the A427 
non small-cell lung cancer nude mouse xenograft model. Daily treatment with AZD1775 
led to 51% tumour regression (n=10) and mean body weight loss did not exceed 5% over 
the course of the study. AZD1775 single agent treatment also led to tumour growth 
inhibition in additional xenograft models: 92% TGI (Day 28) in SKMES1 model of non-
small-cell-lung cancer (NSCLC), 13% regression (day 11) in LoVo colorectal cancer 
model and 64% TGI(day 19) in NCI-H2122 NSCLC. 
 
The anti-tumour effect of AZD1775 in combination with gemcitabine was investigated in 
the WiDr (human colorectal adenocarcinoma) nude rat xenograft model. Several 
schedules of gemcitabine + AZD1775 were explored. A 10 mg/kg dose of AZD1775 
significantly enhanced the anti-tumour effect of gemcitabine in WiDr tumours with % 
treated/control (T/C) = -2%. 
 
The anti-tumour effect of AZD1775 in combination with carboplatin was investigated in 
the HeLa-luc (human cervical adenocarcinoma) nude rat xenograft model. AZD1775 

 
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dose-dependently enhanced the anti-tumour effect of carboplatin tumors with %T/C = 85, 
39 and 28% at doses of 10, 20 and 30 mg/kg, respectively. 
 
The anti-tumour effect of AZD1775 in combination with carboplatin or cisplatin was also 
investigated in the HeLa-luc model. These experiments showed that AZD1775 dose-
dependently enhanced the anti-tumour effect of cisplatin with %T/C = -5 and -16% at 
doses of 10 and 20 mg/kg respectively, compared to or cisplatin alone (24% T/C)  
 
AZD1775 enhanced the anti-tumour efficacy of 5-FU and capecitabine when used in 
combination with these agents, as well; and experiments with nude mouse xenograft 
models of A549 (p53 wild type) and Calu-6 (p53 null) NSCLC cell lines showed 
enhanced antitumour growth effect of radiotherapy preferentially in p53 mutant xenograft 
tumors. Please refer to the AZD1775 Investigator Brochure (IB) for more detailed 
information regarding these experiments and findings. 
 
 
 
1.31 Pharmcodynamics 
 
Inhibition of CDC2 (Y15) phosphorylation and induction of Histone H3 (Ser10) 
phosphorylation were observed upon Wee1 inhibition in vitro. In vivo PD effects of 
AZD1775 were evaluated using the WiDr xenograft nude rat model. AZD1775 (0.5, 1.0, 
3.0 and 7.0 mg/kg/hr) was intravenously infused for 8 hrs, 24 hrs after administration of 
gemcitabine (50 mg/kg, IV). PD marker analyses were performed on tumor tissue 
isolated immediately after the infusion. Continuous infusion of AZD1775 caused 
reduction of phospho-CDC2 (Y15) in WiDr xenograft tumor tissue in a dose-dependent 
manner. The EC50 value was 0.28 μM, and about 80% inhibition was achieved at 1.0 
mg/kg/hr (0.45 μM at 8hr). Similar dose dependency was observed in the CEA (induction 
of phospho-Histone H3 [Ser10]) in tumor tissue. EC50 value was 0.21 μM, and maximal 
effect was observed at approximately 1.0 mg/kg/hr. These data suggest that phopsho-
CDC2 (Y15) and phospho-Histone H3 (Ser10) could be useful as AZD1775 PD 
biomarkers in tumors.  
 
Similar PD marker changes were observed in surrogate tissues, such as skin hair follicle 
and peripheral blood cells in the presence or absence of the DNA damaging agent 
gemcitabine. Strong pCDC2 (Y15) immunopositivity was observed in skin hair bulb in 
the hair follicle. In combination with gemcitabine (50 mg/kg, IV: 24 hr before AZD1775 
dosing), AZD1775 (0.5, 1.0 and 3.0 mg/kg/hr x 8 hrs, IV-infusion) dose-dependently 
decreased these signals. An almost complete reduction of phospho-CDC2 signal was 
achieved at 3.0 mg/kg/hr. Phospho-CDC2 (Y15) signal in peripheral blood cells were 
also reduced in a dose dependent manner with significant reduction at 1.0 and 3.0 
mg/kg/hr. These results suggest that hair follicles and blood cells are surrogate tissues in 
which phospho-CDC2 (Y15) can be used as a marker to predict PD/efficacy in tumors 
treated with gemcitabine. 
 
Similar dose dependent reduction of phospho-CDC2 (Y15) by AZD1775 (0.5, 1.0 and 
3.0 mg/kg/hr x 8 hrs, IV-infusion) was observed without gemcitabine pretreatment in 
both skin hair follicles and tumors. Thus, these PD markers may be available to predict 
PD/efficacy in tumors in the presence or absence of DNA damaging agents. 
 
 
 
1.32 
Nonclinical pharmacokinetics and metabolism 
 
The pharmacokinetics of AZD1775 were evaluated in male Sprague-Dawley rats and 

 
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Beagle dogs following intravenous (IV) and oral administration. AZD1775 exhibited 
high plasma clearance in rats and dogs (57.3 and 50.8 mL/min/kg, respectively). The 
terminal half-life (T1/2) of the compound was short in both species (1.6 and 1.1 hr in rats 
and dogs, respectively). The oral bioavailability was 59.7% in rats and 33.6% in dogs. 
AZD1775 (1 μM) was moderately bound to plasma proteins from rat, dog and human, 
with the unbound fractions being 23.2, 40.0, and 39.5%, respectively. Metabolism was 
the major route of elimination of AZD1775 in rat and dog. The major metabolic pathway 
of AZD1775 in human liver preparations was oxidative metabolism. All metabolites 
observed in human liver preparations were also formed in the rat and dog. Oxidative 
metabolism of AZD1775 was mediated predominantly by cytochrome P450 (CYP) 3A4 
and FMO3. AZD1775 was a weak reversible inhibitor of CYP2C8, CYP2C9, CYP2C19 
and CYP3A4. In addition, AZD1775 was a time-dependent inhibitor of CYP3A4. 
Collectively, these data indicate that the pharmacokinetics of AZD1775 could be altered 
if AZD1775 is coadministered with CYP3A4 inhibitors and/or inducers, and depending 
on AZD1775 therapeutic plasma concentrations, there is also some potential for drug 
drug interactions when coadministered with CYP3A4 substrates. 
 
 
 
1.33 
Toxicity and safety Studies with AZD1775 
 
In rats, the toxicologic profile of AZD1775 was evaluated using 4 separate dosing 
schedules; single-dose, once weekly for three weeks, and daily for 7 consecutive days or 
one month. A recovery (treatment-free period) was included in each study design. With 
each of these schedules, the toxicologic profile for physical signs, hematological changes, 
and gross and histomorphological findings were expected based on the cytotoxic 
mechanism of action of AZD1775. The major organs affected were proliferation 
dependent organs such as lymphoid and hematopoietic organs and gastrointestinal tract. 
Evidence of reversibility of all changes, based on drug-related effects observed in early 
death rats, was generally demonstrated by the end of the 2-week recovery period.  
 
In the fifteen-day oral toxicity study, conducted in rats dosed once weekly for three 
weeks (Study Days 1, 8, and 15), no mortality or severe toxicity was observed at 300 
mg/kg/day, however treatment-related body weight changes and hematological changes 
were observed. The magnitude of change of absolute reticulocyte counts and white blood 
cell parameters observed after the first dose were generally similar to those after the third 
dose, indicating that additive toxicity was not seen after 3 weekly intermittent doses. A 
trend toward recovery was observed for many of these changes following the 14 day 
recovery period, however recovery of hematological changes appeared to be delayed. 
Since the histomorphologic examination of the bone marrow revealed normal cellularity 
at the completion of the 14 day recovery, it is expected that hematological changes will 
fully recover as was seen in dogs. The magnitude of the decreased WBC and erythroid 
parameters were close to those observed in the previous single dose toxicity study in rats. 
No histological findings were noted at the completion of the 14 day recovery period in 
the 300 mg/kg/day once weekly group. 
 
In a single dose oral toxicity study, severe irreversible toxicity (mortality) was seen in 1 
female out of 10 female rats after a single dose at 300 mg/kg (1800 mg/m2). In a 
consecutive 7-day repeat dose study, expected toxicity of hematopoietic organs and the 
gastrointestinal tract were observed and associated with mortality at 75 mg/kg/day and 
300 mg/kg/day. At 25 mg/kg/day (14.2 μM/hr), all animals survived to scheduled 
necropsies and all observed toxicities were demonstrated to be reversible during the 2-
week recovery period. In a 1 month rat toxicity study, toxicity of hematopoietic organs 

 
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(including bone marrow, spleen, thymus, mesenteric lymph nodes, Peyer's patches) were 
observed at ≥10 mg/kg/day in females and at 25 mg/kg/day in males. Serum biochemical 
changes were observed at 25 mg/kg/day only and consisted mainly of very slight to slight 
decreases in total protein, albumin, and globulin and very slight increases in alanine 
aminotransferase (ALT) and alkaline phosphatase (ALP) in females whereas in males, the 
changes were limited to a slight decrease in globulin. Very slight to slight liver 
hepatocellular vacuolation, very slight centrilobular degeneration and slight cardiomegaly 
were observed at ≥10 mg/kg/day in females (except for cardiomegaly observed in 
females at 25 mg/kg/day only) and at 25 mg/kg/day in males; these findings in the liver 
and heart were considered to be correlated with anemia. At 25 mg/kg/day (25 μM/hr in 
females and 10 μM/hr in males), all animals survived to scheduled necropsies. In general, 
findings at 25 mg/kg/day were more marked in females compared to males, and all 
findings showed a trend towards recovery following a 4-week recovery period. 
 
In dogs, similar dosing schedules as studied in rats were evaluated (single dose, once 
weekly for three weeks, and daily for 7 consecutive days or one month). Severe 
irreversible toxicity was not observed at the highest dose tested of 36 mg/kg (720 mg/m2) 
after a single dose and 3-intermittent doses (mean area under the plasma concentration 
time curve [AUC] from time 0 to 24 hours postdose [AUC0-24hr] for sexes combined = 
17.4 μM/hr and 17.6 μM/hr, respectively). As reported in rats studies, similar 
hematologic changes were observed in dogs as was reported in rats; notably decreases in 
reticulocytes. In both the single-dose and 3 intermittent dose studies, reticulocyte counts 
returned to baseline following the 14-day recovery period and histomorphologic 
examination revealed normal cellularity in the bone marrow in these studies. In dogs 
receiving AZD1775 for 7 days, 15 mg/kg/day (9.5 μM/hr) was well tolerated and 
demonstrated expected toxicities to hematopoietic organs and the gastrointestinal tract. 
During a 2-week recovery period, test article-related changes recovered or showed a 
trend towards reversibility. In a 1-month dog repeat dose study, dose levels of 3 
mg/kg/day and 10 mg/kg/day were administered daily for about 1 month. Dose dependant 
toxicity of hematopoietic organs (including bone marrow, thymus, lymph nodes, Peyer's 
patches), gastrointestinal tract, testes as well as serum biochemical changes (very slight 
or slight decreases in total protein, albumin, and globulin) were observed. At 10 
mg/kg/day (3.60 μM/hr), all animals survived to scheduled necropsies. All findings 
showed a trend towards recovery following the 4-week recovery period. 
 
AZD1775 was negative in the Microbial Mutagenesis Assay but positive in 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. 
 
Combination treatment with AZD1775 and 5-FU was administered to tumor-bearing 
female nude rats for up to 5 days with several administration schedules. Test article 
related hematological changes (decreases in erythroid parameters, reticulocytes, 
leukocytes, and/or platelets) were observed with the combination treatment with 
AZD1775 plus 5-FU. There were no remarkable differences in the severity of these 
changes across the different AZD1775 administration schedules in combination with 5-
FU. 
 
These preclinical observations were expected based on the intended pharmacologic action 
(cytotoxicity) of the compound. The toxicity profile of AZD1775 in rats and dogs 
following 1 month of daily dosing was generally consistent with the toxicity profile 

 
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previously observed in studies of shorter duration. Observations in rat and dog toxicology 
studies are generally monitorable and with evidence of reversibility within a 4-week 
recovery period were demonstrated to be reversible following a 2 week recovery period. 
These studies support continued clinical trials in subjects with advanced stage cancer. 
 
 
 
 
1.4  
Clinical Experience with AZD1775 
 
The following overview of the clinical experience with AZD1775 is based on the 
knowledge available at the time this protocol was written and is based on Edition 12 of 
the Investigator’s Brochure, Edition 12, dated 18 February 2015, with a data cut-off date 
of 11 November 2014.  For more detailed and up-to-date information, please consult the 
current Investigator’s Brochure. 
As of 11 November 2014, a total of 372 patients have been exposed to AZD1775 in 
AstraZeneca-sponsored or Merck-sponsored clinical studies, which include 1 completed 
study (Study PN001), 2 studies that were terminated early (Studies PN005 and PN008) 
and 3 ongoing studies (Studies PN004, D6011C00001, and D6011C00002). 
 
PN001: a first-time-in-patients (FTIP), Phase I, dose-escalation study evaluating 
AZD1775 both as monotherapy and combination therapy with gemcitabine, cisplatin, 
or carboplatin in adult patients with advanced solid tumours.  This study has been 
completed except for Part 3. 
 
PN005: a Phase I, dose-escalation study evaluating AZD1775 as monotherapy (Part 
1), combination therapy with 5-FU (Part 2), and combination therapy with 5-FU plus 
cisplatin (Part 3) in adult Japanese patients with advanced solid tumours.  This study  
was terminated early due to portfolio prioritization in oncology at Merck after 3 
patients had been enrolled in Part 1 and 8 patients had been enrolled in Part 2.  Part 3 
was not initiated. 
 
PN008: a Phase I/IIa, dose-escalation study evaluating AZD1775 in combination 
with topotecan plus cisplatin in adult patients with cervical cancer was terminated 
early due to portfolio prioritization in oncology at Merck after 7 patients had been 
enrolled in the dose-escalation part of the study.  The Phase IIa part was not initiated. 
 
PN004: a Phase II study evaluating AZD1775 combined with carboplatin and 
paclitaxel in patients with platinum-sensitive p53-mutant ovarian cancer.  This study 
is ongoing. 
 
D6011C00001: a lead-in Phase II multicentre, randomised, double-blind study 
comparing AZD1775 plus docetaxel with placebo plus docetaxel in previously 
treated patients with non-small-cell lung cancer.  This study is ongoing. 
 
D6011C00002: a Phase II study of AZD1775 plus pemetrexed and carboplatin 
followed by a randomised comparison of pemetrexed and carboplatin with or without 
AZD1775 in patients with previously untreated stage IV non-squamous non-small 
cell lung cancer.  This study is ongoing. 
In addition, 93 patients have also received AZD1775 as part of externally-sponsored 
scientific research.  These patients have received single doses per cycle as high as 1300 
mg of AZD1775 as monotherapy, 325 mg of AZD1775 in a single-dose in combination 

 
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with chemotherapy, and 325 mg twice a day (BID) in a multiple-dose regimen in 
combination with chemotherapy. 
 
 
 
 
1.41 
Clinical Safety 
 
Several clinical studies with AZD1775 alone and in combination with (mostly full dose) 
cytotoxic chemotherapy have been conducted.   
 
The MTD of AZD1775 monotherapy has not been established. Single doses of AZD1775 
up to 1300 mg were well tolerated. 
 
The MTDs of AZD1775 when administered with chemotherapy are presented in the table 
below: 
Maximum-tolerated doses of AZD1775 when administered in combination with chemotherapy 
Chemotherapy 
Dose Frequency 
AZD1775 (mg) 
Gemcitabine 1000 mg/m2 on Day 1 weekly for 
3 consecutive weeks out of every 4 weeks 
Single-dose 
200 
Cisplatin 75 mg/m2 on Day 1 every 21 days 
Single-dose 
200 
Carboplatin AUC 5 on Day 1 every 21 days 
Single-dose 
325 
Gemcitabine 1000 mg/m2 on Day 1 weekly for 
3 consecutive weeks out of every 4 weeks 
Multi-dose 
175 QD x2 days 
Cisplatin 75 mg/m2 on Day 1 every 21 days 
Multi-dose 
200 BID x 2.5 days 
Carboplatin AUC 5 on Day 1 every 21 days 
Multi-dose 
225 BID x 2.5 days 
BID = twice daily; QD = once daily 
 
 
 
There were no DLTs observed for patients receiving monotherapy with AZD1775.  For 
combination treatments, DLT rates at all MTDs were less than 30% in Study PN001.  
Oral administration of AZD1775 both as monotherapy and in combination with 
gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumours was 
tolerable. 
Based on the safety data from the 3 completed clinical studies, the most frequently 
reported drug-related AEs were blood and lymphatic disorders (neutropenia, 
thrombocytopenia, anaemia), gastrointestinal disorders (diarrhoea, vomiting, nausea), and 
general disorders and administration site conditions (fatigue, pyrexia). 
 
The most frequently reported SAEs occurred within the gastrointestinal, infections and 
infestations, and blood and lymphatic disorders system organ classes.  The SAEs reported 
to be related to study medication in PN001 included nausea, vomiting, diarrhoea, gastric 
ulcer, colitis, dehydration, pyrexia, hemiparesis, renal impairment, renal failure, urinary 
tract infection, dyspnoea, recall phenomenon, palpitations, lung infiltration, agitation, 
neutropenia, febrile neutropenia, anaemia, thrombocytopenia, leukopenia, increased 
blood creatinine, and hyperbilirubinaemia. Events that led to death in that study included 
malignant neoplasm progression, renal failure, respiratory failure, pneumonia, hypoxia, 
and lung infiltration. 
Cardiac disorders (tachycardia, palpitations, QTc prolongation) and gastrointestinal 
haemorrhage were not observed frequently, but are considered to be important potential 
risks. 
 

 
14  
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The single-dose maximum tolerated dose (MTD) for both the gemcitabine and 
cisplatin combination therapies was 200 mg of AZD1775. Dose-limiting 
toxicities (DLTs) tended to be hematological in nature (i.e. leukopenia, 
neutropenia and thrombocytopenia) in the gemcitabine group and constitutional 
(i.e. diarrhea and dehydration) in the cisplatin group. The single-dose MTD for 
the combination with carboplatin was 325 mg of AZD1775. DLTs in this group 
were related to serum chemistry. 
 
