Conditions: Myelofibroses Acute Myeloid Leukemia Myelodysplastic Syndromes
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6
Healthy volunteers: no

Brief summary:
A phase II study testing the efficacy of combined AZD1775 with AraC or single agent activity of AZD1775 in three arms: Arm A has subjects age 60 years or older who are newly diagnosed with AML receiving the combination of the drugs; Arm B has subjects who are have relapsed/refractory AML and HMA failure MDS patients being allocated to either the combination Arm B or single agent AZD1775 Arm C.

Detailed description:
A phase II study testing the clinical efficacy of combined AZD1775 with AraC or single agent activity of AZD1775 in three patient strata: Elderly(\> 60 years) 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 of up to 20 and 21 eligible patients in each arm respectively 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.

Arms:
arm 1: Combination AZD1775 with AraC

Elderly, newly diagnosed AML arm 2: Combination AZD1775 with AraC

Relapsed/Refractory AML \& HMA failure AML/ MDS arm 3: AZD1775 only

Relapsed/Refractory AML \& HMA failure AML/ MDS and Relapsed/Refractory Primary \& Secondary MF

Interventions: intervention 1: Combination AZD1775 with AraC intervention 2: AZD1775 only
Intervention descriptions: intervention 1: AZD1775 days 1-5 \& 8-12 AraC days 1-5 \& 8-12 intervention 2: AZD1775 days 1-5 \& 8-12

Protocol document:
Prot_SAP_000.pdf: 
Version 2019 Aug 23 
 
AZD1775 in AML and MDS 
 
1 
 
 
 A Phase 2 study of WEE1 Inhibition with AZD1775 alone or combined with Cytarabine in Patients 
with advanced Acute Myeloid Leukemia, Myelodysplastic Syndrome and Myelofibrosis 
 
 
 
Study Principal Investigator: 
Mohammad Maher Abdul Hay, MD 
 
 
 
 
 
 
        240 East 38th Street 19th Floor 
                          
 
 
 
        New York, NY 10016 
        raoul.tibes@nyumc.org 
 
 
646-501-4818 
 
 
 
 
 
 
Study Investigators:  
 
 
 
 
 
Michael Grossbard, MD 
 
 
Kenneth Hymes, MD 
 
 
Bruce Raphael, MD  
 
 
Tibor Moskovits, MD  
 
 
David Kaminetzky, MD  
 
 
Catherine Diefenbach, MD 
 
 
Shella Saint Fleur 
 
 
Kelly Davey, NP 
 
 
Matija Snuderl, MD  
 
 
 
 
 
 
 
 
Nicole LaNatra, MD 
 
 
Jennifer Wu, MD 
 
 
 
 
 
 
 
 
 
 
Statistician: 
Andrea Troxel, ScD 
 
 
 
 
 
Participating Sites:                      NYU Langone Health 
                                                    Mayo Clinic Cancer Center 
 
Coordinating  Site:   
 
NYU Langone Health 
Perlmutter Cancer Center 
Clinical Trials Office 
                                                    PCC-QAU@nyumc.org 
 
Study # S17-01816 
NCT # NCT03718143  
 
 
Drug Availability  
Supplied Investigational Agents:  AZD1775 
Commercial Agents:  Cytarabine (cytosine arabinoside or AraC) 
 


 
2  
AZD1775 in AML and MDS 
 
 
 
2 
 
 Study contributor(s) not responsible for patient care. 
 
Initial version:  February 6, 2018 
Amended: August 24th, 2018 
Amended: October 26, 2018 
Amendet: August 23, 2019 
 
 
Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any 
other 
applicable US government research regulations, and institutional research policies and 
procedures. The International Conference on Harmonisation (“ICH”) Guideline for Good Clinical 
Practice (“GCP”) (sometimes referred to as “ICH-GCP” or “E6”) will be applied only to the extent 
that it is compatible with FDA and DHHS regulations. The Principal Investigator will assure that 
no deviation from, or changes to the protocol will take place without prior agreement from the 
sponsor and documented approval from the 
Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the 
conduct of this study have completed Human Subjects Protection Training 
 
 
 


 
3  
AZD1775 in AML and MDS 
 
 
 
3 
 
PROTOCOL APPROVAL SIGNATURES 
 
 
Protocol Title: A Phase 2 study of WEE1 Inhibition with AZD1775 alone or combined with Cytarabine 
in Patients with advanced Acute Myeloid Leukemia, Myelodysplastic Syndrome and Myelofibrosis 
 
 
Protocol Number: s17-01816 
 
This study will be conducted in compliance with the clinical study protocol (and amendments), 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use guidelines for current Good Clinical Practice, and applicable 
regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
Date 


 
4  
AZD1775 in AML and MDS 
 
 
 
4 
Index 
 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Grouping  Factors 
  6.0 
Enrollment Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care/Concomitant Medications 
10.0 
Safety and Adverse Events 
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 
Source Documents and Access to Source Data 
18.0 
Ethics/Protection of Human Subjects 
19.0 
Data Handling and Record Keeping 
20.0 
Quality Assurance and Quality Control 
 
21.0 
Ethical Considerations 
 
22.0 
Budget Considerations 
 
23.0 
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 


 
5  
AZD1775 in AML and MDS 
 
 
 
5 
Appendix VIII – EORTC QLQ-C30 & Myeloproliferative Neoplasm Symptom Assessment Form Total 
Symptom Score (MPN-SAF TSS) 
Appendix IX – Childbearing Potential & Contraception


Version 2019 Aug 23 
 
AZD1775 in AML and MDS 
 
6 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a does not start first dose of treatment, please refer to Section 13.0 for 
follow-up information. 
 
Cycle length=28 days 
NOTE: The Safety portion of this trial will monitor six patients in each arm (combination and single 
agent) and observe them for a minimum of 28 days to assess toxicities.   
Primary & Secondary MF: Primary Myelofibrosis (PMF) and Secondary MF after Polycythemia Vera 
(PV) and Essential Thrombocytosis (ET) (post-PV/ post-ET MF) 
 
Generic name: AZD1775, Adavosertib 
Brand name(s): n/a 
 
Availability: Provided by AstraZeneca  
Generic name: Cytosine arabinoside 
 
Brand name(s): Cytosar, ® 
Availability: Commercially available 
 
Arm B; 
AZD1775 days 1-5 & 8-12 
AraC days 1-5 & 8-12 
Registration 
Event monitoring 
per Section 18.0 
Disease progression 
Unacceptable adverse events 
Patient refusal 
Relapsed/Refractory 
AML &  
HMA failure AML/ 
MDS 
Elderly, newly 
diagnosed AML 
Arm C: 
AZD1775 days 1-5, 8-12 
Arm A: 
AZD1775 days 1-5 & 
8-12 
AraC days 1-5 & 8-12 
Randomization 
Relapsed/Refractory 
Primary & Secondary 
MF  


 
 
 
AZD1775 in AML and MDS 
 
7 
1.0 
Background 
 
1.1 
Acute Myeloid Leukemias (AML), Myelodysplastic Syndrome (MDS) and Myelofibrosis 
(MF) 
 
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 agent (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 is unknown 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 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. 


 
 
 
AZD1775 in AML and MDS 
 
8 
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.  
 
Myeloproliferative neoplasms (MPN) - Primary (PMF) and Secondary Myelofibrosis: MPNs are clonal 
stem cell malignancies classified as Philadelphia chromosome negative myeloproliferative neoplasms 
(MPN) by the World Health Organization (WHO) (Vardiman et al., 2009). Myelofibrosis is divided into 
Primary Myelofibrosis (PMF) and Secondary or so called post-Polycythemia Vera (PV) and post-
Essential Thrombocythemia (ET) MF, which is evolution of preceeding ET and PV into MF. Post-PV/ET 
MF occurs in around 5-15% of PV and ET patients (Tibes et al 2012) and resembles the clinical picture of 
PMF (Tibes et al, 2012).  
Patients with MF suffer from severe constitutional symptoms, progressive hepatosplenomegaly, 
peripheral blood cytopenias often requiring transfusion (Tibes et al, 2012) and an increased risk of 
leukemia transformation, termed MPN-Blast Phase (BP), which clinically resembles acute leukemia 
(Kundranda et al, 2012). At progression PV and ET proceed through an accelerated phase (MF-AP) 
which upon further progression can lead to MPN-BP. Currently treatment options for MF patients are 
determined by risk assessment of individual patients by prognostic scoring systems that are based on 
various clinical parameters including age, leukocyte count, hemoglobin level, platelet count, monocyte 
count, peripheral blast count, presence of splenomegaly, constitutional symptoms and degree of bone 
marrow fibrosis (BMF) (Tibes et al, 2012). Patients that are symptomatic can be treated with the JAK2 
inhibitor Ruxolitinib (Tibes et al, 2012a). Patients under the age of 65-70 without significant co-
morbidities and intermediate/high risk disease are considered candidates for allogeneic stem cell 
transplant (allo-SCT) (Tibes et al, 2012), which is the only modality offering a potential cure although at 
significant risk of transplant related mortality (TRM) as well as complications (morbidity and mortality) 
from graft versus host disease (GVHD) and other long term complications (Kundranda et al, 2012). 
Therefore, patients older than 65-70 years or with substantial co-morbidities are considered not to be 
candidates for allo-SCT and upon JAK2 failure or intolerance become candidates for experimental 
therapies as propsoed in this protocol.  
For patients not candidates for allo-SCT, patients with accelerated MF and/or those failing JAK2 
inhibitor therapy there are no standard approved treatments. Cytotoxic induction chemotherapy has no 
role for those patients not canduidates/ proceeding to allo-SCT (Tibes et al, 2012). These advanced MF 
patients have poor outcome to current therapies with response rates < 5-10% and median survivial of < 6-
12 months. Hydroxyurea is commonly given for count (WBC) control but does not alter the disase course 
as a single agent. Therefore novel therapeutic approaches are urgently needed for this disease.  
 
 
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). 


 
 
 
AZD1775 in AML and MDS 
 
9 
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 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 WEE1 inhibition and combination with Cytarabine (AraC)  
 
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 


 
 
 
AZD1775 in AML and MDS 
 
10 
preliminary data that shows potent sensitization with synergy of AZD1775 and combined with AraC in 
vitro and ex vivo (Tibes et al. 2012). Other groups have shown potent activity in vivo mouse models as 
well (Porter et al. 2012). In addition WEE1 is highly expressed in myeloid leukemias (Tibes et al. 2012). 
Based on these data we hypothesize that the WEE1 kinase inhibitor AZD1775 alone and in combination 
with AraC 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. 
 
The molecular pathogenesis of MPNs and MF involves high replicative stress (Chen et al, 2014 and 2015). 
In MF, recent data indicates that PARP inhibitors may have activity (Pratz et al 2016 and 2017). WEE1 
inhibition by AZD1775, similarly to PARP inhibitors effectively targets cancers with high replication stress 
(Pfister et al 2015). We have generated preliminary data that AZD1775 alone is active and when combined 
with HU exhibits strong sensitization in pre-clinical models (Tibes, unpublished data). Given the lack of 
effective therapeutic regimens in advanced, JAK2 failure MF patients we plan to include these patients in 
the protocol treatment.  
 
 
1.3  
Overview of AZD1775 
 
 
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. 
 


 
 
 
AZD1775 in AML and MDS 
 
11 
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 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 ofAZD1775 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) 


 
 
 
AZD1775 in AML and MDS 
 
12 
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 
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 


 
 
 
AZD1775 in AML and MDS 
 
13 
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 (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. 
 


 
 
 
AZD1775 in AML and MDS 
 
14 
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 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 16 of the Investigator’s Brochure, , dated 
January 2018, with a data cut-off date of 11 November 2017.  For more detailed and up-to-date 
information, please consult the current Investigator’s Brochure. 
As of 11 November 2017, a total of approximately 713 patients have been exposed to 
AZD1775 in AstraZeneca-sponsored or Merck-sponsored clinical studies. In addition, 
approximately 559 patients have also received AZD1775 as part of externally-sponsored 
scientific research. These patients include those who have received single doses per cycle as 
high as 1300 mg of AZD1775 as monotherapy, 325 mg of AZD1775 in a single-dose in 
combination with chemotherapy, and 325 mg twice a day (BID) in a multiple-dose regimen in 
combination with chemotherapy.The completed or terminated early studies include: 
 
• 
PN001 (NCT00648648) (except for Part 3): 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 
 
• 
PN004 (NCT01357161): a Phase II study evaluating AZD1775 combined with carboplatin and 
paclitaxel in patients with platinum-sensitive p53-mutant ovarian cancer 
 
• 
PN005 (NCT01047007): 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 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 (NCT01076400): 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. 
 
• 
D6011C00001 (NCT02087176; SCRI LUN 262): 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 (NSCLC) 
 
• 
D6011C00002 (NCT02087241; SCRI LUN 261): 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 NSCLC 
 


 
 
 
AZD1775 in AML and MDS 
 
15 
Ongoing: 
 
• 
D6010C00004 (NCT02272790; SCRI GYN 49): a multicentre Phase II study of AZD1775 plus 
either paclitaxel, gemcitabine, carboplatin, or pegylated liposomal doxorubicin in patients with 
platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer 
 
• 
D6010C00005 (NCT02511795; SCRI REFMAL 384): a Phase I study evaluating AZD1775 in 
combination with olaparib in refractory solid tumours. 
 
• 
D6011C00003 (NCT02341456): a Phase Ib dose-finding study evaluating AZD1775 as 
monotherapy and in combination with carboplatin and paclitaxel in adult Asian patients with 
advanced solid tumours 
 
• 
D6015C00001 (NCT02482311; SCRI REFMAL 383): a Phase I, dose escalation, safety and 
pharmacokinetic study of AZD1775 monotherapy (Schedule 1) in patients with advanced or 
metastatic solid tumours 
 
• 
D6015C00002 (NCT02617277; SCRI REFMAL 412): a Phase I study assessing the safety, 
tolerability, and pharmacokinetics of AZD1775 in combination with MEDI4736 in patients with 
advanced solid tumours 
 
• 
D6015C00003 (NCT02610075; SCRI REFMAL 398): a Phase Ib study to determine the 
maximum-tolerated dose (MTD) of AZD1775 monotherapy (Schedule 2) in patients with locally 
advanced or metastatic solid tumours. 
 
• 
NCT01748825: A Phase I Study of Single-agent AZD1775 (MK-1775), a Wee1 Inhibitor, in 
Patients With Advanced Refractory Solid Tumors.  
 
