Conditions: Metastatic Pancreatic Adenocarcinoma Stage III Pancreatic Cancer AJCC v6 and v7 Stage IV Pancreatic Cancer AJCC v6 and v7 Unresectable Pancreatic Carcinoma
Keywords: Metastatic Pancreatic Adenocarcinoma Nab-paclitaxel Gemcitabine AZD1775
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 8
Healthy volunteers: no

Brief summary:
This partially randomized phase I/II trial studies the side effects and best dose of WEE1 inhibitor AZD1775 when given together with paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride and how well they work in treating patients with previously untreated pancreatic cancer that has spread to another place in the body or cannot be removed by surgery. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. WEE1 inhibitor AZD1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride are more effective with or without WEE1 inhibitor AZD1775 in treating patients with pancreatic cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the toxicity of combination therapy with nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation), gemcitabine (gemcitabine hydrochloride) and AZD1775 (WEE1 inhibitor MK-1775) in patients with treatment-naive metastatic adenocarcinoma of the pancreas or locally-advanced adenocarcinoma of the pancreas which is not surgically resectable. (Phase I) II. To determine the dose of AZD1775 to be used in combination with nab-paclitaxel and gemcitabine chemotherapy in the phase II portion of the trial. (Phase I) III. To determine the pharmacokinetics of AZD1775 in combination with nab-paclitaxel and gemcitabine. (Phase I) IV. To evaluate progression-free survival (PFS) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate overall survival (OS) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II) II. To evaluate response rate (complete response \[CR\] + partial response \[PR\]) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II) III. To evaluate disease control rate (CR + PR + stable disease \[SD\]) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II)

TERTIARY OBJECTIVES:

I. To evaluate the ability of AZD1775 to inhibit Wee1 and increase deoxyribonucleic acid (DNA) damage and tumor cell death when combined with nab-paclitaxel/gemcitabine compared to nab-paclitaxel/gemcitabine/placebo. (Phase II) II. To evaluate if biomarker changes in tumor tissue associated with Wee1 inhibition may also be present in hair follicles. (Phase II) III. To evaluate the change in tumor fludeoxyglucose (FDG) uptake (maximum standardized uptake value \[SUVmax\]) between baseline FDG-positron emission tomography (PET) and week 4 FDG-PET as a predictor of response using Response Evaluation Criteria in Solid Tumors (RECIST) as the reference standard for response. (Phase II) IV. To evaluate the change in tumor FDG uptake (SUVmax) between baseline FDG-PET and week 4 FDG-PET as a predictor of progression-free survival. (Phase II) V. To compare the change in tumor FDG uptake (SUVmax) between baseline FDG-PET and week 4 FDG-PET between the patients from treatment arms C and D. (Phase II) VI. To evaluate if an early increase in tumor fluorothymidine (FLT) uptake (FLT-flare) is observed within 24 hours after initiation of treatment with nab-paclitaxel/gemcitabine/placebo. (Phase II) VII. To evaluate if an early (within 24 hours \[h\]) increase in tumor FLT uptake (FLT-flare) is abrogated after initiation of treatment with nab-paclitaxel/gemcitabine/AZD1775. (Phase II) VIII. To compare the change in tumor FLT uptake (SUVmax) from baseline to 24 hours after initiation of treatment between the patients from treatment arms C and D. (Phase II)

OUTLINE: This is a phase I, dose escalation study of WEE1 inhibitor AZD1775 followed by a randomized phase II study. Patients in phase I are assigned to arm A or B and patients in phase II are randomized to arm C or D.

ARM A (PHASE I, DOSE LEVEL 1): Patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 orally (PO) daily on days 1, 2, 8, 9, 15, and 16.

ARM B (PHASE I, DOSE LEVEL -2): Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.

ARMS C - G (PHASE I, DOSE LEVEL -1 to DOSE LEVEL 4): Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A at various dose levels. These arms did not enroll any patients.

ARM H (PHASE II, Control): Patients receive paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride as in Arm A. The study did not move forward to the phase II part.

ARM I (PHASE II, WEE1 INHIBITOR AZD1775): Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A. The study did not move forward to the phase II part.

In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Arms:
arm 1: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 PO daily on days 1, 2, 8, 9, 15, and 16. arm 2: Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.

Interventions: intervention 1: AZD1775 intervention 2: Gemcitabine intervention 3: Nab-paclitaxel
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Given IV

Protocol document:
Prot_SAP_000.pdf: 
i
28 State Street, Suite 1100, Boston, MA 02109
p: 857.504.2900
f:617. 589.0914
ecog-acrin.org
October 18, 2016
Martha Kruhm, MS RAC
Head, Protocol and Information Office
Quality Assurance Section
CTEP, DCT, NCI
6130 Executive Blvd, EPN Room 7000
Bethesda, MD   20892
Dear Ms. Kruhm:
Enclosed is Addendum #3 to EA2131, A Phase I and Randomized Phase II Study of Nab-
Paclitaxel/Gemcitabine with or without AZD1775 for Treatment of Metastatic Adenocarcinoma of 
the Pancreas. This amendment is in response to CTEP’s Request for Rapid Amendment on 
September 23, 2016 from Dr. Naoko Takebe.
The following revisions to EA2131 protocol have been made in this addendum:
Section
Change
1.
Cover Page
Updated Version Date
2.
Section 5.1
Replaced CAEPR with updated Version 2.4 dated August 3, 2016 
The following revisions to EA2131 Informed Consent Document have been made in this 
addendum:
Section
Change
1.
Phase I Cover Page 
Updated Version Date 
2.
Phase I Risk Section
Updated Risk List based on new CAEPR Version 2.4 dated August 3, 
2016
3.
Phase II Cover Page
Updated Version Date 
4.
Phase II Risk 
Section
Updated Risk List based on new CAEPR Version 2.4 dated August 3, 
2016
If you have any questions regarding this addendum, please contact 
spiers.madeline@jimmy.harvard.edu or 857-504-2900
We request review and approval of this addendum to EA2131 so ECOG-ACRIN may activate it
promptly.  
Thank you.
Sincerely,
Pamela Cogliano
Protocol Development Manager
Operations Office – Boston 


ii 
Enclosure 
CC: Jennifer Eads, MD 
Neal J. Meropol, MD 
Al B. Benson III, MD 
Paul Catalano, ScD 
Zheng Zhang, PhD 
Peter O’Dwyer, MD 
Terence Z. Wong, MD, PhD 
Afshin Dowlati, MD 
Norbert Avril, MD 
Jeanne Sheehan 
George Carro, R.Ph., MS, BCOP 
Ivan Reveles 
Carol Chami, RN 
Melinda Flood  
Bruce Giantonio, MD 
Robert L. Comis, MD 
Kerry Higgins 
Mary Steele 
Jean MacDonald  
Madeline Spiers 
Lauren Lambert 
Mike Blaco 
Becky Fillingham 
Brad Hughes, PharmD 
 
 
 


EA2131 
 
1 
 
A Phase I and Randomized Phase II Study of Nab-
Paclitaxel/Gemcitabine with or without AZD1775 for 
Treatment of Metastatic Adenocarcinoma of the Pancreas 
STUDY CHAIR: Jennifer Eads, MD 
STUDY CO-CHAIRS: Neal J. Meropol, MD  
 Al B. Benson III, MD 
 Cheng Chee, MD 
STUDY STATISTICIAN: Paul Catalano, ScD 
IMAGING STATISTICIAN: Zheng Zhang, PhD 
GI COMMITTEE CO-CHAIRS Peter O’Dwyer, MD 
Terence Z. Wong, MD, PhD 
LABORATORY STUDIES CO-CHAIR: Afshin Dowlati, MD 
IMAGING STUDIES CO-CHAIR Norbert Avril, MD 
Version Date:  October 18, 2016 
NCI Update Date:  June 26, 2014 
STUDY PARTICIPANTS 
ACTIVATION DATE 
Phase I – Limited Institutions: 
June 26, 2014 
OH029 / Case Western Reserve University (ECOG-ACRIN) Update #1 – Incorporated Prior to Activation 
PA086 / Fox Chase Cancer Center (ECOG-ACRIN) 
Addendum #1 – 7/14 
IL036 / Northwestern University (ECOG-ACRIN) 
Addendum #2 – 4/16 
PA075 / University of Pennsylvania (ECOG-ACRIN) 
Addendum #3 – 11/16 
TN008 / Vanderbilt Ingram Cancer Center (ECOG-ACRIN) 
 
 
 
Phase II – US Sites only 
 
FDG Imaging Studies –ACRIN Qualified Institutions  
(See Section 10) 
 
FLT Imaging Studies – Limited Institutions: 
 
Case Comprehensive Cancer Center 
 
Karmanos Cancer Institute, Wayne State 
University of Pennsylvania 
 
Agents 
NSC# 
Supply 
Gemcitabine 
NSC#613327 
Commercially Available 
Nab-Paclitaxel 
NSC#736631 
Commercially Available 
AZD1775 
NSC#751084 
NCI-Supplied 
18F-FLT 
NSC#743144 
Commercially Available 
18F-FDG 
NSC#723398 
Commercially Available 
 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
2 
Table of Contents 
Phase I Schema .......................................................................................................... 6 
Phase II Schema ......................................................................................................... 7 
1. Introduction ........................................................................................................ 8 
1.1 
Adenocarcinoma of the Pancreas ............................................................. 8 
1.2 
Systemic Therapy in Metastatic Pancreatic Ductal Adenocarcinoma ...... 8 
1.3 
The Cell Cycle, DNA Damage Checkpoints, and Wee1 Signaling .............. 8 
1.4 
AZD1775 (Wee1 inhibitor) ........................................................................ 9 
1.5 
Pre-Clinical Study of Nab-Paclitaxel/Gemcitabine/AZD1775 .................. 13 
1.6 
Rationale for Clinical Study ..................................................................... 14 
1.7 
Summary of Phase I Toxicity Review ....................................................... 16 
1.8 
Rationale for Imaging Research Studies ................................................. 17 
2. Objectives ......................................................................................................... 24 
2.1 
Phase I Objectives ................................................................................... 24 
2.2 
Phase II Objectives .................................................................................. 24 
3. Selection of Patients ......................................................................................... 26 
3.1 
Phase I Study – Arm A (Closed to Accrual), Arms B, C, D, E, F and G ...... 26 
3.2 
Randomized Phase II Study – Arms H and I ............................................ 30 
4. Registration and Randomization Procedures ................................................... 35 
4.1 
Phase I Registration Procedures (Phase I Arms) ..................................... 36 
4.2 
Phase II Randomization Procedures (Arms H and I) ............................... 39 
5. Treatment Plan ................................................................................................. 42 
5.1 
Phase I (Arms B, C, D, E, F and G) ............................................................ 42 
5.2 
Phase II (Arms H and I) ............................................................................ 50 
5.3 
Adverse Event Reporting Requirements ................................................. 51 
5.4 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
AZD1775 (NSC 751084) ........................................................................... 62 
5.5 
Comprehensive  Adverse Events & Potential Risks Lists (CAEPRs) for 3'-
deoxy-3'-[F-18]fluorothymidine (NSC 743144) ....................................... 67 
5.6 
Dose Modifications ................................................................................. 69 
5.7 
Supportive Care ....................................................................................... 85 
5.8 
Duration of Therapy – Phase I and Phase II ............................................ 87 
5.9 
Duration of Follow-up – Phase I and Phase II ......................................... 87 
6. Measurement of Effect ..................................................................................... 88 
6.1 
Antitumor Effect – Solid Tumors ............................................................. 88 
7. Study Parameters .............................................................................................. 95 
7.1 
Phase I Therapeutic Parameters ............................................................. 95 
7.2 
Phase II Therapeutic Parameters ............................................................ 98 
8. Drug Formulation and Procurement ............................................................... 101 
8.1 
Nab-Paclitaxel ....................................................................................... 101 
8.2 
Gemcitabine .......................................................................................... 106 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
3 
8.3 
AZD1775 (NSC 751084) ......................................................................... 108 
8.4 
3'-deoxy-3'-[F-18]fluorothymidine (FLT)-PET ........................................ 111 
9. Statistical Considerations ................................................................................ 116 
9.1 
Endpoints .............................................................................................. 116 
9.2 
Sample Size With Power Justification ................................................... 116 
9.3 
Analysis Plan Including Plans for Formal Interim Analysis .................... 116 
9.4 
Study Monitoring .................................................................................. 119 
9.5 
Gender and Ethnicity ............................................................................ 120 
9.6 
Statistical Analysis for Advanced Imaging Studies ................................ 120 
9.7 
Statistical analysis of laboratory biomarkers ........................................ 122 
10. Imaging Studies ............................................................................................... 124 
10.1 Research Objectives: ............................................................................. 124 
10.2 Imaging Sub-Study Site Review and Qualification ................................ 124 
10.3 ACRIN Regulatory Oversight ................................................................. 125 
10.4 Imaging Sub-Study Time Points and Procedures: FDG and FLT Cohorts126 
10.5 Imaging Submissions for Quality Control and Central Reader Study .... 130 
11. Phase I Biospecimen Submissions and Research Studies ............................... 132 
11.1 Sample submissions .............................................................................. 132 
11.2 ECOG-ACRIN Sample Tracking System .................................................. 134 
11.3 Storage for Future Research ................................................................. 135 
11.4 Sample Inventory Submission Guidelines ............................................. 135 
11.5 Lab Data Transfer Guidelines ................................................................ 135 
12. Phase II Biospecimen Submissions and Research Studies .............................. 136 
12.1 Specimen Collection and Submission ................................................... 136 
12.2 Phase II Research Studies ...................................................................... 140 
12.3 Sample Inventory Submission Guidelines ............................................. 146 
12.4 Lab Data Transfer Guidelines ................................................................ 146 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
4 
13. Electronic Data Capture .................................................................................. 147 
14. Patient Consent and Peer Judgment .............................................................. 147 
15. References ...................................................................................................... 147 
 Appendix I  Pathology Submission Guidelines...................................................... 155 
 Appendix II  Patient Thank You Letter .................................................................. 158 
 Appendix III  Patient Capsule Calendar ................................................................ 159 
 Appendix IV  CRADA/CTA ..................................................................................... 161 
 Appendix V  ECOG Performance Status ................................................................ 163 
 Appendix VI  Select CYP3A4, CYP2C8, CYP2C9, CYP2C19, P-gp Inhibitors or BCRP 
Inhibitors or Substrates With Narrow Therapeutic Range ............................. 164 
 Appendix VII  Medications That May Cause QTc Prolongation ............................ 168 
 Appendix VIII  Information On Possible Interactions With Other Agents For 
Patients And Their Caregivers And Non – Study Health Care Team ............... 171 
 Appendix IX  Information for Local Radiology Team – Quality Control for Images173 
 Appendix X  Instructions for Reporting Pregnancies on a Clinical Trial ................ 175 
 Appendix XI  Phase I AZD1775 Pharmacokinetic Collection and Shipping Kits .... 177 
 Appendix XII  Covance Specimen Shipment Pre-Alert Form ................................ 180 
 Appendix XIII  EA2131 PHASE II Collection and Shipping Kits Order Form ........... 182 
 