Hematologic DLTs were most commonly observed in the multiple-dose 
AZD1775 combination treatment groups with gemcitabine and cisplatin. An 
MTD of AZD1775 in combination with gemcitabine was established with a dose 
of 175 mg QD x 2 days during Week 1 with gemcitabine 1000 mg/m2 once 
weekly for 3 consecutive weeks, every 4 weeks. Two DLTs (grade 3 febrile 
neutropenia and grade 3 aspartate aminotransferase and alanine aminotransferase 
(AST/ALT) increase) were observed at 200 mg once daily for 2 days with the 
regimen in combination with gemcitabine. The dose was adjusted to 175 mg once 
daily for 2 days, and one DLT has been reported to date. The MTD for 
combination with cisplatin has been exceeded at the 250 mg dose level, and 
tolerability of the MTD at 200 mg BID has been confirmed. DLTs observed in 
the multiple-dose carboplatin combination have been both hematological and 
constitutional in nature. The multiple-dose MTD in combination with carboplatin 
is AZD1775 225 mg BID. 
 
The MTD for AZD1775 in combination with 5-FU was not reached due to early 
study termination. DLTs of encephalopathy and hyponatraemia were observed in 
the AZD1775 20 mg BID in combination with 1000 mg/m2 5-FU treatment 
group. 
 
Triplet-based therapy was administered in the study PN004 with AZD1775, 
carboplatin, and paclitaxel. The starting dose of 225 mg AZD1775 (BID for 5 
total doses) in Part 1 was generally well tolerated. One patient experienced a 
DLT in the first six patients treated and the dose remained at 225 mg BID 2.5 
days. A total of 15 patients were treated, with 3 DLTs being reported (grade 3 
and 4 febrile neutropenia and grade 4 thrombocytopenia). The study expanded to 
Part 2 and is ongoing. Other toxicities were generally blood and lymphatic 
system disorders and gastrointestinal. 
 
For the combination of AZD1775 with topotecan plus cisplatin in study PN008, 
toxicities were generally hematological and gastrointestinal in nature. No 
unexpected toxicities were observed. 
 
In study PN009 and the premarket formulation substudy to PN001 (both 
combining 2.5-day BID dosing of AZD1775 with carboplatin) there were no 
appreciable differences in toxicity from the ones observed in the carboplatin arm 
of study PN001. However, increased hematological toxicity was observed, which 
is considered to be a function of a drug-drug interaction with aprepitant (which 
was administered as anti-nausea medication in these studies). 
 

 
15  
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1.42  
Clinical Efficacy 
 
In Study PN001, of 176 evaluable patients who received AZD1775 (either single or 
multiple doses) as monotherapy or in combination with gemcitabine, cisplatin, or 
carboplatin, a partial response (PR) (confirmed and unconfirmed) was observed in 17 
(9.7%) patients, and stable disease (SD) was observed in 94 (53.4%) patients.  The table 
below shows the efficacy outcome in Study PN001 by treatment arm. 
Study PN001 Efficacy 
Treatment 
Dose 
Frequency 
Patients 
Treated (N) 
Patients Evaluable 
[N (%)] 
PR* 
(N) 
SD 
(N) 
PD 
(N) 
NE 
AZD1775 in 
combination with 
gemcitabine 
Single-dose 
14 
12 (85.7) 
1 c 
8 
2 
1 
AZD1775 in 
combination with 
cisplatin 
Single-dose 
13 
12 (92.3) 
1 c 
1 u 
7 
3 
 
AZD1775 in 
combination with 
carboplatin 
Single-dose 
16 
15 (93.8) 
1 c 
1 u 
3 
9 
1 
AZD1775 in 
combination with 
gemcitabine 
Multi-dose 
67 
55 (82.1) 
1 c 
2 u 
35 
17 
 
AZD1775 in 
combination with 
cisplatin 
Multi-dose 
45 
38 (84.4) 
3 c 
4 u 
16 
15 
 
AZD1775 in 
combination with 
carboplatin 
Multi-dose 
46 
44 (95.6) 
2 u 
25 
16 
 
* confirmed and unconfirmed 
NE=not evaluable, c=confirmed, u=unconfirmed 
 
No complete or PRs were observed in either of Studies PN005 or PN008 at the time that they were 
terminated. 
 
 
 
 
1.43  
Clinical Pharmacokinetics and pharmacodynamics 
 
Clinical Pharmacokinetics 
 
The PK data of AZD1775 following a single oral administration showed a 
moderate rate of absorption with a Tmax occurring at 3 to 4 hours.  Post-peak 
plasma concentrations declined essentially in a mono-exponential manner with a 
t1/2 in the region of 10 hours.  Exposure as measured by maximum plasma drug 
concentration observed (Cmax) and area under the curve (AUC 0-∞) increased in 
a dose-proportional manner over the dose range of 325 to 1300 mg. The urinary 
excretion of AZD1775 was investigated after single-oral-dose monotherapy at 
325, 650, and 1300 mg of AZD1775. The mean percent of total AZD1775 

 
16  
MC1488 WEE1 
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excreted unchanged in urine over a 24-hour period was 5.15% to 11.9%, which is 
comparable to what was observed in preclinical species (urinary excretion as 
unchanged drug in rats and dogs were ~8.6% and 11.8% of the dose, 
respectively, over a 48-hour collection interval). The mean renal clearance of 
AZD1775 at 325 mg was approximately 2.30 L/hour (38.3 mL/minute), below 
that expected due to filtration alone (based on an AZD1775 unbound fraction of 
39.5% and a typical glomerular filtration rate of 120 mL/minute) of 
47.4 mL/minute, indicating that net reabsorption appeared to be taking place. 
Overall, the results suggest that urinary excretion is not the major route of 
AZD1775 elimination 
 
Following single (100 to 325 mg) and multiple dose administrations of AZD1775 
(25 to 325 mg BID and 100 to 200 mg once daily [QD]) with carboplatin, 
cisplatin, and gemcitabine, plasma exposure of AZD1775 was consistent with 
predictions based on the single-dose regimen. The median Tmax values were 
between 1.02 and 4.25 hours. Given a t1/2 of approximately 10 hours, steady-
state was expected to be achieved after approximately 3 days of AZD1775 
treatment in adult patients. Accumulation ratios for AZD1775 BID doses 
(geometric mean ratio = Day 3/Day 1) for the area under the plasma-
concentration time curve from time 0 to 8 hours post dose (AUC0-8hr), Cmax, and 
plasma drug concentration observed at 8 hours post dose (C8hr) averaged 0.991 to 
3.82, 0.928 to 3.32, and 1.01 to 2.98, respectively, across tested AZD1775 BID 
doses in combination with gemcitabine, cisplatin, and carboplatin. 
 
Preliminary investigation of drug-drug interactions in Study PN001 suggest a 40 
up to 60% increase in the exposure of AZD1775 in the presence of aprepitant 
(moderate CYP3A4 inhibitor), but no effect with the concomitant administration 
of steroids (moderate CYP3A4 inducers). 
Preliminary studies also suggested that the Pre-marketed Oral Formulation 
(PMF) of AZD1775 was similar to that of the Fit-For-Purpose (FFP) formulation. 
  Preliminary PK data from a Japanese combination study with AZD1775 and 5-
fluorouracil (5-FU)5FU suggests that the pharmacokinetics of AZD1775 in 
Japanese and Caucasian patients were similar, however, further work is ongoing. 
 
Pharmacodynamics evaluation  
PN001: Skin biopsies were obtained from patients in all 3 parts of this study in 
order to evaluate the pharmacodynamic effects of AZD1775 in a surrogate tissue. 
Formalin-fixed and paraffin- embedded skin samples were analysed by 
immunohistochemical staining for the presence of total and phosphorylated 
levels of the WEE1 kinase substrate CDC2 (CDK1). Since CDC2 is expressed 
and phosphorylated in a cyclical manner and only observed in proliferating cells 
in the epidermis, the data was reported as the percent of CDC2-positive cells that 
were also pCDC2 positive. Post treatment values obtained from this scoring 
method were divided by the same value derived from the matched pre-treatment 
biopsy to generate a post/pre ratio to reflect the changes in pCDC2 observed at 
the time of the biopsy (see IB v12 for additional details). 
 
Additional pharmacodynamic inhibtion has been observed in a monotherpy study 
run by the NCI. Paired tumor biopsies were obtained at baseline and 2 to 5 hours 

 
17  
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after the 5th dose of the first week of administration of drug. Dramatic reductions 
in pY15-Cdk levels (67%, 84%, and 90% compared to baseline) were found in 3 
of 5 paired tumor biopsies with 2 of those patients also demonstrating concurrent 
evidence of DNA damage response based on increased levels of γH2AX level on 
post-treatment tumor biopsy (Do et al., ASCO 2014) 
 
 
 
1.5 
Study Design and Treatment  
 
This study is a phase II study testing the clinical efficacy of combined AZD1775 with 
AraC or single agent activity of AZD1775 in three patient strata:  Elderly newly 
diagnosed AML patients (Arm A) will only receive the combination; whereas 
relapsed/refractory AML patients and HMA failure MDS patients will be allocated to 
either the combination (Arm B) or single agent AZD1775 (Arm C). The study will have a 
run in safety cohort of six patients in each of the three arms to determine the safe use of 
combined AraC /AZD1775 or single agent AZD1775 in the patient populations. This will 
be followed by an expansion phase where elderly patients with newly diagnosed AML 
will receive a combination of AZD1775 and AraC (Arm A) while patients with relapsed 
or refractory AML or HMA failure MDS will be allocated to receive either AZD1775 
with AraC (Arm B) or AZD1775 alone (Arm C).  An early toxicity check will be 
conducted to determine safety and tolerability.  If indicated, dose levels will be reduced.  
The study will continue to enroll the rest of the patients at the tolerated dose.  
 
1.51 
Rationale for AraC and AZD1775 Dosing Schedule, Dose Selection and Dosing 
Arms:  
 
Dose and Schedule of AraC: AraC is a pyrimidine nucleoside analog that 
functions as an antimetabolite in a cell cycle specific manner. When given in 
high doses and in combination with other cytoreductive agents AraC can be too 
toxic in the elderly patients and those with relapsed/refractory disease. 
Subcutaneously administered low-dose AraC (defined as 5 to 10 mg/m2/d or 
20mg fixed dose twice daily) for 10-12 days has been employed for specific 
AML subpopulations since 1979, with complete remission (CR) rates generally 
around 10-20% at maximum  (Cheson et al. 1986). It is frequently used as a 
comparator arm in large phase 3 trials or in combination studies with other agents 
(Kantarjian et al. 2012, Fenaux et al. 2009).  Clinically, AraC can be given at 
low, intermediate and high dose concentration schedules. The strongest pre-
clinical ex vivo and in vitro sensitization effects to AZD1775 occurred at low to 
moderate AraC concentrations of 9-120 nanoMolar (nM) (Tibes et al.2012). 
Whereas, antagonism was seen at very high concentrations (AraC > 1000nM, 
AZD1775 > 1000nM), concentrations that clinically resemble high dose AraC 
dosing schedules. As the mechanism is not yet fully understood, we postulate that 
for maximum anti-leukemic activity of combined AraC and AZD1775, there has 
to remain a low level proliferation with incorporation of AraC into the DNA of 
dividing leukemia cells upon concurrent inhibition of WEE1 kinase. This results 
in abrogation of the DNA repair machinery (Tibes, ASCO 2014) and cell 
death/apoptosis originating directly from the damaged DNA. Therefore, we 
propose to use AraC that can achieve concentrations of up to 50-100nM, 
comparable to the pre-clinical data.  
 

 
18  
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Dose and Schedule of AZD1775: The optimal concentrations of AZD1775 in 
combination with AraC are in the range of 100-600nM based on in vitro and ex 
vivo data (Tibes et al, Blood 2012). Pharmacokinetic data for AZD1775 is 
available from the ongoing solid tumor Phase 1 trial. AZD1775 at once or twice 
daily dosing up to 200 to 225 mg orally (po) in combination with full doses of 
Gemcitabine, Cisplatin or Carboplatin was well tolerated (Schellens et al. 2011, 
Leijenet al. 2010, IB AZD1775, Feb. 2015).  The half-life of AZD1775 is ~9 hrs 
and C trough for AZD1775 is up to  570nM, with an unbound concentration of  
225nM. Based on preliminary population PK model, simulations suggest that 
once daily dosing of 200 mg AZD1775 for 7 days will result in a median  plasma 
trough total concentration level of 172 nM (range: 8-740 nM) for AZD1775. The 
unbound concentration will be 67 nM (3-292 nM). This would be in the range at 
which pre-clinically single agent activity and sensitization has been observed 
(Tibes et al, Blood 2012).    
 
AZD1775 dosing length: Currently there is a Phase 1/2 solid tumor single agent 
AZD1775 trial ongoing at the National Cancer Institute at 225mg orally BIDX5 
for 2 weeks of a 3 week schedule. Additional studies investigating alternative 
more prolonged dosing schedules are underway. Information of toxicity and 
tolerability will be available prior to opening this protocol and inform the initial 
AZD1775 dosing strategies: to be given either 225mg continuously for 28 days 
as proposed; or alternative dosing may be explored i.e. 5 days on, 2 days off, 5 
days on or only concurrently for 10 days during days of AraC administration. 
Either scheduling has a clinical rationale as there are 10 and 12 day dosing 
schedules for AraC given subcutaneously. If continuous dosing of AZD1775 is 
tolerated in ongoing studies, AraC will be given for 10 days. If a 5 on, 2 off, 5 on 
AZD1775 schedule is selected than AraC will be given for 12 days.   
 
1.52 
AZD1775 alone vs. AZD1775 plus AraC 
 
AZD1775 ex vivo and in vitro has single agent activity against myeloid 
malignant cells from relapsed/refractory AML and HMA failure MDS patients.  
Pre-clinical data provides support for concurrent exposure to both agents at lower 
AraC and moderate AZD1775 concentrations and these dosing concentrations are 
hypothesized to have the optimal biological effect. Further, the available clinical 
trial data of AZD1775 alone or with full dose cytotoxic chemotherapies is 
showing good tolerability without excessive cytopenias [cytopenias are less 
concern for the patient population under study in this protocol].  Clinical trials, 
including single investigational agents are recommended standard interventions 
for the patient population in this protocol. Therefore patients with relapsed or 
refractory AML or HMA failure MDS will be allocated to, either AZD1775 or 
AZD1775 plus AraC treatment. For patients with newly diagnosed AML, AraC 
should in most cases be part of the upfront therapeutic regimens, therefore newly 
diagnosed untreated elderly AML patients will only be allocated to the 
combination treatment Arm of AZD1775 plus AraC. The dosing length/schedule 
of AZD1775 will be informed by the emerging clinical data from the ongoing 
continuous single agent AZD1775 trial.  
 
2.0 
Goals 
 
2.1 
Primary Goals 

 
19  
MC1488 WEE1 
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2.11 
To estimate the clinical efficacy of AZD1775 in combination with AraC in 
patients with newly diagnosed AML by assessing complete response (CR plus 
CRi) rates 
 
2.12 
To estimate the clinical efficacy of AZD1775 alone or in combination with AraC 
in patients with relapsed/refractory AML and hypomethylating agent failure 
MDS by assessing complete response (CR plus CRi) rates 
 
2.2 
Secondary Goals 
 
2.21  
To determine the safety and tolerability of AZD1775 alone or combined with 
AraC in the study population.  
2.22 
To estimate additional measures of clinical benefit (i.e. hematological 
improvements, transfusion requirements). 
2.23 
To measure the duration of response of AZD1775 alone or combined with AraC. 
2.24  
To measure time to response of AZD1775 alone or combined with AraC. 
2.25 
To measure time to progression of AZD1775 alone or combined with AraC. 
2.26 
To measure overall survival of AZD1775 alone or combined with AraC. 
2.27 
To measure time to AML (for MDS subjects) of AZD1775 alone or combined 
with AraC 
 
 
2.3 
Correlative Research 
 
2.31 
To determine the pharmacokinetics (PK) of AZD1775 alone or combined with 
AraC in the study population   
 
2.32 
To conduct correlative research studies characterizing underlying molecular 
events and solidifying putative mechanism of action in vivo and to identify 
potential pharmacodynamic/biomarkers of response to AZD1775 alone or 
combined with AraC 
 
2.33 
To evaluate quality of life (QOL) and patient-reported symptoms in subjects 
treated with AZD1775 alone or combined with AraC. 
 
3.0 
Patient Eligibility  
 
 3.1 
Inclusion Criteria  
 
 
 
3.11 
Age 18 years. 
 
 
 
3.12 
Patient population (histological or cytologically confirmed diagnosis):  
 
untreated elderly (>60 years) AML if in the intermediate and poor-risk 
cytogenetic group (please reference Appendix V) and not candidates (as 
judged by treating MD) for or willing to undergo standard induction 
therapy (i.e. elderly unfavorable cytogenetic AML) or any untreated 
AML age > 65 years  
 
Note: previous therapy with a hypomethylating agent (HMA) for a 
diagnosis of MDS is allowed  

 
20  
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 
relapsed or refractory AML (≥ 18 years) 
 
 
any MDS (≥ 18 years) having failed or been intolerant to prior 
hypomethylating agent (HMA) treatment.  
o Failure is defined as any disease progression while on HMA, 
relapse after HMA treatment or no response after 4 cycles of 5-
Azacitidine or  decitabine 
o Patients with isolated 5q-/5q- syndrome must have failed, not 
tolerated, or progressed on lenalidomide in addition to having 
failed or been intolerant to HMA treatment. 
 
Note: Patients with CMML and MDS/MPN overlap are allowed if 
meeting other study eligibility criteria.  
  
NOTE: For all patient groups, therapy as part of a plan as a bridge to transplant is 
allowed. 
 
 
 
3.13 
The following laboratory values obtained 7 days prior to registration.  
 
Total bilirubin ≤ 1.5 mg/dL (except Gilbert’s syndrome or known hemolysis 
or leukemic infiltration) 
 
AST (SGOT) and ALT (SGPT) ≤ 2.5 x Upper Limit normal (ULN) or < 5 x 
ULN if organ involvement  
 
Alkaline Phosphatase < 5 x ULN 
 
Serum creatinine ≤ 2 x ULN or 24 hour Cr clearance >30ml/min  
 
3.14 
ECOG Performance Status (PS) 0, 1 or 2 (Appendix I). 
 
 
 
3.15 
Ability to provide informed written consent and be able to adhere to the study 
visit schedule and other protocol requirements. 
 
3.16 
Willing to return to enrolling institution for follow-up (during the Active      
             Monitoring Phase of the study). 
 