 
 
1.41 
Clinical Safety  
 
 
Several clinical studies with AZD1775 alone and in combination with (mostly full dose) cytotoxic 
chemotherapy have been conducted.   
 
The RP2D of AZD1775 monotherapy has been established as 300mg QD day1-5, and 8-10 in week 1 and 
2 of a 3 week schedule.  
 
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 


 
 
 
AZD1775 in AML and MDS 
 
16 
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 
 
 
 
 
 
Based on the safety data from the completed AZD1775 clinical studies and preliminary data from 
ongoing studies adverse drug reactions to AZD1775 monotherapy include: anaemia, neutropenia, 
thrombocytopenia, QTc prolongation, gastrointestinal events such as dyspepsia, diarrhoea, nausea and 
vomiting (with or without dehydration or serum electrolyte decreases), as well as decreased appetite. In 
addition, the following events are also considered expected during treatment with AZD1775 in 
combination with cytotoxic chemotherapy: febrile neutropenia, leukopenia, stomatitis, asthenia, fatigue, 
mucosal inflammation and myalgia. 
 
Based on information emerging during the clinical development programme of AZD1775, potential risks 
where a causal relationship with AZD1775 monotherapy has not been established include 
asthenia/fatigue, febrile neutropenia, gastrointestinal haemorrhage, lymphopenia/lymphocyte count 
decreased, leukopenia/WBC count decreased, myalgia, stomatitis, sepsis and transaminases elevation. 
 
In addition, the following events are also considered potential risks for AZD1775 in combination with 
cytotoxic chemotherapy: tachycardia and pancytopenia.  
 
Refer to the IB for AZD1775 for information on the potential benefits and assessment of potential and 
known risks. 
 
 
 
1.42  
Clinical Efficacy 
 
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 AML and MDS 
 
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 
 
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 (AZD1775 Investigator’s Brochure[IB])In Study PN001, 9 patients received 
AZD1775 monotherapy. Single ascending doses of AZD1775 up to 1300 mg were well tolerated; the 
maximum tolerated dose (MTD) was not established. 
 
In Study PN004, all patients were treated at the 225 mg AZD1775 BID 2.5 day dose level in 
combination with paclitaxel and carboplatin. Of the 14 evaluable patients by RECIST v1.1 in 
Part 1, there were 11 PRs (6 confirmed and 5 unconfirmed), and 3 SDs; 7 patients were 
evaluable by CA-125 with 3 CRs and 4 PRs. Final data for Part 2 is not available as of the 
cut-off date for this protocol. 
 
In Study PN005, patients in Part 1 received single-cycle BID dosing of AZD1775 for 5 days at 1 of 2 
dose levels as monotherapy. A cohort of 3 patients was enrolled at the starting dose level of AZD1775 65 
mg BID and no serious adverse events (SAEs) were experienced. 
No complete responses (CRs) or PRs were observed in either of Studies PN005 or PN008 at 
the time that they were terminated. 
 
In Study PN011, patients received single-agent AZD1775 PO BID over 2.5 days per week for 2 weeks in 
3-week treatment cycles. Twenty-five patients were enrolled to determine the MTD using a 3+3 design. 
The MTD was established at 225 mg by mouth (PO) BID for 5 doses on Weeks 1 and 2 of a 3-week 
schedule. Six patients with BRCA-mutated solid tumours were enrolled at the MTD. Partial responses 
were confirmed in two of the patients carrying BRCA mutations (ovarian cancer patient and head/neck 
cancer patient). Paired tumor biopsies were obtained from 5 patients treated at the MTD at baseline and 
after the 5th AZD1775 dose to determine the levels of pY15-Cdk and γH2AX. The biopsies showed a 
decrease in pY15-Cdk levels (2/5 paired biopsies). The same biopsies were analyzed for increases in 
γH2AX, an indicator of DNA damage. Three of the 5 biopsy pairs showed an increase in γH2AX levels. 
DNA damage response was observed in this study through provided paired tumor biopsies (Do et al 
2015). 
 
In Study D6011C00001, 32 patients with NSCLC were treated with 225 mg AZD1775 BID 
over 2.5 days in combination with docetaxel (75 mg/m2 IV) administered on Day 1 followed 
by pegfilgrastim on Day 4 of each 21-day cycle. The 3 patients (9.4%) that achieved PR by 
RECIST v1.1 had TP53 mutations. Twenty-one patients (65.6%) had SD and 10 (47.6%) of 
these patients had TP53 mutations. The planned Interim Analysis of 32 patients in the single cohort lead-
in (Part A) suggested that toxicities associated with AZD1775 given in combination with docetaxel were 
greater in frequency and severity than with docetaxel alone. 
Additionally, the analysis revealed that it was very unlikely the target response rate would be 
reached in this study and a decision was made to terminate enrolment. 


 
 
 
AZD1775 in AML and MDS 
 
18 
 
In Study D6011C00002, 14 patients with NSCLC were treated with 225 mg AZD1775 BID 
over 2.5 days in combination with pemetrexed 500 mg/m2 IV and carboplatin AUC 6 IV, both 
administered on Day 1 of each 21-day cycle. Enrolment was stopped because of the 
introduction of new therapies for the treatment of first-line NSCLC, such as immunotherapy, 
which resulted in challenges in patient recruitment. In addition, the planned Interim Analysis 
of Study D6011C00001 revealed that it was very unlikely that the target response rate would 
be reached, and increased gastrointestinal and hematologic toxicities associated with 
AZD1775 were observed. 
 
 
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 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) of47.4 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% 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. 


 
 
 
AZD1775 in AML and MDS 
 
19 
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 v16 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 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.,  JCO 33: 3409-3415 (2015) 
 
 
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(> 60 years) 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 of up to 20 and 21 eligible patients in each arm respectively 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 


 
 
 
AZD1775 in AML and MDS 
 
20 
low to moderate AraC concentrations of 9-120 nanoMolar (nM) (Tibes et al.2012). Whereas, antagonism 
was seen at very high concentrations (AraC > 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 in a 
twice daily s.c. schedule that can achieve concentrations of up to 50-100nM of AraC, comparable to the 
pre-clinical data.  
 
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, Jan.. 2018).  The 
half-life of AZD1775 is ~9 hrs and C trough for AZD1775 is up to  570nM, with an unbound 
concentration of  225nM. Preliminary population PK model simulations by Astra Zeneca (Robert Godin, 
personal communication, AZD1775 Lead) suggest that once daily dosing of 200 mg AZD1775 for 5 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). In the 
ongoing Phase 1 Study at the National Cancer Institute (and REFMAL 398, see IB) alternative dosing 
was explored. NCT01748825Arm B explored the MTD of once daily dosing of AZD1775. The DLT dose 
level was reached at 400mg daily on a 5-2-5 schedule (5 days on and 2 days off for 2 weeks every 21 
days), and the MTD was 300mg AZD1775 (Takebe, 2018). On a 5/2 schedule, 300 mg daily dose 
provides the greatest cover over the targeted concentration range (500-1000 nM) and is predicted based 
on preclinical data to result in good clinical activity. On that schedule 18 pateints have/ are currently 
being treated for 2-14 cycles as of the presentation (ASCO 2018, Takebe 2018). Thus, AZD1775 at 
300mg on a 5days on -2 days off - 5 days on days schedule every 21 days is well tolerated in advanced 
cancer patients and these data provide a rationale for the single agent AZD1775 dosing schedule for Arm 
C and the pilot MF patient cohort in this protocol.    
 
AZD1775 dosing and cycle length: In ongoing   Phase 1 solid tumor single agent AZD1775 trial at the 
National Cancer Institute (NCT01748825 and REFMAL 384, see IB), current information of toxicity and 
tolerability supports the initial AZD1775 dosing to be 300mg  QD on a 5 days on 2 day off schedule for 2 
weeks every on a  21 days (3 weeks) scheduled as proposed for Arm C.  For AraC there is a clinical 
rationale for 10 and 12 day dosing schedules if given subcutaneously. AZD1775 at 200-225mg BID x 5 
doses was tolerated with full dose (strength) chemotherapy in solid tumor patients (Leijens, JCO 2016). 
Therefore, taken the safety and tolerability data from various studies with AZD1775, as well as our 
preclinical data of optimal sensitization with concurrent AraC and AZD1775 treatment, the proposed 
AZD1775  dose in combination with AraC is AZD1775 at 200mg once daily on a 5-2-5 schedule every 4 
weeks (28 days), the latter to account and mirror the commonly used clinical s.c. AraC cycle length of 4 
weeks. However, it should be noted that cycle length is often 4-6 weeks for s.c. AraC, which will be 
reflected in the dose adjustment and toxicity study criteria.  
 
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 as well as MF.  Pre-clinical data provides 
support for concurrent exposure to both agents at lower AraC and moderate AZD1775 concentrations and 


 
 
 
AZD1775 in AML and MDS 
 
21 
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 A of AZD1775 plus AraC.  
 
1.53 
Biologically effective dose  
 
Ideally current trial designs incorporate a biologically effective dose in assessing responses in relation to 
safety, toxicity and maximum tolerated doses. However, for AZD1775 even though inhibition of one of 
WEE1 kinases’ direct substrate CDK1 was used in some studies as a readout of effective target 
engagement, p-CDK1 Y15 inhibition was not complete and varied (Leijens, JCO 2016). In addition the 
biology around WEE1 kinase and its’ inhibition are not fully elucidated and other target/ substrates of 
WEE1 kianse are either known (i.e. CDK2) or are starting to be discovered. Thus, there is currently no 
single marker and/ or a reliable readout of effective WEE1 kinase inhibition. Conseqeuntly, conventional 
DLT and MTD criteria, PK information from ongoing and previous trials as well as preclinical data (for 
target dose/ concentration of AZD1775) in leukemias will be used in this protocol. The proposed 
correlative studies are aimed at addressing and identifying pharmacodynamic and predictive biomarkers 
of WEE1 kinase inhibition and AZD1775 response.   
 
 
2.0 
Goals 
 
2.1 
Primary Goals 
 
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 
 
2.13 
To evaluate the clinical efficacy (best overall response including clinical 
improvement) of AZD1775 in patients with advanced MF defined as 
intermediate and high risk MF (primary or secondary MF) 
 
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, spleen size reduction). 
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. 


 
 
 
AZD1775 in AML and MDS 
 
22 
2.26 
To measure overall survival of AZD1775 alone or combined with AraC. 
2.27 
To measure time to AML (for MDS, MF 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):  
 
 
Dose escalation part of trial for combined AraC + AZD1775 (Arm A)  
• 
untreated elderly (>60 years) AML if in the poor-risk cytogenetic group 
(please reference Appendix V). 
Note: previous therapy with a hypomethylating agent (HMA) for a 
diagnosis of MDS is allowed  
 
 
 
 
Dose expansion part of trial for combined AraC + AZD1775 (Arm A) 
• 
untreated elderly (>60 years) AML if in the intermediate and poor-risk 
cytogenetic group (please reference Appendix V)  
 
Note: previous therapy with a hypomethylating agent (HMA) for a 
diagnosis of MDS is allowed  
 
• 
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. 
 


 
 
 
AZD1775 in AML and MDS 
 
23 
Note: Patients with CMML and MDS/MPN overlap are allowed if 
meeting other study eligibility criteria.  
 
• 
advanced progressive MF, defined as intermediate and high risk primary 
and secondary MF, or any other MF failed or intolerant to JAK2 
inhibitor therapy requiring medical therapy  
 
 
 
 
 
Note:  
o If appropriate, patients can have failed other prior therapies for 
their disease (i.e. JAK2 inhibitor, interferon, hydroxyurea or 
IMIDs). Patients may have failed more than one JAK2 inhibitor 
and JAK2 inhibitor must not have been the most recent treatment 
(e.g. other therapies as last therapy prior to study given after 
failure of previous JAK2 inhibitor).   
o Primary (PMF) and secondary MF (post PV/post ET) are 
allowed.  
Failure/ intolerance of Ruxolitinib is defined as loss of optimal response in a responder to Ruxolitinib, 
based on growth of the spleen [appearance of a new splenomegaly that is palpable at least 5 cm below 
the LCM, or a ⩾100% increase in palpable distance, below LCM, for baseline splenomegaly of 5–10 cm, 
or a 50% increase in palpable distance, below LCM, for baseline splenomegaly of >10 cm], loss of 
symptom improvement [MPN-SAF], worsening cytopenias [currently or previously treated with 
ruxolitinib for at least 28 days and either required RBC transfusion on ruxolitinib, or required a dose 
adjustment of ruxolitinib to less than 20 mg twice a day and also had anaemia; grade 3 
thrombocytopenia] or intolerable side effects [in the assessment of the treaing physician]. Further 
increase of blood or marrow blasts to > 5% if previously < 2% and > 10% if previously < 7% qualify as 
progression to Ruxolitinib. 
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 ≤1.5 x ULN, or measured creatinine clearance (CrCl) ≥45 
mL/min as calculated by the Cockcroft-Gault method (confirmation of 
creatinine clearance is only required when creatinine is >1.5 x institutional 
ULN)  
CrCl (glomerular filtration rate [GFR]) = (140-age) x (weight/kg) x Fa 
 
 
         (72 x serum creatinine mg/dL) 
a where F= 0.85 for females and F=1 for males 
 
3.14 
ECOG Performance Status (PS) 0, 1 (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      


 
 
 
AZD1775 in AML and MDS 
 
24 
             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  Female patients who are not of child-bearing potential and fertile females of 
childbearing potential who agree to use adequate contraceptive measures from 2 
weeks prior to the study and until 1 month after study treatment discontinuation, 
who are not breastfeeding, and who have a negative serum or urine pregnancy 
test within 3 days prior to the start of study treatment. 
 
3.19b Male patients should be willing to abstain or use barrier contraception  
(i.e., condoms) for the duration of the study drug exposure and for 3 months after study 
treatment discontinuation. 
 
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, 
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 longer) 
• 
For steroids or other non-cytotoxics (exception, HU) 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 ≤ 28 days prior to registration 
• 
Patients with persistent toxicities of > Grade 1 from prior AML treatment 
(including chemotherapy, kinase inhibitors, immunotherapy, experimental 
agents, radiation, or surgery). 
 


 
 
 
AZD1775 in AML and MDS 
 
25 
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 treatment will all 
available therapies known to be active for treatment of APL.   
 