 
 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
5 
STUDY CHAIR 
STUDY CO-CHAIR  
Jennifer Eads, MD 
Division of Hematology and Oncology 
University Hospitals Seidman Cancer Center 
Case Comprehensive Cancer Center 
Case Western Reserve University 
11100 Euclid Avenue, Lakeside 1200 
Cleveland, OH 44106 
Phone: 216-844-6031 
Fax: 216-844-5234 
E-mail: jennifer.eads@uhhospitals.org 
Neal J. Meropol, MD 
Division of Hematology and Oncology 
University Hospitals Seidman Cancer Center 
Case Comprehensive Cancer Center 
Case Western Reserve University 
11100 Euclid Avenue, Wearn 145 
Cleveland, OH 44106 
Phone: 216-844-5220 
Fax: 216-844-5234 
E-mail: Neal.Meropol@UHhospitals.org 
 
 
STUDY CO-CHAIR  
STUDY CHAIR LIAISON (SCL) 
Al B. Benson III, MD 
Robert H. Lurie Comprehensive Cancer 
Center 
Northwestern University  
676 North St. Clair Street  
Chicago, IL 60611 
Phone: 312-695-6180 
Fax: 312-695-6189 
E-mail: a-benson@northwestern.edu 
Carol E. Smith, RN, BSN, CCRP 
Clinical Research Nurse Specialist II 
Case Comprehensive Cancer Center 
University Hospitals Seidman Cancer Center 
Southwest Feneral Health Cancer 
18697 Bagley Road 
Middleburg Heights, OH 44130 
Phone: 440-816-6067 
Fax: 440-816-6053 
Email: carol.smith@UHHospitals.org 
 
PHASE I INSTITUTION CONTACT INFORMATION 
Case Comprehensive Cancer Center 
 
 
Investigator: Jennifer Eads, MD 
Nurses/CRA: Carol E. Smith 
(216) 844-6031 
(216) 844-5176 
jennifer.eads@uhhospitals.org  
carol.smith@UHHospitals.org 
Fox Chase Cancer Center  
 
Investigator: Efrat Dotan, MD 
Nurses/CRAs: 
C. Rebecca Marlow RN, BSN, MBA, CCRP 
Alison Berry 
(215) 728-8128 
 
(215) 214-1451 
(215) 728-5623 
efrat.dotan@fccc.edu 
 
becky.marlow@fccc.edu 
alison.berry@fccc.edu 
Northwestern University 
Investigator: Al B. Benson III, MD 
Nurses/CRA: Erin Alonso 
(312) 926-3023 
(312) 695-4168 
a-benson@northwestern.edu 
erin.alonso@northwestern.edu 
University of Pennsylvania 
Investigator: Peter O’Dwyer, MD 
Nurses/CRA: Maryanne Redlinger, RN 
(215) 662-7268 
(215) 662-7452 
peter.odwyer@uphs.upenn.edu 
maryann.redlinger@uphs.upenn.edu 
Vanderbilt Ingram Cancer Center 
Investigator: Dana B. Cardin, MD 
Nurses/CRA: Shaunita A. Michael, RN, BSN 
(615) 936-6925 
(615) 343-0798- 
dana.backlund@vanderbilt.edu 
shaunita.a.michael@vanderbilt.edu 
Rev. 4/16 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
6 
Phase I Schema 
Phase I will follow a traditional 3+3 design. 
Phase I Accrual Goal = Maximum of 50 patients
IV doses are based on actual weight.
Cycle = 4 weeks (28 days)
R
E
G
I
S
T
E
R
Nab-Paclitaxel 100 mg/m2 IV days 1, 8, 
and 15 of each cycle
Gemcitabine 750 mg/m2 IV days 1, 8, 
and 15 of each cycle
AZD1775 100 mg PO days 1, 2, 8, 9, 
15 and 16 of each cycle
1.
Slot registration is required prior to beginning eligibility verification. Only after a slot has been reserved should the patient be worked up for the study. Slots will automatically EXPIRE after 10 days. If the 
patient is found to be ineligible, the site must withdraw the slot.
2.
Patients will be evaluated during each cycle for toxicity. Treatment will continue until progression or unacceptable toxicity. See Section 5.6.
3.
If no dose limiting toxicity (DLT) is encountered on the first 3-6 patients enrolled, then 3 more patients will be treated with the combination at the next higher Phase I AZD1775 dose. If there is 1 DLT among 
the first 3 patients, then 3 more patients will be enrolled at that same dose. See Section 9.3.1.
4.
If AZD1775 150 mg is the highest achievable dose – Arm D – (DLTs observed in Arm E), proceed to Arm F and continue with dose escalation of gemcitabine and Nab-Paclitaxel using the highest tolerated 
AZD1775 dose.
5.
If AZD1775 175 mg is achievable in Arm E, proceed to Arm F and continue with dose escalation of gemcitabine and Nab-Paclitaxel using AZD1775 175 mg. If unacceptable toxicity is observed with 
AZD1775 175 mg in either Arm F or Arm G, each/either of these dose levels may be reassessed (Arm F 150, Arm G 150) using AZD1775 150 mg.
S
L
O
T
R
E
S
E
R
V
A
T
I
O
N
Step 1:
1
Nab-Paclitaxel 100 mg/m2 IV days 1, 8, 
and 15 of each cycle
Gemcitabine 750 mg/m2 IV days 1, 8, 
and 15 of each cycle
AZD1775 125 mg PO days 1, 2, 8, 9, 
15 and 16 of each cycle
Long–Term Follow-Up
 Dose Level: -2 (Arm B) 2,3
 Dose Level: -1 (Arm C) 2,3
Nab-Paclitaxel 100 mg/m2 IV days 1, 8, 
and 15 of each cycle
Gemcitabine 750 mg/m2 IV days 1, 8, 
and 15 of each cycle
AZD1775 150 mg PO days 1, 2, 8, 9, 
15 and 16 of each cycle
Dose Level: 1 (Arm D) 2,3
Nab-Paclitaxel 100 mg/m2 IV days 1, 8, 
and 15 of each cycle
Gemcitabine 750 mg/m2 IV days 1, 8, 
and 15 of each cycle
AZD1775 175 mg PO days 1, 2, 8, 9, 
15 and 16 of each cycle
Dose Level: 2 (Arm E) 2
Nab-Paclitaxel 125 mg/m2 IV days 1, 8, 
and 15 of each cycle
Gemcitabine 1000 mg/m2 IV days 1, 8, 
and 15 of each cycle
AZD1775 100 mg PO days 1, 2, 8, 9, 
15 and 16 of each cycle
CLOSED TO ACCRUAL (Arm A)
Nab-Paclitaxel 125 mg/m2 IV days 1, 8, 
and 15 of each cycle
Gemcitabine 750 mg/m2 IV days 1, 8, 
and 15 of each cycle
AZD1775 see footnotes 4 and 5
Dose Level: 3 (Arm F) 2
Nab-Paclitaxel 125 mg/m2 IV days 1, 8, 
and 15 of each cycle
Gemcitabine 1000 mg/m2 IV days 1, 8, 
and 15 of each cycle
AZD1775 see footnotes 4 and 5
Dose Level: 4 (Arm G) 2
 
Rev. 4/16 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
7 
Phase II Schema 
Phase II Accrual Goal = 84 patients
Phase II Imaging Sub-Study Accrual Goals:
FDG PET/CT = 60 patients (30 in each Arm)
FLT PET/CT = 10 patients (5 in each Arm)
Cycle = 4 weeks (28 days)
IV doses are based on actual weight.
R
A
N
D
O
M
I
Z
E
Nab-Paclitaxel: 125 mg/m2 IV days 1, 8 and 
15 of each cycle
Gemcitabine: 1000 mg/m2 IV days 1, 8 and 15 
of each cycle
Imaging Sub-Studies (Limited Institutions)3
FDG PET-CT at baseline and Cycle 1 Day 25 
+/- 3 days
FLT PET/CT at baseline and Cycle 1 Day 2
1.
Nab-Paclitaxel, Gemcitabine, and AZD1775 dose for patients on Arm I of the Phase II to be determined in the Phase I portion of the study.
2.
Treatment will continue until progression or unacceptable toxicity. See Section 5.6.
3.
FDG PET/CT open to ACRIN qualified institutions. FLT PET/CT open to limited institutions. FLT PET/CT at Cycle 1 Day 2 must be performed 20-24 
hours after Cycle 1 initiation. FDG PET/CT at Cycle 1 Day 25 may be performed +/- 3 days, but must be before Cycle 2 initiation. Patients may not 
participate in both the FDG PET/CT and FLT PET/CT imaging studies. See Section 10 for more information.
Nab-Paclitaxel RP2D mg/m2 IV days 1, 8 and 
15 of each cycle
Gemcitabine RP2D mg/m2 IV days 1, 8 and 15 
of each cycle
AZD1775 RP2D mg PO days 1, 2, 8, 9, 15 
and 16 of each cycle
Imaging Sub-Studies (Limited Institutions)3
FDG PET-CT at baseline and Cycle 1 Day 25 
+/- 3 days
FLT PET/CT at baseline and Cycle 1 Day 2
Long–Term Follow-Up
Long–Term Follow-Up
Arm H  2
Arm I 1, 2
Stratify:
• PS: 0 or 1
• Intent to participate 
in Imaging Sub-
Studies: No 
imaging, FDG 
PET/CT imaging 
study or FLT PET/
CT imaging study
 