3.17 
Willing to provide blood and bone marrow aspirate samples for correlative 
research purposes 
  
  
3.18 
Negative serum pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.19a  Men and women must be willing to use appropriate contraception throughout 
study and for 6 months after (please refer to Appendix IX for details). 
 
3.19b Male patients who are sexually active with a female partner of childbearing 
potential must be either surgically sterilized or agree to use barrier contraception 
(ie, condoms) for the duration of study participation, and for 90 days after the 
final dose of study drug; cessation of birth control after this point should be 
discussed with a responsible physician.   
 
 
3.19c  Patients who have undergone stem cell transplantation (SCT), autologous or 
allogeneic, are eligible provided that they are > 60 days from stem cell infusion, 

 
21  
MC1488 WEE1 
MCCC  
 
have GVHD < grade 1 and are off immunosuppressive agents for > 28 days at 
time of registration. 
 
  
 
 3.2 
Exclusion Criteria  
 
3.21 
Uncontrolled intercurrent illness including, but not limited to, active uncontrolled 
infection,  known positive for active infectious hepatitis, type A, B or C (past 
infection allowed), or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
 
 
 
Note: ongoing infection controlled on antibiotics/antifungal/antiviral medications 
are allowed.  
 
 
 
3.22 
Any of the following prior therapies: 
 
Cytotoxic Chemotherapy 14 days prior to registration 
 
Immunotherapy 14 days prior to registration 
 
Biologic therapy (i.e. antibody therapies)  14 days prior to registration 
 
Radiation therapy 14 days prior to registration 
 
Targeted therapies (i.e. kinase inhibitors, 7 days or 5 half-life’s whichever 
is shorter) 
 
For steroids or other non-cytotoxics given for blast count control, patient 
must be off for > 24 hrs before starting therapy. NOTE: Hydroxyurea (HU) is 
allowed for blast count control throughout study  
 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm ≤ 14 days prior to registration 
 
3.23 
Active uncontrolled CNS leukemia. NOTE: Positive (cyto)pathology is allowed 
and patient can receive intrathecal chemotherapy 
 
3.24 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy.  NOTE:  Patients known to be HIV 
positive, but without clinical evidence of an immunocompromised state, are 
eligible for this trial. 
 
3.25 
Any previous treatment with AZD1775 or allergic reactions to excipients of 
AZD1775. 
 
3.26  
Acute Promyelocytic Leukemia (APL, M3) unless failed regimens that included 
tretinoin, arsenic trioxide, anthracyclines and cytarabine and currently NOT 
candidates for stem cell transplantation.  
 
3.27  
Major surgery ≤ 28 days prior to registration  
 
3.28 
Clinically significant heart disease, including the following: 
 
Active severe angina pectoris within 3 months prior to registration 
 
Acute myocardial infarction within 3 months prior to registration 
 
New York Heart Association classification IV cardiovascular disease or 
symptomatic class III disease (Appendix III). 

 
22  
MC1488 WEE1 
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Note: patients with any of the above may be allowed after discussion amongst the 
investigators including the principal investigator  
 
3.29a  Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
 
Pregnant women 
 
Nursing women 
 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.29b Subject has had prescription or non-prescription drugs or other products known 
to be sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow 
therapeutic index, or to be moderate to strong inhibitors / inducers of CYP3A4 
which cannot be discontinued two weeks prior (alternatively 5 half lives if T1/2 
is known) prior to Day 1 of dosing and withheld throughout the study until 2 
weeks after the last dose of study drug (Appendix VI ).  
NOTE: Co-administration of aprepitant or fosaprepitant during this study is 
prohibited.  
 
Note: Individiual drugs exerting CYP interactions as listed in tables in Appendix 
VI may be continued on a case by case basis if felt essential for patient 
managment, after discussions and discretion of the treating physician.  
 
The preferred azole anti-fungal medication is Fluconazole (alternatively 
Posaconazole) which can be given during treatment with AZD1775 at the 
treating physician’s discretion, however with dose reductions of AZD1775 by 
25-75% (i.e. from AZD1775 200mg to 150 or 100mg).    
3.29c  Pateints may not be on an inhibitor of BCRP as outlined in Appendix VI.  
NOTE: AZD1775 is an inhibitor of breast cancer resistance protein (BCRP). The 
use of statins including Atorvastatin which are substrates for BCRP are therefore 
prohibited and patients should be moved on to non-BCRP alternatives. 
 
3.29d   Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville 
oranges, pummelos, and exotic citrus fruits from 7 days prior to the dose of study 
medication and during the entire study due to potential CYP3A4 interaction with 
the study medication. NOTE:  Orange juice is allowed. 
3.29e  Corrected QT interval (QTc) >470 msec (as calculated per institutional 
standards) at study entry or congenital long QT syndrome. 
   
 

 
23  
MC1488 
 
4.0 
Test Schedule 
 
 
 
Table 4.1: Test Schedule for Elderly Newly Diagnosed and Relapsed/Refractory AML patients 
 
 
 
Active Monitoring Phase 
 
 
Tests and procedures 
14 days 
prior to 
registration 
≤7 days  
prior to 
registration 
Cycle 1  
Days 1, 
8, 15, & 
28(+3 
days)5, 13 
Cycles 2 & 3 Days 
1, 15, and 28 (+ 3 
days)5, 13 
Cycles 4+Day 1 
and Beyond(+/-3 
days)5, 17 
EOS2 
History and exam, wt, PS, 
vitals   
X 
 
X 
X13 
X13 
X 
Height 
X 
 
 
 
 
 
Adverse event assessment 
X 
 
X 
X 
X 
X 
Hematology group 
 
WBC 
 
ANC 
 
Hgb 
 
PLT 
 
X 
X 
X 
X9 
X 
Chemistry group: sodium, 
potassium, calcium, 
creatinine, 
bicarbonate, glucose, 
chloride, albumin, 
BUN, alkaline 
phosphatase, AST, 
ALT, total protein, 
total bilirubin, LDH 
 
X 
X 
X 
X 
X 
TLS monitoring (for 
selected AML 
patients): BUN, 
calcium, CO2, 
chloride, creatinine, 
glucose, potassium, 
sodium, uric acid, 
phosphorus 
 
 
X14 
X14 
 
 

 
24  
MC1488 WEE1 
MCCC  
 
PT/PTT and D-dimer 
 
 
X19 
 
 
 
Serum pregnancy test1 
 
X 
 
 
 
 
Bone marrow biopsy and 
aspirate procedure 
(cytogenetics or 
FISH)15 
X11  
 
 
X3 
 
 
X3 
 
X3 
X10 
Bone marrow  aspirate 
research specimens 
(see Section 14.0)R 
X8 
 
X7 
X7 
X7 
X6 
Blood specimens (see 
Section 14.0)R 
X4, 8 
 
 
X4 
 
 
X4 
 
 
X4 
 
X4 
Buccal swab (optional, 
see Section 14.0) R 
X 
 
 
 
 
 
Patient Questionnaire 
Booklet12 
X 
 
X16 
X16 
X16 
X16 
ECG (12 lead)18 
 
X 
 
 
 
X 
1. 
 For women of childbearing potential only.   
 
2. 
30 days (+/-3days) post last dose of study drug 
 
3. 
For AML patients: marrow aspirates and biopsies will be done after cycle 1 (at physician’s discretion), after cycles 2 and 4, and then at physician discretion).  In addition, bone marrow 
should be performed at time of suspected CR/CRi and/or disease progression and at physician discretion as clinically indicated. Note: Bone Marrow Aspirate and biopsy may be avoided 
aftercycle 4 as determined by study chair or treating physician (i.e. if determined to not yield information that would change clinical management).  
4. 
Blood specimens for research sampling to be collected as defined in Section 14. 
5. 
Day 1 assessments do not need to be repeated if pre-registration or Day 28 assessments completed within 48 hours of Day 1. 
6. 
Only if an EOS marrow sample is collected as part of standard of care  
7. 
Research bone marrow samples are to be collected at the same time when a marrow is done as part of patient’s standard of care, including research marrow samples should be 
drawn at time of marrow for suspected CR/CRi and/or disease progression.  
8. 
To be collected on all patients at baseline. If no baseline marrow samples obtained, the peripheral blood research sample becomes mandatory to participate in study.  Bone 
marrow aspirate specimens must be collected and submitted per section 14.0.  If bone marrow performed at end of study as part of patient’s standard of care, collect sample per 
section 14.0. 
9.  
After 2 cycles, CBC frequency may be reduced at treating physician’s discretion but needs to be performed at least once per cycle.  
10.  Progression marrow can be used as EOS marrow if patient is taken off trial based on the results. Additional EOS bone marrow can be omitted if a progression marrow was 
done, or an EOS marrow can be done at physician discretion and is optional. 
11. ≤ 28 days prior to registration; for patients with an outside marrow biopsy within 4 weeks of study start, outside results can serve as baseline after review at Mayo Clinic. In these 
cases, samples for correlative laboratory studies will be drawn from peripheral blood prior to study start. 
12. Patient questionnaire booklet must be used; copies are not acceptable for this submission. Booklet should be completed by patient prior to review of treatment response and 
discussions of patient’s general health since last treatment evaluation. 

 
25  
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13.   Patients with AML will be monitored per Table 4.1  during cycle 1 and 2, and thereafter at least once per cycle, i.e. at end of each/prior to a new cycle or as otherwise defined in 
the test schedule.  
14.   For patients at high risk of tumor lysis syndrome (TLS), that is for selected AML patients as determined by the treating physician, a daily basic metabolic panel, uric acid, and 
phosphoruswill be drawn for three to five days in Cycle 1, when maximum TLS risk is usually abated. Additional monitoring will be done on a case by case basis.  
15. Either conventional cytogenetics or FISH panel (or both based on physician discretion) for AML to be performed at baseline. If diploid cytogentics at baseline, subsequent 
cytogenetic studies may be omitted unless disease progression is suspected. For FISH based cytogenetic assessments, an entire AML FISH panel should be performed at 
baseline, while on subsequent marrows only positive specific FISH abnormalities/probes need to be repeated unless disease progression is suspected, in which case a full AML 
FISH panel or instead conventional cytogenetics should be performed. 
16. Booklets to be completed at end of all cycles. 
17.  Prior to the start of treatment. 
18.  ECG to be repeated if cardiac symptoms occur or as otherwise defined in the test schedule. 
19. To be tested on C1D1 prior to treatment. 
R 
Research funded (see Section 19.0). 
 
 
 
 
 
 
 
 

 
26  
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Table 4.2: Test Schedule for HMA failure MDS patients 
 
 
 
Active Monitoring Phase 
 
 
Tests and procedures 
14 days 
prior to 
registration 
≤7 days  
prior to 
registration 
Cycles 1  
Days 1, 8, 
15, & 
28(+3 
days)12 
Cycle 2  Days 1, 
15, and 28 (+ 3 
days)10, 12 
Cycles 3+ Day 1 
and Beyond(+/-3 
days)10, 12 
EOS2 
History and exam, wt, PS, 
vitals   
X 
 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Adverse event assessment 
X 
 
X 
X 
X 
X 
Hematology group 
 
WBC 
 
ANC 
 
Hgb 
 
PLT 
 
X 
X 
X 
X 
X 
Chemistry group: sodium, 
potassium, calcium, 
creatinine, 
bicarbonate, glucose, 
chloride, albumin, 
BUN, alkaline 
phosphatase, AST, 
ALT, total protein, 
total bilirubin, LDH 
 
X 
X 
X 
X 
X 
Serum Erythropoietin 
level 
X 
 
 
 
 
 
Serum pregnancy test1 
 
X 
 
 
 
 
Bone marrow biopsy and 
aspirate procedure 
(cytogenetics or 
FISH9) 
X6 
 
 
X3 
 
X3 
 
X7 
Blood specimens (see 
Section 14.0)R 
X4 
 
X4 
X4 
X4 
X4 
Buccal swab (see Section 
X 
 
 
 
 
 

 
27  
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14.0) R 
Bone marrow aspirate 
research specimens 
(see Section 14.0)R 
X6 
 
 
X5 
X5 
X5  
Patient Questionnaire 
Booklet8 
X 
 
X8 
X8 
X8 
X 
ECG (12 lead)11 
 
X 
 
 
 
X 
1. 
 For women of childbearing potential only 
 
2. 
30 days (+/-3days) post last dose of study drug 
 
3. 
Marrow biopsies only to be done at End of cycle 2, End of cycle 4, at time of suspected CR/CRi and thereafter at physician discretion as clinically indicated (i.e. disease progression). 
4. 
Blood specimens for research sampling to be collected as defined in Section 14.  
5. 
Research marrow samples (aspirates) to be done at times of clinical standard of care marrow tests at End of cycle 2, End of cycle 4, at time of suspected CR/CRi or disease 
progression and thereafter at physician discretion as clinically indicated. A sample will be obtained at end of study (EOS) if a bone marrow is performed as part of patient’s 
standard of care; sample will be collected per section 14.0 
6.  
≤ 28 days prior to registration; for patients with an outside marrow biopsy within 4 weeks of study start, outside results can serve as baseline after review at Mayo Clinic. In 
these cases, samples for correlative laboratory studies will be drawn from peripheral blood prior to study start. 
7.      Bone marrow at end of study is only to be done at physician discretion and is optional. Progression marrow can be used as EOS marrow if patient is taken off trial based on the 
results. 
8. 
Patient questionnaire booklet must be used; copies are not acceptable for this submission. Booklet should be completed by patient prior to review of treatment response and 
discussions of patient’s general health since last treatment evaluation. Booklets to be completed at end of all cycles. 
9. 
Either conventional cytogenetics or FISH panel (or both based on physician discretion) for MDS should be performed at baseline. If diploid cytogentics at baseline subsequent 
cytogenetic studies may be omitted unless disease progression is suspected. For FISH based cytogenetic assessments, an entire MDS FISH panel should be performed at 
baseline, while on subsequent marrows only positive specific FISH abnormalities/probes need to be repeated unless disease progression is suspected. 
10. Prior to the start of treatment. 
11.  ECG to be repeated if cardiac symptoms occur or as otherwise defined in the test schedule.  
12.   Day 1 assessments do not need to be repeated if pre-registration or Day 28 assessments completed within 48 hours of Day 1. 
R 
Research funded (see Section 19.0). 
 
 
 
 

 
28  
MC1488 
 
5.0 
Grouping Factors:  
 
5.1 
Grouping Factor   
 
 
Study Stage: 
1=Safety Portion vs 2=Expansion Portion  
 
5.2 
Grouping Factor  
 
 
Disease type:  1=Elderly newly diagnosed AML (assigned treatment Arm A) vs 
2=Relapsed/refractory AML vs 3=HMA failure MDS  
 
 
 
NOTE: HMA failure MDS patients include MDS, CMML and MDS/MPN 
overlap patients. 
 
 
NOTE: Disease type groups 2 and 3 are randomized to arm B or C.   
 
 
6.0  
Registration/Randomization Procedures 
 
6.1 
Safety Portion 
 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office 
 for dose level and to insure that a place on the protocol is 
open to the patient.  
 
6.11 
Registration Procedures 
 
6.111 To register a patient, 
 a completed eligibility checklist 
to the Mayo Clinic Cancer Center (MCCC) Registration Office between 
8 a.m. and 4:30 p.m. central time Monday through Friday.   
 
 
6.2 
Expansion Portion 
 
6.12 
Registration Procedures 
 
6.121 To register a patient, access the Mayo Clinic Cancer Center (MCCC) 
web page and enter the registration/randomization application.  The 
registration/randomization application is available 24 hours a day, 7 days 
a week.  Back up and/or system support contact information is available 
on the Web site.  If unable to access the Web site, call the MCCC 
Registration Office at 
 between the hours of 8 a.m. and 
4:30 p.m. Central Time (Monday through Friday). 
 
The instructions for the registration/randomization application are 
available on the MCCC web page 
 
and detail the process for completing and confirming patient registration.  
Prior to initiation of protocol treatment, this process must be completed 
in its entirety and a MCCC subject ID number must be available as noted 
in the instructions.  It is the responsibility of the individual and 
institution registering the patient to confirm the process has been 
successfully completed prior to release of the study agent.  Patient 
registration via the registration/randomization application can be 
confirmed in any of the following ways: 

 
29  
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 
Contact the MCCC Registration Office 
  If the 
patient was fully registered, the MCCC Registration Office staff can 
access the information from the centralized database and confirm the 
registration. 
 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
 
6.3 
Safety & Expansion Portions 
 
6.31 
Correlative Research 
 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Section 3.17 and 14.0). 
 
6.32 
Prior to accepting the registration, registration/randomization application will 
verify the following: 
 
IRB approval at the registering institution 
 
Patient eligibility 
 
Existence of a signed consent form 
 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.33 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
6.34 
At the time of registration, the following will be recorded: 
 
Patient has/has not given permission to store and use his/her sample(s) for 
future research of Acute Myeloid Leukemia or Myelodysplastic Syndrome at 
Mayo. 
 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
 
6.35 
Treatment on this protocol must commence at a participating institution, Mayo 
Clinic Rochester, Mayo Clinic Arizona, Mayo Clinic Florida, or the University of 
Colorado, under the supervision of a hematologist. 
 
6.36 
Treatment cannot begin prior to registration and must begin  14 days after 
registration. 
 
6.37 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 

 
30  
MC1488 WEE1 
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6.38 
All required baseline symptoms (see Section 10.3) must be documented and 
graded. 
 
6.39a 
Study drug is available on site.  
 
6.39b Blood draw kit is available on site.   
 
6.39c 
Patient questionnaire booklet is available on site; copies are not acceptable for 
this submission.  
 
6.39d Randomization Procedures  
 
6.39d1 The factors defined in Section 5.0, together with the registering 
membership, will be used as stratification factors. 
 
6.39d2  After the patient has been registered into the study, the values of the 
grouping factors will be recorded.  An elderly newly diagnosed AML 
patient will be allocated to arm A.  A relapsed/refractory AML or HMA 
failure MDS patient will be randomized to treatment group arm B or arm 
C.     
 
- 
Elderly (age 60+) newly diagnosed AML patients assigned to Arm 
A: AZD1775 days 1-5, 8-12 and AraC days 1-5, 8-12 
- 
Relapsed/Refractory AML and HMA failure MDS patients 
randomized to Arm B: AZD1775 days 1-5, 8-12 and AraC days 1-5, 
8-12 or Arm C: AZD1775 days 1-5, 8-12, 15-19, 22-26. 
 
All patients must be registered within 14 days before starting therapy or within 
72 hours after starting treatment if over a weekend or holiday.  If therapy must be 
started when the MCCC Registration Office is closed, a telephone call must be 
made when the MCCC Registration Office is open as indicated above.  Under no 
circumstances will non-registered patients be retrospectively eligible for the 
study. 
 