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). 
Note: patients with any of the above may be allowed after discussion amongst the 
investigators including the principal investigator  
 
3.29 
AML patients who are suitable for and willing to receive intensive chemotherapy 
 
3.30 
 
a  
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 
 
3.30b 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.  


 
 
 
AZD1775 in AML and MDS 
 
26 
 
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 (section 
9.5).  
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   
Mean resting corrected QTc interval using the Fridericia formula (QTcF) >450 
msec/male and >470 msec/female (as calculated per institutional standards) 
obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or 
congenital long QT syndrome 
 
3.30 
Herbal preparations/medications are generally 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 
7-14 days prior to first dose of AZD1775. If there is no known potential 
interaction between an herbal medication and AZD1775, the protocol principal 
investigator can give a waiver to continue such medication, with the expection of 
St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng, that are 
not allowed at any stage.  
 


Version 2019 Aug 23 
 
AZD1775 in AML and MDS 
 
27 
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, 4, 
8, 15, & 
28(+ 3 
days)5, , 16 
Cycles 2 & 3 
Days 1, 15, and 
28 (+ 3 days)5, , 
16 
Cycles 4+ and 
Beyond Day 1 
(+3 days)5, 16 
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 
XA 
XB 
X9 
X 
Chemistry group: 
sodium, potassium, 
calcium, creatinine, 
bicarbonate, glucose, 
chloride, albumin, 
BUN, alkaline 
phosphatase, AST, 
ALT, total protein, 
total bilirubin, LDH 
 
X 
XA 
XB 
X 
X 
TLS monitoring (for 
selected AML 
patients): BUN, 
calcium, CO2, 
chloride, creatinine, 
glucose, potassium, 
sodium, uric acid, 
phosphorus 
 
 
X13 
 
 
 
PT/PTT and D-dimer 
 
 
X18 
 
 
 
Serum pregnancy test1 
 
X 
 
X 
X 
 
Bone marrow biopsy 
and aspirate 
procedure 
(cytogenetics or 
FISH)14 
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 


 
 
 
AZD1775 in AML and MDS 
 
28 
 
 
 
Saliva Sample, see 
Section 14.0) R 
X 
 
 
 
 
 
Patient Questionnaire 
Booklet12 
X 
 
X15 
X15 
X15 
X15 
ECG (12 lead)17 
 
X 
XC 
X 
X 
X 
1. 
 For women of childbearing potential only.  Day 1 of each cycle 
 
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 72  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 NYU.  
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. 
13.   For patients at high risk of tumor lysis syndrome (TLSTLS labs will be performed  at least twice during the first week of therapy, when maximum TLS 
risk is highest. . Additional monitoring will be done on a case by case basis.  
14. Either conventional cytogenetics or FISH panel (or both based on physician discretion) for AML to be performed at baseline. If diploid 
cytogenetics 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. 
15. Booklets to be completed at end of all cycles. 
16.  Prior to the start of treatment. 
17.  ECG in triplicate on day1 of each cycle, for cycle 1, ECGs will be conducted at least weekly. 
18. To be tested on C1D1 prior to treatment. 
A. 
For AML patients, CBC and blood chemistries will be collected at least twice weekly for Cycle 1 
B. 
For AML patients, CBC and blood chemistries will be collected weekly for Cycle 2  
C. 
For cycle 1, ECGs will be conducted at least weekly. 
R 
Research funded (see Section 19.0). 
 
 
 
 
 
 
 
 


 
 
 
AZD1775 in AML and MDS 
 
29 
Table 4.2: Test Schedule for HMA failure MDS/ 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)12, 
10 
Cycle 2  Days 1, 
15, and 28 (+ 3 
days)10, 12 
Cycles 3+ and 
Beyond Day 1 
(+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 
XA 
XB 
X 
X 
Serum Erythropoietin 
level 
X 
 
 
 
 
 
Serum pregnancy test1 
 
X 
 
X 
X 
 
Bone marrow biopsy 
and aspirate 
procedure 
(cytogenetics or 
FISH9) 
X6 
 
 
X3 
 
X3 
 
X7 
Blood specimens (see 
Section 14.0)R 
X4,13 
 
X4 
X4 
X4 
X4 
Saliva Sample (see 
Section 14.0) R 
X 
 
 
 
 
 
Bone marrow aspirate 
research specimens 
(see Section 14.0)R 
X6, 13 
 
 
X5 
X5 
X5  
Patient Questionnaire 
Booklet8 
X 
 
 
 
X8 
X 
ECG (12 lead)11 
 
X 
XC 
X 
X 
X 
1. 
 For women of childbearing potential only Day 1 of each cycle 
 
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). 


 
 
 
AZD1775 in AML and MDS 
 
30 
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 NYU.  
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 baseline, 
cycles 3, 6, 9, and EOS. 
9. 
Either conventional cytogenetics or FISH panel (or both based on physician discretion) for MDS should be performed at baseline. If diploid 
cytogenetics 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  in triplicate on day1 of each cycle,  
12.   Day 1 assessments do not need to be repeated if pre-registration or Day 28 assessments completed within 72 hours of Day 1. 
13.   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.  If collected 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 bone marrow sample per section 14.0. 
A 
For AML patients, CBC and blood chemistries will be collected at least twice weekly for Cycle 1. TLS labs will be performed  at least twice 
during the first week of therapy 
B 
For AML patients, CBC and blood chemistries will be collected weekly for Cycle 2  
C 
For cycle 1, ECGs will be conducted at least weekly. 
R 
Research funded (see Section 19.0). 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
AZD1775 in AML and MDS 
 
31 
Table 4.3: Test Schedule for MF patients 
 
 
 
Active Monitoring Phase 
 
 
Tests and procedures 
14 days 
prior to 
registration 
≤7 days  
prior to 
registration 
Cycle 1  
Days 1, 
15, & 28(+ 
3 days)12, 
10 
Cycle 2  Days 1, 
15, and 28 (+ 3 
days)10, 12 
Cycles 3+ and 
Beyond Day 1 
(+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 
 
X 
X 
 
Bone marrow biopsy 
and aspirate 
procedure 
(cytogenetics or 
FISH9) 
X6 
 
 
X3 
 
X3 
 
X7 
Blood specimens (see 
Section 14.0)R 
X4,13 
 
X4 
X4 
X4 
X4 
Saliva Sample (see 
Section 14.0) R 
X 
 
 
 
 
 
Bone marrow aspirate 
research specimens 
(see Section 14.0)R 
X6, 13 
 
 
X5 
X5 
X5  
Patient Questionnaire 
Booklet8 
X 
 
X8 
X8 
X8 
X 
ECG (12 lead)11 
 
X 
X 
X 
X 
X 
1. 
 For women of childbearing potential only Day 1 of each cycle 
 
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). 


 
 
 
AZD1775 in AML and MDS 
 
32 
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 8 weeks of study start, outside results can serve as baseline 
after review at NYU.  
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 
cytogenetics 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 in triplicate on day1 of each cycle.  NOTE: for cycle 1, ECGs will be conducted at least weekly. 
12.   Day 1 assessments do not need to be repeated if pre-registration or Day 28 assessments completed within 72 hours of Day 1. 
13.   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.  If bone marrow aspirate specimens obtained 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 peripheral blood sample instead per section 14.0. 
R 
Research funded (see Section 19.0). 
 
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/ AML vs 4=MF 
 
 
 
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.  Disease type 4 only receives 
single agent (Arm C) 
 
 
6.0  
Enrollment  Procedures 
 
The inclusion and exclusion criteria in this study should not have a negative effect on the enrollment of the 
desired populations. 
Target enrollment at NYU Langone Health for this study is a minimum of 40 patients over 3 years.  The target 
accrual goal for the run in safety is each 6  patients in the single (Arm C) and combination  Arms  (Arms A and 
B); once the safe use of combined AraC/AZD1775 or single agent AZD1775 is determined, the study will expand 
to 20-21 subjects in each arm  distributed over the study duration of 3 years.  An explorative cohort of MF 
patients (n=7) will be assigned to single agent AZD1775 treatment as in Arm C, however, these patients will not 
be counted into the statistical analysis for Arm C. Patients will be recruited from the physician participating in this 
study.   


 
 
 
AZD1775 in AML and MDS 
 
33 
Consenting, screening, and treatment will take place at the NYU Langone Health PCC or participating sub-sites 
under the supervision of the Site PI.  Prospective subjects will receive detailed information regarding this study; 
its investigational nature, required study procedures, alternative treatments, risks and potential benefits of the 
study.  They will also receive the informed consent document to read.  All questions are answered by the PI and 
qualified research personnel. 
The Principal Investigator(s) or their representatives will: 
1.  Obtain signed and dated informed consent from the potential subject before any study specific 
procedures are performed (can be obtained by study investigators). 
 
 
2.  Determine patient eligibility; see Section 3.1 and 3.2  
 
 
3.  Submit registration to NYU Langone Health Perlmutter Cancer Center CTO 
4.  Receive registration confirmation from the NYU Langone Health Perlmutter Cancer Center CTO, 
including a unique study identification number assigned to the patient that will be distributed to the study 
team upon registration of the patient. 
Recruitment and consenting will take place in a private area such as an exam room to protect the patient’s privacy.  
The informed consent process and documentation follows the established procedures of the NYU Langone Health 
Perlmutter Cancer Center Clinical Trials Office. 
6.1  Use of DataCore/Epic Information for Recruitment Purposes 
Although, primary recruitment will be done via participating physicians contacting potential participants; 
recruitment will also be done utilizing EPIC. 
Any recruitment information sent by email will utilize Send Safe email.  
 
Once potential subjects have been identified, the study team will notify the treating physician (TP) that they have 
patients eligible to participate. Should the potential subjects agree, the study team will provide the subjects with 
information regarding the next steps for participation.  
 
If a subject requests information regarding opting out of further recruitment for all research, subjects will be 
directed to contact research-contact-optout@nyumc.org or 1-855-777-7858. 
 
6.2  Registration Procedures 
 
6.21  General Guidelines 
 
Each patient must sign and date an informed consent form before undergoing any study specific procedure unless a 
procedure is being performed as part of the patient’s standard of care. 
 
Enrollment in the study requires that all inclusion and exclusion criteria have been met.  Enrollment occurs upon 
confirmation of registration from the NYU Langone Health PCC Clinical Trials Office.  The following materials 
must be submitted to the CTO for subject registration: 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated eligibility checklist 


 
 
 
AZD1775 in AML and MDS 
 
34 
3. All supporting documentation verifying each eligibility criterion has been met 
 
Registration will occur within 48 hours of research coordinator receipt of all of the above documents.  A written 
confirmation of enrollment including a unique study identification number assigned by the research coordinator 
will be disbursed to the study team upon registration. 
 
Once eligibility is verified, a unique patient study number will be issued within 48 hours of receiving all required 
registration material.  The patient will not be identified by name.  This is the point, at which, the patient is 
considered accrued on study.  
 
 
6.22  Multi-Site Surveillance 
As the lead investigator in a multi-site trial, the Principal Investigator is responsible for organizing and 
conducting monthly teleconferences with all participating sites. The PI will also be responsible for including 
data from all of the participating sites within the overall trial’s quarterly Data and Safety Monitoring report to the 
DSMC to include minutes from monthly PI teleconferences. Each participating site will be responsible for 
submitting the results and recommendations from the DSMC’s quarterly reviews to their IRB of record at the time 
of continuing review. Additionally, the NYU Langone Health PCC Clinical Trial Office, Quality Assurance 
Unit will provide a remote extensive monitoring including real-time review of all eCRFs to ensure completeness 
and compliance with the protocol (100% source documentation verification).  Additionally, a first subject audit 
is to be completed within four weeks of enrollment. 
 
 
 
6.23  Patient Registrations at Additional Sites 
Enrollment at additional sites can begin once each site’s IRB has approved this protocol, a copy of each site’s 
IRB approval, Citi training certificates, Medical Licenses and signed CVs are provided to NYU Langone Health 
Perlmutter Cancer Center (PCC) Clinical Trials Office. Once, all required documents are provided to NYU Clinical 
Trials Office an activation notification will be sent to the PI and research coordinator of that site. Central 
registration for this study will take place at NYU Langone Health PCC 
Quality Assurance Unit (PCC-
QAU@nyumc.org). 
 
Each patient must sign and date an informed consent form before undergoing any study specific procedures 
unless a procedure is being performed as part of the patient’s standard of care. Once a patient has signed 
consent, each site must notify the NYU Langone Health PCC Quality Assurance Unit and forward a copy of the 
signed consent to NYU Langone Health PCC Clinical Trials Office within 24 hours. 
 
Enrollment in the study requires that all inclusion and exclusion criteria have been met. Enrollment occurs 
upon confirmation of registration from the NYU Langone Health PCC Clinical Trials Office. The following 
materials must be submitted to the Quality Assurance Unit at NYU Langone Health via email 
(PCC-
QAU@nyumc.org): 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated informed consent checklist 
3. Complete signed and dated eligibility checklist 
4. All supporting documentation verifying each criterion has been met. 


 
 
 
AZD1775 in AML and MDS 
 
35 
 
Registration will occur once the Senior Research Nurse for Quality Assurance conducts a central review of the 
submitted materials. Once eligibility is verified, a unique subject study number will be issued within 48 hours of 
receiving all required registration material. This number is unique to the participant and must be written on all data 
and correspondence for the participant. The NYU Langone Health PCC CTO will 
return a signed eligibility 
confirmation worksheet email with the subject’s unique study number. 
 
The subject will not be identified by name. This is the point, at which, the patient is considered accrued on study. 
Protocol treatment should  begin within  designated timeframe; issues  that would cause treatment delays 
should be discussed with the overall PI, Dr. Tibes. All screen failures/ineligible subjects, as well as subject’s 
who withdraw consent prior to initiation of protocol therapy must be submitted to the CTO in a manner 
analogous to the procedures noted above. Applicable source documentation will be required within the 
corresponding submissions. 
 
Subjects must not start any protocol procedures prior to registration; each participating institution will order the 
study agent through NYU Investigational Pharmacy. 
 
Each site is responsible for reporting all unexpected problems involving risks to participants or others to NYU 
Langone PCC Clinical Trials Office and to their IRB as per site institutional policy. 
 
Please email all SAEs to NYUPCCsafetyreports@nyumc.org, Dr. Tibes, and the NYU Langone Health CTO QA 
specialist. 
 
 
 
6.3 
Safety & Expansion Portions 
 
6.31 
Correlative Research 
 
6.311 A mandatory correlative research component is part of this study, the subject will be 
automatically registered onto this component (see Section 3.17 and 14.0). 
 