Rev. 4/16 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
8 
1. 
Introduction 
1.1 
Adenocarcinoma of the Pancreas 
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer 
mortality in the United States with approximately 45,220 new cases and 38,460 
deaths in 2013.1 PDAC is rarely curable and patients with advanced disease 
have an overall survival rate of < 1% at 5-years, with most patients dying within 1 
year. Therefore, there is a strong need for more effective systemic therapy in this 
devastating disease. 
1.2 
Systemic Therapy in Metastatic Pancreatic Ductal Adenocarcinoma  
Gemcitabine is the only approved single agent in treatment of metastatic PDAC, 
with a median survival of 5.7 months and 20% 1-year survival.2 It is a pyrimidine 
antimetabolite that inhibits DNA synthesis by inhibition of DNA polymerase and 
ribonucleotide reductase and is cell cycle-specific for the S-phase of the cycle 
(also blocks cellular progression at G1/S phase). A recent meta-analysis of 
randomized trials showed a general survival benefit for gemcitabine-based 
chemotherapies for patients with good performance status.3 Unfortunately, the 
current standard gemcitabine and gemcitabine-based regimens only have 
moderate activity.  
Recently, results of the MPACT study, a randomized phase III study of Nab-
Paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic 
PDAC, showed significant overall survival benefit with Nab-Paclitaxel and 
gemcitabine over gemcitabine alone (8.5 months vs. 6.7 months, HR 0.72, 
p=0.000015).5 The combination treatment was well-tolerated and has become a 
new standard of care option for first-line treatment of metastatic PDAC. The 
selection of Nab-Paclitaxel, a 130-nm albumin-bound formulation of paclitaxel 
particles (Abraxane, Celgene, Summit, NJ), in combination with the standard 
gemcitabine was based on a molecular profiling of PDAC tumor samples,5 in 
which secreted protein acidic and rich in cysteine (SPARC), an albumin-binding 
protein, was noted to be overexpressed.7 Nab-Paclitaxel has shown antitumor 
activity in various advanced cancer types that overexpress SPARC8-10 including 
breast,11-13 lung4,14 and melanoma.15 
1.3 
The Cell Cycle, DNA Damage Checkpoints, and Wee1 Signaling 
Treatment efficacy of DNA damaging agents is determined not only by the 
amount of therapy-induced DNA damage but also by the capacity of tumor cells 
to repair the damaged DNA.  When cells are treated with DNA damaging agents, 
multiple checkpoints in the cell cycle are activated, including G1, intra-S, and 
G2/M, leading to cell cycle arrest, thus providing time for the cell to repair the 
damage and to evade apoptosis before resuming the cell cycle. Tumor cells can 
exploit these repair mechanisms in response to DNA damaging agents, 
rendering tumors resistant to current therapeutic interventions. Therefore, 
abrogation of checkpoint function may drive tumor cells toward apoptosis and 
enhance the efficacy of anti-neoplastic agents.   
The cell cycle is a series of events that take place in a cell which leads to its 
division and replication. Checkpoints are biological stoplights which delay cells 
from transitioning from one cell cycle phase to the next when there is genotoxic 
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and replicative stress. The three key checkpoints in the cell cycle are: G1, S- and 
G2/M checkpoints. The G1 checkpoint is regulated by p53. Checkpoint 1 (Chk1) 
is a serine/threonine kinase which regulates the S- and G2/M checkpoints. Wee1 
is an atypical tyrosine kinase which regulates the G2/M checkpoint. Wee1 
inactivates Cdc2 through selective phosphorylation of its Tyr15 residue and 
consequently leads to G2 arrest that gives tumor cells survival advantage by 
allowing time to repair their damaged DNA.16 Wee1 has also been shown to be a 
regulator of genomic stability during S-phase in protection against replication 
stress-associated DNA breakage.17 It was shown that Wee1 depletion by siRNA 
transfection rapidly induces DNA damage in S-phase in replicating areas, which 
is accompanied by a marked accumulation of ssDNA. Similar to effects of Chk1 
inhibition, these deleterious S-phase effects of Wee1 depletion are highly 
dependent on CDK activity.18  
1.4 
AZD1775 (Wee1 inhibitor) 
AZD1775, previously known as MK-1775, is an oral, small molecule inhibitor of 
the Wee1 kinase with high potency, selectivity and oral bioavailability.19 It exerts 
its mechanism of action by inhibiting Wee1 and thus phosphorylation of 
Cdc2Tyr15.20 (Figure 1) 
Figure 1: DNA damage and Wee1 (Adapted from Chen et al.21 ) 
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1.4.1 
In Vitro Studies of AZD1775 
AZD1775in combination with gemcitabine inhibited phosphorylation of 
Cdc2Tyr15 by 50% at a concentration of 81.87 ± 17.04 nM (EC50; the 
concentration causing 50% effect), as well as induced the G2 
checkpoint escape (EC50 of 84.09 ± 9.1 nM) in the p53-deficient 
human colon adenocarcinoma cell line, WiDr.19, 22 The two agents also 
demonstrated synergy in the induction of apoptosis. Context-specific 
(p53-negative background) sensitization of gemcitabine by AZD1775 
was confirmed when gemcitabine-induced apoptosis was enhanced 
by AZD1775 selectively in a p53-deficient human ovarian 
adenocarcinoma cell over-expressing the construct (TOV21G-shp53); 
whereas, it remained unchanged in the p53-positive parental cells 
(TOV21G- wild-type).19 
1.4.2 
In Vivo Studies of AZD1775 
AZD1775 (10 mg/kg) administered orally (PO) once a week, 24 hours 
following gemcitabine (5 mg/kg intravenously [IV]) for 3 weeks, 
significantly enhanced the anti-tumor effect of gemcitabine in the WiDr 
(p53-deficient human colon adenocarcinoma) tumor nude rat 
xenograft model (measured 1 week after the third dose). There were 
no significant differences between the various dosing schedules: 
AZD1775 given either weekly x 3 or biweekly on week 1 and 2 or 
week 1 and 3. Gemcitabine monotherapy alone showed anti-tumor 
efficacy with % treated/control (%T/C) value of 59%; whereas, 
AZD1775 monotherapy at this dose level and frequency demonstrated 
no anti-tumor activity. 19 Target modulation was assessed by Western 
blotting and immunohistochemistry. Single agent AZD1775 treatment 
produced greater than 50% inhibition of tumor growth in 2 xenografts 
(PANC286, p53 wild-type xenograft and PANC198, p53 mutated 
xenograft). However, 5 of 9 xenografts treated with gemcitabine and 6 
of 9 xenografts treated with gemcitabine plus AZD1775 produced 
complete tumor growth inhibition and in fact resulted in tumor 
shrinkage compared to control, suggesting that the combination 
should be further tested.23 Combination of gemcitabine and AZD1775 
resulted in greater than 50% regression of initial tumor volume in 4 of 
6 xenografts (66.66%) with p53-deficient status.23 All five 
combinations of AZD1775 (gemcitabine, carboplatin, cisplatin, 
capecitabine, and 5-FU) were well tolerated at the active dose levels 
demonstrating minimal weight reduction. Moderate but transient 
reduction in white blood cells and platelet counts compared to 
untreated controls were observed after treatment with AZD1775 in 
combination with gemcitabine, carboplatin, and cisplatin. AZD1775 did 
not enhance hematologic toxicities induced by cytotoxic therapies.19 
1.4.3 
Pharmacokinetics of AZD1775 
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 the rat and dog.19 The major metabolic pathway of 
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human hepatocytes, the major metabolites formed were an N-
desmethyl metabolite and an N-oxide derivative.19  All metabolites 
observed in human liver preparations were also formed in vivo in the 
rat and dog. Oxidative metabolism of AZD1775 was mediated 
predominantly by cytochrome P450 3A4 (CYP3A4) and flavin-
containing monooxygenase 3 (FMO3). AZD1775 was a weak 
reversible inhibitor of CYP2C8, CYP2C9, CYP2C19, and CYP3A4 
(IC50 of 51, 56, 12, and 14 µM, respectively).19 In addition, AZD1775 
was a time-dependent inhibitor of CYP3A4. Despite AZD1775 (0.1-20 
μM) being a weak inducer of CYP1A2, at the target concentration of 
0.24 μM maintained for 8 hours while on intermittent dosing regimen, 
the potential risk of drug-drug interactions when co-administered with 
CYP1A2 substrates is low.19 Pending additional data, moderate and 
strong inhibitors or inducers of CYP3A4, including aprepitant, are 
excluded in clinical trials. AZD1775 is a substrate of P-glycoprotein 
(Pgp).19 
1.4.4 
Pharmacology and Toxicology of AZD1775 
In the anesthetized cardiovascular dog study, AZD1775marginally 
prolonged QTc by an average of 5% and 7%, at the 3 and 10 mg/kg 
doses, respectively.19 Only minimal effects on blood pressure (-5%) 
and heart rate (-5%) were observed at the 10 mg/kg dose. There were 
no effects on other cardiographic measures, i.e., QRS duration or PR 
interval, at either dose.19 AZD1775 partially reversibly inhibited the 
human ether-a-go-go-related gene (hERG) current with an IC50 value 
of 6.9 μM in whole-cell voltage clamp studies. The maximum plasma 
concentration (Cmax) of AZD1775 at 325 mg which likely exceed the 
combination dose, is less than 1 μM. Taking into account the effect of 
human plasma protein binding (~60%), this provides a significant 
margin to anticipated clinical exposures. In mice, AZD1775 had no 
effect on CNS function (at a dose of 10 mg/kg), including gross 
behavior, spontaneous activity, neural reflexes, or thermoregulation 
during the 24-hour post dose period.19 
uThe single-dose PO toxicity studies (30, 100, or 300 mg/kg) and the 
exploratory single-dose PO range-finding studies (100, 300, or 750 
mg/kg with a 7-day-recovery period) in rats showed dose-related, 
generally reversible, acute toxic effects on hematopoietic, lymphoid, 
and gastrointestinal (GI) tract tissues.19 A 15-day PO toxicity study 
was conducted in rats dosed at 30, 100, or 300 mg/kg, once weekly, 
on study Days 1, 8, and 15. No mortality or severe toxicity was 
observed at 300 mg/kg/day, but treatment-related body weight 
changes and hematological changes were observed.19 The magnitude 
of absolute reticulocyte counts and WBC 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. In the 7-day PO toxicity studies, AZD1775 (monohydrate form) 
was administered PO at 25, 75, or 300 mg/kg in rats, and at 5 or 15 
mg/kg in dogs19 Reproductive toxicity studies have not been 
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assay but positive in in vitro chromosomal aberrations assays and in 
vivo micronucleus assay.19 
1.4.5 
Clinical Development of AZD1775 
AZD1775 has been administered to 215 patients as of 13 April 2012 
(178 in study PN001, 7 in study PN004, 11 in study PN005, 7 in study 
PN008, and to 12 patients in PN009) as of 13 April 2012.19 The 
monotherapy portion of study PN001 is currently closed, as pre-
defined in the protocol. In this portion of the study, a single dose of 
AZD1775 up to 1300 mg as monotherapy was generally well tolerated 
without DLTs. The single-dose combination portion of the study has 
also been completed, and a maximum tolerable dose (MTD) has been 
determined in each of the single-dose combination therapy arms, 
while the multiple dose combination therapy portion of the study is still 
ongoing.19 To date, AZD1775 has been sufficiently well tolerated to 
permit further evaluations, including evaluations of longer dosing 
regimens, and evaluations of regimens combining the compound with 
standard doses of two chemotherapeutic agents. 
The most common adverse events (AEs) observed in studies of 
combination of MK-1775 with chemotherapy include blood and 
lymphatic disorders, (i.e., thrombocytopenia, neutropenia, leukopenia, 
anemia, febrile neutropenia), gastrointestinal disorders (i.e., diarrhea, 
vomiting, nausea, abdominal pain, and constipation), and 
investigations (hematology and serum chemistries).19 
The single-dose MTD for both the gemcitabine and cisplatin 
combination therapies is 200 mg of AZD1775.19, 24 DLTs tended to be 
hematological in nature in the gemcitabine group and constitutional in 
the cisplatin group. The single-dose MTD for the combination with 
carboplatin was 325 mg of AZD1775. DLTs in this group were related 
to serum chemistry.19, 24 
Hematologic DLTs have been observed in the multiple-dose AZD1775 
combination treatment groups with gemcitabine and cisplatin. An MTD 
of AZD1775 in combination with gemcitabine has been established 
with an interim dose of 50 mg BID on Day 1, 25 mg BID on Day 2, and 
25 mg on Day 3.19 An attenuated QD for 2 days schedule in 
combination with gemcitabine is currently enrolling. Two DLTs have 
been observed to date with this regimen, which is being used 
exclusively in combination with gemcitabine. One patient experienced 
Grade 3 febrile neutropenia and the other experienced Grade 3 
AST/ALT increase. The MTD for combination with cisplatin has been 
exceeded at the 250 mg dose level, and tolerability of the MTD at 200 
mg BID has been confirmed.19, 24 DLTs observed in the multiple-dose 
carboplatin combination have been both hematological and 
constitutional in nature. The multiple-dose MTD in combination with 
carboplatin is 225 mg BID.19, 24 
Analyses of preliminary pharmacokinetic data from study PN001 
appear to suggest that the area under the plasma concentration-time 
curve from time 0 to infinity in a single-dose regimen, the AUC from 
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maximum plasma drug concentration observed (Cmax) increase 
approximately in a dose proportional manner; the time to maximum 
plasma drug concentration observed (Tmax) appeared to occur at 1.0 
to 8.0 hours and the T1/2 ranged between 7.9 to 12.2 hours.19 
There is a potential for drug-drug interactions when AZD1775 is 
coadministered with drugs that are known to be moderate or potent 
CYP3A4 inhibitors or inducers, and when it is coadministered with 
substrates of CYP3A4.19 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 weak drug interaction between AZD1775and 
aprepitant, as exposure to AZD1775 increased by ~60% when 
aprepitant was coadministered 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, it is recommended that AZD1775 should not be 
coadministered with aprepitant until further evaluation.19 
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 become available. In vitro studies have also 
suggested that AZD1775 may be a weak inhibitor of CYP2C19, 
CYP2C8 and CYP2C9, a weak inducer of CYP1A2, substrate and 
inhibitor of P-glycoprotein (P-gp) and inhibitor of BCRP. Caution is 
advised when drugs which may interact with AZD1775 are used (see 
Appendix VI).19 AZD1775 may inhibit MATE1 and MATE2K renal 
efflux transporters and may result in a meaningful drug interaction due 
to inhibition of these transporters. 
1.5 
Pre-Clinical Study of Nab-Paclitaxel/Gemcitabine/AZD1775 
In a KPC mouse model of PDAC (mutant Kras and Trp53 alleles), it has been 
shown that Nab-Paclitaxel and gemcitabine have synergistic antitumor effects.25 
Nab-Paclitaxel exhibits monotherapeutic antineoplastic effects and 
simultaneously depresses Cda levels through induction of reactive oxygen 
species to stabilize gemcitabine and thereby sensitize the PDAC tumor to 
combination treatment.25 In the evaluation of AZD1775 in combination with 
gemcitabine and Nab-Paclitaxel in a p53-mutant Mia-PaCa-2 human pancreas 
tumor xenograft model, it appeared that AZD1775 did not antagonize the 
combination of Nab-Paclitaxel and gemcitabine and appeared to have increased 
efficacy.26 (Figure 1 – courtesy of Dr. Han, Translational Genomics Research 
Institute) 
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Figure 2: Effect of gemcitabine, Nab-Paclitaxel and AZD1775 on tumor weight in 
a p53-mutant Mia-PaCa-2 human pancreas tumor xenograft model 
 