 

 
31  
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7.0 Protocol Treatment 
 
7.1 
Pre-Treatment Recommendation 
 
 
 
7.11 
Pretreatment medication recommendations (this is not a study requirement, but 
simply a recommendation)   
 
Agent 
Dose 
Route 
Day(s) 
Ondansetron* 8mg 
PO  or IV 
1-5, 8-12, ^  
 
*Or serotonin receptor antagonist of institutional standard 
 
^ if study drug schedule is days 1-10, give Ondansetron days 1-10 
 
 
7.2 
Treatment Plan for AZD1775 combined with AraC (Arms A and B) 
 
7.21 Safety Portion 
 
 
 
The Safety portion of this trial will treat and monitor six patients in each arm and 
observe them for a minimum of 28 days to assess toxicities.   
 
Starting Doses: Multiple Agent 
Agent 
Dose 
Route 
Day(s) 
ReRx 
AraC1 
20 mg 
SC twice daily 2 
1-5 & 8-123 
Every 28 days4 
AZD1775 
200 mg  
PO daily 
1-5& 8-123 
Every 28 days4 
1 Starting dose of a fixed dose of 20 mg s.c. per a single dose twice daily. In individual 
cases, a 10 mg/m2 not to exceed 20 mg can be used alternatively.   
2SC administration preferred 
3 AZD1775 should be taken either 2 hours before or 2 hours after a meal.  A day 1-10 
dosing schedule will be permitted as an alternative, in which case AZD1775 should be 
given days 1-10 as well.  
4Cycle length can be increased to 6 and maximally 8 weeks   
Note: if the starting dose is not tolerated, lower dosing cohort combination will be 
explored and follow the recommendation as outlined in Section 8.1 Table 8.11.  
 
 
 
7.22 Expansion Portion 
 
 
 
The Expansion portion of this trial will commence for Arms A and B as soon as 
the Safety portions for BOTH arms are completed. 
 
 
Starting Doses 
Agent 
Dose 
Route 
Day(s) 
ReRx 
AraC1 
20 mg 
SC twice daily 2 
1-5 & 8-123 
Every 28 days4 
AZD1775 
MTD 
PO daily 
1-5& 8-123 
Every 28 days4 
1 Starting dose of a fixed dose of 20 mg s.c. per a single dose twice daily. In individual 
cases, a 10 mg/m2 not to exceed 20 mg can be used. 
2SC administration preferred 

 
32  
MC1488 WEE1 
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3AZD1775 should be taken either 2 hours before or 2 hours after a meal.  A day 1-10 
dosing schedule will be permitted as an alternative, in which case AZD1775 should be 
given days 1-10 as well.  
4Cycle length can be increased to 6-8 weeks (maximally)  
 
 
7.3 
Treatment Plan for AZD1775 single agent (Arm C) 
 
7.31 Safety Portion 
 
The Safety portion of this trial will treat and monitor up to six patients in the arm 
and observe them for a minimum of 28 days to assess toxicities.   
 
 
 
Starting Dose:  Single Agent 
Agent 
Dose 
Route 
Day(s) 
ReRx 
AZD1775 
200 mg 
PO daily 
1-5, 8-12, 15-19, 
22-262 
Every 28 days1 
 
 
1Cycle length can be increased to 6-8 weeks   
 
 
2AZD1775 should be taken either 2 hours before or 2 hours after a meal. 
Note: if the starting dose is not tolerated, a lower dosing cohort will be explored and 
follow the recommendation as outlined in Section 8.1 Table 8.12.  
 
 
 
 
 
7.32 Expansion Portion 
 
 
 
 
The Expansion portion of this trial will commence for Arm C as soon as the 
Safety Portion is completed. 
 
 
 
 
Starting Dose 
Agent 
Dose 
Route 
Day(s) 
ReRx 
AZD1775 
MTD 
PO daily 
1-5, 8-12, 15-19, 
22-262 
Every 28 days1 
 
1Cycle length can be increased to 6-8 weeks 
 
2AZD1775 should be taken either 2 hours before or 2 hours after a meal. 
 
7.4 
Toxicity Assessment for Safety Portion (first 6 patients on each Arm) 
 
Toxicity will be measured per NCI-CTCAE version 4.  DLT is defined as an 
adverse event occurring during the first cycle of treatment that is not clearly 
related to the patient’s underlying disease and that meets one of the following: 
 
Grade 3 AST, ALT or alkaline phosphatase will be considered dose limiting 
on an individual basis or if lasts more than 5 days 
 
Grade 3 as per NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 that does not resolve to ≤ Grade 2 within 7 days 
 
Grade 4 as per NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 
NOTE: Myelosuppression will not be considered in evaluating toxicity in 
patients with acute leukemias or similar advanced myeloid malignancies 

 
33  
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(MDS) except where bone marrow (BM) hypoplasia occurs for >52 days 
with BM cellularity <5% in the absence of residual leukemia/disease. 
 
 
 
7.7 
MTD Determination 
 
This MTD determination applies to the Safety Portion.  MTD for the safety portion will 
be defined as the dose level below the lowest dose that induces dose-limiting toxicity in 
at least one-third of patients (at least 2 of a maximum of 6 new patients).  
 
7.71 
Three patients will be treated at a given dose level combination and observed for 
one cycle to assess toxicity (accrual will be suspended while the 3 patients are 
treated and observed). 
 
7.72 
If DLT is not seen in any of the 3 patients or in 1 of 3 patients, 3 new patients 
will be accrued. and treated at the same dose level (accrual will be suspended 
while the 3 patients are treated and observed). If DLT is seen in 2 or 3 of 3 
patients treated at a given dose level, then the next 3 patients will be treated at the 
next lower dose level, if only 3 patients were enrolled and treated at this lower 
dose level.  
 
7.73After enrolling 6 patients on a specific dose level, if DLT is observed in  1 or less 
patients, then the combination dose will be considered safe for the expansion 
phase.  If DLT is observed in at least 2 of 6 patients, then the MTD will have 
been exceeded and defined as the previous dose unless only 3 patients were 
treated at the lower dose level. In that case, 3 additional patients will be treated at 
this lower dose level. 
             
7.75 
If a patient fails to complete  one cycle of treatment for reasons other than dose-
limiting toxicity defined adverse events, the patient will be regarded as non-
informative for estimating the MTD and an additional patient will be treated at 
the current dose level. 
 
 
7.8       Dose escalation will not be allowed for a patient. 
   
7.9a       For this protocol, the patient must return to the consenting institution for evaluation at           
least once every 28 days.   
 
 
7.9b  
Local Medical Doctor (LMD) 
When it has been determined that a patient’s malignant disease is stable or objective 
tumor regression has been observed and the patient is tolerating therapy without 
excessive toxicity, the drug(s) may be administered by the patient’s Local Medical 
Doctor (LMD).  The registering physician retains responsibility for the patient.   
 
In this case, a written statement outlining drug dosage, method of administration, follow-
up tests required, and telephone number to call to discuss any questions with the 
responsible investigator must be sent with the patient to provide necessary information to 
the LMD.  The LMD will be required to supervise the administration of the study drugs 
as stipulated in the protocol and provide written documentation that the drug was 
administered.   
 

 
34  
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8.0 
Dosage Modification Based on Adverse Events - If multiple adverse events are seen, administer 
dose based on greatest reduction required for any single adverse event observed.  Dose 
modifications apply to the treatment given in the preceding cycle and are based on adverse events 
observed since the prior dose. Dose modification recommendations listed below are general 
guidelines, and appropriate dose adjustments for patient safety should be done if needed per 
treating physician discretion. 
 
 
 
 
ALERT:  ADR reporting may be required for some adverse events.  See Section 10.0. 
 
 
 
  
 
 
8.1  
Dose Modification  
 
 
Individual drugs can be dose reduced as per the table below depending on 
the adverse event attribution. The dose reductions outlined in table 8.11  should first 
generally apply to AraC. If,  however, the AE is clearly due to AZD1775, then AZD1775 
can be reduced first as indicated in Table 8.11.  After cycle 2, these modifications 
should be regarded as guidelines to produce mild‐to‐moderate, but not debilitating, 
side effects.  If multiple adverse events are seen, administer dose based on greatest 
reduction required for any single adverse event observed.  The treating MD, in 
discussions with the principal investigator, may reduce dose of either AraC or 
AZD1775 or the length of treatment at his or her discretion if it is in the best interest 
of the patient. 
 
 
 
 
8.11 
AZD1775 combined with AraC (Arms A and B) 
Dose  
AZD1775 
[reduce AZD1775 first if clearly 
attributed to AZD1775] 
Cytarabine (AraC) 
[generally reduce AraC first] 
0* 
200 mg PO daily days 1-5 & 8-12 
20 mg SC twice daily days 1-5 & 8-12 
-1 
200 mg PO daily days 1-5 & 8-121 
10 mg SC twice daily days 1-5 & 8-12 
 
-2 
100 mg PO daily days 1-5 & 8-12 
10 mg SC twice daily days 1-5 & 8-122  
 
 
 
*Starting dose.  
1If toxicity is clearly attributable to AZD1775, AZD1775 can be reduced to 100 mg 
PO daily (days 1-5, 8-12) with continued AraC 20 mg SC twice daily days 1-5, 8-12. 
2AraC may be decreased to 10 mg or 20 mg SC once daily at physicians discretion 
based on myelosupression, tolerance and clinical benefit (see also dose modification 
section . 
NOTE: intermediate dose levels of 150 mg PO daily days 1-5 & 8-12 may be explored 
as a dose level -1a, based on PK, PD and clinical efficacy parameters and evaluation.  
 
 
 
 
 
8.12 
AZD1775 single agent (Arm C) 
Dose  
AZD1775 
0* 
200 mg PO daily days 1-5, 8-12, 15-19, 22-26 

 
35  
MC1488 WEE1 
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-1a** 
200 mg PO daily days 1-5, 8-12, 15-19  
or  
further reduction to 200 mg PO daily days 1-5 & 8-
12 as tolerated 
-1b** 
100 mg PO daily days 1-5, 8-12, 15-19, 22-26  
 
-2 
100 mg PO daily days 1-5 & 8-12 
 
 
*Presumed starting dose of Expansion Portion.  
**If at dose -1a leukemia breakthrough is observed, dose modification level -1b can be 
explored if continuous treatment may bring clinical benefit.  
Note: Further dose modifications can be made, i.e. 150 mg PO daily days  1-5, 8-12, 
15-19. 
The above dose modification tables consider the fact that at present it is not clear if 
dose (Cmax) or continuous (length of therapy, AUC, trough) dosing of AZD1775 will 
achieve better disease control, hence the dose modification scheme (i.e. compared to 
hydroxyurea experience and titration).  
 
 
  
 
8.2  
A new course of treatment may begin on the scheduled Day 1 of a new cycle if:  
•  
AZD1775 or AraC related adverse event that may have occurred has resolved to 
≤ Grade 2 severity, except hematological adverse events for WBC, ANC, 
Platelets and Hemoglobin, or per table 8.3 guidelines.  
 
If these conditions are not met on scheduled Day 1 of a new cycle, the subject will be 
evaluated as clinically indicated (i.e. weekly but at least every other week) and the new 
cycle of treatment will not be initiated until the adverse event has resolved as described 
above. Treatment can be continued on the drug that is not associated with the 
adverse event at the start of the following cycle and the drug associated with the 
adverse event may be reintroduced when the adverse event resolves to ≤ Grade 1 if 
the treating physician feels that the patient will derive benefit from continued AraC 
or AZD1775 alone. 
 
NOTE:  If the patient experiences a significant adverse event requiring a dose 
reduction at the start of the next cycle, then the dose will remain lowered for that 
entire subsequent cycle.  If that cycle is completed with no further adverse events 
>Grade 2, then the dose may be increased, at the investigator’s discretion, one level 
at a time, in the following cycles.  
 
 
 
 
 
8.3 
Dose modification table for adverse events felt to be at least possibly related to AZD1775*** or 
AraC  
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   

 
36  
MC1488 WEE1 
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CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT*** 
Blood and Lymphatic 
System Disorders 
Febrile neutropenia ≥ 
Grade 3 
AZD1775 
 
May omit dose until fever has resolved or 
returned to baseline. Dose to be restarted 
at same dose level.  Treating physician 
may discuss possible dose reduction with 
one of the study chairs after the patient 
has completed 2 cycles. 
If clinical benefit is derived, AZD1775 
may be continued if the infection is 
managed/controlled with appropriate 
medical intervention. 
Investigations 
Neutrophil & Platelet 
count decrease > grade 
4  
 
NOTE: only applicable 
for patients with 
absolute neutrophil 
count (ANC) of > 
1000mm3 and platelet 
count > 100,000/mm3 at 
baseline (i.e. MDS 
patients) 
AZD1775 
Omit dose until ANC and/or platelets 
have recovered to < grade 2. 
 
If clinical benefit is derived, AZD1775 
may be continued if not recovered to < 
grade 2 after discussion of treating 
physician and study chair. 
Investigations 
Creatinine increased  
Grade 2 
AZD1775 
 
Omit dose until resolved to ≤ grade 1, 
then:  
 
If resolved in ≤ 7 days, then maintain 
dose level 
 
If resolved in > 7 days, then decrease 
by 1 dose level 
 
[If clinical benefit is derived, AZD1775 
may be continued if the renal function is 
elevated but stable] 
AraC 
Continue treatment at current dose level 
 
Creatinine increased  
Grade 3 and 4 
AZD1775 
 
Omit dose until resolved to ≤ grade 1, 
then decrease dose by 1 dose level 
AraC 
Omit dose until resolved to ≤ grade 1, 
then decrease dose by 1 dose level  

 
37  
MC1488 WEE1 
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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Investigations 
Blood bilirubin 
increased > Grade 3 
AZD1775 
 
Omit dose until resolved to ≤ grade 1, 
then: 
 
If resolved in ≤ 7 days, then maintain 
dose level 
 
If resolved in > 7 days, then decrease 
by 1 dose level 
AraC 
Continue treatment at next lower dose 
level  
Blood bilirubin 
increased Grade 4  
AZD1775 
 
Omit dose until resolved to ≤ grade 1, 
then decrease dose by 1 dose level 
AraC 
Continue treatment at Dose level -1once 
resolved to ≤ Grade 1 
Alanine 
aminotransferase 
(ALT) increased and/or 
Aspartate 
aminotransferase (AST) 
increased Grade 3 
AZD1775 
 
Omit dose until resolved to ≤ grade 1 or 
baseline then: 
 
If resolved in ≤ 7 days, then maintain 
dose level 
 
If resolved in > 7 days, then decrease 
dose by 1 dose level 
AraC 
Continue treatment at next lower dose 
level 
Alanine 
aminotransferase 
(ALT) increased and/or 
Aspartate 
aminotransferase (AST) 
increased Grade 4 
AZD1775 
 
Omit dose until resolved to ≤ grade 1 or 
baseline, then decrease dose by 1 dose 
level 
AraC 
Continue treatment at Dose level -1 
Cardiac Disorders 
Cardiac disorders – 
Other ≥ Grade 4 
AZD1775 
 
Omit dose and discontinue patient from 
study 
Other Non-
Hematologic events 
≥ Grade 4 
 
 
 
 
 
AZD1775 
 
Omit drug and follow patient at least 
weekly or at least every other week until 
adverse event has resolved to grade ≤ 2, 
restart drug at next lower dose level.  
AT TIME OF RETREATMENT 

 
38  
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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Non Hematologic 
All Non-Hematologic 
Toxicities 
Grade > 4 (With the 
exception of nausea, 
vomiting or diarrhea 
controlled with 
appropriate 
medications.) 
AZD1775 
 
Hold AZD1775 and AraC. Re-check 
patient at weekly or at least every other 
week. When event returns to ≤ grade 2, 
resume AZD1775 and AraC 
treatment at next lower dose level.  
*   Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
** Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for the day that is omitted, but treatment may resume once 
the adverse event has resolved as mandated in Table 8.2. For example, if treatment is 
omitted on Day 8, but the adverse event has resolved by Day 10, treatment may resume 
on Day 10 to complete the cycle. Missed doses will not be made up.  
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped 
***AraC can be continued each cycle regardless of dose hold or adjustments for AZD1775, if patient is 
presumed to derive clinical benefit from the intervention.   
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event including 
abnormal laboratory values must be followed by their treating physician as clinically indicated.  The 
maximum time allowed for treatment interruption due to toxicity is 6 weeks from the intended dosing 
day. If interruption is > 6 weeks, continuation of treatment is allowed on a case by case basis (i.e. clinical 
benefit) as determined by the treating physician. However, the patient will continue to be followed for 
toxicity. Dose interruptions should be reported on the appropriate Dosage Administration CRF. 
 
 
9.0 
Ancillary Treatment/Supportive Care/Concomitant Medications 
 
 
9.1 
Routine use of colony-stimulating factors (G-CSF or GM-CSF) is not recommended. 
Prophylactic use of colony-stimulating factors should be discussed with the study chair. 
Therapeutic use in patients with serious neutropenic complications may be considered at 
physician discretion.  Recombinant erythropoietin to maintain adequate hemoglobin 
levels is discouraged and only allowed after discussion with the study chair. 
 
 
9.2 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such as 
antidiarrheals, analgesics, anti-emetics received from the first administration of study 
drugs until 30 days after the final dose are to be recorded in the medical record. For more 
severe diarrhea (i.e. Grade 3 or 4) supportive measures such as hydration and anti-
diarrheals are recommended according to instutitional practice guidelines and as deemed 
appropriate by the medical situation (i.e. IV rehydration as in- or outpatient, antibiotics). 
 
 
9.3  
Anti-emetic therapy (excluding aprepitant) may be used in accordance with standard 
practice and/or the discretion of the investigator. 

 
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9.4 
Hydroxyurea is allowed during the trial to control blast counts/WBC if the patient is felt 
to derive benefit from study treatment. 
 
9.5 
Patients on metformin should be closely watched for elevated metformin levels that could 
put them at risk for hypoglycemia. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site:  
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm)    
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Section 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
 
10.12 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).  Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same 
as serious AE which is defined in the table in Section 10.4. 
 
 
10.13  Medical conditions/diseases present before starting study treatment are only 
considered adverse events if they worsen after starting study treatment (any 
procedures specified in the protocol). Adverse events occurring before starting 
study treatment but after signing the informed consent form are not recorded. 
Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms or require therapy, and are recorded. 
 