6.32 
At the time of registration, the following will be recorded: 
• 
Subject has/has not given permission to store and use his/her sample(s) for future research of 
Acute Myeloid Leukemia or Myelodysplastic Syndrome at NYU Langone Health. 
• 
Subject has/has not given permission to store and use his/her sample(s) for future research to 
learn, prevent, or treat other health problems. 
• 
Subject has/has not given permission to give his/her sample(s) to researchers at other 
institutions. 
 
6.33 
Treatment on this protocol must commence at a participating institution, NYU Langone Health, 
under the supervision of a hematologist. 
 
6.34 
Treatment cannot begin prior to registration and must begin  14 days after registration. 
 


 
 
 
AZD1775 in AML and MDS 
 
36 
6.35 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines specified 
on the test schedule. 
 
6.36 
All required baseline symptoms (see Section 10.3) must be documented and graded. 
 
6.37a 
Study drug is available on site.  
 
6.37b Blood draw kit is available on site.   
 
6.37c 
Subject questionnaire booklet is available on site; copies are not acceptable for this submission.  
 
6.37d Randomization Procedures  
 
6.37d1  After the subject has been registered into the study, the values of the grouping factors will 
be recorded.  An elderly newly diagnosed AML subject will be allocated to arm A.  A 
relapsed/refractory AML or HMA failure MDS/ AML subject will be randomized to 
treatment group arm B or arm C. MF patients will be allocated to Arm C but not included 
in the statistical analysis for Arm C, rather descriptive response rates will be summarized 
separately. 
 
- 
Elderly (age 60+) newly diagnosed AML subjects assigned to Arm A: AZD1775 
days 1-5, 8-12 and AraC days 1-5, 8-12 
- 
Relapsed/Refractory AML and HMA failure MDS/ AML subjects 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. 
- 
MF patients allocated to Arm C 
 
 
 


 
 
 
AZD1775 in AML and MDS 
 
37 
7.0 Protocol Treatment 
 
7.1 
Pre-Treatment Requirement 
 
 
 
7.11 
 
All patients will receive a 5-HT3 antagonist, ondansetron (Zofran) 8 mg PO QD or granisetron (Kytril) 1 mg PO QD prior 
to each dose of AZD1775.  If nausea and vomiting continue, a second dose of antiemetics can be taken 8 hours later if 
necessary. In addition, dexamethasone 4 mg PO may be given with each AZD1775 dose unless contraindicated or not 
well-tolerated.  Dexamethasone or the 5-HT3 antagonist may be given by IV route as needed.  
Promethazine (Phenergan), prochlorperazine (Compazine), and benzodiazepine may still be used as additional adjunctive 
treatments during AZD1775 therapy.   
Please note: aprepitant [Emend] and fosaprepitant are not permitted due to known DDIs. 
Patients should be encouraged to maintain liberal oral fluid intake. 
Suitable alternative medications may be used, with adequate justification, in those studies where the use of any of the 
above medications might interfere with other study procedures or are deemed insufficient.  
 
 
7.2 
Treatment Plan for AZD1775 combined with AraC (Arms A and B) 
 
7.21 Safety Portion  
 
 
 
The safety portion of this trial will consist of a limited dose escalation and subsequently assess 
the safe combination dose of AZD1775 with standard AraC s.c.twice daily dosing. A limited 
safety run in dose escalation of AZD1775 will be performed as outlined in Table 7.21. Three 
subjects from either arm will be treated and and observed for a minimum of 28 days to assess 
toxicities. Toxicity and DLT/ MTD criteria will follow a classical three by three dose escalation 
toxicity assessment:   
 
 
 
In the run-in portion of the trial, 3 patients who are eligible for the trial will be treated at dose 
level 0 (AZD1775 200 mg PO once daily and AraC 20 mg s.c.twice daily days 1-5 & 8-12) and 
observed for a minimum of 28 days. If there are no DLT defining toxicities, the following 3 
patients will be treated at dose level 1 (AZD1775 250 mg PO once daily and AraC 20 mg s.c. 
twice daily days 1-5 & 8-12). If there are no DLT defining toxicities at dose leve 1, the next 3 
will be treated at dose level 2 (AZD1775 300 mg PO once daily and AraC 20 mg s.c. twice daily 
days 1-5 & 8-12). If there are no DLTs in the first 3 pateints at dose level 2, an additional 3 
patients will be treated. If </+ 1/6 patients at dose level 2 expereince DLT, the Expansion portion 
(cohort) of the trial will be opened for the remaining patients.  
 
 
If 1/3 patient experiences a DLT at a given dose level, an additional 3 patients will be enrolled at 
this dose level. If there are no further DLTs (maximum of </= 1/6 patients with DLT at any given 
dose level) this dose level will be defined as the MTD dose level and advanced to the Expansion 
portion of the study. If 2/3 patients experience a DLT, dose will be de-escalated by one dose level 
and an (additional) 3 patients treated at the next lower dose level, unless six pateints have been 
treated already and there were </= 1/6 DLT, than this level will be defined as MTD dose level 
and advanced to the Expansion portion. If >/= 2/6 patients experience at any dose level, then 
enrollment into that study arm will be placed on hold, and a meeting of all participating 
investigators, the NYU DSMC Medical Monitor, the Astra Zeneca Trial/ Program Lead will be 
called to determine how best to proceed, as well as available PK data will be reviewed.  
 
 
If DLT occurs at dose level 0, study will be de-escalated to dose level -1 (AZD1775 150 mg PO 
once daily and AraC 20 mg s.c. twice daily days 1-5 & 8-12). If </= 1/3 patients have DLT 
another 3 patients will be enrolled and if </= 1/6 patients have DLT, than this level will be 


 
 
 
AZD1775 in AML and MDS 
 
38 
defined as MTD dose level and advanced to the Expansion portion. If 2/3 patients at dose level -1 
have DLT, the combination will be deemed as not tolerable in combination with LD-AraC.  
 
 
 
NOTE: the Safety/ Escalation portion and MTD determination for Arm A (newly diagnosed/ 
untreated AML) and Arm B (relapsed/ refractory AML, HMA failure MDS) as outlined above 
will be performed together with patients from both Arms eligible.  .  
 
 
 
 
Table 7.21: Safety run in dose escalation  
Dose Level 
 
AZD17752 
 
 
Cytarabine (AraC) 1 
 
-1 
150 mg PO once daily days 1-5 & 8-12 
20 mg SC twice daily days 1-5 & 8-12 
0 
200 mg PO once daily days 1-5 & 8-12 
20 mg SC twice daily days 1-5 & 8-12 
1 
250mg PO once daily days 1-5 & 8-121 
20 mg SC twice daily days 1-5 & 8-12 
2 
300 mg PO once daily days 1-5 & 8-12 
20 mg SC twice daily days 1-5 & 8-12 
1 AraC dose is a fixed dose of 20 mg s.c. per a single dose twice daily.  
2 AZD1775 should be taken either 2 hours before or 2 hours after a meal.   
 
 
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. The MTD/ Expansion cohort dose can be differernt for 
Arm A and B.  
 
 
Table 7.22: Dose for Expansion cohort 
Agent 
Dose 
Route 
Day(s) 
ReRx 
AraC1 
20 mg 
SC twice daily  
1-5 & 8-122 
Every 28 days 
AZD1775 
MTD  
(from escalation 
portion) 
PO once daily 
1-5& 8-122 
Every 28 days 
1 AraC dose is a fixed dose of 20 mg s.c. per a single dose twice daily.  
2AZD1775 should be taken either 2 hours before or 2 hours after a meal.    
 
 
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 subjects in the arm and observe 
them for a minimum of 21 days to assess toxicities. The Safety portion will first treat 3 patients at 
a single dose AZD1775 of 300mg daily (dose level 0) on days 1-5 and 8-12 for 21 days. If 0/3 
patients experience DLT, another 3 patients will be treated. If </= 1/6 patients have DLT, 300mg 
will be the tolerated dose (MTD) and advanced to the Expansion portion of the study. If </= 2/6 


 
 
 
AZD1775 in AML and MDS 
 
39 
patients have DLT, dose will be de-escalated to dose level -1 (AZD1775 250mg daily on days 1-5 
and 8-12 for 21 days) and 3 patients treated. If </= 1/3 patients have DLT another 3 patients will 
be treated. If </= 1/6 patients have DLT, 250 mg AZD1775 will be the tolerated dose (MTD) and 
advanced to the Expansion portion of the study. If </= 2/6 patients have DLT at dose level -1 
(250 mg AZD1775) dose will be further de-escalated to dose level -2 (AZD1775 200mg daily on 
days 1-5 and 8-12 for 21 days) and 3 patients treated. If </= 1/3 patients have DLT another 3 
patients will be treated. If </= 1/6 patients have DLT, dose level -1 (200 mg AZD1775) will be 
the tolerated dose (MTD) and advanced to the Expansion portion of the study.  
If </= 2/6 patients have DLT at dose level -2 (200 mg AZD1775) dose will be further de-
escalated to dose level -3 (AZD1775 150 mg daily on days 1-5 and 8-12 for 21 days) and 3 
patients treated. If </= 1/3 patients have DLT another 3 patients will be treated. If </= 1/6 patients 
have DLT, dose level -3 (150 mg AZD1775) will be the tolerated dose (MTD) and advanced to 
the Expansion portion of the study. If </= 2/6 patients have DLT at dose level -3 (150 mg 
AZD1775) or if >/= 2/6 patients experience DLT at any dose level, then enrollment into that dose 
level will be placed on hold, and a meeting of all participating investigators, the NYU DSMC 
Medical Monitor, the Astra Zeneca Trial/ Program Lead will be called to determine how best to 
proceed, as well as available PK data will be reviewed. 
 
 
 
 
 
 
Table 7.31 Single agent AZD1775  (Arm C) 
Dose  
AZD17751 
0 
300 mg PO once daily days 1-5 & 8-12 every 21 
days 
-1 
250 mg PO once daily days 1-5 & 8-12 every 21 
days 
-2 
200 mg PO once daily days 1-5 & 8-12 every 21 
days  
-3 
150 mg PO once daily days 1-5 & 8-12 every 21 
days 
 
1AZD1775 should be taken either 2 hours before or 2 hours after a meal. 
 
 
 
 
 
 
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 
AZD17751 
MTD 
PO once daily 
1-5 & 8-12,  
Every 21 days 
 
 


 
 
 
AZD1775 in AML and MDS 
 
40 
 
1AZD1775 should be taken either 2 hours before or 2 hours after a meal. 
 
 
 
7.33  Hydroxyurea (HU) 
For patients randomized to Arm C single agent AZD1775, HU may be added after the first cycle 
of therapy at the physicians discretion after discussion with the PI. HU dose should be started 
according to clinical judgement at 500-1000mg/ day and titrated for additional myelosuppression 
as needed. Note: for patients with Myelofibrosis, HU can be given during cycle 1 at the 
previously tolerated dose.  
 
 
7.4a 
Toxicity Assessment for Safety Portion: DLT definition and RP2D 
 
Toxicity will be measured per NCI-CTCAE version5.0.  DLT is defined as an adverse event 
occurring during the first cycle of treatment that is not clearly related to the subject’s underlying 
disease and that meets one of the following: 
 
• 
Grade 3 or higher toxicity as per NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0  not clearly resulting from the underlying leukemia and that does not 
resolve to ≤ Grade 2 within 24 hours with the following exceptions; 
• 
Grade 3 fatigue, asthenia, fever, anorexia, or constipation;  
• 
Grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total 
parenteral nutrition, or requiring or prolonging hospitalization;  
• 
infection, bleeding or other expected direct complication of cytopenias due to 
active underlying disease;  
• 
Grade 3 or 4 tumor lysis syndrome (TLS) if it is successfully managed 
clinically and resolves within 7 days without end-organ damage;  
• 
Grade 3 or 4 isolated electrolyte abnormalities that last < 72 hours. 
• 
Grade 3 AST, ALT or alkaline phosphatase will be considered dose limiting  if it last > 72 
hours 
• 
treatment-related deaths are dose limiting 
• 
confirmed Hy’s law cases are dose limiting 
 
NOTE: Myelosuppression will not be considered in evaluating toxicity in subjects with 
acute leukemias or similar advanced myeloid malignancies (MDS, MF) except where 
bone marrow (BM) hypoplasia occurs for >42 days with BM cellularity <5% in the 
absence of residual leukemia/disease. 
 
 
 
7.4.b 
RP2D for the combination of AZD1775 with Cytarabine; DLT, MTD and Biological dose 
 
Despite a lack of a clear biomarker/ PD marker for WEE1 kinase inhibition, based on preclinical 
data an effective pharmacological dose is up to the range of 750 nM, possibly higher to 
maximally 1000 nM. From recent PK data (REFMAL 984 and NCI study), daily dosing for 5 
days for one or two weeks with AZD1775 was determined as the RP2D, that yielded an AUC (0-
8 hrs) of ~8000nM. Therefore we would expect that 300mg AZD1775 daily would yield around 
600-800 to maximally 1000 nM concentrations of AZD1775 in the first 8 hours.  
For the combination arms (Arms A and B) in the Escalation portion we will escalate dose starting 
at AZD1775 200 mg daily on a 5-2-5 schedule. We will escalate up to/ until  
 


 
 
 
AZD1775 in AML and MDS 
 
41 
a) the current MTD/ RP2D of 300 mg daily (5-2-5 schedule) is reached at acceptable toxicity 
(AEs) regardless of preclinical PK efficacy  
b)  DLT defining toxicities/ AEs are observed  
c) clinical efficacy is observed that would meet the primary response endpoint already below the 
currnet RP2D of 300 mg AZD1775 daily  
d) Clinical PK (AUC) of AZD1775 reaches approx. > 1000 nm/ hr 
 
We will accomplish above goals with real-time assessment of safety, efficacy, PK and/or PD in 
each chohrt. 
 
 
 
 
 
 
7.5 
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 subjects (at 
least 2 of a maximum of 6 subjects).  
 
7.51 
Three subjects will be treated at a given dose level combination and observed for one cycle to 
assess toxicity (accrual will be suspended while the 3 subjects are treated and observed – only 
applicable to the dose escalation cohort/ part of study). 
 