1.6 
Rationale for Clinical Study 
Given that p53-deficient cancer cells rely on S- and G2/M-checkpoints in 
response to DNA damage, a Wee1 inhibitor (regulator of S-phase and inhibitor of 
G2 checkpoint) will synergize with DNA damaging chemotherapy in enhancing 
tumor cell death. We therefore hypothesize that therapy with a checkpoint 
inhibitor plus gemcitabine-based chemotherapy will be more effective than 
gemcitabine-based chemotherapy alone in patients with metastatic PDAC, a 
tumor characterized by frequent p53 mutation. Therefore, we have designed a 
phase I/II randomized study of Nab-Paclitaxel/gemcitabine with or without 
AZD1775 (Wee1 inhibitor)in patients with treatment-naïve metastatic PDAC. This 
study uses Nab-Paclitaxel/gemcitabine chemotherapy backbone as it has been 
shown that this chemotherapy combination is superior to gemcitabine 
monotherapy and is a new standard of care for treatment of metastatic PDAC in 
2013. As there are no phase I studies with Nab-Paclitaxel/gemcitabine/AZD1775, 
a phase I study has been incorporated to ensure safety of the drug combination. 
1.6.1 
Correlation Between p53 Status and Tumor Response 
p53 status will be assessed as studies have suggested preferential 
killing of p53-deficient cells with S-/G2-checkpoint inhibitors.27 
However, some studies have also suggested p53-proficient tumors 
are killed with S-/G2-checkpoint inhibitors.28-31 Combination of 
AZD1775 and gemcitabine potentiates the efficacy of gemcitabine in 
established human pancreatic cancer xenografts.23 Nine individual 
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wild-type p53 and 6 with deficient p53 [mutant]) were implanted in 
athymic mice. Five of 9 xenografts treated with gemcitabine and 6 of 9 
xenografts treated with combination of gemcitabine and AZD1775 
produced complete tumor growth inhibition resulting in tumor 
shrinkage.23  Combination treatment caused greater than 50% 
regression in tumor size in 4 of 6 xenografts with p53-deficient 
tumors.23 The p53 pathway can also be inactivated by genetic or 
epigenetic events that occur upstream or downstream of p53.32 
Therefore, it is important to assess the integrity of the p53 pathway to 
determine optimal timing of administration of S-/G2-checkpoint 
inhibitors and for correlations to be drawn between p53 functional 
status and tumor response.32 p53 mutation status will be assessed by 
DNA sequencing. 
1.6.2 
Tissue Correlative Studies for AZD1775 
Inhibition of Cdc2Tyr15 phosphorylation and induction of Histone H3Ser10 
phosphorylation were observed upon Wee1 inhibition in vitro. In vivo 
pharmacodynamic (PD) effects of AZD1775 were evaluated using the 
WiDr xenograft nude rat model.19,24 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). 19,24 PD marker analyses 
were performed on tumor tissue isolated immediately after the 
infusion. Continuous infusion of AZD1775 caused reduction of 
phospho-Cdc2Tyr15 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 
H3Ser10) in tumor tissue. EC50 value was 0.21 μM, and maximal effect 
was observed at approximately 1.0 mg/kg/hr. 19,24 These data suggest 
that phospho-Cdc2Tyr15 and phospho-Histone H3Ser10 could be useful 
as AZD1775 PD biomarkers in tumors. 19,24 As Wee 1 inactivates 
Cdc2 through selective phosphorylation of its Tyr15 residue and 
consequently leads to G2 arrest, measurement of Cyclin B can also 
be used as a surrogate marker for G2/M-phase entry.33 
Similar PD marker changes were observed in surrogate tissues, such 
as skin hair follicle which include proliferating cells in the presence or 
absence of the DNA damaging agent gemcitabine. Strong phospho-
Cdc2Tyr15 immunopositivity was observed in skin hair bulb in hair 
follicle on WiDr xenograft nude rats.19 In combination with 
gemcitabine, AZD1775 dose-dependently inhibited phospho-Cdc2Tyr15 
signals in skin hair follicles and almost complete inhibition was 
achieved at 3.0 mg/kg/hr, which was consistent with that in 
tumor.(Figure 3)19 (Ref. IB MK1775) An almost complete reduction of 
phospho-Cdc2 signal was achieved at 3.0 mg/kg/hr.19,22 Therefore, 
phospho-Cdc2Tyr15 inhibition in skin hair follicle is a promising 
surrogate marker for pharmacodynamics effects in tumor tissue and 
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Figure 3: Decreased expression of phospho-Cdc2Tyr15 in rat hair 
follicles when AZD1775 was added to gemcitabine. 22 
 
 
 
 
 
 
 
 
 
 
1.7 
Summary of Phase I Toxicity Review 
The phase I portion of the study was open to accrual in August 2014 and two 
patients were enrolled at dose level 1—Nab-Paclitaxel 125 mg/m2 and 
Gemcitabine 1000 mg/m2 on days 1, 8 and 15 as well as AZD1775 100 mg daily 
on days 1, 2, 8, 9, 15, 16. Given the toxicities observed in these two patients, the 
trial was suspended and the phase I dose levels redesigned. 
Patient 1 received full dose treatment on days 1 and 2. This patient was 
subsequently admitted to the hospital with grade 3 dehydration and was noted to 
have liver function abnormalities with a grade 3 bilirubin. The grade 3 
dehydration was thought to possibly be related to any of the three treatment 
agents (AZD1775, gemcitabine, Nab-Paclitaxel) while the grade 3 bilirubin was 
thought to possibly be related to AZD1775 but unlikely related to either 
gemcitabine or Nab-Paclitaxel. The patient was treated with supportive care 
measures with resolution of all issues. Imaging obtained during the 
hospitalization showed no evidence of biliary obstruction. The patient 
subsequently went on to receive gemcitabine and Nab-Paclitaxel at a 20% dose 
reduction (off study), which was well tolerated. 
Patient 2 received full dose treatment on days 1 and 2. This patient was admitted 
to the hospital with grade 3 dehydration as well as difficulty with eating and grade 
3 mucositis. Labs during hospitalization revealed a grade 3 AST. All of these 
grade 3 adverse events were thought to possibly be related to any of the three 
treatment agents (AZD1775, gemcitabine and/or Nab-Paclitaxel. The patient was 
treated with supportive care measures and was discharged from the hospital 
where they went on to receive single agent gemcitabine at a 10% dose reduction, 
which was poorly tolerated and resulted in additional hospitalizations. This 
patient transitioned to hospice less than 2 months after her initial evaluation 
suggesting a rapid clinical decline. 
 Figure 3 
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Administration of AZD1775 at doses exceeding the doses proposed in this trial 
has been successful in both the monotherapy setting and in combination with 
chemotherapy with acceptable toxicity as outlined above. Previous results show 
that pCDK1 was decreased at a dose of 125 mg BID and new preliminary data 
suggests that at least 150 mg daily of AZD1775 is needed to achieve 
pharmacodynamic effect. By adopting a dose escalation strategy whereby we 
begin with lower doses of gemcitabine and Nab-Paclitaxel and dose escalate the 
AZD1775 to an optimal dose, followed then by escalation of gemcitabine and 
Nab-Paclitaxel (if possible), we believe that administration of AZD1775 at an 
optimal dose is feasible, particularly if aggressive antiemetic therapy is instituted. 
1.8 
Rationale for Imaging Research Studies 
1.8.1 
FDG-PET 
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) 
detects increased glucose metabolism associated with neoplastic 
lesions. 18F-FDG is transported into cells and phosphorylated by the 
enzyme hexokinase to 18F-FDG-6-phosphate, which cannot proceed 
down the glycolytic pathway and therefore is accumulated in the 
malignant tissue. PET allows accurate quantification of FDG uptake in 
tissue, and previous studies have demonstrated that standardized 
uptake values (SUVs) provide highly reproducible parameters of 
tumor glucose use.34 The hybrid PET-CT scanners allow functional 
and anatomic data to be obtained in a single examination, improving 
lesion localization and resulting in significant diagnostic 
improvement.35 FDG-PET is a useful imaging modality to stage and 
diagnose cancer and studies have shown that its uptake often 
declines after successful treatment.36-38 However, the utility of FDG-
PET as a reflection of tumor biology and treatment response in 
pancreatic cancer is unknown.  In this study, we intend to evaluate the 
accuracy of change in SUVmax between baseline and week 4 with 
FDG-PET as a predictor of progression-free survival (PFS), overall 
survival (OS) and response assessed by RECIST in patients with 
metastatic PDAC. 
1.8.2 
FLT-PET 
18F-fluoro-3’deoxy-3’-D-fluorothymidine (FLT) (half life = 110 mins) 
has been developed as a proliferation tracer for PET.39, 40 FLT is taken 
up by cells and follows the salvage pathway of DNA synthesis and, 
like thymidine, undergoes phosphorylation by thymidine kinase 1 
(TK1), which leads to intracellular trapping within the cell.41, 42 FLT is a 
selective substrate for TK1. In quiescent cells, TK1 activity is virtually 
absent but in proliferating cells, it is increased about 10-fold, as cells 
enter the DNA synthetic phase of the cell cycle.43-45 The uptake of FLT 
has been found to increase with increasing TK1 activity in human 
tumor cell lines.42, 46 As FLT is not incorporated into DNA, FLT uptake 
has been validated with an independent measure of DNA synthesis in 
tissue.47 The protein Ki-67 identified by MIB-1 antibody staining is a 
histopathologic measure of proliferation, which correlates with the 
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As FLT is a PET-tracer with uptake in the S-phase of the cell cycle, its 
utility as a functional imaging modality in providing information on the 
molecular and cellular response of checkpoint inhibitors is of interest 
in this study. FLT has not been studied in pancreatic carcinoma with 
Wee1 inhibition. The exploratory imaging sub-study associated with 
this trial is intended to successfully show uptake with FLT. Future 
study will define whether FLT can be a prognostic imaging biomarker 
for treatment response, and guide clinical decision making in the 
future for pancreatic cancer. The opportunity to assess FLT in this 
study will act as a proof of concept and guide how FLT will be applied 
in larger studies. 
In vitro models of radio-labeled thymidine uptake has been performed 
in a mouse PDAC cell line from a spontaneous pancreatic cancer 
mouse model (KrasG12DPdx1-cre). When the cells were treated with 
gemcitabine for 24 hours, cell viability assays indicated that the IC50 
was 7.3 ng/ml. When the PDAC cell line was treated with gemcitabine 
for 24 hours and 3[H] Thymidine, uptake of radio-labeled thymidine 
(measured by the H-3-thymidine assay) was observed. As depicted in 
Figure 4a, the viable PDAC cells treated with 8 ng/ml and 15 ng/ml of 
gemcitabine for 24 hours had almost twice the uptake of radio-labeled 
thymidine compared to control. The increase in uptake of radio-
labeled thymidine was not increased when the cells were treated with 
gemcitabine for 6 hours. This in vitro observation is supportive of the 
“flare” phenomenon observed shortly after treatment with 
gemcitabine. (Unpublished data courtesy of N. Avril, Case Western 
Reserve University). 
Figure 4a: Thymidine uptake in PDAC cells normalized to viable 
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Figure 4b: Cell viability of PDAC cells treated with gemcitabine 
 