 
10.14  Any serious adverse event occurring after the patient has provided informed 
consent, has started taking the study medication, and until 4 weeks after the 
patient has stopped study participation must be reported. This includes the period 
in which the study protocol interferes with the standard medical treatment given 
to a patient (e.g. treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication). The period after 
discontinuing study drug may be extended if there is a strong suspicion that the 

 
40  
MC1488 WEE1 
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drug has not yet been eliminated. 
 
10.2  
Expected vs. Unexpected Events  
 
 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol and the study specific 
consent form. 
 
 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol and the study specific consent form. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 
10.31  AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
 
NOTE:  When a commercial agent(s) is (are) used on the same 
treatment arm as the investigational agent/intervention (also, 
investigational drug, biologic, cellular product, or other 
investigational therapy under an IND), the entire combination (arm) is 
then considered an investigational intervention for reporting. 
 
Routine Reporting 
 
 Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent 
is stated in the protocol.  See Section 10.6. 
 
 Routine AE reporting using an investigational agent/intervention and a 
commercial agent in combination must be reported as defined by the 
general guidelines provided by sponsors, Groups, Cancer Centers, or 
Principal Investigators. See Section 10.6. 
 
Expedited Reporting 

 
42  
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NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in Section 10.41 
of the protocol. These only apply to those events that are not attributed to AZD1775 (Unlikely or 
Unrelated as defined in Section 10.3). 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
 All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
 Grade >2 AEs resulting in hospitalization or prolongation of hospitalization 
Additional Instructions: 
1. Use the AdEERS Multiple Agent Template. :  
 
Mayo Clinic Cancer Center (MCCC) Institutions: Provide copies of the AdEERS Multiple 
Agent Template, along with the UPIRTSO cover sheet, by fax 
 to the MCCC 
Regulatory Affairs Unit (RAU) Risk Information Specialist who will determine and 
complete IRB reporting. The RAU will submit to the MCCC SAE Coordinator and the 
MCCC IND Coordinator to determine if FDA submission is needed. 
 
2.  Reporting of SAEs to AstraZeneca 
Fax or email a copy of the AdEERs report to SCRI at 
 or 
 within 24 hour of the event. The investigator 
must then ensure that the form and coversheet are accurately and fully completed with 
follow-up information and fax or email those to SRCI  within 2 to 3 calendar days for deaths 
or life-threatening events and 5 calendar days for other serious adverse events. The original 
and the duplicate copies of the AdEERs report, SRCI  SAE coversheet, and the fax 
confirmation sheet must be kept with the case report forms at the study site.  
 
Follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not, and whether the patient continued 
or discontinued study participation. The AdEERs report, SRCI  SAE coversheet, and fax 
confirmation sheet must be retained. Pregnancy follow-up should describe the outcome of 
the pregnancy, including any voluntary or spontaneous termination, details of the birth, and 
the presence or absence of any congenital abnormalities or birth defects. 
 
EVENT TYPE 
REPORTING PROCEDURE 

 
43  
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Other Grade 4 or 5 Events 
and/or Any Hospitalizations 
During Treatment Not 
Otherwise Warranting an 
Expedited Report 
Complete a Notification Form*: Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form electronically via 
the MCCC Remote Data Entry System or paper form within 
5 working days of the date the clinical research associate 
(CRA) is aware of the event(s) necessitating the form. 
If an expedited written report has been submitted, this form 
does not need to be submitted. 
  
* This form is not required for those adverse events listed in section 10.41 
 
10.41  Special Situations for Expedited Reporting 
 
Exceptions to Expedited Reporting and Submission of Notification Forms: 
EXPECTED Serious Adverse Events 
 
An expedited report  or notification form may not be required for specific Grade 1, 2 and 
3 Serious Adverse Events where the AE is EXPECTED. Any protocol specific reporting 
procedures MUST BE SPECIFIED BELOW and will supercede the standard Expedited 
Adverse Event Reporting Requirements (Note: These adverse events must still be 
reported through the routine reporting mechanism [i.e. Nadir/adverse events form]; see 
footnote 1):  
NOTE: These only apply to those events that are not attributed to AZD1775 
(Unlikely or Unrelated as defined in Section 10.3).  
 
System Organ Class 
(SOC) 
 
Adverse event/ Symptoms 
 
CTCAE Grade at which the event 
will not be expeditedly reported1 
General disorders and 
administrations site 
conditions 
 
Fatigue  
Grade 3 
 
Gastrointestinal 
Disorders 
 
 
Nausea 
Grade 3 
 
Vomiting 
Diarrhea 
Investigations 
Neutrophil count decreased 
Grade 3 and Grade 4 
 
White blood cell count decreased 
Platelet count decreased 
Blood and lymphatic 
system disorders 
Anemia 
Grade 3 and Grade 4 
Febrile Neutropenia (in AML 
patients only) 
Grade 3 and Grade 4 
 
 
1.  These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
 

 
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10.5 
Other Required Reporting 
 
10.51 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
abnormities or birth defects, must be reported immediately if they occur at any time 
following treatment with an agent under an IND/IDE since they are considered to be a 
serious AE and must be reported to  SRCI  database as specified in 21 CFR 312.64(b). 
 
10.52  Death 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
Reportable categories of Death  
 
 
Death attributable to a CTCAE term. 
 
 
Death Neonatal:  A disorder characterized by cessation of 
life during the first 28 days of life. 
 
 
Death NOS:  A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
 
 
Sudden death NOS:  A sudden (defined as instant or within 
one hour of the onset of symptoms) or an unobserved 
cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
 
 
Death due to progressive disease should be reported as Grade 
5 “Neoplasms benign, malignant and unspecified (incl 
cysts and polyps) – Other (Progressive Disease)” under the 
system organ class (SOC) of the same name.  Evidence that 
the death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: 
clinical deterioration associated with a disease process) 
should be submitted. 
 
10.53 Secondary Malignancy 
 
 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 

 
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 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE must be reported.  
 
 
Any malignancy possibly related to cancer treatment should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 
10.54 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. 
 
10.55 Pregnancy  
To ensure patient safety, each pregnancy occurring while the patient is on study 
treatment  and for up to 20 months from the patient’s last dose must be reported 
to the SRCI Database within 24 hours of learning of its occurrence. The 
pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported 
by the investigator to SCRI Safety Database. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible 
relationship to the AstraZeneca study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
 
In addition, each pregnancy occurring for a female partner of a male study 
participant must be reported while the patient is on study treatment and for up to 
6 months after the patient’s last dose.  Pregnancy outcomes must be collected for 
the female partners of any males who took study treatment in this study.  Consent 
to report information regarding these pregnancy outcomes should be obtained 
from the mother. 
 
10.6 
Required Routine Reporting  
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
System Organ Class 
(SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
General disorders and 
administrations site 
conditions 
Fatigue  
X 
X 
Fever (Pyrexia) 
X 
X 
 
 
 
Blood and lymphatic 
system disorders 
Anemia 
X 
X 
Gastrointestinal 
Disorders 
Nausea 
X 
X 
Vomiting 
X 
X 
# of stools 
X 
 
Diarrhea 
 
X 

 
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Investigations 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
AST Increased 
X 
X 
ALT Increased 
X 
X 
 
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified 
in Section 10.6: 
10.611 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.612 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.613  Grade 5 AEs (Deaths) 
 
10.6131  
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.6132 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
 
10.62    Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the Active 
Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
11.0 
Treatment Evaluation Guideline  
 
 
Note:   Novel combinations in AML/MDS may be expected to result in different response 
kinetics than “conventional” cytotoxic regimens. Thus initial blast % increase may not 
accurately reflect later stage responses. AraC, if given SC may lead to differentiation. 
There will be no pre-specified number of cycles and patients can remain on study as long 
as they tolerate the combination and/or derive clinical benefit.  
 
11.1  
AML response criteria 
 
11.11 Complete hematologic response (CR) 
Less than 5% blasts in a non-hypocellular marrow with a granulocyte count ≥ 
1.0, and a platelets count of ≥ 100 with complete resolution of  
extramedullary disease and absence of peripheral blood blasts.  
 
CR incomplete (CRi) is called if patient meets all CR criteria except for residual 
neutropenia (ANC<1 x109/L) or thrombocytopenia (platelets<100 x109/L) 
 
11.111  Complete cytogenetic remission (CCyR) 

 
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The absence of chromosome abnormalities (if present at diagnosis) on 
conventional cytogenetic study using G-banding (at least 10 metaphases 
present). 
 
11.12  Morphologic leukemia-free state (MLFS): 
If bone marrow blasts <5%, absence of Auer rods blasts, absence of 
extramedullary disease without hematological recovery. 
 
11.13  Partial remission (PR) 
The presence of trilineage hematopoiesis in the bone marrow with recovery of 
ANC and platelet count to above levels, but with 5-25% bone marrow blasts and 
≥50% decrease in bone marrow blast percentage from baseline. 
 
11.14 No response (NR) 
Failure to achieve a PR, MLFS, CRi, or CR. 
 
11.15 Relapse:  
Disease recurrence after achieving CR. Disease recurrence is defined by blast  
≥5% in the bone marrow, or recurrence of peripheral blood blasts or 
extramedullary involvement. 
 
11.2  
MDS and CMML response criteria 
 
Category  
Hematologic Response  
Response Criteria (responses must last at least 4 weeks)a  
Complete remission (CR)  
Bone marrow: ≤5% myeloblasts with maturation of all cell lines.  
If present, persistent dysplasia will be noted (dysplastic changes 
should consider the normal range of dysplastic changes.)  
Peripheral blood:  
 
Hemoglobin (Hgb) ≥11 g/dL (untransfused, patient not on 
erythropoietin)  
 
Neutrophils ≥1.0 x 109/L (not on myeloid growth factor)  
 
Platelets ≥100 x 109/L (not on a thrombopoietic agent)  
 
Blasts 0%;  
Partial remission (PR)  
All CR criteria (if abnormal prior to treatment), except:  
Bone marrow blasts decreased by ≥50% compared with 
pretreatment but still >5%.  
Cellularity and morphology not relevant.  
Marrow CR 
Bone marrow: ≤ 5% myeloblasts and decrease by ≥50% over 
pretreatment if > 10% at baseline  
Peripheral blood: if hematologic improvement (HI) responses, 
they will be noted in addition to the marrow CR  
Stable disease (SD) 
Failure to achieve at least PR, but no evidence of progression for 
>8 weeks.  
Failure  
Death during treatment or disease progression characterized by 
worsening of cytopenias, increase in percentage of bone marrow 
blasts, or progression to an MDS FAB subtype more advanced 
than pretreatment after 6 months/cycles of therapy   

 
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Relapse after CR or PR  
At least one of the following:  
 
Return to pretreatment bone marrow blast percentage  
 
Decrement of ≥50% from maximum remission/response 
levels in granulocytes or platelets  
 
Reduction in hemoglobin concentration by ≥1.5 g/L or 
transfusion dependence if previously had become 
transfusion independent for > 8 weeksc  
Cytogenetic response  
Complete:  
     Disappearance of the chromosomal abnormality without    
     appearance of new ones  
Partial:  
     At least 50% reduction of the chromosomal abnormality  
Disease progression 
For patients with:  
 
Less than 5% blasts: ≥50% increase in blasts to >5% 
blasts  
 
5%-10% blasts: ≥50% increase in blasts to >10% blasts  
 
10%-20% blasts: ≥50% increase in blasts to >20% blasts  
 
20%-30% blasts: ≥50% increase in blasts to >30% blasts  
Any of the following:  
 
At least 50% decrement from maximum 
remission/response levels in granulocytes or platelets  
 
Reduction in hemoglobin concentration by ≥2 g/dL  
 
Transfusion dependence if previously had become 
transfusion independent for > 8 weeksc  
a    For a designated response (CR, PR), relevant response criteria must be noted on at least 2  
     successive determinations at least 1 week apart after an appropriate period following therapy  
     (e.g., 1 month or longer).  
c    In the absence of another explanation, such as acute infection, gastrointestinal bleeding,  
      hemolysis, etc.  
 
 
Hematologic Improvement*  
Response Criteria (responses must last at least 8 weeks)a  
Erythroid response 
(pretreatment, Hgb < 11 g/dL)  
Hgb increase by ≥1.5 g/dL  
Relevant reduction of units of red blood cell (RBC) transfusions 
by an absolute number of at least 4 RBC transfusions/8 wk 
compared with the pretreatment transfusion number in the 
previous 8 wk. Only RBC transfusions given for an Hgb of ≤ 9.0 
g/dL pretreatment will count in the RBC transfusion response 
evaluation.  
Platelet response 
(pretreatment, < 100 x 109/L)  
Absolute increase of ≥ 30 x 109/L for patients starting with >20 x 
109/L  
Increase from < 20 x 109/L to >20 x 109/L and by at least 100%  
Neutrophil response 
(pretreatment, < 1.0 x 109/L)  
At least 100% increase and an absolute increase >0.5 x 109/L.  
Progression or relapse after HI  
At least 1 of the following:  
 
At least 50% decrement from maximum response levels 
in granulocytes or platelets  
 
Reduction in Hgb by ≥1.5 g/dL  
 
Transfusion dependenceb  

 
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*    Pretreatment count averages of at least 2 measurements (not influenced by transfusions) ≥1    
      week apart (modification)  
a    For a designated response (CR, PR, HI), relevant response criteria must be noted on at least 2  
      successive determinations at least 1 week apart after an appropriate period following therapy      
      (e.g., 1 month or longer).  
b   In the absence of another explanation, such as acute infection, gastrointestinal bleeding,  
     hemolysis, etc.  
 
 
12.0 
Descriptive Factors 
 
12.1 
Transfusion Dependent:  Yes vs No 
 
12.2 
MDS subcategory: MDS vs MDS/MPN overlap vs CMML 
 
12.3 
Previous cytotoxic chemotherapy: yes vs no 
 
12.4 
AML subcategory: without prior HMA vs prior HMA 
 
12.5 
HMA failure: refractory vs relapsed vs progressed on HMA 
 
12.6 
AML: De novo vs secondary AML 
 
12.7 
AML: newly diagnosed vs relapsed/refractory  
 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
 
 
13.1 
Patients who have not developed PD will continue treatment per protocol. 
 
 
13.2 
Patients who develop PD while receiving therapy will go to the event monitoring phase. 
 
 
13.3 
Patients who go off protocol treatment for reasons other than PD will go to the event 
monitoring phase per Section 18.0. 
 
13.4 
If a patient in the initial safety portion fails to complete 28 days of treatment for reasons 
other than dose-limiting toxicity defined adverse events, the patient will be regarded as 
uninformative in regard and an additional patient will be treated; however, all toxicity 
information will be utilized in the analysis.    
 
13.5 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient will go directly to the event monitoring phase of the study (or off study, if 
applicable).  
 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 

 
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is necessary.  
 
13.6 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary endpoint is 
questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event monitoring phase of the study.  Event 
monitoring will be required per Section 18.0 of the protocol. 
 
13.7 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 
 

 
51  
MC1488 
 
 
14.0 
Body Fluid Biospecimens   
 
Body Fluid Biospecimen Submission  
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
 
Correlative 
Study 
(Section for 
more 
information) 
Mandatory 
or 
Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume 
to collect 
per tube 
(# of 
tubes to 
be 
collected) 
Baseline 
Cycle 
1 Day 
2 (+1 
Day) 
Cycle 
1 Day 
5 (+1 
Day) 
Cycle 
2 Day 
5 (+1 
Day) 
& Day 
5 of 
Subse
quent 
Odd 
Cycles 
 
At 
time of 
bone 
marro
w 
after 
cycles 
1 
(AML 
only), 
2 and 
43 
 
 
EOS 
Proces
s at 
site? 
(Yes or 
No) 
Temperature 
 Conditions 
for Storage 
/Shipping  
Biomarkers 
Mandatory 
Whole 
Blood 
1 x Red 
top 
2 x Na 
Heparin 
Green top 
10 mL 
(3) 
X 
X1 
 
 
 
 
X 
 
 
X 
Yes 
Cold Pack 
Biomarkers 
Mandatory 
Bone 
marrow 
aspirate 
Hepariniz
ed Green 
top 
10 mL 
(2) 
X4 
 
 
 
 
 
X 
 
 
X2 
Yes 
Cold Pack 
Buccal swab 
Optional 
Saliva 
n/a 
n/a 
X 
 
 
 
 
 
No 
ambient 
Pharmacokin
etics 
Mandatory 
Plasma 
Lavender 
Top 
2 ml 
 
 
Pre-
Dose, 
1, 2, 4, 
6, & 8 
hrs 
post-
dose 
Pre-
Dose 
 
 
Yes 
-20oC 
1.  
Only to be done in those patients with circulating tumor cells in their blood 

 
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2.  
End of study bone marrow sample is optional and to be collected only if bone marrow performed as part of patient’s standard of care. 
3.  
Bone marrow aspirates will be done at times of standard clinical marrow tests. Follow Tables 4.1. (AML) and 4.2. (MDS) for study   
schedule. In brief after cycle 1 (for AML only, at physician’s discretion can be omitted, see Table 4), after cycles 2 and 4,  and then at 
physician discretion.   
4. 
This is only mandatory IF a BM biopsy has not been done within 4 weeks of study start. 
NOTE: marrow bisopies will not be done soley for the purpose of drawing a research sample , but should be performed to coincide at times of 
standard clinical marrow biopsies/aspirates.  
 
 

 
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14.2  
Collection and Processing  
 
14.21 Biomarkers: Process on site per lab manual. Send all samples in original tubes to 
 lab per section 14.32.  
 
14.22 Pharmacokinetics: Samples are collected at the time intervals presented in the 
protocol. Whole blood will be collected in 2 mL BD Vacutainer tubes containing 
K2EDTA (lavender top) as anti-coagulant for the analysis of AZD1775. 
Following collection, gently invert the samples 10 times and immediately place 
on ice. Within 30 minutes of blood collection centrifuge at 1500 xg, at 4°C for 10 
minutes. From each blood sample, transfer roughly equal volumes into a total of 
two 1.8 mL polypropylene cryovials using a disposable polypropylene pipette. 
Store plasma samples at -20°C in an upright position within 30 minutes of 
plasma preparation and keep frozen at this temperature until shipment and during 
shipment.  
 
Labels will be provided. Tubes should be labeled with the following information: 
Study, Subject ID, Visit, Draw Time, and Biological Matrix (e.g., blood or 
plasma). When applying the label, place the label in a vertical position. Do not 
wrap the label around the tube horizontally.  Place the label as close to the cap as 
possible, but do not adhere the label to the cap of the tube. Do not cover any 
written information with the label. 
 