7.52 
If DLT is not seen in any of the 3 subjects or in 1 of 3 subjects, 3 new subjects will be accrued. 
and treated at the same dose level (accrual will be suspended while the 3 subjects are treated and 
observed). If DLT is seen in 2 or 3 of 3 subjects treated at a given dose level, then the next 3 
subjects will be treated at the next lower dose level, if only 3 subjects were enrolled and treated at 
this lower dose level.  
 
7.53 
After enrolling 6 subjects on a specific dose level, if DLT is observed in  1 or less subjects, then 
the combination dose will be considered safe for the expansion phase.  If DLT is observed in at 
least 2 of 6 subjects, then the MTD will have been exceeded and defined as the previous dose 
unless only 3 subjects were treated at the lower dose level. In that case, 3 additional subjects will 
be treated at this lower dose level. 
             
7.55 
If a subject fails to complete  one cycle of treatment for reasons other than dose-limiting toxicity 
defined adverse events, the subject will be regarded as non-informative for estimating the MTD 
and an additional subject will be treated at the current dose level. 
 
 
7.6       Dose escalation (intrapatient) will not be allowed for a subject. 
   
7.7a       For this protocol, the subject must return to the consenting institution for evaluation at least once per 
cycle. 
 
 
7.7b  
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, after the first cycle of 
treatment, the standard of care drug AraC may be administered by the patient’s Local Medical Doctor 


 
 
 
AZD1775 in AML and MDS 
 
42 
(LMD). However, study drug AZD1775 can only be dispensed by an investigator or investigational site of 
the study.  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, post cycle 1 of treatment therapy.  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.   
 
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 at least possibly related 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.   
 
 
 
 
8.11 
AZD1775 combined with AraC (Arms A and B) 
Dose  
AZD1775 
[reduce AZD1775 first if at least 
possibly attributed to AZD1775] 
Cytarabine (AraC) 
 
0 
300 mg PO once daily days 1-5 & 8-12 20 mg SC twice daily days 1-5 & 8-12 
-1 
250mg PO once daily days 1-5 & 8-121 20 mg SC twice daily days 1-5 & 8-122 
 
-2a 
 
-2b 
200 mg PO once daily days 1-5 & 8-12 
 
200 mg PO once daily days 1-5 & 8-12 
20 mg SC twice daily days 1-5 & 8-122  
 
10 mg SC twice daily days 1-5 & 8-122 
 
 
 
  
1If toxicity is clearly attributable to AZD1775, AZD1775 will be reduced to 250mg 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 SC 
twice daily at physicians discretion based on myelosupression, tolerance and clinical benefit.. 
NOTE: intermediate dose levels may be explored based on PK, PD and clinical efficacy parameters 
and evaluation under future amendments based on PK, PD and safety assessments.  
 
 


 
 
 
AZD1775 in AML and MDS 
 
43 
 
 
 
8.12 
AZD1775 single agent (Arm C) 
Dose  
AZD1775 
0* 
300 mg PO once daily days 1-5 & 8-12 
-1 
250 mg PO once daily days 1-5 & 8-12  
-2 
200 mg PO once daily days 1-5 & 8-12 
-3 
150mg PO once daily days 1-5 & 8-12 
 
 
*Presumed starting dose of Expansion Portion.  
Note: Further dose modifications such as intermittent dosing or proloned longer dosing can be made 
under future amendments. 
 
 
  
 
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 8.32 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 the remainder of the study   
 
 
 
 
8.3 
Dose modification table for adverse events felt to be at least possibly related to AZD1775*** or AraC  
 
Non-hematologic toxicity management guidelines 
Substantial acute toxicities should be managed as medically indicated and with temporary suspension of investigational 
product, as appropriate. Dose reductions or holds and initiation of supportive care are allowed as clinically indicated by 
the treatment physician.  
Dose reductions of AZD1775 should be consideredif toxicity is considered to be at least possibly related to AZD1775, i.e. 
in monotherapy studies or in combination studies if relationship cannot be wholly attributed to the combination agent 
(each combination agent should be considered on an individual basis). Dose re-escalation is not permitted.  
In general, if a patient experiences a G1/G2 non-hematological toxicity, no dose modification is required (except QTc 
prolongation, see Table 8.31). If a patient experiences a G3 or G4 non-hematological toxicity which is not attributable to 
the disease or disease related processes under investigation, dosing will be interrupted and/or the dose reduced and 


 
 
 
AZD1775 in AML and MDS 
 
44 
supportive therapy administered as required.  Any patient who develops a Grade 3 or 4 non-hematologic toxicity that does 
not resolve to ≤ Grade 1 within 21 days should be removed from the study treatment unless approved by the Medical 
Monitor and Study Chair.   
No more than two dose reductions will be allowed for any patient. Patients requiring further dose reduction due to toxicity 
must discontinue study treatment. Dose re-escalation is not allowed. If the patient has concurrent neutropenia and 
thrombocytopenia, please follow the most conservative guidance in the table below and discuss with Medical Monitor as 
needed. 
If haematological parameters do not recover within 21 days, the patient should be removed from the study treatment.   
 
 
 
 
Table 8.31 
Electrocardiogram QT corrected interval prolonged 
QTc Value (triplicate)a 
AZD1775 
QTc 450-480 ms (males) or 
470-480 (females) 
Hold.  Once QTc interval has returned to pretreatment status 
and correction of possible electrolyte imbalance has been made, 
resume at next lower dose level. 
QTc 481-500 ms 
Hold. Seek cardiologist advice, patient may resume at next 
lower dose level if cardiologist agrees. 
QTc ≥ 501 ms  
Discontinue treatment. Seek cardiologist advice 
Shift from baseline of ≥ 60ms 
Discontinue treatment. Seek cardiologist advice 
 
Table 8.32 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless otherwise 
specified   
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 or treating physician may 
discuss possible dose reduction (per Table 
8.12) with the Study Chair.   If clinical benefit 
is derived, AZD1775 may be continued if the 
infection is managed andcontrolled with 
appropriate medical intervention 
(i.e.antibiotics) and the patient is felt to derive 
benefit from the treatment with AZD1775 
(Rationale: AML, MDS and MF patients may 
have persistent and/ or prolonged neutropenia 
and will only recover if underlying disease is 
adequately treated]. 


 
 
 
AZD1775 in AML and MDS 
 
45 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
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 or MF 
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. 
 
For a second event reduce by 1 dose level 
(Table 8.12)  
 
For a third event discontinue from treatment.  
    [If clinical benefit is derived, AZD1775 may 
be continued per physician assessment and 
after discussion with Study Chair and Medical 
Monitor (NYU DSMC)] 
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 (Table 8.12) 
 
[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  
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 


 
 
 
AZD1775 in AML and MDS 
 
46 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
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 reduced AraC of 
10mg s.c. twice daily days 1-5 & 8-12 
Cardiac Disorders 
Cardiac disorders – Other 
≥ Grade 4 
AZD1775 
 
Omit dose and discontinue patient from study 
Other Non-Hematologic 
events 
Grade 3 
 
 
 
 
 
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. Contact protocol chair anda 
medical monitor if resumption of AZD1775 at 
previous dose may be clinically indicated 
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.  
 
For a repeated Grade 4 event discontinue 
patient from study 
AT TIME OF RETREATMENT (at beginning of each next cycle) 
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 
weekly or at least every other week. When 
event returns to ≤ grade 2, resume AZD1775 
and/ or AraC treatment at next lower dose 
level. 
 
For a repeated Grade 4 event present/ recurred 
at beginning of each next cycle patient will be 
discontinued from therapy.  
*   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 


 
 
 
AZD1775 in AML and MDS 
 
47 
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 4 weeks from the intended dosing day for the 
combination arms (Arm A and B) and 3 weeks for the single agent AZD1775 arm (Arm C) . If interruption is > 4 and 3 
weeks for Arms A, B and C respectively, continuation of treatment may be allowed on a case by case basis (i.e. clinical 
benefit) as determined by the treating physician in discussions with the Medical Monitor (NYU DSMC) and the Stuyd 
Chair. However, any discontinued 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 
Diarrhea 
Due to frequent reports of diarrhea with AZD1775 administration, anti-diarrhoeal treatment with loperamide (Imodium) is 
required at the first onset of diarrhea according to American Society of Clinical Oncology (ASCO) guidelines. Oral 
loperamide  4mg should be administered at the first onset of diarrhoea and then 2mg every 2 hours until patient is 
diarrhea-free for at least 12 hours. The first dose of loperamide could be lowered to 2mg if the diarrhea is recurrent and if, 
in the opinion of the treating physician, the diarrhoea is not severe. The dose of loperamide should not exceed 16mg in a 
24-hour period.   
Patients should be instructed to notify the Investigator or research staff of the occurrence of bloody or black stools, 
symptoms of dehydration, fever, inability to take liquids by mouth, and inability to control diarrhoea within 24 hours of 
using loperamide or other prescribed anti-diarrheal medications 
If diarrhea is severe (i.e., requiring intravenous [IV] rehydration) and/or associated with fever or severe neutropenia 
(Grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients with severe diarrhea or any diarrhea associated 
with severe nausea or vomiting should be hospitalised for IV hydration and correction of electrolyte imbalances. 
Nausea and vomiting 
All patients must receive a 5-HT3 antagonist, ondansetron (Zofran) 8 mg PO QD or granisetron (Kytril) 1 mg PO QD 
prior to each dose of AZD1775.  If nausea and vomiting continue, a second dose of antiemetics can be taken 8 hours later 
if necessary. In addition, dexamethasone 4 mg PO may be given with each AZD1775 dose unless contraindicated or not 
well-tolerated.  Dexamethasone or the 5-HT3 antagonist may be given by IV route as needed.  
Promethazine (Phenergan), prochlorperazine (Compazine), and benzodiazepine may still be used as additional adjunctive 
treatments during AZD1775 therapy.   
Please note: aprepitant [Emend] and fosaprepitant are not permitted due to known DDIs. 
Patients should be encouraged to maintain liberal oral fluid intake. 
Suitable alternative medications may be used, with adequate justification, in those studies where the use of any of the 
above medications might interfere with other study procedures or are deemed insufficient.  
 
Febrile neutropenia 
Patients experiencing febrile neutropenia with significant symptoms should be managed in a hospital setting according to 
standard procedures, with the urgent initiation of IV antibiotic therapy. Patients with febrile neutropenia without 
symptoms should be managed according to standard guideline.  


 
 
 
AZD1775 in AML and MDS 
 
48 
 
 
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. 
 
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 
Antifungal treatment on protocol: The preferred azole anti-fungal medication is Fluconazole,  
(alternatively Posaconazole may be given (same below criteria apply for posaconazole) which can be 
given during treatment with AZD1775 at the treating physician’s discretion, however with dose 
reductions of AZD1775 as outlined below. Based on the DDI simulations with Fluconazole (moderate 
inhibitor), there is an approximately 35% increase in AZD1775 exposure. Therefore if Fluconazole (or 
Posaconazole) are given the following AZZD1775 dose reductions need to be followed:  
 
 
AZD1775 200 mg dose → reduce to AZD1775 150 mg  
 
AZD1775 250mg dose  → reduce to AZD1775 200 mg  
 
AZD1775 300mg dose  → reduce to AZD1775 250mg 
 
 
10.0 
Safety and Adverse Events 
 
10.1   Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as the IRB-
approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a reasonable 
possibility that the incident experience, or outcome may have been caused by the procedures involved in the 
research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, psychological, 
economic, or social harm). 
 
 
Adverse Event 


 
 
 
AZD1775 in AML and MDS 
 
49 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the course 
of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major clinical 
significance.   They may jeopardize the subject, and may require intervention to prevent one of the other serious outcomes 
noted above.  For example, drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the initiation of 
any study procedures to the end of the study treatment follow-up.  For this study, the study treatment follow-up is defined 
as 30 days following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be recorded as an 
adverse event if the frequency, intensity, or the character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the end of the study, 
any new clinically significant findings/abnormalities that meet the definition of an adverse event must also be recorded 
and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the subject is lost to 
follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the investigator should instruct each 
subject to report any subsequent event(s) that the subject, or the subject’s personal physician, believes might reasonably 
be related to participation in this study.  The investigator should notify the study sponsor of any death or adverse event 
occurring at any time after a subject has discontinued or terminated study participation that may reasonably be related to 
this study.  The sponsor should also be notified if the investigator should become aware of the development of cancer or 
of a congenital anomaly in a subsequently conceived offspring of a subject that has participated in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following conditions is met:  


 
 
 
AZD1775 in AML and MDS 
 
50 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, discontinuation of the drug, 
more frequent follow-up assessments, further diagnostic investigation, etc. 
 
 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and reported as a 
serious adverse event unless specifically instructed otherwise in this protocol.  Any condition responsible for surgery 
should be documented as an adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse event in the 
following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a preexisting 
condition.  Surgery should not be reported as an outcome of an adverse event if the purpose of the surgery was 
elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a worsening 
or increase in frequency of hospital admissions as judged by the clinical investigator. 
 
10.2  Recording of Adverse Events 
 
At each contact with the subject, the investigator must seek information on adverse events by specific questioning and, as 
appropriate, by examination.  Information on adverse events should be recorded immediately in the source document, and 
also in the appropriate adverse event module of the case report form (CRF).  All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should recorded in the source document, though should be grouped under one 
diagnosis. 
 
As outlined in Section 10.8, adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period must be followed 
up to determine the final outcome.  Any serious adverse event that occurs after the study period and is considered to be 
possibly related to the study treatment or study participation should be recorded and reported immediately. 
 
10.3  Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats and requirements of 
the various entities to which they are responsible, but at a minimum those events that must be reported within 5 days of PI 
notification are those that are: 
• related to study participation, 
• unexpected, and  
• Harmful or have the potential to cause harm (see definitions, section 10.1) 
   
Events should be reported using the NYU CTO Medical Events Form. 
 
Adverse events that do not fit the above immediately reportable criteria must still be reported to the IRB at each annual 
review, either in a summary or tabular format. 
 


 
 
 
AZD1775 in AML and MDS 
 
51 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP report form. It is the 
site investigator’s responsibility to report UPs to their IRB and to the study sponsor. The UP report will include the 
following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or outcome represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or are proposed in 
response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• UPs that are SAEs will be reported to the IRB and to the DSMC/study sponsor within 24 hours of the investigator 
becoming aware of the event. 
• Any other UP will be reported to the IRB and to the DSMC/study sponsor within 24 hours of the investigator 
becoming aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s written reporting 
procedures), the supporting agency head (or designee), and OHRP within 5 days of the IR’s receipt of the report of 
the problem from the investigator. 
 