Investigators have shown that in PC-3 human prostate cancer 
xenografts, gemcitabine induced a 8-fold increase in tumoral uptake 
of FLT at 21 hours that correlated with a 3-fold increase in thymidine 
kinase activity and S-phase arrest. Treatment with PF-477736 (a 
Chk1 inhibitor) at 17 hours after gemcitabine abrogated the early FLT-
flare at 21 hours by 82% (p< 0.001).50 This was associated with both 
an increased fraction of cells in mitosis and G1-phase of the cell 
cycle.50 Furthermore, the combination of gemcitabine and PF-477736 
enhanced DNA damage as measured by γ-H2AX and significantly 
delayed tumor growth when compared to tumors treated with 
gemcitabine alone.50 Therefore, FLT-PET is a promising strategy in 
monitoring responses to therapeutic agents that target cell cycle 
checkpoints. A pilot study in humans was performed looking at the 
flare of FLT-PET imaging after capecitabine. Five patients (2 breast 
cancer, 2 colon cancer and 1 esophageal cancer) were imaged before 
and 1 day after the start of capecitabine (after 3 doses) and increased 
FLT uptake was observed in 3 of the 5 patients. In those 3 patients, 
SUVmax was increased by 26%, 55% and 155%, respectively. 
(Personal communication with A. Shields, Wayne State University) 
There are currently no studies with Wee1 inhibitors and FLT-PET. 
However, recent studies have shown that Wee1 controls CDK activity 
to support genome integrity during DNA replication in S-phase.17 It 
was also shown that Wee1 depletion by siRNA transfection also 
rapidly induces DNA damage in S-phase in replicating areas, which is 
accompanied by a marked accumulation of ssDNA. Similar to effects 
of Chk1 inhibition, these deleterious S-phase effects of Wee1 
depletion are highly dependent on CDK activity.18 Based on these 
C e ll v ia b ility  o f P D A C  c e lls  tre a te d  w ith  G e m c ita b in e
0
2 0
4 0
6 0
0
5 0
1 0 0
1 5 0
C o n  o f G e m  2 4 h r  (n g /m l)
C e ll s u r v iv a l
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findings, it would be reasonable to extrapolate the findings with Chk1 
inhibition to Wee1 inhibition using FLT-PET. The current study will be 
a pilot and feasibility study of FLT-PET in pancreas cancer whereby, 
we intend to explore the following hypothesis: treatment with 
gemcitabine-based chemotherapy will induce tumoral uptake of FLT 
i.e. “flare” and treatment with a Wee1 inhibitor (AZD1775) after 
gemcitabine-based chemotherapy would abrogate the early FLT-flare 
indicating therapeutic inhibition of a cell cycle checkpoint. The 
exploratory FLT findings will be correlated with DNA damage, PFS 
and response in patients with metastatic pancreatic cancer. 
Previous Human FLT Imaging Studies 
Several preliminary studies using FLT imaging in human subjects 
have been performed in Germany and the United States (UCLA, 
University of Washington in Seattle, Wayne State University). The 
imaging protocols were pre-approved by their respective regulatory 
committees and conducted under the RDRC process or under NCI 
IND, with patients receiving between 1.4 and 13 mCi of FLT. Some of 
the imaging results have been published (Table 1). The group in 
Seattle, which has the most experience with this agent in the US, has 
performed numerous studies in patients with lung cancer as well as a 
few in patients with primary brain tumors. Their findings demonstrate 
the feasibility and merit of tumor imaging with FLT.  FLT-PET showed 
increased uptake in tumor lesions outside the liver or bone marrow 
(standardized uptake value [SUV] 4-7), which were delineated from 
surrounding tissue (SUV 0.5-2). 
Table 1. Summary of published manuscripts reporting [F-18]FLT human imaging studies 
Year 
Organ System 
N 
mCi 
injected 
MBq 
Injected 
Range (Mean) 
Specific Activity 
Reference (#) 
2008 
Brain 
12 a 
4.2 – 5.2 
185 
> 1.25 Ci/umol 
Spence51 
2008 
Bone & Soft 
Tissue 
22 
 
350-425 
120 GBq/mmol 
Buck52 
2008 
Pancreas 
5 
5.2 - 7 
 
Not reported 
Quon53 
2008 
Lung 
55 
 
300-400 
Not reported 
Tian54 
2008 
Brain 
13 b 
 
111-370 (322±85) 
Not reported 
Ullrich55 
2008 
Lung 
54 c 
 
101-238 (158) 
Not reported 
Yamamoto56 
2008 
Lung 
34 c 
 
3.5 /kg 
Not reported 
Yamamoto57 
2008 
Brain 
18 
3.5 - 6.4 
129-236 (161) 
Not reported 
Hatakeyama58 
2007 
Sarcoma 
10 
 
320-430 (399 med), 
120-430 (363 med)  
> 10 TBq/mmol 
Been59 
2007 
Brain 
21 d 
 
2.0 /kg  
Not reported 
Chen60 
2007 
Lymphoma 
22 
 
300-370 
Not reported 
Herrmann61 
2007 
Gastric 
45 
 
270-340 
Not reported 
Herrmann62 
2007 
Lymphoma 
48 
3.9 
148.6 
Not reported 
Kasper63 
2007 
Breast 
15 
 
153-381 
15-227 GBq/umol 
Kenny64 


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2007 
Brain 
9 d 
 
1.5 kg 
Not reported 
Schiepers65 
2007 
Head/Neck 
10 
6.76 
250 
10 TBq/mmol 
Troost66 
2007 
Lung 
20 e 
0.07 /kg 
2.59 kg  
0.12 -1.6 Ci/umol 
Turcotte67 
2007 
Rectal 
10 
8.1 
300 
Not reported 
Wieder68 
2007 
Lung 
18 c 
 
145 ± 26 
Not reported 
Yamamoto69 
2006 
Bone marrow 
18 
10.8 
400 
10 TBq/mmol 
Agool70 
2006 
Brain 
12 a 
5 
185 
7.4 GBq/umol 
Muzi71 
2006 
Brain 
25 
10 
370 
Not reported 
Saga72 
2006 
Brain 
10 
4 
104-202 
37-222 GBq/umol 
Yamamoto73 
2006 
Lymphoma 
34 
9.3 
265-370 
Not reported 
Buck74 
2006 
Lung & SPN 
22 
5 
185.2 
Not reported 
Yap75 
2006 
Breast 
14 
4 
150 
74 TBq/mmol 
Pio76 
2005 
Lung 
17 
5 
2.6/kg; max 185 
> 37 GBq/mmol 
Muzi77 
2005 
Multiple 
33 
8.4-9.7  
310-360 (350) 
> 220 GBq/mmol 
Shields78 
2005 
Breast 
15 
401-10.5 
153-380 
25-465 GBq/umol 
Kenny79 
2005 
Brain 
23 d 
8.6 
111-370 (321) 
Not reported 
Jacobs80 
2005 
Esophageal 
10 
11.1 
340-450 (410) 
> 10 TBq/mmol 
vanWestreenen81 
2005 
Lung 
47 f 
9.5 
265-370 
Not reported 
Buck82 
2005 
Breast 
10 
 
390-420 [3 pts] 
60-250 [7 pts] 
> 10 TBq/mmol 
Been83 
2005 
Brain 
25 
4.7 
141-218 (174) 
~74 Bq/mmol 
Chen84 
2005 
Brain 
26 d 
10 
370 
3.2-7.7 Ci/umol 
Choi85 
2004 
Lymphoma 
7 g 
4.3 -13.2 
159-489 (324) 
Not reported 
Buchmann86 
2004 
Lung 
17 
5.7 
130-420 (210) 
> 10TBq/mmol   
Cobben87 
2004 
Lung 
28 h 
9 
265-370 (334) 
Not reported 
Halter88 
2004 
Breast 
12 
8.1-12.1 
300-450 
Not reported 
Smyczek-Gargya89 
2004 
Colorectal 
11 i 
9.7 
360 ± 25 
Not reported 
Visvikis90 
2004 
HEENT 
21 
9.2 
165-650 (340) 
> 10TBq/mmol    
Cobben91 
2004 
Soft Tissue 
19 
10.8 
115 -430 (400) 
> 10TBq/mmol    
Cobben92 
2003 
Lymphoma 
11 
7.5 
280 
Not reported 
Wagner93 
2003 
Colorectal 
10 i 
9.5 
351± 52 
Not reported 
Francis94 
2003 
Colorectal 
17 i 
9.4 
312-412 (360) 
Not reported 
Francis95 
2003 
Lung 
18 
5 
185 max 
37 GBq/umol 
Vesselle96 
2003 
Lung 
16 
5.4 -10.8 
200 - 400 
Not reported 
Dittmann48 
2003 
Melanoma 
10 
10.8 
185-430 (med 400) 
> 10TBq/mmol    
Cobben97 