 
 
14.3 
Shipping and Handling 
 
14.31 Kits will be used for this study for the pharmacokinetics. 
 
 
14.32 Shipping Specimens 
 
14.321 For Biomarkers including saliva: Verify ALL sections of the 
Specimen Submission Forms (i.e. blood, bone marrow, saliva – see 
Forms Packet) are completed and filled in correctly.  
 
 
For Pharmacokinetics: Ship the aliquots frozen on dry ice. The 
samples must be securely packed in boxes to avoid breakage 
during transit, double-bagged to contain leaks, and where 
applicable, packed with a sufficient quantity of dry ice to ensure 
they remain frozen for at least 72 hours.  
 
Samples should be placed in a courier box with a paper copy of the 
Sample Inventory. Samples should be boxed up with each subject’s 
samples in profile order and listed in the same order on the Sample 
Inventory for ease of checking at the bioanalytical laboratory 
(BioA Lab). 
 

 
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Objectives and overview of correlative studies: 
The below assays and studies to be performed are suggested at the time of 
protocol writing. Based on novel insights into the biology of WEE1 inihibition 
and AML/MDS that will arise during the protocol duration, below experiments 
may be adjusted to reflect the current state of the art knowledge.  
 
1. WEE1 inhibition causes DNA damage and apoptosis. The degree of DNA 
damage in combination with AraC is unknown. Assessment of DNA damage 
induction by γH2AX and apoptosis by cleaved caspase 3 (CC3) as measured by 
flow cytometry on patient specimens at baseline and on follow up specimens, 
preferably on marrow aspirates, alternatively on peripheral blood samples will be 
conducted. Cell cycle distribution analysis and co-staining for total and 
phosphorylated CDK1/2 may be performed (using propidium iodide staining) at 
the same time points for samples with sufficient material. 
 
2. Preclinical experiments (R.Tibes Lab) suggest that the damage and cell death 
induction is mainly/stronger in an earlier, leukemia “stem cell like” population. 
Therefore the “stemness” of a γH2AX/CC3 dual positive population will be 
assessed by co-staining for CD34+/38- cell surface markers in parallel with 
γH2AX/CC3 by multi-color flow cytometry. Alternatively, selection of 
CD34+/38- cells can be performed with subsequent staining for γH2AX/CC3. 
 
3. In vitro we have shown that WEE1 protein expression may correlate with 
sensitivity to the AraC/AZD1775 combination. WEE1 protein expression levels 
in baseline marrow or peripheral blood may be assessed as well as WEE1 mRNA 
expression levels (could be deduced from RNAseq experiments below).  
 
4. In unpublished work we have found a potential modulation of DNA damage 
response genes/proteins by WEE1 kinase inhibition. We will examine changes in 
total and phosphorylation forms of essential DNA repair proteins within the HR 
repair pathway, transcript genes changes under treatment with single agent 
AZD1775 and in the combination with AraC.  
 
5. The role of myeloid specific mutations is unknown. Hence mutational/targeted 
sequencing of hematology/myeloid specific genes will be performed by targeted 
sequencing of gene panels or WES at baseline, at time of best response and at 
disease progression. A saliva sample will be used as germline control.  
 
6. It is hypothesized that AZD1775 activity is independent of mutated/functional 
p53. p53 mutation status will be assessed by direct sequencing of the p53 gene 
(i.e. Sanger, Roche AmpliChip). Potentially, induction of p21 in fresh samples 
will be assessed as a transcriptional readout of functional p53 status.  
  
7. Next Generation Sequencing - RNA sequencing: WEE1 target genes are 
master transcriptional regulators.  Therefore we will use next generation 
sequencing for RNA and microRNAs to assess transcriptional changes before, 
during and after therapy. Expression and differential regulation for the WEE1 
published signature genes [claspin, FBXO5, MCM10, CCNE 1 and 2] in patient 
specimens at baseline and follow up samples will be assessed, as well as p21 and 
HR pathway genes. 
 

 
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15.0 
Drug Information 
 
15.1 
AZD1775   
 
15.11 Background: AZD1775 is a highly selective, adenosine-triphosphate (ATP) 
competitive, small molecule inhibitor of Wee1 kinase, that is involved in 
regulation of intra-S and G2 cell cycle checkpoints through phosphorylation and 
inhibition of CDK2 and CDK1, respectively.  AZD1775 has significant 
selectivity over other tested protein kinases. In vitro, AZD1775 inhibits Wee1 
activity and induces DNA damage as well as G2 checkpoint escape in cell based 
assays. AZD1775 increases cytotoxicity when used in combination with DNA 
damaging agents, such as gemcitabine, cisplatin, carboplatin and topotecan, in 
p53-deficient cell lines. In vivo, AZD1775 was well tolerated and showed 
enhancement of anti-tumor efficacy by gemcitabine, carboplatin, cisplatin, 5-
fluorouracil (5-FU) and capecitabine in nude rat xenograft tumor  models. 
Similarly, in nude mouse xenograft models, AZD1775 treatment resulted in 
significant tumor growth inhibition at tolerated doses, and also enhanced the anti-
tumor growth effect of gemcitabine, carboplatin, and radiation therapy. 
 
15.12 Formulation: AZD1775 is currently available as dry filled capsules for oral 
administration containing 25, 100 or 200 mg of AZD1775 with the following 
excipients:  lactose, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. 
 
15.13 Preparation and storage: Capsules are packaged in high density 
polyethylene (HDPE) bottles, and should be stored at room temperature, 
no more than 30° C. For further information, refer to the investigational 
product label.  Provided by AstraZeneca. 
 
15.14 Administration: 200 mg PO (or respective dose) once daily either 2 hours 
before or 2 hours after a meal   
 
 
15.15 Pharmacokinetic information: The PK data of AZD1775 following a 
single oral administration showed a moderate rate of absorption with a 
Tmax occurring at 3 to 4 hours.  Post-peak plasma concentrations declined 
essentially in a mono-exponential manner with a t1/2 in the region of 10 
hours.  Exposure as measured by maximum plasma drug concentration 
observed (Cmax) and area under the curve (AUC)0-∞ increased in a dose-
proportional manner over the dose range of 325 to 1300 mg.  Following 
single (100 to 325 mg) and multiple dose administrations of AZD1775 (25 
to 325 mg BID and 100 to 200 mg once daily [QD]) with carboplatin, 
cisplatin, and gemcitabine, plasma exposure of AZD1775 was consistent 
with predictions based on the single-dose regimen. AZD1775 was 
moderately bound to plasma proteins in all species tested, with the 
unbound fractions (at AZD1775 concentration of 1 μM) in plasma from 
the rat, dog and human being 23.2, 40.0, and 39.5%, respectively. Binding 
to plasma proteins was independent of AZD1775 concentration (0.1-10 
μM) in the rat and human, but an increase in unbound fraction from 30.6% 
at 0.1 μM to 45.4% at 10 μM was observed in the dog.  CYP3A4 is the 

 
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major CYP isoform involved in the oxidative metabolism of AZD1775, to 
the N-demethylated product. In addition, studies with flavin-containing 
monooxygenase (FMO) enzymes indicated that FMO3 and FMO5 were 
involved in formation of the N-oxide derivative of AZD1775. 
 
 
 
 
15.16 Potential Drug Interactions: The following treatments and all the medications listed in 
Appendix VI are prohibited while in this study. Any further questions regarding concomitant 
treatments should be referred to the sponsor: 
 
No other investigational therapy should be given to patients.  No anticancer agents other than the 
study medications should be given to patients.  If such agents are required for a patient, then the 
patient must first be withdrawn from the study. 
 
No formal clinical drug interaction studies have been performed with AZD1775.  An exploratory 
assessment of the effect of aprepitant on AZD1775 exposure in oncology patients suggests that 
there is a drug interaction between AZD1775 and aprepitant, as exposure to AZD1775 increased 
by ~60% when aprepitant was co-administered with AZD1775.  The observed increase in 
AZD1775 exposure is likely the result of CYP3A4 inhibition by aprepitant.  This increase in 
exposure is statistically significant.  At the selected MTDs, this increase may also be of clinical 
importance.  Therefore, concomitant treatment with aprepitant and fosaprepitant is not allowable 
per protocol until further evaluation. 
Potent or moderate inhibitors or inducers of CYP3A4, sensitive CYP3A4 substrates, and 
CYP3A4 substrates with a narrow therapeutic window should be avoided until additional data on 
drug-drug interaction becomes available (Appendix VI). 
 
In vitro data suggests that AZD1775 may also be a weak reversible inhibitor of CYP2C19.  
Caution should be exercised with concomitant administration of AZD1775 and agents that are 
sensitive substrates of CYP2C19, or substrates of this enzyme with narrow therapeutic range; 
refer to Appendix VI for a list of sensitive substrates of CYP2C19, or substrates of this enzyme 
with narrow therapeutic range. 
 
AZD1775 has been shown to be a weak inducer of CYP1A2 in vitro with a maximum measured 
response between donors of 39.9% to 93.1% (at 10 μM) and 18.6% to 32.5% (at 5 μM) of the 
positive control omeprazole (50 μM), respectively.  Given the nature of the AZD1775 dosing 
schedule, however, the risk of induction in the clinic is considered low.  No specific precautions 
are recommended at this time, except to be initially vigilant when using substrates of CYP1A2 
with a narrow therapeutic range. 
 
In vitro studies have shown that AZD1775 may be a substrate and inhibitor for human 
P-glycoprotein (P-gp).  Caution should be exercised when agents that are inhibitors or substrates 
of P-gp are administered concomitantly with AZD1775 (see Appendix VI). 
 
Recent in vitro transporter studies have shown AZD1775 to be an inhibitor of BCRP (IC50 5.1 
µM).  This finding is particularly relevant for drugs administered orally where exposure is 
normally limited by BCRP-mediated efflux, in particular some statins.  Modelling has predicted a 
substantial increase in the exposure of Atorvastatin when co-administered with AZD1775 and the 

 
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use of Atorvastatin is therefore prohibited in the current study.  Other drugs where the 
disposition is mediated via BCRP should be administered with caution, dose modification 
considered or substituted by an alternative drug (Appendix VI). 
 
AZD1775 has been shown to be an inhibitor or MATE1 and MATE2K transporters.  A drug 
interaction with substrates of either transporter cannot be ruled out, the most important substrate 
known to date being metformin. 
 
Herbal preparations/medications are not allowed throughout the study.  These herbal medications 
include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.  Patients should stop 
using these herbal medications 14 days prior to first dose of AZD1775.  
  . 
 
15.17 Known potential toxicities:  Based on the preliminary safety data 
available, the most frequent adverse events observed were blood and 
lymphatic disorders (anemia, febrile neutropenia), gastrointestinal 
disorders (diarrhea, vomiting, nausea, abdominal pain, constipation), 
general disorders and administration site conditions (fatigue, fever, chills), 
and investigation findings (thrombocytopenia, neutropenia, hematology 
and serum chemistry). 
 
 
15.18 Drug procurement:  Drug will be provided by AstraZeneca. 
 
 
  
 
 
15.2 
Cytarabine (AraC)  
 
15.21 Background: Cytarabine (cytosine arabinoside) inhibits DNA synthesis. 
Cytosine gains entry into cells by a carrier process, and then must be converted to 
its active compound, aracytidine triphosphate. Cytosine is a pyrimidine analog 
and is incorporated into DNA; however, the primary action is inhibition of DNA 
polymerase resulting in decreased DNA synthesis and repair. Cytarabine is 
specific for the S phase of the cell cycle (blocks progression from the G1 to the S 
phase). 
 
 
15.22 Formulation: Commercially available for injection, powder for reconstitution: 
100 mg, 500 mg, 1 gram, 2 gram 
 
15.23 Preparation, storage, and stability: Store intact vials of powder at room 
temperature 15ºC to 30ºC (59ºF to 86ºF). Reconstitute with bacteriostatic 
water for injection. Reconstituted solutions are stable for up to 8 days at 
room temperature, although the manufacturer recommends use within 48 
hours. Further dilution in 250-1000 mL of D5W or 0.9% NaCL is stable 
for 8 days at room temperature (25C). Note: Solutions containing 

 
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bacteriostatic agents should not be used for the preparation of either high 
doses or intrathecal doses of cytarabine. 
 
15.24 Administration: Low-dose cytarabine (LD-AraC) will be administered at a 
starting dose of  20 mg BID subcutaneously (sc) for 10 days of a 28-day cycle., 
with dosing adjustments as outlined in section 8.    
 
 
15.25 Pharmacokinetic information: 
Distribution: Vd: Total body water; widely and rapidly since it enters the 
cells readily; crosses blood-brain barrier with CSF levels of 40% to 50% of 
plasma level 
Metabolism: Primarily hepatic; metabolized by deoxycytidine kinase and 
other nucleotide kinases to aracytidine triphosphate (active); about 86% to 
96% of dose is metabolized to inactive uracil arabinoside. 
Half-life elimination: I.V.: Initial: 7-20 minutes; Terminal: 1-3 hours. 
Excretion: Urine (~80%) within 24 hours. 
 
 
15.26 Potential Drug Interactions:   
 
Decreased Effect: Cytarabine may decrease the effect of Flucytosine; 
cytarabine may decrease digoxin absorption. 
 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Warnings/Precautions: Potent Myelosuppressive agent 
Common known potential toxicities, frequency not defined:   
Other: Fever 
Dermatologic: Rash 
Gastrointestinal: Anal inflammation, anal ulceration, anorexia, diarrhea, 
mucositis, nausea, vomiting 
Hematologic: Myelosuppression, neutropenia, anemia, thrombocytopenia, 
bleeding, leukopenia, megaloblastosis, reticulocytes decreased 
Hepatic: Hepatic dysfunction, transaminases increased (acute) 
Local: Thrombophlebitis 
 
Less common known potential toxicities:  
Cardiovascular: Chest pain, pericarditis 
Central nervous system: Dizziness, headache, neural toxicity, neuritis 
Dermatologic: Alopecia, pruritus, skin freckling, skin ulceration, urticaria 
Gastrointestinal: Abdominal pain, bowel necrosis, esophageal ulceration, 
esophagitis, pancreatitis, sore throat 
Genitourinary: Urinary retention 
Hepatic: Jaundice 
Local: Injection site cellulitis 
Ocular: Conjunctivitis 
Renal: Renal dysfunction 
Respiratory: Dyspnea 
Miscellaneous: Allergic edema, anaphylaxis, sepsis 
 
Infrequent and/or case reports: 
Amylase increased, aseptic meningitis, cardiopulmonary arrest (acute), 
cerebral dysfunction, cytarabine syndrome (bone pain, chest pain, 

 
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conjunctivitis, fever, maculopapular rash, malaise, myalgia); 
exanthematous pustulosis, hyperuricemia, injection site inflammation 
(SubQ injection), injection site pain (SubQ injection), interstitial 
pneumonitis, lipase increased, paralysis, rhabdomyolysis, veno-occlusive 
liver disease 
 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
 
16.0  
Statistical Considerations and Methodology  
 
16.1 
Overview:  
 
This study is a phase II screening study.  It is divided into two portions.  The safety 
portion is designed to determine the dose of the treatment agents.  The expansion portion 
is designed to continue enrollment at the acceptable dose levels to determine efficacy of 
treatment in elderly (age 60+) newly diagnosed AML patients (Arm A: AZD1775 days 1-
5 & 8-12) and AraC days 1-5 & 8-12) and to make a selection of one of the two 
randomized arms for Relapsed/Refractory AML and HMA failure MDS patients (Arm B: 
AZD1775 days 1-5 & 8-12) and AraC days 1-5 & 8-12; Arm C: AZD1775 days 1-5, 8-
12, 15-19, 22-26).   
 
The purpose of this screening design is NOT TO ensure a high probability that the very 
best treatment is selected, but to ensure a low probability that a poor treatment is selected. 
In other words, at the conclusion of this trial, we cannot make a definitive conclusion 
about the superiority of one treatment compared to the other, but we can ensure that there 
is a small probability of bringing the inferior treatment forward.   
  
 
16.2 
Statistical Design and Analysis for the Primary Endpoint 
 
 
16.21 Primary Endpoint 
 
The primary endpoint of this trial is the rate of complete response (CR plus CRi). 
Throughout Section 16.0, complete response will be considered synonymous 
with “success”, unless specified otherwise. All patients meeting the eligibility 
criteria, who have signed a consent form, and have begun treatment at the study 
MTD will be evaluable for complete response, with the exception of patients who 
are determined to be a major treatment violation. 
 
Treatment Responses will be assessed by standard criteria for the respective disease 
per NCCN guidelines or according to specific criteria from expert panels (i.e. the 
International Working Group Criteria for the response in acute myeloid leukemias). 
Response will be assessed by peripheral blood criteria at the end of each cycle and 
every other cycle (for MDS) thereafter (Burnett et al. 2007. Gileset al. 2005,  
Kantarijian et al. 2012,  Fenaux et al. 2009). 
Bone marrow tests to assess responses will be carried as outlined in the study tables 
Table 4.1 and 4.2.   
 

 
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16.22 Arm A:  Efficacy and safety of AZD1775 + AraC in elderly newly diagnosed AML 
 
 
 
Statistical Design, Analysis and Decision Rule 
 
Efficacy and safety of AZD1775 + AraC will be tested in elderly patients with 
newly diagnosed AML using a single-arm single-stage binomial design.  The 
primary endpoint will be the complete response rate, which will be defined as an 
objective status of CR or CRi.   Complete response rate will be evaluated over all 
cycles of study treatment.  The proportion of CR/CRi responses will be estimated 
by the number of CR/CRi responses divided by the total number of evaluable 
patients.  Two-sided 95% confidence intervals will be computed using an exact 
binomial confidence interval.  The frequency and relative frequency of individual 
response categories will also be computed.  For a subject to be considered 
evaluable for statistical analysis, the subject must be eligible, provide consent, 
initiate treatment and not experience a major treatment violation during the first 
cycle of treatment.   
 
 The largest CR/CRi response proportion where the proposed treatment regimen 
would be considered ineffective in this population is 15% (Burnett et al. 2007. 
Gileset al. 2005,  Kantarijian et al. 2012,  Fenaux et al. 2009) and the smallest 
CR/CRi response proportion that would warrant subsequent studies with the 
proposed regimen in this patient population is 40%.   
 
The following one-stage binomial design uses 21 patients to test the null 
hypothesis that the true CR/CRi response proportion in a given patient population 
is at most 15%. 
 