Serious adverse event reporting will begin in conjunction with the date of informed consent. Any SAEs occurring prior to 
study drug administration that the investigator believes may have been caused by a protocol procedure must be reported 
immediately to the Sponsor or its designee and recorded on the case report form. 
 
All fatal or life-threatening adverse events must be immediately reported to the Principal Investigator, 
via appropriate reporting mechanism and the  NYU Langone Health IRB by telephone or e-mail. Within 
24 hours of the event, the Serious Adverse Event Form must be emailed to 
NYUPCCsafetyreports@nyumc.org whether full information regarding the event is known or not. 
Additional follow-up by the investigator will be required if complete information is not known. De-
identified source documentation of all examinations, diagnostic procedures, etc. which were completed 
with respect to the event should be included with the SAE form. Care should be taken to ensure that the 
patient’s identity is protected and the patient’s identifiers (as assigned at the time of study enrollment) 
are properly mentioned on any copy of source document provided to the Sponsor. For laboratory 
results, include the laboratory normal ranges.  
 
 
All other serious adverse events must be reported to the sponsor and DSMC within 24 hours by email 
(NYUPCCsafetyreports@nyumc.org ) or fax (212-263-0715) . The Serious Adverse Event Form can be emailed to the 
principal investigator and Clinical Trials Office (NYUPCCsafetyreports@nyumc.org) or it can be faxed (212-263-0715), 
this documentation will be forwarded to the DSMC’s appointed medical moniotr within 24 hours of the event whether full 
information regarding the event is known or not.  Additional follow-up by the investigator will be required if complete 
information is not known. 
 
Current contact information shall be maintained at the site within the regulatory binder. 
 
All serious adverse events (SAEs) will be evaluated by the DSMC if meeting the requirements for expedited reporting, 
the study Sponsor( NYU Langone Health)  will report serious adverse events to all regulatory authorities with jurisdiction 
over ongoing trials with the study drug, this will be done in accordance with standard operating procedures and policies of 
the IRB, DSMC and FDA. 


 
 
 
AZD1775 in AML and MDS 
 
52 
  
 
 
 
 
10.31 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 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP web site:  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)    
 
10.311 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 5.0.  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). 
 
10.312 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. 
 
 
10.313  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. 
 
 
10.314  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 drug has not yet been eliminated. 
 
 
10.4  Investigator reporting: notifying the study sponsor 
 
Since multiple sites may be participating, the following describes events that must be reported to the study sponsor (NYU 
Langone Health PCC) and Astra Zeneca in an expedited fashion. 


 
 
 
AZD1775 in AML and MDS 
 
53 
 
The following describes events that must be reported to the study sponsor in an expedited fashion. 
 
Initial Report: within 24 hours: 
The following events must be reported to the study sponsor (NYU Langone Health PCC) by email within 24 hours of 
awareness of the event using the NYU CTO Medical Events Form:  
 
• 
Unanticipated problems related to study participation,  
• 
Serious adverse events, regardless of whether they are unexpected.  
 
The investigator shall maintain a copy of the Medical Events Form on file at the study site. All report forms must be 
signed and dated by the Principal Investigator.  If the Principal Investigator is not available at the time of the initial report, 
then the form can be submitted by a Sub-Investigator.  This form should be reviewed by the Principal Investigator, whom 
sign/date initial report upon return. 
   
Report to: 
NYUPCCsafetyreports@nyumc.org 
 
 
 
AND 
 
Raoul Tibes, MD, PhD 
NYU Hematology Associates 
240 East 38th Street, 19th Floor 
New York, NY 10016 
646-501-8205 
Email: raoul.tibes@nyumc.org 
 
Events of Clinical Interest (any medical event that is deemed significant via Principal Investigator’s expertise, but does 
not apply to SAE categories) will be reported within 2-5 days, or as per study Sponsor specifications. 
 
 
Follow-up report:  
As a follow-up to the initial report, the investigator shall provide further information, as applicable, on the unanticipated 
event or the unanticipated problem in  in the form of a written narrative.  This should include any other diagnostic 
information that will assist in the understanding of the event.     
 
Other Reportable events: 
• 
Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval before they are 
initiated. Any protocol deviations initiated without Sponsor and the investigator’s IRB approval that may affect 
the scientific soundness of the study, or affect the rights, safety, or welfare of study subjects, must be reported to 
the Sponsor and to the investigator’s IRB as soon as a possible, but no later than 5 working days of the protocol 
deviation. 
 


 
 
 
AZD1775 in AML and MDS 
 
54 
• 
Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s reviewing IRB as soon 
as a possible, but no later than 5 working days of the IRB notification of withdrawal of approval. 
 
 
 
10.5           
 
 
10.5  Investigator reporting: notifying the collaborator 
 
 
• 
Reporting of SAEs to AstraZeneca 
Investigators must report to the Overall PI any adverse event (AE) that occurs after the initial dose of study 
treatment, during treatment, or within 30 days of the last dose of treatment on the local institutional SAE form.  
 
All SAEs have to be reported, whether or not considered causally related to AZD1775, or to the study 
procedure(s).  All SAEs will be recorded in the eCRF. 
 
If any SAE occurs in the course of the study, then investigators or other site personnel must inform NYU Langone 
Health PCC immediately; procedures for reporting to AstraZeneca will be followed as per outlined below.  
 
SAE information will be sent via secure e-mail connection or via fax. The standard paper SAE Report with 
supporting relevant source documents (e.g. history and physical [H&P], hospital discharge summary, autopsy 
report when available, results of relevant diagnostic tests completed to evaluate the event) will be attached and 
sent via: 
 
Send SAE report and accompanying cover page by way of Email to  
 
AEMailboxClinicalTrialTCS@astrazeneca.com 
 or by fax to AstraZeneca’s designated fax line: US: 302-886-4114, ex-US +46 31 776 37 34 
 
Transmission of the SAE report Form should be confirmed by the site personnel submitting the report. 
 
Follow-up information for SAEs and information on non-serious AEs that become serious should also be reported 
to PI and AstraZeneca as soon as it is available; these reports should be submitted using the SAE Report Form.  
Investigators must report SAEs and follow-up information to their responsible Institutional Review Board (IRB) 
according to the policies of the responsible IRB. For fatal or life- threatening AEs where important or relevant 
information is missing, active follow-up is undertaken immediately. 
AstraZeneca or their representative will provide Regulatory Authorities, Ethics Committees (ECs), IRBs and PIs 
with clinical safety updates/reports according to local requirements. 
 
Overall Investigator to ensure that all the necessary information is provided to the AstraZeneca Safety Department 
within 1 calendar day of initial receipt of the information for fatal and life threatening events and within 5 
calendar days of initial receipt of the information for all other SAEs. 
 
EVENT TYPE 
REPORTING PROCEDURE 


 
 
 
AZD1775 in AML and MDS 
 
55 
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. 31 
 
10.61  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, 
detailed in Section 10.4 .  
 
 
10.6    Other Required Reporting 
 


 
 
 
AZD1775 in AML and MDS 
 
56 
10.61 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  the AstraZeneca  database as specified in 
21 CFR 312.64(b). 
 
10.62  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. 
 
10.63 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. 
 
• 
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. 
 


 
 
 
AZD1775 in AML and MDS 
 
57 
10.64 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. 
 
 
 
10.7 
Investigator reporting: notifying the IRB 
 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems posing risks to 
subjects or others.  The following describes the NYU Langone Health IRB reporting requirements, though Investigators at 
participating sites are responsible for meeting the specific requirements of their IRB of record.  The NYU IRB address is: 
 
 
 
 
NYU School of Medicine IRB 
 
 
 
1 Park Avenue, 6th Floor 
New York, NY 10016 
 
Report promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 working days from the 
time the investigator becomes aware of the event: 
• 
Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately reflected in the 
protocol-related documents, such as the IRB-approved research protocol, any applicable investigator brochure, 
and the current IRB-approved informed consent document and other relevant sources of information, such as 
product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the opinion of the 
principal investigator or sponsor, the event was more likely than not to be caused by the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint cannot be resolved 
by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations from the IRB 
approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under Subpart C and the investigator 
believes it is in the best interest of the subject to remain on the study. 
• New Information indicating a change to the risks or potential benefits of the research, in terms of severity or 
frequency. (e.g. analysis indicates lower-than-expected response rate or a more severe or frequent side effect; Other 
research finds arm of study has no therapeutic value; FDA labeling change or withdrawal from market) 


 
 
 
AZD1775 in AML and MDS 
 
58 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable Event Form” or as a written 
report of the event (including a description of the event with information regarding its fulfillment of the above criteria, 
follow-up/resolution and need for revision to consent form and/or other study documentation). The contact information 
for submitting IND safety reports is noted below: 
 
 
 
 
 
Email:  NYUPCCsafetyreports@nyumc.org 
 
 
 
 
 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical Investigator’s study 
file. 
 
It is the responsibility of the study sponsor to notify all participating investigators of any adverse event that meets the 
FDA 15-day reporting requirement criteria as note above. The same materials and timeline used to report to the 
FDA are used for notifying participating investigators. 
 
All Internal SAEs reported by the CTO, occurring to patients on clinical trials that are not monitored by any other 
institution or agency, are reported via email: NYUPCCsafetyreports@nyumc.org and reviewed within 48 hours 
by the medical monitor. Based on the review, one of three determinations will be made: 
 
• 
SAE report is considered to be adequate 
• 
Queries for clarification to PI regarding treatment attribution and/or resolution of SAE or 
completeness of other information. The committee may request a cumulative review of all SAEs 
on the study to date. 
• 
Request for full DSMC committee review of protocol at the next scheduled meeting. 
 
The DSMC Coordinator will record the committee’s decision and incorporate it into the study summary for the 
next scheduled study review. 
 
 
 
10.8 
Required Routine Reporting  
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to be evaluated at 
baseline per the CTCAE v5.0 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 


 
 
 
AZD1775 in AML and MDS 
 
59 
Investigations 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
AST Increased 
X 
X 
ALT Increased 
X 
X 
 
 
10.81 Submit via appropriate NYU Case report forms (i.e., paper or electronic, as applicable) all AEs 
regardless of attribution to study treatment.   
 
10.811  Grade 5 AEs (Deaths) 
 
10.8131  
Any death within 30 days of the patient’s last study treatment or procedure 
regardless of attribution to the study treatment or procedure. 
 
10.8132 
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. 
 
 
 
 
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, when given 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) 
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 


 
 
 
AZD1775 in AML and MDS 
 
60 
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   
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:  


 
 
 
AZD1775 in AML and MDS 
 
61 
     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  
*    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.  
 


 
 
 
AZD1775 in AML and MDS 
 
62 
11.3  Response Criteria for MF 
 
Response 
categories 
Required criteria 
 
(for all response categories, benefit must last for ≥12 weeks in order to qualify as a 
response) 
Complete 
Remission 
(CR) 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤Grade 1 myelofibrosis**, 
AND 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; Neutrophil count ≥1 x 109/L and 
<UNL; 
Platelet count ≥100 x 109/L and <UNL; <2% immature myeloid cells***, AND 
Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence 
of EMH 
Partial 
Remission 
(PR) 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; Neutrophil count ≥1 x 109/L and 
<UNL; 
Platelet count ≥100 x 109/L and <UNL; <2% immature myeloid cells***, AND 
Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence 
of EMH 
OR 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤Grade 1 myelofibrosis**, 
AND 
Peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; Neutrophil count ≥1 x 
109/L and <UNL; 
Platelet count ≥50 but <100 x 109/L and <UNL; <2% immature myeloid cells***, AND 
Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence 
of EMH 
Clinical 
improvement 
(CI) 
The achievement of anemia, spleen or symptoms response without progressive disease 
or increase in severity of anemia, thrombocytopenia or neutropenia‡ 
Anemia 
response 
Transfusion-independent patients: a ≥20 g/L increase in hemoglobin level† 
Transfusion-dependent patients: becoming transfusion-independent†† 
Spleen 
response§ 
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not 
palpable§§, OR 
A baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by 
≥50%§§ 
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is not eligible for 
spleen response 
Confirmation by MRI or CT showing ≥35% spleen volume reduction is recommended 
(but not required)  
Progressive 
disease¥ 
Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM, OR 
A ≥100% increase in palpable distance, below LCM, for baseline splenomegaly of 5 to 
10 cm, OR 
A 50% increase in palpable distance, below LCM, for baseline splenomegaly of >10 cm, 
OR 
Leukemic transformation confirmed by a bone marrow blast count of ≥20%, OR 
A peripheral blood blast content of ≥20% associated with an absolute blast count of ≥1 x 
10(9)/L that 
lasts for at least two weeks 
Stable 
Belonging to none of the above listed response categories 


 
 
 
AZD1775 in AML and MDS 
 
63 
disease 
Relapse 
No longer meeting criteria for at least CI after achieving CR, PR or CI, OR 
Loss of anemia response persisting for at least one month, OR 
Loss of spleen response persisting for at least one month 
 
Key: UNL, upper normal limit; LCM, left costal margin; MRI, magnetic resonance imaging; CT, computed tomography; 
EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or imaging study-proven 
non-hepatosplenic EMH) ; 
 
*Baseline and post-treatment bone marrow slides are to be stained at the same time and interpreted at one sitting by a 
central review process. Cytogenetic and molecular responses are not required for CR assignment. 
 
**Grading of myelofibrosis is according to the European classification (Thiele et al. Haematologica 
2005;90:1128) . It is underscored that the consensus definition of “a complete remission bone marrow” is to be used only 
in those patients where all other criteria, including resolution of leukoerythroblastosis, are met. It should also be noted that 
it was a particularly difficult task for the working group to reach a consensus regarding what represents a complete 
histological remission. 
 
***Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood cells. 
In splenectomized patients, <5% immature myeloid cells is allowed. 
 
‡See table for definitions of anemia response, spleen response and progressive disease. Increase in severity of anemia 
constitutes the occurrence of new transfusion dependency or a ≥20 g/L decrease in hemoglobin level from pre-treatment 
baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade 
decline, from pre-treatment baseline, in platelet count or absolute neutrophil count, according to Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. In addition, assignment to clinical improvement (CI) requires a 
minimum platelet count of ≥25,000 x 10(9)/L and absolute neutrophil count of ≥0.5 x 10(9)/L 
 
†Applicable only to patients with baseline hemoglobin of <100 g/L. In patients not meeting the strict criteria for 
transfusion-dependency at the time of study enrollment (see below), but have received transfusions within the previous 
month, the pre-transfusion hemoglobin level should be used as the baseline 
 
††Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red blood cells 
(PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of <85 g/L, in the absence of bleeding or 
treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in the 28 days prior to 
study enrollment. Response in transfusion dependent patients requires absence of any PRBC transfusions during any 
consecutive “rolling” 12-week interval during the treatment phase, capped by a hemoglobin level of ≥85 g/L. 
 