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2003 
SPN 
26 j 
9 
265-370 (334) 
Not reported 
Buck49 
2002 
SPN 
30 j 
9 
265-370 (334) 
Not reported 
Buck98 
2002 
Lung 
10 k 
5 
185 max 
37 GBq/umol 
Vesselle47 
Total # Subjects: 
1045 
a) There appears to be an overlap of two patients reported in the Muzi 200671 and Spence 200851 
manuscripts. 
(b) There appears to be an overlap of two patients reported in the Ullrich 200855 and Jacobs 200580 
manuscripts. 
(c) Comparison of the three Yamamoto lung cancer manuscripts56,57,69 indicates that they represent 72 
unique patients. 
(d) The Chen 200584, Chen 200760, and Schiepers99 manuscripts appear to represent a total of 34 unique 
patients. 
(e) Turcotte67 appears to include an additional 2 patients who were not reported in the Vesselle 200396 
manuscript. 
(f) Only 13 unique patients can be confirmed against the previous manuscripts from this group. 
(g) All 7 patients were previously reported in Wagner 2003.93 
(h) There appear to be 10 additional unique patients who were not described in the Buck 200298 and 
200349 manuscripts. 
(i) It is unclear if the same patients are being described for both of the Francis94,95 manuscripts and the 
Visvikis90 manuscript. 
(j) It is unclear if the same patients are being described in the Buck 200298 and 200349 manuscripts. 
(k) It appears that these patients were described in the 2003 Vesselle96 manuscript. 
Due to the possibility that the same patients are being described in 
some reports, the total number of unique patients represented in the 
published studies appears to be 827.  As evidenced in Table 1, many 
of the published studies did not report the specific activity of the FLT, 
so it is not possible to determine the amount of FLT that was actually 
administered to the patient.  
No adverse events have been reported for FLT at the strength to be 
used for this study. As described above, non-radioactive FLT has 
been investigated as an anti-AIDS drug, and reversible peripheral 
neuropathy was observed in subjects exposed to 50 ng-h/mL plasma 
over a course of 16 weeks (15µg/kg q12h). The FLT dose anticipated 
for this study will be < 6.1µg for a single injection. Assuming a 70 kg 
individual, the maximum concentration of FLT would be expected to 
be equivalent to 0.29 ng-h/mL. The radiation exposure associated 
with this study is comparable to the dose for other widely used clinical 
nuclear medicine procedures.  
In a 2007 study performed at the University of Washington, Turcotte 
et al67 assessed the toxicity of FLT in 20 patients with proven or 
suspected diagnosis of non-small cell lung cancer. Blood samples 
from multiple timepoints before and after FLT-PET were assayed for 
comprehensive metabolic panel, total bilirubin, complete blood and 
platelet counts. A standard neurological examination was also 
performed by a qualified physician for each patient before and 
immediately after FLT-PET.  No side effects were reported by patients 


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or witnessed. No change in the neurological status of patients was 
observed.  
The group in Seattle also recently published the results from safety 
studies performed in patients with recurrent glioma.51 Twelve patients 
were injected with 0.07 mCi/kg (5 mCi maximum) of FLT (specific 
activity 1.25 Ci/umol) and were closely monitored for three hours 
afterward. Additional follow-up was performed at 1 day post- and 1 
month post-injection. Their findings showed no evidence of toxicity at 
this dose. Monitoring of vital signs and ECG, review of systems, 
neurological assessments, and laboratory evaluations revealed no 
evidence of adverse effects. Notably, no signs or symptoms of 
peripheral neuropathy were observed in any patient at any time. 
 


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2. 
Objectives 
2.1 
Phase I Objectives 
2.1.1 
Primary Objectives 
2.1.1.1 
To evaluate the toxicity of combination therapy with Nab-
Paclitaxel, gemcitabine and AZD1775 in patients with  
metastatic adenocarcinoma of the pancreas or locally-
advanced adenocarcinoma of the pancreas which is not 
surgically resectable. 
2.1.1.2 
To determine the dose of AZD1775 to be used in 
combination with Nab-Paclitaxel and gemcitabine 
chemotherapy in the phase II portion of the trial. 
2.1.1.3 
To determine the pharmacokinetics of AZD1775 in 
combination with Nab-Paclitaxel and gemcitabine 
2.2 
Phase II Objectives 
2.2.1 
Primary Objective 
2.2.1.1 
To evaluate the progression free survival (PFS) associated 
with Nab-Paclitaxel/gemcitabine or Nab-
Paclitaxel/gemcitabine/AZD1775 in patients with treatment-
naïve metastatic adenocarcinoma of the pancreas. 
2.2.2 
Secondary Objectives 
2.2.2.1 
To evaluate the overall survival (OS) associated with Nab-
Paclitaxel/gemcitabine or Nab-
Paclitaxel/gemcitabine/AZD1775 in patients with treatment 
naïve metastatic adenocarcinoma of the pancreas. 
2.2.2.2 
To evaluate response rate (CR + PR) associated with Nab-
Paclitaxel/gemcitabine or Nab-
Paclitaxel/gemcitabine/AZD1775 in patients with treatment 
naïve metastatic adenocarcinoma of the pancreas. 
2.2.2.3 
To evaluate disease control rate (CR + PR +SD) 
associated with Nab-Paclitaxel/gemcitabine or Nab-
Paclitaxel/gemcitabine/AZD1775 in patients with metastatic 
adenocarcinoma of the pancreas. 
2.2.3 
Laboratory Studies Objectives 
2.2.3.1 
To evaluate the ability of AZD1775 to inhibit Wee1 and 
increase DNA damage and tumor cell death when 
combined with Nab-Paclitaxel/gemcitabine compared to 
Nab-Paclitaxel/gemcitabine alone. 
2.2.3.2 
To evaluate if biomarker changes in tumor tissue 
associated with Wee1 inhibition may also be present in 
hair follicles.  
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2.2.4 
Advanced Imaging Studies Objectives 
2.2.4.1 
To evaluate the change in tumor FDG uptake (SUVmax) 
between baseline FDG-PET and week 4 FDG-PET as a 
predictor of response using RECIST as the reference 
standard for response. 
2.2.4.2 
To evaluate the change in tumor FDG uptake (SUVmax) 
between baseline FDG-PET and week 4 FDG-PET as a 
predictor of overall survival.  
2.2.4.3 
To evaluate the change in tumor FDG uptake (SUVmax) 
between baseline FDG-PET and week 4 FDG-PET as a 
predictor of progression-free survival. 
2.2.4.4 
 To compare the change in tumor FDG uptake (SUVmax) 
between baseline FDG-PET and week 4 FDG-PET 
between the patients from treatment arms H and I. 
2.2.4.5 
To evaluate if an early increase in tumor FLT uptake (FLT-
flare) is observed within 24 hours after initiation of 
treatment with Nab-Paclitaxel/gemcitabine. 
2.2.4.6 
To evaluate if an early (within 24 h) increase in tumor FLT 
uptake (FLT-flare) is abrogated after initiation of treatment 
with Nab-Paclitaxel/gemcitabine/AZD1775. 
2.2.4.7 
 To compare the change in tumor FLT uptake (SUVmax) 
from baseline to 24 hours after initiation of treatment 
between the patients from treatment arms H and I. 
 
Rev. 4/16 
Rev. 4/16 


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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 29.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Phase I Study – Arm A (Closed to Accrual), Arms B, C, D, E, F and G 
3.1.1 
Patients must be at least 18 years of age. 
3.1.2 
Patients must have histologically or cytologically confirmed metastatic 
or unresectable locally advanced adenocarcinoma of the pancreas. 
Prior therapy with a non-gemcitabine based regimen is permitted. 
3.1.3 
Previous neo-adjuvant or adjuvant treatment is allowed provided that 
it was given ≥ 6 months prior to registration.  
3.1.4 
Patients must NOT be receiving any other investigational agents 
concurrently and must not have received any other investigational 
agents ≤ 4 weeks prior to registration. 
Patient is receiving or has received an investigational agent within the 
last 4 weeks? 
_______ (Yes or No) If yes, date treatment discontinued: _________ 
3.1.5 
Patients must not have a pre-existing > grade 1 motor or sensory 
neuropathy. 
3.1.6 
Patients must NOT have history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to Nab-
Paclitaxel, gemcitabine or AZD1775. 
3.1.7 
Patients must have ECOG performance status of 0 or 1. 
3.1.8 
Patients must have a life expectancy of ≥ 12 weeks. 
3.1.9 
Patients may have had prior radiotherapy for metastatic disease as 
long as it was > 4 weeks prior to registration and the patient has 
recovered from adverse events associated with the radiotherapy. 
_____
_____
_____
_____
_____
_____
_____
Rev. 4/16 
Rev. 4/16 


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3.1.10 
Patients must NOT have undergone major surgical procedures ≤ 28 
days of beginning study treatment, or minor surgical procedures ≤ 7 
days. No waiting requried following port-a-cath placement. 
3.1.11 
Patient must NOT have any of the following cardiac diseases currently 
or within the last 6 months as defined by New York Heart Association 
(NYHA) ≥ Class 2: 
3.1.11.1 
Unstable angina pectoris 
3.1.11.2 
Congestive heart failure 
3.1.11.3 
Acute myocardial infarction 
3.1.11.4 
Conduction abnormality not controlled with pacemaker or 
medication 
3.1.11.5 
Significant ventricular or supraventricular arrhythmias 
(patients with chronic rate-controlled atrial fibrillation in the 
absense of other cardiac abnormalities are eligible.) 
3.1.12 
Patients must NOT be taking current medications or substances that 
are inhibitors of CYP3A4, inhibitors or substrates of P-glycoprotein or 
inhibitors of BCRP. (See Appendix VI for list of medications.) 
3.1.13 
Patients must NOT have uncontrolled serious medical illness 
including, but not limited to, ongoing or active infection, cardiac 
arrhythmia, or psychiatric illness that would limit compliance with 
study requirements.  
3.1.14 
Patients with known human immunodeficiency virus (HIV) are not 
eligible if CD4 count is ≤ 200 cell/mm3 or if receiving antiretroviral 
therapy due to potential unfavorable interactions of the agents with 
the study treatment. 
3.1.15 
Patients must NOT have corrected QT interval QTc > 470 msec (as 
calculated per institutional standards) at study entry or congenital long 
QT syndrome). 
3.1.16 
Patients must be able to swallow capsules whole.  
3.1.17 
Patients must NOT have previous or concurrent malignancy. 
Exceptions are made for patients who meet any of the following 
conditions: 
• 
Non-melanoma skin cancer, in situ cervical cancer, breast cancer 
in situ, or superficial bladder cancer (noninvasive papillary 
carcinoma or carcinoma in situ). 
• 
Prior malignancy completely excised or removed and patient has 
been continuously disease free for >5 years.  
Date of last evidence of disease: ______ 
3.1.18 
Patients must be able to tolerate CT, MRI or PET imaging including 
contrast agents. 
3.1.19 
Women must not be pregnant or breast-feeding as developmental and 
reproductive toxicity studies of AZD1775 have not been performed; 
_____
_____
_____
_____
_____
_____
Rev. 4/16 
_____
_____
_____


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and the drugs used in this study (Nab-Paclitaxel, gemcitabine and 
AZD1775) are genotoxic. 
Females of childbearing potential must have a blood test or urine 
study within 5 days prior to registration to rule out pregnancy. A 
female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Female? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.20 
Women of child-bearing potential and men must agree to use 
adequate contraception (hormonal and barrier method of birth control; 
two barrier methods of birth control; abstinence) for the duration of 
study treatment and for 3 months after the last dose of study 
treatment. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her 
treating physician immediately. Should a man impregnate or suspect 
that he has impregnated a woman while participating in this study, he 
should inform his treating physician immediately. 
3.1.21 
Patients must have normal organ and marrow function as defined 
below within 14 days of registration: 
3.1.21.1 
Leukocytes ≥ 3,000/mcL 
Leukocytes________ 
Date:________ 
3.1.21.2 
Absolute neutrophil count ≥ 1,500/mcL 
Neutrophil count:_______ 
Date:________ 
3.1.21.3 
Hemoglobin ≥ 9 g/dL 
Hemoglobin:________ 
Date:________ 
3.1.21.4 
Platelets ≥ 100,000/mcL 
Platelets: _________ Date:________ 
3.1.21.5 
Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN) 
Bilirubin:_________ Date:________ 
3.1.21.6 
AST(SGOT)/ALT(SGPT) ≤ 3 X institutional upper limit of 
normal (ULN) or ≤ 5 X ULN if the patient has liver 
metastases. 
AST:_________ 
Date:________ 
ALT:_________ 
Date:________ 
_____
_____
_____
_____
_____
_____
_____
_____
_____


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3.1.21.7 
Creatinine ≤ 1.5 mg/dL or creatinine clearance (Cockcroft-
Gault) ≥ 60 mL/min for patients with creatinine levels 
above institutional upper limit of normal (ULN). 
Creatinine:________ 
Date:________ 
Creatinine clearance (Cockcroft-Gault) :________ 
Date:________ 
_____