Decision Rule:  Enter 21 patients into the study. If 5 or fewer CR/CRi responses 
are observed in the first 21 evaluable patients, we will consider this regimen 
ineffective in this patient population. Otherwise, if 6 or more CR/CRi responses 
are observed in the first 21 evaluable patients, we may recommend further testing 
of this regimen in subsequent studies in this population.  We anticipate accruing 
an additional 2 patients to account for ineligibility, cancellation, major treatment 
violation, or other reasons.  Thus, the total maximum accrual to this arm is 23 
patients. 
 
Assuming that the number of CR/CRi responses is binomially distributed, the 
significance level within this arm is </=10% and the probability of declaring that 
this regimen warrants further studies (i.e., statistical power) under various 
CR/CRi response proportions can be tabulated as a function of the true CR/CRi 
response rate as shown in the following table. 
If the true CR/CRi rate is… 
0.15 
0.20 
0.25 
0.30 
0.35 
0.40 
Then the probability of 
declaring that the regimen 
warrants further studies is… 
0.08 
0.23 
0.43 
0.64 
0.80 
0.90 
 
 
 

 
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16.23  Arm B and C:  Efficacy and safety of AZD1775 in combination with AraC 
compared to AZD1775 alone in relapsed/refractory AML or HMA failure MDS 
patients.   
 
 
 
Statistical Design, Analysis and Decision Rule 
 
Efficacy and safety of AZD1775 alone or with AraC will be tested in patients 
with relapsed/refractory AML and patients with HMA failure MDS using a 
flexible randomized phase II selection design.  Patients will be randomized to 
AZD1775 alone or with AraC in a 1:1 fashion using a dynamic allocation 
procedure (Pocock & Simon 1975).  The primary endpoint will be the complete 
response rate, which will be defined as an objective status of CR or CRi.  
Complete response rate will be evaluated over all cycles of study treatment.  The 
proportion of CR/CRi responses will be estimated by the number of CR/CRi 
responses divided by the total number of evaluable patients (by arm).  Two-sided 
95% confidence intervals will be computed using an exact binomial confidence 
interval.  The frequency and relative frequency of individual response categories 
will also be computed.  Estimates will also be computed by arm separately for 
each disease.  For a subject to be considered evaluable for statistical analysis, the 
subject must be eligible, provide consent, initiate treatment and not experience a 
major treatment violation during the first cycle of treatment.   
 
The selected design is a flexible randomized phase II selection design (Sargent & 
Goldberg 2001).  This study will randomize 40 evaluable patients (20 per arm).  
The minimum required number of CR/CRi responses for an arm to be considered 
as having evidence of efficacy is 3 (out of 20 evaluable patients).  This decision 
rule is based on a single-arm single-stage binomial design testing the null 
hypothesis that the true CR/CRi response proportion in a given arm is at most 5% 
(Tawfik et al. 2014, Giles et al. 2005, Jabour et al. 2010, Prevet et al. 2011) with 
the smallest CR/CRi response proportion warranting subsequent studies being 
25%. 
 
In the event that both arms meet this decision rule for efficacy, the combination 
arm will be considered as having additional efficacy over the single-agent arm if 
the CR/CRi response rate on the combination arm is at least 10% greater than the 
single-agent arm.  If the difference is <10%, then the trial is considered 
statistically ambiguous and the selection between the combination and single-
agent arm will be allowed to include other factors (e.g., adverse event data) in 
addition to the CR/CRi response rate.  We anticipate accruing an additional 4 
patients (2 patients per arm) to account for ineligibility, cancellation, major 
treatment violation, or other reasons.  Thus, the total maximum accrual to Arm B 
is 22 patients and to Arm C is 22 patients.  
 
Assuming that the number of CR/CRi responses is binomially distributed, the 
significance level for the single-arm decision rule requiring a minimum of 3 (out 
of 20 evaluable patients) within an arm is </=10% and the probability of 
declaring that a given arm’s treatment regimen warrants further studies (i.e., 
statistical power) under various CR/CRi response proportions can be tabulated as 
a function of the true CR/CRi response rate as shown in the following table. 
 

 
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If the true CR/CRi rate is… 
0.05 
0.10 
0.15 
0.20 
0.25 
Then the probability of 
declaring that a given arm’s 
treatment regimen warrants 
further studies is… 
0.08 
0.32 
0.60 
0.79 
0.91 
 
Probabilities for the combination arm being selected as the overall winner are 
provided in the following table.   
 
CR/CRi rate 
(AZD1775 alone) 
CR/CRi rate  
(AZD1775 + AraC) 
Probability combo selected over 
single-agent arm 
0.05 
0.05 
0.07 
0.25 
0.25 
0.30 
0.20 
0.25 
0.44 
0.15 
0.25 
0.61 
0.10 
0.25 
0.77 
0.05 
0.25 
0.88 
 
 
 
16.3 Sample Size, Accrual Rate, and Study Duration  
 
This design is expected to accrue 18 patients to the safety portion with the possibility of 
enrolling up to 54.  Six patients in each of the safety arms will be treated at the MTD and 
thus will be eligible for primary endpoint analysis.  An additional 15 patients in Arm A 
and 14 patients in both arm B and C will be enrolled per treatment arm in the expansion 
portion with the addition of another 2 per arm to account for ineligibility, cancellation, 
major treatment violation, or other reasons.  Thus the final accrual may be as large as 102 
or as low as 67 (Arm A: 23; Arm B: 22; Arm C: 22). 
 
The anticipated accrual rate is 4-6 evaluable patients per month.  Therefore, the accrual 
period is expected to be approximately 1.5-2 years.  The primary endpoint will be 
evaluated approximately 2.5 years after the trial opens, or after the last patient accrued 
has been observed for at least 4 months.  The total study duration is expected to be 
approximately 2.5 years.   
  
 
 
 
16.4 
Secondary Endpoints 
 
 
 
16.41 Safety and tolerability data will be compiled.  The maximum grade for each type 
of adverse event will be recorded for each patient, and frequency tables will be 
reviewed to determine patterns (by arm, disease and overall).  Additionally, the 
relationship of the adverse event(s) to the study treatment will be taken into 
consideration.  The rate of grade 3 or higher non-hematologic adverse events, and 
the rate of grade 4 or higher adverse event (hematologic and non-hematologic) 
will be computed each with a 95% exact binomial confidence interval.  
 
 
 
16.42 Summary statistics for clinical benefit (mean and standard deviations for 
continuous variables and frequencies and percentages for discrete variables) will 
be compiled for hematologic improvements and transfusion requirements. 

 
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16.43 Duration of response is defined for all evaluable patients who have achieved a 
response as the date at which the patient’s earliest best objective status is first 
noted to be a CR/CRi response to the earliest date progression is documented.  If 
a patient dies subsequent to the response without a documentation of disease 
progression, the patient will be censored at the last date disease was assessed.  In 
the case of a patient failing to return for evaluations before a documentation of 
disease progression, the patient will be censored for progression on the date of 
last evaluation.  The distribution of duration of response will be estimated using 
the method of Kaplan-Meier (1958). 
 
 
 
16.44 Time to response/progression is defined as the time from registration to the 
earliest date of documentation of response/disease progression.  If a patient dies 
without a documentation of disease progression the patient will censored at the 
last date disease was assessed.  In the case of a patient starting treatment and then 
never returning for any evaluations, the patient will be censored for progression 1 
day post-registration.  The distribution of time to progression will be estimated 
using the method of Kaplan-Meier (1958). 
 
 
 
16.45 Survival time is defined as the time from registration to death due to any cause.  
The distribution of survival time will be estimated using the method of Kaplan-
Meier (1958). 
 
 
 
16.46 Time to AML or death is defined for all evaluable patients with MDS as the time 
from registration to leukemic transformation or death due to any cause.  The 
distribution of time to AML or death will be estimated using the method of 
Kaplan-Meier (1958). 
 
 
16.5 
Exploratory Analysis 
 
 
 
An exploratory analysis will be conducted, if there is indication, to determine any 
differences in study endpoints for subgroups of patients within each treatment arm as 
defined by the grouping factors (section 5.0), descriptive factors (section 12.0), dose level 
or any other patient demographics. 
 
 
16.6  
Correlative Research 
 
 
 
 
16.61 Statistical analysis of pharmacokinetics and biomarkers will be primarily 
descriptive.  Continuous biomarker levels will be explored in a graphical manner 
including mean plots and plots of change and percent change from baseline and 
other summary measures.  Any potential relationships between the baseline level 
or change in the level of each biomarker and clinical outcome such as overall 
response, 6-month progression and survival, and adverse event incidence will be 
further analyzed using Wilcoxon rank sum tests or logistic regression methods, as 
appropriate.  Association between a dichotomized biomarker and overall 
response will be assessed using a chi-squared test.  Comparisons with 1-sided p-
values ≤0.10 are considered significant.  As this correlative component is 
exploratory in nature, we have not adjusted for multiple comparisons. 
 
 
 
16.62 Patient-reported outcomes will be assessed at baseline and at the end of each 
cycle of treatment. MPN-SAF TSS was created to address the constellation of 

 
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symptoms. The MPN-SAF includes 1 item measuring fatigue from the previously 
validated Brief Fatigue Inventory (BFI), as well as linear analog scales capturing 
early satiety, abdominal discomfort, inactivity, concentration problems, 
numbness/tingling in the hands/feet, night sweats, itching, bone pain, fever, and 
weight loss. The MPN-SAF TSS has previously been validated for use at a single 
time point by co-administration with previously validated instruments. 
 
Quality of life will be assessed prior to review of treatment response and 
discussions of patient’s general health since last treatment evaluation.  QOL will 
be measured using the EORTC QLQ-C30, a 30-item patient-reported 
questionnaire about patient ability to function, symptoms related to the cancer 
and its treatment, overall health and quality of life, and perceived financial 
impact of the cancer and its treatment.  28 of the 30 items are measured on a 1-4 
scale (1=not at all; 4=very much) with the remaining two items (overall health 
and overall quality of life) scored on a 1-7 numeric analogue scale (1=very poor; 
7=excellent).  The recall period for the EORTC QLQ-C30 is one week.  The 
EORTC QLQ-C30 is the product of more than a decade of collaborative research 
and to date, more than 2200 studies using the EORTC QLQ-C30 have been 
registered with the EORTC (Fayers et al, 2001 [EORTC Scoring Manual]).    
The patient booklet containing this questionnaire will be administered to all 
willing patients via a paper booklet in clinic at baseline and on day 1 of every 
cycle starting with Cycle 2, and will be scored according to the published scoring 
algorithms.   
 
 
Scale score trajectories over time and changes from baseline over time will be 
examined using repeated measures or growth curve models, as appropriate, 
stream plots and mean plots with standard deviation error bars overall.  Scores 
and changes at each cycle will be statistically tested using paired t-tests, and 
standardized response means (i.e. effect sizes) (mean of the change from baseline 
scores at a given cycle, divided by the standard deviation of the change scores) 
will be interpreted (after applying Middel’s (2002) adjustment) using Cohen’s 
(1988) cut-offs:  <0.20 = trivial; 0.20-<0.50 = small; 0.50-<0.80 = moderate; and 
>=/0.80 = large. 
 
16.7 
Early Safety Analysis  
 
An early safety analysis will be performed after 6 patients have been accrued to each arm 
of the study and observed for one cycle.  Accrual will be temporarily halted while these 
patients are evaluated.  If 2 or more of the first 6 patients experience a DLT, as defined 
below, then the dose level will be reduced as defined in Section 8.0 and another six 
patients will be treated. If < 2/6 patients experience toxicities defined as DLT, then this 
dose level will be defined as the operational MTD and moved into the expansion portion. 
Further dose de-escalation to dose level -2 will follow the same guidelines.  
 
Should additional modification be necessary, the study will be closed and evaluated by 
the study team regarding continuation.  Upon determination of the safe dose level, the 
study will re-open for accrual.   
 
 
16.8 
Data & Safety Monitoring: 

 
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16.81 The principle investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
 
16.82 Adverse Event Stopping Rules:   To be evaluated in each arm independently, the 
stopping rules specified below are based on the knowledge available at study 
development.  We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation.  The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as  “possible,” “probable,” or “definite”) that 
satisfy one of the following: 
 
 
if 3 or more patients in the first 10 treated patients in each arm experience a 
grade 4 or higher non-hematologic adverse event at least possibly related to 
treatment. 
 
 
if after the first 10 patients in each arm have been treated, 30% of all patients 
experience a grade 4 or higher non-hematologic adverse event at least 
possibly related to treatment.  
 
NOTE: Only the arm(s) that crosses the stopping boundary rule will be 
closed, not then overall study accrual. 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 
16.9a   Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
along with other required information for this study will be reported on 
www.ClinicalTrials.gov. For purposes of timing of the Results Reporting, the initial 
estimated completion date for the Primary Endpoint of this study is 2.5 years after the 
study opens to accrual. The definition of “Primary Endpoint Completion Date” (PECD) 
for this study is at the time the last patient registered has been followed for at least 4 
months. 
 
16.9b Inclusion of Women and Minorities 
 
16.9b1 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 

 
67  
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16.9b2 There is no information currently available regarding differential effects of 
this regimen in subsets defined by race, gender, or ethnicity, and there is 
no reason to expect such differences to exist. Therefore, although the 
planned analysis will, as always, look for differences in treatment effect 
based on racial and gender groupings, the sample size is not increased in 
order to provide additional power for subset analyses. 
 
16.9b3 The geographical region served by MCCC has a population which includes 
approximately 3% minorities.  Based on prior MCCC studies involving 
similar disease sites, we expect about 3-5% of patients will be classified as 
minorities by race and about 33% of patients will be women. Expected 
sizes of racial by gender subsets are shown in the following table: 
 
Accrual Estimates by Gender/Ethnicity/Race  
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
2 
3 
0 
5 
Not Hispanic or Latino 
32 
65 
0 
97 
Ethnic Category: Total of all subjects* 
34 
68 
0 
102 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
1 
0 
1 
Black or African American 
1 
1 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
33 
66 
0 
99 
Racial Category: Total of all subjects* 
34 
68 
0 
102 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa.  Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

 
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17.0 
Pathology Considerations: None 
 
        18.0 
Records and Data Collection Procedures 
 
18.1 
Submission Timetable (need to be updated) 
 
Initial Material(s)  
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study  
 
 
 
 
2 weeks after registration 
Baseline Adverse Event  
Measurement - Baseline 
Bone marrow biopsy report with 
cytogenetics and/or FISH 
Research Blood Submission (see Section 
14.0) 
Research Bone Marrow Aspirate Submission 
(see Section 14.0) 
 
Research Saliva Submission -Baseline   
Patient Questionnaire Booklet 
≤2 weeks after registration – Patient questionnaire booklet 
must be used; copies are not acceptable for this submission. 
Patient Questionnaire Booklet Compliance  
≤2 weeks after registration – This form must be completed 
only if the Patient Questionnaire Booklet contains absolutely 
NO patient provided assessment information. 
End of Active Treatment/Cancel Notification  
Submit 2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
 
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each evaluation during 
treatment 
At end of treatment 
 
Evaluation/Treatment  
X 
X 
Nadir/Adverse Event  
X 
X 
Measurement  
X3 
X3 
Bone marrow biopsy report with 
cytogenetics and/or FISH 
X3 
X3 
Patient Questionnaire Booklet 
X1 
X 

 
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CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each evaluation during 
treatment 
At end of treatment 
 
Patient Questionnaire Booklet Compliance   
X2 
X 
Research Blood Submission  
X (see Section 14.0) 
X 
Research Bone Marrow Aspirate Submission  
X (see Section 14.0) 
 
  PK Specimen Submission (Cycle 1) 
X (see Section 14.0) (Cycle 1 
only) 
 
  PK Specimen Submission (Cycle 2+) 
 
X (see Section 14.0) (Cycle 
2+) 
X 
End of Active Treatment/Cancel Notification  
 
X 
Notification– Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization  
At each occurrence 
(see Section 10.0) 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
1. Patient questionnaire booklet must be used; copies are not acceptable for this submission. To be 
completed prior to treatment every cycle. 
2. This form must be completed only if the patient questionnaire booklet contains absolutely NO patient 
provided assessment information. 
3. Submit copy of documentation of response (CR, CRi, PR, CI, MLFS, Marrow CR) or 
PD/Relapse/Fail/Failure, Attention 
. 
 
Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
 
 
q. __3__ 
months 
until PD2 
 
 
 
At PD2 
After 
PD q. 
__6__ 
mos. 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring  
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 2 year after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the MCCC Operations Office, Attention: 
 
 
 
19.0 
Budget Considerations 
 
 
19.1 
Costs charged to patient: all standard of care tests and procedures such as physical exams, 
blood CBC and chemistries, bone marrow biopsies, AraC drug and administration costs, 
etc 
 
 
 
 
19.2 
Tests to be research funded:  research blood and bone marrow collection and processing, AZD1775 
drug dispensing 
 

 
70  
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19.3 
Other budget concerns: Drug and PK analysis will be supported by AstraZeneca. 
 
20.0 
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J. H. Schellens, G.S., A. C. Pavlick, R. Tibes, S. Leijen, S. M. Tolaney, I. Diaz-Padilla, R. K. 
Ramanathan, T. Demuth, J. Viscusi, J. D. Cheng, R. Lam, Y. Xu, A. M. Oza. 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. J Clin Oncol 29: (suppl; abstr 3068)(2011). 

 
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Sekulic A, Migden MR, Oro AE, Efficacy and safety of vismodegib in advanced basal-cell 
carcinoma.2012 Jun 7;366(23):2171-9. 
 
Telfer NR, Colver GB, Morton CA (2008). Guidelines for the management of basal cell carcinoma. Br J 
Dermatol ;159(1):35-48.  
 
Tibes R, Mesa RA. Myeloproliferative neoplasms 5 years after discovery of JAK2V617F: what is the 
impact of JAK2 inhibitor therapy? Leuk Lymphoma. 2011 Jul;52(7):1178-87.  
 
Tibes R, Bogenberger JM, Chaudhuri L, Hagelstrom RT, Chow D, Buechel ME, Gonzales IM, Demuth T, 
Slack J, Mesa RA, Braggio E, Yin HH, Arora S, Azorsa DO. RNAi screening of the kinome with 
cytarabine in leukemias. Blood. 2012 Mar 22;119(12):2863-72. 
 
Tawfik B, Sliesoraitis S, Lyerly S, Klepin HD, Lawrence J, Isom S, Ellis LR, Manuel M, Dralle S, 
Berenzon D, Powell BL, Pardee T. Efficacy of the hypomethylating agents as frontline, salvage, 
or consolidation therapy in adults with acute myeloid leukemia (AML). Ann Hematol. 2014 
Jan;93(1):47-55.  
 