§In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy 
 
§§Confirmation of spleen or liver responses by imaging studies is recommended (but not required), where a ≥35% 
reduction in spleen volume, asassessed by magnetic resonance imaging (MRI) or computed tomography (CT), is required. 
Furthermore, a≥35% volume reduction in the spleen or liver, by MRI or CT, constitutes a response regardless of what is 
reported with physical examination. 
 
¶Symptoms are evaluated by the Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-
SAF TSS).17 The MPN-SAF TSS is assessed by the patients themselves and includes fatigue, concentration, early satiety, 
inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as 


 
 
 
AZD1775 in AML and MDS 
 
64 
good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all 
the individual scores (0-to-100 scale). Symptoms response requires ≥50% reduction in the MPN-SAF TSS. 
 
Confirmation by MRI or CT is recommended (but not required) to confirm progressive disease assignment for 
splenomegaly, where a ≥25% increase in spleen volume from baseline is required for confirmation. Baseline values for 
both physical examination and imaging studies refer to pre-treatment baseline and not to post-treatment measurements. 
 
 
 
11.4. 
Symptom Assessment Package for MF 
 
 
Given there is no currently validated instrument of patient-reported outcomes (PRO) for serial administration in 
patients with ET or PV to be used in a clinical trial setting we have adopted a standard validation approach used for new 
PRO instruments. The new PRO instrument to be tested (MPN-SAF) and a well validated questionnaire for assessing 
health related quality of life will be given to patients at baseline and prior to treatment on cycles 3, 6, and 9, and at study 
discontinuation. The symptom assessment package of instruments will be completed by enrolled patients on-site at the 
time of their study visits. 
 
 
 
MPN-SAF: The MPN-SAF (Appendix IV) was created to address the constellation of symptoms most frequent in 
MPN patients based on the results of our internet based survey of 1179 MPN patients ((PV (N=405); ET (N=304); MF 
(N=456))(2). Our survey demonstrated that the vast majority of the MPN patients have very significant fatigue compared 
to age matched published data. Given the central importance of this symptom, and need for accurate measurement on a 
trial, the previously validated Brief Fatigue Inventory (BFI) is included as item 1-9 (3), and a composite score is generated 
for the BFI (the score is the mean result of all 9 items). Items 10-13 address spleen related symptoms (early satiety, 
abdominal pain), inactivity, and cough. Items 14-18 address the central MPN symptoms of night sweats, pruritus, bone 
pain, fever, and weight loss. Although some of these symptoms are more frequent in PMF, they are still present in 
significant numbers of ET and PV patients and are of relevance in this trial given the high risk patients included on study 
will also include those who already have mild features of post ET/PV MF respectively. Item 19 includes a single item 
overall quality of life measure. Items 10-16 and 19 are measured on a linear analog scale assessments (LASA). The LASA 
methodology has proven very valid in the past (4). Additionally, the lack of a composite score overall for the MPN-SAF is 
a positive attribute for this instrument for serial assessment in a clinical trial for MPN patients as individual symptoms 
may respond (or worsen) independently with therapy. 
 
 
 
The MPN-SAF has previously been validated for use at a single time point(5) by co-administration with 
previously validated instruments. Measurement of individual symptoms which existed on other validated instruments was 
highly correlated with single item results on the MPN-SAF. Additionally, patient anonymous feedback demonstrated the 
MPN-SAF was easy to understand. Additionally patients were questioned to respond to any major symptoms which were 
not included in the MPN-SAF, and no symptom was mentioned by more than one patient demonstrating the relatively 
comprehensive nature of the instrument for MPN patients. 
 
 
 
EORTC-QLQ C30 (Appendix V): The EORTC-QLQ-C30 version 3.0 (6) is included as our main instrument for co-
validation on these trials, and redundant capture of information for impact of protocol therapy on patient’s symptoms, 
mood, and quality of life. The initial EORTC QLQ-C36 questionnaire, later shortened and validated with 30 questions, 
has the following advantages namely being a) cancer specific b) multidimensional in structure c) appropriate for self-
administration d) applicable across a range of cultural settings. This instrument has been thoroughly validated for serial 
use in cancer clinical trial setting. This instrument although highly valid for a portion of the symptom changes we wish to 
capture with this trial, never-the-less is not as comprehensive for MPN. 
 
 
 


 
 
 
AZD1775 in AML and MDS 
 
65 
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  
 
12.8 
MF: with or without HU 
 
 
 
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.  This phase consist of 
obtaining follow up/survival data  for up to 5 years by phone and medical record review of subjects. 
 
 
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 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. 
 


 
 
 
AZD1775 in AML and MDS 
 
66 
13.7 
A patient is deemed ascreen failure  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. 
 


 
 
AZD1775 in AML and MDS 
 
 
67 
 
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 (+/- 
2 Day) & 
Day 5 of 
Subsequent 
Odd Cycles 
 
At time of 
bone 
marrow 
after 
cycles 1 
(AML 
only), 2 
and 43 
(+/- 3 
days) 
 
 
EOS 
Process 
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 
 
 
X 
 
 
X 
Yes 
Cold Pack 
Biomarkers 
Mandatory 
Bone 
marrow 
aspirate 
(if no 
marrow 
obtained 
whole blood 
becomes 
mandatory) 
Heparinized 
Green top 
4 mL 
(2) 
X4 
 
 
 
 
 
X 
 
 
X2 
Yes 
Cold Pack 
Saliva Sample 
Mandatory 
Saliva 
n/a 
n/a 
X 
 
 
 
 
 
No 
ambient 
Pharmacokinetics 
Mandatory 
Plasma 
Lavender 
Top 
2 ml 
 
 
Pre-
Dose, 1, 
2, 4, 6, 
& 8 hrs 
post-
dose5 
Pre-Dose 
 
 
Yes 
-20oC 
1.  
Only to be done in those patients with circulating tumor cells in their blood 
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. 


 
 
 
AZD1775 in AML and MDS 
 
68 
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, an at relapse/ 
progression. Note: there is a +/- 3 day window for marrow biopsies.  
4. 
This is only mandatory IF a BM biopsy has not been done within 4 weeks of study start for MDS and AML and 8 weeks for MF patients. 
5. 
Post-dose pks have a 10% window as follows:  1hr post-dose + 6min; 2hr post-dose + 12 min; 4hrs post-dose + 24 min; 6hrs post-dose + 36 min; 8 hrs 
post-dose + 48 min.  
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.  
 
 


 
 
AZD1775 in AML and MDS 
 
 
69 
 
14.2  
Collection and Processing  
 
14.21 Biomarkers: Process on site. Send all samples in original tubes to Center for 
Biospecimen Research & Development 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 (Covance 
Central Laboratory Services). 
 


AZD1775 in AML and MDS 
 
70 
Once the courier has collected the samples, the sample receiver at 
Covance should be notified via email of the courier name, airway 
bill number, expected delivery date/time and shipment contact. An 
electronic sample inventory (Excel format, Request file) should 
also be attached to this email. 
 
14.322 Transport specimens immediatelyto: 
 
For Biomarkers: 
 
Center for Biospecimen Research & Development 
Medical Science Building  
550 First Avenue, Berg 3rd Fl., 
Rm. 381 New York, NY 10016  
cbrd@nyumc.org 
Tel: 646-501-4268  
 
For Phamacokinetics:  Ship specimens via Priority Overnight service, 
Monday – Wednesday ONLY, to: 
 
Covance Central Laboratory Services 
Special Handling 
Attn:  Phyllis Sellars 
8211 SciCor Drive 
Indianapolis, Indiana 46214 
Phone:  317-271-1200 
Do not send samples the day before, the day of, or the observed day 
of a national holiday.  
 
All specimens must be shipped Monday – Wednesday ONLY. 
 
14.4 
Suggested Correlative Studies and Experiments: 
 
The correlative studies are designed based on the pre-clinical data in AML, MDS 
and other tumor types and the general mechanisms of WEE1 and AraC in 
pathophysiology of cancer and the diseases under study. These studies are 
suggestions at the time of protocol development. Specific assays may change 
based on the current knowledge at time of biomarkers analysis.  
 
Patients will be asked in the informed consent to provide a research bone marrow 
aspirate and blood samples as outlined in the schedule of events. Research bone 
marrow and aspirates will be collected as outlined in Table 14.1 in conjunction 
with a patient’s standard of care bone marrow biopsy or aspirate procedures. 
Peripheral blood research samples will be drawn at times of routine clinical 
draws, in parallel with the marrow biopsies as defined in Table 14.1.  
 
 
Objectives and overview of correlative studies: 


AZD1775 in AML and MDS 
 
71 
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- and other hematopoetic/ leukemic stem 
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. Asaliva sample will be used as germline control.  
 
6. It is hypothesized that AZD1775 activity is independent of mutated/functional 
p53, SETD2, ASXL-1 and RAS mutations status. Therefore all samples will be 
assayed by the NYU NGS for a 580 gene panel including pertinent mutations in  
hematological tumors. 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 


AZD1775 in AML and MDS 
 
72 
specimens at baseline and follow up samples will be assessed, as well as p21 and 
HR pathway genes. 
 
 
 
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 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: 300 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 


AZD1775 in AML and MDS 
 
73 
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 
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  40% 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 
or change in medications  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). 


AZD1775 in AML and MDS 
 
74 
• 
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 
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. Thus patients taking these medication should be carefully 
monitored for their glycemic control. Patients on metformin should be closely watched for 
elevated metformin levels that could put them at risk for hypoglycemia. 
• 
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 


AZD1775 in AML and MDS 
 
75 
 
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 
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 


AZD1775 in AML and MDS 
 
76 
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, 
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  in the patient cohorts of the respective study criteria. (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/ AML patients 
(Arm B: AZD1775 days 1-5 & 8-12) and AraC days 1-5 & 8-12; Arm C: AZD1775 days 
1-5, 8-12).  In addition on Arm C single agent AZD1775, a cohort of n=7 MF patients 
will be treated to obtain pilot efficacy data. These MF patients will not be formally 
included in the statistical calculations for Arm C. 
 
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. 


AZD1775 in AML and MDS 
 
77 
 
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.   
 
 
 
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 


AZD1775 in AML and MDS 
 
78 
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 
 
 
 
 
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 
and AML 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 


AZD1775 in AML and MDS 
 
79 
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. 
 
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 + 7 MF patients. 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 
AML patients in Arm A and 14 AML or MDS 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 + 7 MF pateints or as low as 67 + 7 MF 
patients (Arm A: 23; Arm B: 22; Arm C: 22 + 7 MF patients). 
 
The anticipated accrual rate is 2-4 evaluable patients per month.  Therefore, the accrual 
period is expected to be approximately 1.5-2.5 years.  The primary endpoint will be 
evaluated approximately 2 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 3.5 years.   
  
 
 
 
16.4 
Secondary Endpoints 
 


AZD1775 in AML and MDS 
 
80 
 
 
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. 
 
 
 
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 and MF 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 


AZD1775 in AML and MDS 
 
81 
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, cycles 3, 6, 9, and EOS.. 
MPN-SAF TSS was created to address the constellation of 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  
 


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82 
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 
Ongoing Safety Analysis  
 
Ongoing safety monitoring will occur continuously; patient-level unacceptable toxicity 
will be defined as per DLT criteria (Section 7.4) and we will require a toxicity rate of of 
no more than 20%. Monitoring for toxicity will follow a Bayesian-based rule for the 
probability that the unacceptable toxicity rate exceeds a maximal tolerated level of 20%.  
We will use a flat Beta(1,1) prior.  Early termination for toxicity will be based on a 
posterior probability above 80% (in parentheses) that the toxicity rate exceeds 20%. 
Termination will be considered if DLT occurs in: 2 of 6 patients (0.85), 3 of 9 patients 
(0.88), 4 of 12 patients (0.90),  5 of 15 patients (0.92), 6 of 18 patients (0.93), or 6 of 21 
patients (0.87).   
 
 
16.9 
Inclusion of Women and Minorities 
 
16.91 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.92 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. 
 
 
17.0 
Source Documents and Access to Source Data 
 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Source documentation refers to original records of observations, clinical findings, and 
evaluations that are subsequently recorded as data.  All entries should be printed legibly in black ink.  If 
any entry error has been made, to correct such an error, draw a single straight line through the incorrect 
entry and enter the correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE 
OR WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the clarification 
above the item, then initial and date it. 
 


AZD1775 in AML and MDS 
 
83 
TrialMaster, an electronic database capture system will be created to record the data for this 
trial. Research coordinators will input clinical trial data into the database. This database is password 
protected and only the PI, assigned study team members, and CTO staff will have access to 
the database. DataCore, a core resource of the institution, will provide the primary data collection 
instrument for the study. All data requested in the system must be reported. All missing data 
must be explained. The quality assurance specialists will monitor this trial every 4-6 weeks for data 
entry accuracy. 
 
 
Source documentation should be consistent with data entered into any electronic medical record or the 
electronic data capture system.  Relevant source documentation to be reviewed by the DSMC throughout 
the study includes: 
 
1.  Baseline measures to assess pre-protocol disease status 
2.  Treatment records 
3.  Adverse events 
 
Access to study records will be limited to IRB-approved members of the study team. The investigator will 
permit study-related monitoring, audits, and inspections by the CTO, IRB/EC, the sponsor, government 
regulatory bodies, and University compliance and quality assurance groups of all study related documents 
(e.g. source documents, regulatory documents, data collection instruments, study data etc.).  The 
investigator will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 
18.0  Ethics/Protection of Human Subjects 
18.1  Ethical Standard 
 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
 
 
18.2  Institutional Review Board 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented participants 
need to be re-consented. 
 


AZD1775 in AML and MDS 
 
84 
18.3  Informed Consent Process 
18.31  Consent/Assent and Other Informational Documents Provided to Participants 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the participant 
and written documentation of informed consent is required prior to starting intervention/administering 
study product.  
 
18.32  Consent Procedures and Documentation 
The consenting process and documentation will follow Standard Operating Procedures (Obtaining 
Informed Consent for Clinical Trials) of the NYU Langone Health PCC CTO. 
 