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3.2 
Randomized Phase II Study – Arms H and I 
3.2.1 
Patients must be at least 18 years of age. 
3.2.2 
Patients must have histologically or cytologically confirmed metastatic 
adenocarcinoma of the pancreas with no prior systemic therapy for 
metastatic disease. 
3.2.3 
Patients must NOT have locally advanced disease. 
3.2.4 
Patients must have measurable disease outside of the primary tumor 
(pancreas) by RECIST 1.1 criteria as defined in Section 6.1.2. 
Baseline measurements and evaluations of all sites of disease must 
be obtained ≤ 4 weeks prior to randomization. 
3.2.5 
Previous neo-adjuvant or adjuvant treatment is allowed provided that 
there was no evidence of recurrent disease for at least 6 months after 
completion of neo-adjuvant/adjuvant treatment. 
3.2.6 
Patients must NOT have undergone major surgical procedures ≤ 28 
days prior to beginning study treatment, or minor surgical procedures 
≤ 7 days. No waiting requried following port-a-cath placement. 
3.2.7 
Patient must NOT have any of the following cardiac diseases currently 
or within the last 6 months as defined by New York Heart Association 
(NYHA) ≥ Class 2: 
3.2.7.1 
Unstable angina pectoris 
3.2.7.2 
Congestive heart failure 
3.2.7.3 
Acute myocardial infarction 
3.2.7.4 
Conduction abnormality not controlled with pacemaker or 
medication 
3.2.7.5 
Significant ventricular or supraventricular arrhythmias 
(patients with chronic rate-controlled atrial fibrillation in the 
absense of other cardiac abnormalities are eligible.) 
3.2.8 
Patients may have had prior radiotherapy for metastatic disease as 
long as it was > 4 weeks prior to randomization and the patient has 
recovered from adverse events associated with the radiotherapy. 
3.2.9 
Patients must NOT be taking current medications or substances that 
are inhibitors of CYP3A4, inhibitors or substrates of P-glycoprotein or 
inhibitors of BCRP. (See Appendix VI for list of medications.) 
3.2.10 
Patients must NOT have received prior Wee1 inhibitors or AZD1775. 
3.2.11 
Patients must NOT have corrected QT interval QTc > 470 msec (as 
calculated per institutional standards) at study entry or congenital long 
QT syndrome). 
3.2.12 
Patients must NOT have received gemcitabine or Nab-Paclitaxel in a 
metastatic setting. 
_____
_____
_____
_____
_____
_____
_____
Rev. 4/16 
Rev. 4/16 
_____
_____
_____


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3.2.13 
Patients must NOT be receiving any other investigational agents 
concurrently and must not have received any other investigational 
agents ≤ 4 weeks prior to randomization. 
Patient is receiving or has received an investigational agent within the 
last 4 weeks? 
_______ (Yes or No) If yes, date treatment discontinued: _________ 
3.2.14 
Patients must not have a pre-existing > grade 1 motor or sensory 
neuropathy. 
3.2.15 
Patients must NOT have history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to Nab-
Paclitaxel, gemcitabine or AZD1775. 
3.2.16 
Patients must have ECOG performance status of 0 or 1. 
3.2.17 
Patients must have a life expectancy of ≥ 12 weeks. 
3.2.18 
Patients must NOT have uncontrolled serious medical illness 
including, but not limited to, ongoing or active infection, cardiac 
arrhythmia, or psychiatric illness that would limit compliance with 
study requirements.  
3.2.19 
Patients must be able to swallow capsules whole. 
3.2.20 
Patients with bilary stents are allowed. 
3.2.21 
Patients must NOT have previous or concurrent malignancy. 
Exceptions are made for patients who meet any of the following 
conditions: 
• 
Non-melanoma skin cancer, in situ cervical cancer, breast cancer 
in situ, or superficial bladder cancer (noninvasive papillary 
carcinoma or carcinoma in situ). 
• 
Prior malignancy completely excised or removed and patient has 
been continuously disease free for > 5 years.  
Date of last evidence of disease: ______ 
3.2.22 
Patients must be able to tolerate CT, MRI or PET imaging including 
contrast agents. 
3.2.23 
Women must not be pregnant or breast-feeding as developmental and 
reproductive toxicity studies of AZD1775 have not been performed; 
and the drugs used in this study (Nab-Paclitaxel, gemcitabine and 
AZD1775) are genotoxic. 
Females of childbearing potential must have a blood test or urine 
study within 5 days prior to randomization to rule out pregnancy. A 
female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Female? ______ (Yes or No)      
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____


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Date of blood test or urine study: ___________ 
3.2.24 
Women of child-bearing potential and men must agree to use 
adequate contraception (hormonal and barrier method of birth control; 
two barrier methods of birth control; abstinence) for the duration of 
study treatment and for 3 months after the last dose of study 
treatment. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her 
treating physician immediately. Should a man impregnate or suspect 
that he has impregnated a woman while participating in this study, he 
should inform his treating physician immediately. 
3.2.25 
Patients must have normal organ and marrow function as defined 
below within 14 days of randomization: 
3.2.25.1 
Leukocytes ≥ 3,000/mcL 
Leukocytes________ 
Date:________ 
3.2.25.2 
Absolute neutrophil count ≥ 1,500/mcL 
Neutrophil count:_______ 
Date:________ 
3.2.25.3 
Hemoglobin ≥ 9 g/dL 
Hemoglobin:________ Date:________ 
3.2.25.4 
Platelets ≥ 100,000/mcL 
Platelets: _________ Date:________ 
3.2.25.5 
Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN) 
Bilirubin:_________ Date:________ 
3.2.25.6 
AST(SGOT)/ALT(SGPT) ≤ 3 X institutional upper limit of 
normal (ULN) or ≤ 5 X ULN if the patient has liver 
metastases. 
AST: _________ 
Date:________ 
ALT: _________ 
Date:________ 
3.2.25.7 
Creatinine ≤ 1.5 mg/dL or creatinine clearance (Cockcroft-
Gault) ≥ 60 mL/min for patients with creatinine levels 
above institutional upper limit of normal (ULN). 
Creatinine:________ Date:________ 
Creatinine clearance (Cockcroft-Gault) :________ 
Date:________ 
3.2.26 
For participation in the Imaging Research Studies outlined in Section 
10, patients must meet the additional following critiera: 
3.2.26.1 
The patient is participating in the trial at an institution which 
has agreed to perform the imaging research studies, 
completed the ACRIN defined scanner qulification 
procedures and received ACRIN approval as outlined in 
Section 10.  
_____
_____
_____
_____
_____
_____
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3.2.26.2 
The patient has consented in writing to participate in one of 
the imaging research studies. 
3.2.26.3 
The patient meets the criteria required for the imaging 
study in which the site is participating: 
NOTE: 
Eligibility for participating in either imaging sub-
study will depend on the availability of the 
imaging sub-study at a particular institution.  
3.2.26.3.1 
For participation in the FDG-PET sub-study: 
• 
Patients must NOT have poorly 
controlled diabetes (defined as fasting 
glucose level ≥ 200 mg/dL) despite 
efforts to improve glucose control by 
fasting duration and adjustment of 
medications. 
• 
Patient must NOT weigh more than the 
maximum weight limit for the PET table. 
• 
Patients must have an evaluable lesion 
of > 20 mm in size on standard practice 
imaging study as assessed by site 
(either primary pancreas mass or 
metastasis).  
Eligible for FDG-PET? ______ (Yes or No)  
Date: _______ 
3.2.26.3.2 
For participation in the FLT-PET substudy: 
• 
Patients must be able to lie still for a 1.5 
hour PET scan. 
• 
Patient must NOT have a history of 
allergic reaction attributable to 
compounds of similar chemical or 
biologic composition to 18F-
fluorothymidine.  
• 
Patient must NOT weigh more than the 
maximum weight limit for the PET table.  
• 
Patients must have an evaluable lesion 
in the pancreas > 20 mm in size on 
standard practice imaging study as 
assessed by site (lesion must be likely 
primary adenocarcinoma of the 
pancreas that is not primarily fibrotic or 
mucinous in nature). 
Eligible for FLT-PET? ______ (Yes or No) 
Date: __________ 
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Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 