University of Washington, Department of Pharmaceutics (2008). Metabolism and Transport Drug 
Interaction Database, Version 4.0 (Internet) Available from: 
<http://www.druginteractioninfo.org> (Accessed 30 Nov 2010) 
 
US Department of Health and Human Services (2007) Guidance for Industry Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics. FDA 
 
Van Linden AA, Baturin D, Ford JB, Fosmire SP, Gardner L, Korch C, Reigan P, Porter CC. Inhibition of 
Wee1 sensitizes cancer cells to antimetabolite chemotherapeutics in vitro and in vivo, 
independent of p53 functionality. Mol Cancer Ther. 2013 Dec;12(12):2675-84. 
 
Vantuchova Y, Curik R (2006). Histological types of basal cell carcinoma. Scripta Medica (BRNO) ; 
78:261-70 
 
Visani G, Malagola M, Piccaluga PP, Isidori A. Low dose Ara-C for myelodysplastic syndromes: is it still 
a current therapy? Leuk Lymphoma. 2004 Aug;45(8):1531-8. 
 
Von Hoff, D. D. et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N  
 
Engl J Med 361, 1164-1172, (2009). 
 
Wang, Y., McMahon, A. P. & Allen, B. L. Shifting paradigms in Hedgehog signaling. Curr Opin  
 
Cell Biol 19, 159-165, (2007). 
 
Weiss GJ, Tibes R et al. Long-Term Safety, Tolerability, and Efficacy of Vismodegib in Two  
Patients with Metastatic Basal Cell Carcinoma and Basal Cell Nevus Syndrome. Dermatology 
Reports: 2011-12-01 10:05:25. 
 
Wong C S M, Strange R C, Lear J T (2003) Basal Cell Carcinoma. BMJ; 327:794-798. 
 
Zhao, C. et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid  
 
leukaemia. Nature 458, 776-779, (2009). 
 

 
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Appendix I 
ECOG Performance Status Scale 
 
SCORE 
DESCRIPTION  
0 
Fully active, able to carry on all pre-disease performance without 
restriction.  
1 
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.  
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.  
4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.  
5 
Dead.  
 
 
 

 
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Appendix II: MEDICATION DIARY 
Name _________________ 
 
Mayo Clinic No_____________________ 
 
 
Study Name/Number_____________ 
 
 
Patient Instructions 
 
Please indicate on the calendar below every day that you take your study medication by placing a 
check mark for each day that you take AZD1775. 
 
Avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville oranges, pummelos, and exotic 
citrus fruits.  
 
Please take your medication either 2 hours before or 2 hours after a meal.   
 
Start Date: ________________________ 
 
 
Medication(s) 
Dose 
AZD1775 
MG 
 
 
 
 
 
 
 
 
 
Date:__________________                   Participants Signature:___________________________________ 
 
 
Area Below Only To Be Completed only by Coordinator 
 
Number of pills returned_____     
 
Study Coordinator Initials________ 
 
Date______________________ 
 
Discrepancy Yes____ No_____ 
 
 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
AZD1775 
 
 
 
 
 
 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
AZD1775 
 
 
 
 
 
 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
AZD1775 
 
 
 
 
 
 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
AZD1775 
 
 
 
 
 
 
 

 
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Appendix III  
 
New York Heart Association Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease: 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix IV: Revised International Prognostic Scoring System (IPSS-R) for MDS 
 
 
IPSS-R Cytogenetic risk groups*,**  
Cytogenetic prognostic 
subgroups 
Cytogenetic abnormalities 
Very good 
-Y, del(11q) 
Good 
Normal, del(5q), del(12p), del(20q), double including del(5q) 
Intermediate 
del(7q), +8, +19, i(17q), any other single or double independent clones 
Poor 
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 
abnormalities 
Very poor 
Complex: >3 abnormalities 
IPSS-R Prognostic Score Values*  
Prognostic variable 
0 
0.5 
1 
1.5 
2 
3 
4 
Cytogenetics 
Very 
Good 
 
Good 
 
Intermediate 
Poor 
Very 
Poor 
BM Blast % 
<=2 
 
>2-<5% 
 
5-10% 
>10% 
 
Hemoglobin 
=>10 
 
8-<10 
<8 
 
 
 
Platelets 
=>100 
50-<100 
<50 
 
 
 
 
ANC 
=>0.8 
<0.8 
 
 
 
 
 
IPSS-R Prognostic Risk Categories/Scores*  
RISK CATEGORY 
RISK SCORE 
Very Low 
<=1.5 
Low 
>1.5 - 3 
Intermediate 
>3 - 4.5 
High 
>4.5 - 6 
Very High 
>6 
*Greenberg, Tuechler, Schanz et al, Revised International Prognostic Scoring System (IPSS-R) for 
Myelodysplastic Syndrome, Blood 120: 2454, 2012. 
**Schanz J et al, J Clin Oncology 2012; 30:820 
 

 
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Appendix V: 
 
 
Version 2.2014, 03/28/2014. National Comprehensive Cancer Network, Inc. 2014. 
 
 

 
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Appendix VI: List of prohibited concomitant medications and concomitant medications 
requiring caution 
 
DISALLOWED MEDICATIONS AND MEDICATIONS TO BE 
ADMINISTERED WITH CAUTION 
Formal drug-drug interaction studies have not yet been performed with AZD1775, therefore, the 
potential for drug-drug interaction described in this protocol are based on findings from in vitro 
studies and clinical experience. 
In vitro data has shown that AZD1775 is metabolised predominantly by CYP3A4, with an 
FMO3 and/or FMO5 component.  As a result, there is potential for the exposure of AZD1775 to 
be effected by drugs which inhibit or induce the metabolism of CYP3A4.  In the clinic, 
coadministration of  AZD1775 with the moderate CYP3A4 inhibitor, aprepaitant, resulted in a 
60% increase in the plasma levels of AZD1775.  Drugs known to be moderate to strong 
inhibitors/inducers of CYP3A4 are therefore prohibited for use in the current study, including 
aprepitant.   
In vitro data suggests that AZD1775 may be a weak reversible inhibitor of CYP2C19 (IC50 12 
uM).  Caution should therefore be exercised when AZD1775 is coadministered with agents that 
are sensitive substrates of CYP2C19, or substrates of this enzyme with a narrow therapeutic 
range. 
Based on in vitro studies, AZD1775 has been show to be a weak reversible inhibitor (IC50 14 
µM) and a time-dependent inhibitor of CYP3A4 (Kinact 0.061/min, Ki 6.04 µM).  The full impact 
of the time dependent inhibition is currently unknown, however, modelling data has predicted an 
8-10 fold increase in the exposure of sensitive CYP3A4 substrates when administered with 
AZD1775 (250 mg BID for 5 doses).  To date, no significant DDI effects have been reported in 
the clinic that may be related to the TDI finding.  However, sensitive CYP3A4 substrates or 
substrates of CYP3A4 with a narrow therapeutic window are prohibited. 
AZD1775 has been shown to be a weak inducer of CYP1A2 in vitro (39% increase in activity of 
positive control).  Given the nature of the AZD1775 dosing schedule, however, the risk of 
induction in the clinic is considered low.  No specific precautions are recommended at this time, 
except to be initially vigilant when using substrates of CYP1A2 with a narrow therapeutic range. 
Transporter studies (in vitro) have shown that AZD1775 is both a substrate and inhibitor (IC50 20 
µM) of P-gp. Maximum impact of these finding is likely to occur for drugs administered orally at 
the same time as AZD1775.  Caution should therefore be exercised when agents that are 
inhibitors or substrates of P-gp are administered concomitantly with AZD1775. 
Recent invitro transporter studies have shown AZD1775 to be an inhibitor of BCRP (IC50 5.1 
µM).  This finding is particularly relevant for drugs administered orally where exposure is 
normally limited by BCRP-mediated efflux, in particular some statins.    Modelling has predicted 
a substantial increase in the exposure of Atorvastatin when coadministered with AZD1775 and 
the use of Atoravastatin is therefore prohibited in the current study. Other drugs where the 
disposition is mediated via BCRP should be administered with caution, dose modification 
considered or substituted by an alternative drug.  
Herbal preparations/medications can be substrates, inhibitors and inducers, similar to any 
registered medication.   Herbal preparations are therefore not allowed throughout the study.  

 
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These herbal medications include, but are not limited to: St. John’s wort, kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.   
In addition, any other drugs should be avoided at the Investigator’s discretion if, in their opinion, 
the co-administration with AZD1775 may increase the risk of a clinically significant drug 
interaction. 
A list of the main CYP3A4 substrates, inhibitors (strong and moderate) and inducers, CYP2C19 
substrates, P-gp substrates and inhibitors and BCRP substrates are shown below. This is not an 
exhaustive list and further details can be found at Expert Opin. Drug Metab. Toxicol. (2013) 
9(6):737-751.    
 
 

 
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CYP3A4  Inhibitors 
Strong 
Boceprevir 
Clarithromycin 
Cobicistat (GS‐9350) 
Conivaptan 
Danoprevir 
Elvitegravir 
Fosamprenavir 
Grapefruit juice 
Idelalisib 
Indinavir 
Itraconazole  
Ketoconazole 
LCL161 
Lopinavir 
Mibefradil 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telaprevir 
Telithromycin 
Tipranavir 
Troleandomycin 
Voriconazole 
 
Moderate 
ACT‐178882 
Amprenavir 
Aprepitant 
Atazanavir 
Casopitant 
Ciprofloxacin 
Crizotinib 
Darunavir 
Dronedarone 
Diltiazem 
Erythromycin 
FK1706 
Fluconazole* 
Fosamprenavir  
Imatinib 
Ledipasvir 
Lomitapide 
Netupitant 
Schisandra sphenanthera 
Tofisopam 
Verapamil 
 
 
*The preferred azole anti-fungal medication is Fluconazole (alternatively Posaconazole) which can be 
given during treatment with AZD1775 at the treating physician’s discretion, however with dose 
reductions of AZD1775 by 25-75% (i.e. from AZD1775 200mg to 150 or 100mg). 
 
 
CYP3A4 Inducers (Strong and Moderate) 
Avasimibe 
Bosentan 
Carbamazepine 
Nafcillin 
Phenobarbital 
Phenytoin 
Rifabutin 

 
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Efavirenz 
Enzalutamide 
Etravirine 
Genistein 
Lersivirine 
Lopinavir 
Mitotane 
Modafinil 
 
Rifampin 
Ritonavir 
Semagacestat 
St John's Wort 
Thioridazine 
Tipranavir  
 
 
CYP3A4 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 
 
ABT‐384 
Alfentanil 
Aprepitant 
Alfuzosin 
Almorexant 
Alpha‐
Dihydroergocryptine 
Amiodarone 
Aplaviroc 
Aprepitant 
Astemizole 
Atazanavir 
Atorvastatin 
Avanafil 
Bexarotine 
BIRL 355 
Bortezomib 
Bosutinib 
Brecanavir 
Brotizolam 
Budesonide 
Buspirone 
Capravirine 
Carbamazepine 
Casopitant 
Cisapride, 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danoprevir 
Darifenacin 
Darunavir 
Ranolazine 
Ridaforolimus 
Romidepsin 
Saquinavir 
Sildenafil 
Simeprevir 
Simvastatin 
Sirolimus 
Tacrolimus 
Temsirolimus 
Terfenadine 
Ticagrelor 
Theoophylline 
Thioridazine 
Thiotepa 
Tilidine 
Tipranavir 
Tolvaptan 
Triazolam 
Tretinoin 
Ulipristal 
Vardenafil 
Vicriviroc 
Voclosporin 
Elvitegravir 
Eplerenone 
Ergotamine 
Erlotinib 
Etoposide 
Everolimus 
Felodipine 
Fentanyl 
Fluticasone 
Gefitinib 
Halofantrine 
Ibrutinib 
Ifosfamide 
Imatinib 
Indinavir 
Ironotecan 
Ivacaftor 
Ixabepilone 
L‐771,688 
Lapatinib 
Levomethadyl 
(LAAm) 
Lomitapide 
Lopinavir 
Lovastatin 
Lurasidone 
Maraviroc, 
Midazolam 
Midostaurin 
Mosapride 
Neratinib 
Nilotinib 
 

 
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Dasatinib 
Dihydroergotamine 
Disopyramide 
Dronedarone 
Docetaxol 
Dofetilide 
Doxorubicin 
Ebastine 
Eletriptan 
Nisoldipine 
Paclitaxel 
Pazopanib 
Perospirone 
Pimozide 
Propafenone 
Propofol 
Quetiapine 
Quinidine 
 
CYP2C19 Sensitive Substrates or Substrates with a Narrow Therapeutic 
Range 
Diazepam 
Gliclazide 
Lansoprazole 
(R)‐Lansoprazole 
(S)‐Lansoprazole 
(S)‐Mephenytoin 
(R)‐Mephobarbital 
Omeprazole 
(R)‐Omeprazole 
Pantoprazole 
(+)‐Pantoprazole 
Rabeprazole 
Tilidine 
 
 
 
 

 
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CYP1A2  Sensitive Substrates or Substrates with a Narrow Therapeutic 
Range 
Alosetron 
Caffeine 
Duloxetine 
Melatonin 
Ramelteon 
Tacrine 
Theophylline 
Tizanidine  
 
P-gp Substrates 
^Colchicine 
*Digoxin 
Fexofenadine 
Indinavir 
Paclitaxel 
Toptecan 
Vincristine 
*If a patient requires initiation of digoxin during the study, or is already receiving treatment 
with digoxin, monitoring of digoxin levels is recommended according to local practice (as 
the levels of digoxin may increase).  Monitoring of digoxin levels is also recommended 
when the patient has completed dosing with study treatment (as the levels of digoxin may 
then decrease). 
^Colchicine may be given during study, with expected less clinical efficacy and patients 
should be carefully monitored clinically.  
P-gp Inhibitors (Strong) 
Cyclosporine 
Elacridar 
Erythromycin 
Itraconazole 
Ketocoanzole 
LY335979Quinidine 
Ritonavir 
Valspodar 
Verapamil  
 
BCRP Substrates 
Daunorubicin 
Doxorubicin 
Rosuvastatin 
Sulfasalazine 
Topotecan 
 

 
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Appendix VII: Patient Information Sheet 
 
 
PATIENT INFORMATION SHEET 
Patient Completed Quality of Life Booklet 
______________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
1. 
This booklet contains two sets of questions: 
 EORTC QLQ-C30 (30 questions) 
 MPN-SAF TSS (11 questions) 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. Please complete the booklet during your scheduled clinical visit and return it to your 
nurse, physician, or research coordinator. 
 
Thank you for taking the time to help us. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix VIII: EORTC QLQ-C30 and 
Myeloproliferative Neoplasm Symptom Assessment Form 
 
 
 Total Symptom Score (MPN-SAF TSS) 
 
EORTC QLQ - C30 (Version 3) 
________________________________________________________________________ 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling 
the number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
 
 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2.  Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3.  Do you have any trouble taking a short walk outside 
 
of the house? 
1 
2 
3 
4 
 
4.  Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
 
5.  Do you need help with eating, dressing, washing 
 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week: 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
6.  Were you limited in doing either your work or other 
 
daily activities? 
1 
2 
3 
4 
 
7.  Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8.  Were you short of breath? 
1 
2 
3 
4 
 
9.  Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
 
 

 
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During the past week: 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
For the following questions please circle the number between 1 and 7 that best  
applies to you. 
 
29. How would you rate your overall health during the past week? 
 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
 
 
 
 
 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
 
 
1 
2 
3 
4 
5 
6 
7 
     Very poor 
 
 
 
 
 
Excellent 
 
 
 
 
 
 
 
 

 
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Myeloproliferative Neoplasm Symptom Assessment Form 
Total Symptom Score (MPN-SAF TSS) 
 
 
Symptom 
1 to 10  (0 if absent) ranking 
1 is most favorable and 10 least favorable 
Please rate your fatigue (weariness, 
tiredness) by circling the one number that 
best describes your WORST level of 
fatigue during  past 24 hours 
 
(No Fatigue)   0  1  2  3  4  5  6  7  8  9  10 (Worst Imaginable) 
Circle the one number that describes, during the past week how much 
difficulty you have had with each of the following symptoms 
Filling up quickly when you eat (Early 
satiety) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Abdominal discomfort 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Inactivity 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Problems with concentration - Compared 
to prior to my MPD 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Numbness/ Tingling (in my hands and feet) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Night sweats 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Itching (pruritus) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Bone pain (diffuse not joint pain or 
arthritis) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Fever (>100 F) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Daily) 
Unintentional weight loss last 6 months 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
 
 
Thank you for taking the time to help us. 
 
 
 
 
 

 
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Appendix IX: Childbearing Potential & Contraception 
 
Female patients are considered to be of childbearing potential unless  
 
they are post-menopausal (defined as older than 50 years and amenorrhoeic 
for at least 12 months following cessation of all exogenous hormonal 
treatments), 
 
there is documentation of irreversible surgical sterilisation by hysterectomy, 
bilateral oophorectomy or bilateral salpingectomy (but not tubal ligation), or 
 
they are 50 years or younger but have been amenorrhoeic for at least 12 
months following the cessation of exogenous hormonal treatments, and have 
serum follicle-stimulating hormone (FSH) and luteinising hormone (LH) 
levels in the postmenopausal range for the institution. 
 
Female patients who are of childbearing potential must agree to use adequate 
contraceptive measures (as defined below) for the duration of study participation, 
and for 6 months after the final dose of study drug; cessation of birth control after 
this point should be discussed with a responsible physician.  They also may not 
be breast feeding and must have a negative serum or urine pregnancy test within 
72 hours prior to start of study treatment. 
 
 
Acceptable methods of contraception include true abstinence in line with the 
preferred and usual lifestyle ch
mised 
partner, and methods listed in 
  
All methods of contraception (with the exception of total abstinence) should be 
used in combination with the use of a condom by their male sexual partner for 
intercourse.  Periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of birth control. 
Should a woman become pregnant or suspect she is pregnant while participating 
in this study, she should inform her treating physician immediately. 
 
 
Effective Methods of Contraception 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
 
Cap plus spermicide 
 
Sponge plus spermicide 
 
Diaphragm plus spermicide 
 
Copper T 
 
Levonorgestrel-releasing 
intrauterine system (eg, 
Mirena®)a 
Any registered and marketed 
contraceptive agent that contains 
an estrogen and/or a 
progestational agent (including 
oral, subcutaneous, intrauterine, 
or intramuscular agents) such as 
 
Implants 
 
Hormone shot or injection 
 
Combined pill 
 
Minipill 
 
Patch 
 
a 
This is also considered a hormonal method.