 
 
18.33 Informed Consent 
A participating investigator who has completed requisite training for human subject research and has been 
instructed by the Principal Investigator about the potential participant; also must address any 
questions/concerns prior to obtaining written informed consent for participation and HIPAA authorization 
can also obtain consent. 
 
Patients will be given adequate time to read the consent form.  They will be given time to ask questions 
about the study in private exam rooms.  Questions will be answered by a participating physician, or 
qualified research study team member all of whom have completed requisite training for human subject 
research.  Investigators will review the informed consent form with patients and address any questions or 
concerns prior to obtaining written informed consent for participation.  Investigators will stress that 
participation in the study is completely voluntary and will not affect the care patients receive or result in 
any loss of benefits to which patients are otherwise entitled. 
 
The Investigator will explain to each potential participant the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved, potential 
compensation and or costs incurred by the patient and any discomfort this trial may entail.  This informed 
consent should be given by means of standard written statement, written in non-technical language.  All 
patients will be required to sign a written informed consent prior to being registered on this study. No 
patient can enter the study before his/her informed consent has been obtained. Every effort will be made 
to answer questions raised by patients and their families or advocates regarding the protocol and 
alternative therapies prior to asking a patient to sign the consent form. 
 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB approval. 
 
If applicable 
For non-English speaking patients, institutional translation services will be utilized.  All procedures for 
consenting non-English speaking patients will be in accordance with NYU Langone Health PCC CTO 
guidelines and policies.   
 
For patients who cannot read. A witness, not related to the research study will be present. The consent 
will be read to the patient. The patient will also be allowed to ask any questions s/he may have. The 


AZD1775 in AML and MDS 
 
85 
investigator will ask the patient questions to ensure s/he understands the study. If the investigator 
determines the subject understands the study, the patient will mark an X where his/her name would go 
and the witness will sign the consent form.  
18.34 Documentation of Consent 
The Principal Investigator or IRB approved sub-investigator will be responsible for documentation in the 
medical record that consent has been obtained from all participants. A signed copy of the consent form 
will be given to each participant. Original consent forms will be stored in the subject’s medical chart. 
 
18.4 Participant and Data Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at NYU Langone Medical Center. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management systems 


AZD1775 in AML and MDS 
 
86 
used by clinical sites and by NYU Langone Medical Center research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived at the NYU 
Langone Medical Center. 
 
18.41 Research Use of Stored Human Samples, Specimens, or Data 
 
• Intended Use: Samples and data collected under this protocol may be used to  evaluate the clinical 
efficacy of AZD1775  in combination with AraC in patients with newly diagnosed AML, 
relapsed/refractory AML, and hypomethylating agent failure MDS by perfroming state of the art 
molecular biomarker analysis .  No hereditary genetic testing will be performed. 
• Storage: Access to stored samples will be limited to the study team. Samples and data will be 
stored using codes assigned by the investigators. Data will be kept in password-protected 
computers. Only investigators will have access to the samples and data. 
• Tracking: Data will be tracked using Trialmaster. 
o Disposition at the completion of the study: All stored samples will be sent to CBRD. 
Study participants who request destruction of samples will be notified of compliance with 
such request and all supporting details will be maintained for tracking. 
 
 Future Use of Stored Specimens 
 
Data collected for this study will be analyzed and stored at the NYU Langone Health.  After the study is 
completed, the de-identified, archived data will be transmitted to and stored via an electronic database 
system, under the supervision of Dr. Raoul Tibes, with the potential for use by other researchers including 
those outside of the study. Permission of storage of samples, specimens, and data are required to 
participate in this study and will be included in the informed consent. 
 
With the participant’s approval and as approved by local IRs, de-identified biological samples will be 
stored at the NYU Center for Biospecimen Research & Development. These samples could be used for 
research into the most appropriate treatment combinations for individuals with MPM and Hodgkin 
Lymphoma.  The stored specimen and data will be coded and de-identified; the linking key will be 
maintained by the Principal Investigator.  The CBRD will also be provided with a code-link that will 
allow linking the biological specimens with the phenotypic data from each participant, maintaining the 
masking of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to biosample 
storage will not be possible after the study is completed. 
 
When the study is completed, access to study data and/or samples will be provided through the 
supervision of the principal investigator, Dr. Raoul Tibes, these sample will be stored indefinitely. 
 
 
 
        19.0 
 Data Handling and Record Keeping   
 
19.1 Data Collection and Management Responsibilities  
 
 


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87 
NYU’s Datacore will be responsible for the development of a relevant database and data transfer 
mechanisms, along with appropriate validation of data and resolution of queries. Data generated within 
this clinical study will be handled according to the relevant standard operating procedures of the Clinical 
Trials Office at NYU. 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data. Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, 
cross out the original entry with a single line, and initial and date the change. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained and 
captured in a progress note and maintained in the participant’s official electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into Trialmaster, a 21 CFR Part 11-compliant data capture system 
provided by Omnicom. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data 
will be entered directly from the source documents. 
 
 
20.0 
Quality Assurance and Quality Control 
 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site. 
This safety monitoring will include careful assessment and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan detailed below. Serious adverse events are evaluated regularly by the principal 
investigator in conjugation with the research team, the DSMC is notified of serious adverse events 
via email initially, reviewed offline by the designated medical monitor, and presented at the next 
DSMC monthly meeting. The Data Safety and Monitoring Committee (DSMC) will review the 
study at least quarterly. Medical monitoring will include a regular assessment of the number and 
type of serious adverse events. 
 
Data and Safety Monitoring Committee 
This investigator-initiated study will be monitored by the Data Safety Monitoring Committee 
(DSMC) of the New York University (NYU) Perlmutter Cancer Center (PCC). The DSMC 
operates based on the National Cancer Institute approved Charter. It is an existing and 
multidisciplinary committee (consisting of clinical investigators/oncologists, biostatisticians, 
nurses, and research administration staff knowledgeable of research methodology and design 
and in proper conduct of clinical trials) that is responsible for monitoring safety, conduct and 


AZD1775 in AML and MDS 
 
88 
compliance in accordance with protocol data monitoring plans for interventional clinical trials 
conducted in the NYU Langone Health Perlmutter Cancer Center that are not monitored by another 
institution or agency. The DSMC reports to the Director of the NYU Langone Health  PCC. 
 
Per the NYU PCC Institutional Data Safety and Monitoring Plan, this phase II trial will be 
monitored by DSMC quarterly (from the date the first patient is enrolled), at protocol-specified 
interim time points, and at the completion of the study prior to study closure. This review 
includes accrual data, subject demographics and adverse events. Principal Investigators are 
required to attend the review of their studies. Additional reviews can be scheduled based on 
SAE reports, investigator identified issues, external information, etc. The DSMC will review 
safety data every 3 months. 
 
20.1 Study Monitoring Plan 
Overall study monitoring will be conducted through a combination of on-site visit (NYU Langone 
Health), and remote monitoring (Subsite locations). A risk-based, data-driven monitoring approach will 
be used to verify data for this trial which will also include a centralized review of data for quality, 
trends, consistency and general safety review. A quality assurance specialist, will conduct regularly 
scheduled reviews of the trial, and study data.  At each visit, the monitor will review various aspects of 
the trial including, but not limited to:  screening and enrollment logs; compliance with the protocol and 
study manual and with the principles of Good Clinical Practice; completion of case report forms; 
source data verification; study drug accountability and storage; facilities and staff. 
 
During scheduled monitoring visits, the investigator and the investigational site staff must be available 
to meet with the quality assurance specialist in order to discuss the progress of the trial, make 
necessary corrections to case report form entries, respond to data clarification requests and respond to 
any other trial-related inquiries of the monitor. In addition to on-site monitoring visits, the Sponsor 
and/or representatives will also be routinely reviewing data. Any queries identified through this review 
will be managed within the systems established for query resolution and tracking. Inquiries related to 
study conduct, which require further information or action will be discussed within the study team for 
appropriate and documented escalation plans. It is expected that response to data clarification requests 
and other trial-related inquiries will occur throughout the course of the study through regular 
communication with the site monitor, the Sponsor or representatives, and review/entry of data into the 
electronic study database. 
 
At any time during the course of the study, representatives of the FDA and/or local regulatory agencies 
may review the conduct or results of the study at the investigational site. The investigator must 
promptly inform  AstraZeneca of any audit requests by health authorities, and will provide 
AstraZeneca with the results of any such audits and with copies of any regulatory documents related to 
such audits. 
 
In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use personal 
identifiable health information may be required from each patient before commencement of research 


AZD1775 in AML and MDS 
 
89 
activities. This authorization document must clearly specify what parties will have access to a patient’s 
personal health information, for what purpose and for what duration. 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and 
has adequate space to conduct the monitoring visit. 
 
At the NYU Langone Health  Perlmutter Cancer Center, all investigator-initiated protocols are subject to 
a standardized data and safety monitoring, which includes scientific peer review, IRB review and DSMC 
review as well as internal auditing.  
 
The review of AEs and trial conduct for this trial occurs at several levels: 
 
(1) Principal Investigator: Adverse events are evaluated monthly by the principal investigator in 
conjunction with the research nurses, data manager and research team.  
 
 
 
(2) DSMC, quarterly 
 
(3) Institutional Review Board (IRB): An annual report to the IRB is submitted by the trial PI for 
continuation of the protocol. It includes a summary of all AEs, total enrollment with demographics, 
protocol violations, and current status of subjects as well as available research data. 
 
(4) In addition, the quality assurance unit the quality assurance unit will monitor this trial every 4-6 
weeks, this includes real- time review of all eCRFs to ensure completeness and to verify 
adherence to the protocol; the completeness, accuracy and consistency of the data; and adherence 
to ICH Good Clinical Practice guidelines. Additionally, a first subject audit is to be conducted 
within four weeks of enrollment. 
 
Subsite monitoring 
Monitoring visits are done remotely unless otherwise specified, via remote EMR access. If not 
possible, secure email exchange will be utilized. The quality assurance specialist will confirm an 
upcoming monitoring visit with a Subsite Investigator and staff. If remote EMR access is not 
available, then the Subsite Coordinator will ensure that all source documents for subjects are de-
identified and labeled only with the subject ID number(s), and emails all requested documents to 
the quality assurance specialist by the specified visit date. All documents are reviewed and a 
monitoring report is submitted within 5  business days from the date of the visit. Any outstanding 
documents will be listed in the report as a high- priority request for the next monitoring visit. It is 
expected that response to data clarification requests and other trial-related inquiries will occur 
throughout the course of the study through regular communication with the site monitor, the 
Sponsor or representatives, and review/entry of data into the electronic study database. Continued 
non-compliance and failure to submit documentation will result in the suspension of subject 
enrollment at the site, until the documents have been received. 
 
 


AZD1775 in AML and MDS 
 
90 
20.2  Study Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents should be retained for a longer 
period if required by an agreement with the sponsor.  In such an instance, it is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be retained.  
 
20.3  Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
All protocol deviations must be addressed in study source documents, and reported to the Quality 
Assurance Unit and the DSMC. 
 
Protocol deviations must be reported to the local IRB per guidelines. The site PI/study staff is responsible 
for knowing and adhering to IRB requirements.  
 
 
 
21.0  Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional Review Board 
(IRB) or independent Ethics Committee (EC) in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the IRB/EC concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of IRB/EC members and their 
affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.    This 
consent form will be submitted with the protocol for review and approval by the IRB/EC for the study.  
The formal consent of a subject, using the IRB/EC-approved consent form, must be obtained before that 
subject undergoes any study procedure.  The consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining the consent.  
 
22.0  Budget Considerations 


AZD1775 in AML and MDS 
 
91 
 
 
22.1 
Costs charged to subjects: all standard of care tests and procedures such as physical 
exams, blood CBC and chemistries, bone marrow biopsies, AraC drug and administration 
costs, etc 
 
 
 
 
22.2 
Tests to be research funded:  research blood and bone marrow collection and processing, AZD1775 
drug dispensing 
 
 
22.3 
Other budget concerns: Drug and PK analysis will be supported by AstraZeneca. 
 
 
22.4  No subjects will receive payments or stipends for participation in this research study. 
 
23.0 
References 
 
Abe Y. et al, Hedgehog signaling overrides p53-mediated tumor suppression by activating  
 
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AZD1775 in AML and MDS 
 
99 
 
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.  
 
 
 


AZD1775 in AML and MDS 
 
100 
Appendix II: MEDICATION DIARY 
Name _________________ 
 
NYU 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 
 
 
 
 
 
 
 


AZD1775 in AML and MDS 
 
101 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


AZD1775 in AML and MDS 
 
102 
 
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 
 


 
 
AZD1775 in AML and MDS 
 
 
103 
Appendix V: 
 
 
Version 2.2014, 03/28/2014. National Comprehensive Cancer Network, Inc. 2014. 


 
 
AZD1775 in AML and MDS 
 
 
104 
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 40% 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.  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. 


AZD1775 in AML and MDS 
 
105 
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.    
 
 


AZD1775 in AML and MDS 
 
106 
 
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 may be given. For 
dose modification see section 9.5.   
 
 
 
CYP3A4 Inducers (Strong and Moderate) 
Avasimibe 
Bosentan 
Carbamazepine 
Efavirenz 
Enzalutamide 
Nafcillin 
Phenobarbital 
Phenytoin 
Rifabutin 
Rifampin 


AZD1775 in AML and MDS 
 
107 
Etravirine 
Genistein 
Lersivirine 
Lopinavir 
Mitotane 
Modafinil 
 
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 
Dasatinib 
Dihydroergotamine 
Disopyramide 
Dronedarone 
Docetaxol 
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 
Nisoldipine 
Paclitaxel 
Pazopanib 
Perospirone 
Pimozide 
 


AZD1775 in AML and MDS 
 
108 
Dofetilide 
Doxorubicin 
Ebastine 
Eletriptan 
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 
 
 
 
 


AZD1775 in AML and MDS 
 
109 
 
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 
 
 


AZD1775 in AML and MDS 
 
110 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


AZD1775 in AML and MDS 
 
111 
 
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 
 
 
 


AZD1775 in AML and MDS 
 
112 
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 
 
 
 
 
 
 
 
 


AZD1775 in AML and MDS 
 
113 
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. 
 
 
 
 
 


AZD1775 in AML and MDS 
 
114 
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 choice of the subject, tubal ligation, vasectomised 
partner, and methods listed belowError! Reference source not found..  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.