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4. 
Registration and Randomization Procedures 
Submitting Regulatory Documents 
Before an ECOG-ACRIN Institution may enter patients, protocol specific 
regulatory documents must be submitted to the CTSU Regulatory Office at the 
following address: 
CTSU Regulatory Office 
Coalition of National Cancer Cooperative Groups 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
FAX: (215) 569-0206 
Required Protocol Specific Regulatory Documents 
1.  CTSU Regulatory Transmittal Form. 
2.  Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning 
risks or alternative procedures contained in the sample informed 
consent document must be justified in writing by the investigator 
and approved by the IRB. 
3.  A.  CTSU IRB Certification Form. 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
Or 
C.  IRB Approval Letter 
NOTE:  
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
The CTSU encourages you to go to the following CTSU RSS webpage so that 
more information on RSS2.0 as well as the submission forms can be accessed. 
Log in to http://www.ctsu.org and click on the Regulatory tab to access the RSS 
webpage. If you have questions regarding regulatory document submission, 
please telephone the CTSU Help Desk at 1-888-823-5923 or E-mail 
CTSUContact@westat.com. 
All site staff will use OPEN to enroll patients to this study. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org   
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Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria has been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool 
to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable).   
Access requirements for OPEN:  
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for the CTSU 
members' web site.  
• 
To perform registrations, the site user must have been assigned the 'Registrar' role 
on the relevant Group or CTSU roster.  
• 
To perform registrations on protocols for which you are a member of the Lead Group, 
you must have an equivalent 'Registrar' role on the Lead Group roster.  Role 
assignments are handled through the Groups in which you are a member  
• 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead 
Group registrations) you must have the role of Registrar on the CTSU roster. Site 
and/or Data Administrators can manage CTSU roster roles via the new Site Roles 
maintenance feature under RSS on the CTSU members' web site. This will allow 
them to assign staff the "Registrar" role. 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  Please print this confirmation for your 
records. 
Further instructional information is provided on the CTSU members' web site OPEN tab 
or within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-
888-823-5923 or ctsucontact@westat.com. 
4.1 
Phase I Registration Procedures (Phase I Arms) 
Phase I registration will be a two step process: Slot reservation followed by 
Step 1 treatment registration. 
Patients must not start protocol treatment prior to registration to Step 1. 
4.1.1 
Slot Reservation 
Please note that a slot must be reserved prior to starting eligibility 
verification. Slots will automatically EXPIRE after 10 days. Only after a 
slot has been reserved should the patient be worked up for the study. 
If the patient is found to be ineligible, the site must withdraw the slot 
via the OPEN Registration System. The expired slot will then be made 
available for reassignment. 
The following information will be requested for Phase I: 
4.1.1.1 
Protocol Number 
4.1.1.2 
Investigator Identification  
4.1.1.2.1 
Institution name (Institution CTEP ID) 
4.1.1.2.2 
Site contact information 
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4.1.1.3 
Patient Identification  
4.1.1.3.1 
Patient’s initials 
4.1.1.3.2 
Patient demographics 
4.1.1.3.2.1 
Gender 
4.1.1.3.2.2 
Birth date 
4.1.1.3.2.3 
Nine-digit ZIP code 
4.1.2 
Registration to Step 1 - All Phase I Arms 
Patients must not start protocol treatment prior to registration 
Step 1. 
Treatment must start within 10 working days after registration. 
The following information will be requested at the time of registration 
to Step 1: 
4.1.2.1 
Protocol Number  
4.1.2.2 
Investigator Identification  
4.1.2.2.1 
Institution and affiliate name (Institution 
CTEP ID) 
4.1.2.2.2 
Investigator’s name (NCI number) 
4.1.2.2.3 
Cooperative Group Credit 
4.1.2.2.4 
Credit Investigator 
4.1.2.2.5 
Protocol specific contact information 
4.1.2.3 
Patient Identification  
4.1.2.3.1 
Patient’s initials (first and last) 
4.1.2.3.2 
Patient’s Hospital ID and/or Social Security 
number 
4.1.2.3.3 
Patient demographics 
4.1.2.3.3.1 
Gender 
4.1.2.3.3.2 
Birth date 
4.1.2.3.3.3 
Race 
4.1.2.3.3.4 
Ethnicity 
4.1.2.3.3.5 
Nine-digit ZIP code 
4.1.2.3.3.6 
Method of payment 
4.1.2.3.3.7 
Country of residence 
4.1.3 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1.  
4.1.4 
Additional Requirements  
4.1.4.1 
Patients must provide a signed and dated, written informed 
consent form. 
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NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office - Boston. 
4.1.4.2 
Plasma samples for pharmacokinetic studies must be 
collected and submitted as outlined in Section 11. 
4.1.4.3 
Data collection for this study will be done exclusively 
through Medidata Rave. Access to the trial in Rave is 
granted through the iMedidata application to all persons 
with the appropriate roles in RSS after IRB approval is 
obtained. To access iMedidata/Rave the site user must 
have an active CTEP IAM account (https://eapps-
ctep.nci.nih.gov/iam). In addition, site users that are a 
member of ECOG-ACRIN must have the mapped ECOG-
ACRIN roles or explicit Rave roles (Rave CRA, Read-Only, 
Site Investigator) in RSS at the enrolling site. Site users 
that are not members of ECOG-ACRIN must have the 
Rave roles on the CTSU roster at the enrolling sites. The 
Site Administrator or Data Administrator at the enrolling 
site may assign the appropriate roles from the Site Roles 
tab on the CTSU website. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
roster will be sent study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select 
Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be listed in the 
upper right pane of the iMedidata screen. 
Users that have not previously activated their 
iMedidata/Rave accounts will also receive a separate 
invitation from iMedidata to activate their account. Account 
activation instructions are located on the CTSU website, 
Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on 
the CTSU website under the Rave tab at 
http://www.ctsu.org/RAVE/ or by contacting the CTSU Help 
Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.1.5 
Instructions for Patients Who Do Not Start Assigned Protocol 
Treatment  
If a patient registers to Step 1 and does not start therapy, the reason 
the patient did not start protocol therapy will be collected; no 
additional data will be collected.  
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If the above scenario occurs, please notify the EA2131 study team at 
the ECOG-ACRIN Operations Office – Boston and Study Chair so that 
an additional patient may be accrued to that cohort to replace the 
patient who did not receive treatment. If a patient does start therapy 
and leaves the study prior to completion of 1 cycle of treatment, 
baseline and follow-up data will still be collected and must be 
submitted by Medidata Rave according to the schedule in the EA2131 
Forms Completion Guidelines. 
4.2 
Phase II Randomization Procedures (Arms H and I) 
Patients must not start protocol treatment prior to randomization. 
Treatment must start within 10 working days after registration. 
Please note that when a patient has been successfully randomized, the 
confirmation of registration will indicate that the patient is on either arm H or I. 
The following information will be requested: 
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
4.2.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2.2 
Investigator’s name (NCI number) 
4.2.2.3 
Cooperative Group Credit 
4.2.2.4 
Credit Investigator 
4.2.2.5 
Protocol specific contact information 
4.2.3 
Patient Identification  
4.2.3.1 
Patient’s initials (first and last) 
4.2.3.2 
Patient’s Hospital ID and/or Social Security number 
4.2.3.3 
Patient demographics 
4.2.3.3.1 
Gender 
4.2.3.3.2 
Birth date 
4.2.3.3.3 
Race 
4.2.3.3.4 
Ethnicity 
4.2.3.3.5 
Nine-digit ZIP code 
4.2.3.3.6 
Method of payment 
4.2.3.3.7 
Country of residence 
4.2.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.2.   
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4.2.5 
Stratification Factors 
Patients will be stratified according to the following factors for 
purposes of balancing arms: 
4.2.5.1 
ECOG Performance Status 
4.2.5.1.1 
ECOG PS 0 or 1: Randomized to Arm H or 
Arm I 
4.2.5.2 
Imaging sub-studies – Intent to Participate 
4.2.5.2.1 
No imaging, FDG-PET imaging study, or 
FLT-PET imaging study: Randomized to 
Arm H or Arm I 
4.2.6 
Additional Requirements  
4.2.6.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office - Boston. 
4.2.6.2 
Biological samples to be submitted for laboratory research 
studies as outlined in Section 12. 
4.2.6.3 
This study has two optional imaging sub-studies.  
Availability of the imaging sub-studies will vary depending 
on the status of accrual and whether a given site is 
participating.  Before asking patients to consent, the 
registrar should determine which studies are available.  If 
the FLT study is available, patients should be offered 
participation in this study first.  If the FLT study is not 
available or the patient declines to participate and the FDG 
study is available, the patient should be offered the FDG 
study.  If neither study is available or the patient declines, 
the patient will be stratified into the "no optional imaging 
study" group.  
Imaging studies are to be submitted from participating 
patients as outlined in Section 10. 
4.2.6.4 
Data collection for this study will be done exclusively 
through Medidata Rave. Access to the trial in Rave is 
granted through the iMedidata application to all persons 
with the appropriate roles in RSS after IRB approval is 
obtained. To access iMedidata/Rave the site user must 
have an active CTEP IAM account (https://eapps-
ctep.nci.nih.gov/iam). In addition, site users that are a 
member of ECOG-ACRIN must have the mapped ECOG-
ACRIN roles or explicit Rave roles (Rave CRA, Read-Only, 
Site Investigator) in RSS at the enrolling site. Site users 
that are not members of ECOG-ACRIN must have the 
Rave roles on the CTSU roster at the enrolling sites. The 
Site Administrator or Data Administrator at the enrolling 
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site may assign the appropriate roles from the Site Roles 
tab on the CTSU website. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
roster will be sent study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select 
Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be listed in the 
upper right pane of the iMedidata screen. 
Users that have not previously activated their 
iMedidata/Rave accounts will also receive a separate 
invitation from iMedidata to activate their account. Account 
activation instructions are located on the CTSU website, 
Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on 
the CTSU website under the Rave tab at 
http://www.ctsu.org/RAVE/ or by contacting the CTSU Help 
Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.2.7 
Instructions for Patients Who Do Not Start Assigned Protocol 
Treatment  
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted by 
Medidata Rave according to the schedule in the EA2131 Forms 
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5. 
Treatment Plan 
5.1 
Phase I (Arms B, C, D, E, F and G) 
5.1.1 
Treatment Design – Phase I 
Phase I treatment will employ a standard 3 + 3 dose escalation 
schema. Patients will therefore be treated in cohorts of 3 patients 
starting with Arm B, first with escalating doses of AZD1775, followed 
then by escalation of Nab-Paclitaxel and gemcitabine chemotherapy. 
Gemcitabine and Nab-Paclitaxel will be administered on Days 1, 8 
and 15 with AZD1775 being given by mouth daily on days 1, 2, 8, 9, 
15 and 16. Escalation will continue through all of the armsuntil the 
MTD has been determined. The dose escalation strategy is as 
follows: 
Arm 
Gemcitabine 
(mg/m2) days 1, 8 
and 15 
Nab-Paclitaxel 
(mg/m2) days 1, 8 
and 15 
AZD1775  
(mg) days 1, 2, 8, 
9, 15 and 16 
Arm A (CLOSED TO ACCRUAL) 
Arm B 
750 
100 
100 
Arm C 
750 
100 
125 
Arm D 
750 
100 
150 
Arm E 
750 
100 
175 
Arm F 
750 
125 
*see footnote 
Arm G 
1000 
125 
*see footnote 
* If AZD1775 150 mg is the highest achievable dose—Arm D—(DLTs 
observed in Arm E), proceed to Arm F and continue with dose escalation of 
gemcitabine and Nab-Paclitaxel using the highest tolerated AZD1775 dose. 
* If AZD1775 175 mg is achievable in Arm E, proceed to Arm F and continue 
with dose escalation of gemcitabine and Nab-Paclitaxel using AZD1775 175 
mg. If unacceptable toxicity is observed with AZD1775 175 mg in either Arm 
F or Arm G, each/either of these dose levels may be reassessed (Arm F150, 
Arm G150) using AZD1775 150 mg. 
If no dose limiting toxicity (DLT) (see Section 5.1.5) is observed 
amongst 3 patients enrolled on Arm B, or if 1 DLT is seen amongst 6 
patients enrolled on Arm B, 3 more patients will be treated at the next 
dose level. Each patient is monitored for DLTs for four weeks (cycle 
1). 
If 2 DLTs occur on Arm B, accrual will be suspended and the trial will 
be re-evaluated. 
If 1 DLT is seen across 3 patients at a particular dose level during the 
first 4 weeks after the start of treatment, 3 additional patients will be 
treated at that dose level.  
With the exception of table footnotes outlined above, if at any time 2 
or more DLTs are seen in 3 or 6 patients at any given dose level, the 
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preceeding dose level will be declared the MTD (Maximum Tolerable 
Dose). MTD is defined as the highest dose level at which < 33% of 6 
patients experience a DLT. If 1 DLT is seen out of 6 patients at a 
given dose level, that dose level will be declared the MTD. Dose 
escalation of AZD1775 beyond 175 mg is not permitted. 
If a patient received less than 66.7% of the planned doses of any 
study agent, for reasons at least possibly related to side effects or 
toxicity from the study treatment, during their first cycle on the phase I 
study, the patient will be considered as having had a DLT. 
Furthermore, as the primary safety concern related to potential 
exacerbation of the expected hematologic toxicity of the Nab-
Paclitaxel/gemcitabine regimen with the addition of AZD1775, any 
observed hematologic toxicity except lymphopenia will be considered 
a DLT if it results in treatment delay of more than 14 days. If Arm B 
exceeds the MTD definition, then the study will be suspended and 
additional arms will be considered and discussed with CTEP. 
Arms B, C, D, E and F 
Number of 
Observed DLTs 
Action 
0/3 
Escalate next 3 patients to next dose level 
1/3 
Add 3 more patients to current dose level 
≤ 1/6 
Escalate next 3 patients to next dose level 
≥ 2/3 
Suspend accrual and re-evaluate trial 
≥ 2/6 
Suspend accrual and re-evaluate trial 
* If AZD1775 150 mg is the highest achievable dose—Arm D—(DLTs 
observed in Arm E), proceed to Arm F and continue with dose escalation of 
gemcitabine and Nab-Paclitaxel using the highest tolerated AZD1775 dose. 
* If AZD1775 175 mg is achievable in Arm E, proceed to Arm F and continue 
with dose escalation of gemcitabine and Nab-Paclitaxel using AZD1775 175 
mg. If unacceptable toxicity is observed with AZD1775 175 mg in either Arm 
F or Arm G, each/either of these dose levels may be reassessed (Arm F150, 
Arm G150) using AZD1775 150 mg. 
Arm G 
Number of 
Observed DLTs 
Action 
≤ 1/3 
Add 3 more patients to current dose level Arm G 
> 1/3 
Arm F is MTD if max of 1/6 DLT on Arm F* 
≤ 1/6 
Arm G declared as MTD 
≥ 2/6 
Arm F is MTD if max of 1/6 DLT on Arm F* 
* If only 3 patients were enrolled on Arm F prior to escalation to Arm G, 
another 3 patients will need to be enrolled on Arm F. 
The recommended phase II dose (RP2D) is the highest dose of each 
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can be administered as a combination regimen as determined by the 
phase I dose escalation. A minimum of 6 patients will be treated at the 
RP2D on the Phase I portion of the study to obtain sufficient toxicity 
data prior to proceeding to the comparative phase II evaluation of this 
regimen. 
5.1.2 
Treatment Administration 
1 Cycle = 4 weeks (28 days) 
NOTE: 
Doses associated with the Nab-Paclitaxel and gemcitabine 
regimen will be based on actual body weight. Change the 
dose of Nab-Paclitaxel and gemcitabine if the calculated 
dose changes by > 10%. BSA should be calculated using 
the Mosteller formula. 
• 
AZD1775 will be supplied as both 100 mg and 25 mg capsules, 
depending on the dose level. 
• 
AZD1775 must be administered orally one hour prior to or two 
hours after a meal. 
• 
AZD1775 capsules should be swallowed whole and they cannot 
be crushed. 
• 
A missed or vomited dose of AZD1775 should not be replaced. 
The patient should be instructed to take the next scheduled dose 
at the regularly scheduled time. 
5.1.3 
Administration Schedule – Phase I (Arms B, C, D, E, F and G) 
1 Cycle = 4 weeks (28 days) 
Treatment will continue until development of progressive disease (as 
defined by Section 6.1.4) or unacceptable toxicity. 
5.1.3.1 
Arm A (CLOSED TO ACCRUAL) 
5.1.3.2 
Arm B 
On days 1, 8 and 15: 
CBC and platelet count to be checked prior to drug 
administration. 
Palenosetron 0.25 mg IV/Dexamethasone 16 mg IV over 
15 minutes and premedications (see Section 5.7) will be 
given followed by 
AZD1775 100 mg PO per day. AZD1775 should be 
administered concomitantly or just prior to the start of 
chemotherapy. 
Nab-Paclitaxel 100 mg/m2 IV given first over 30 minutes 
followed by 
Gemcitabine 750 mg/m2 IV over 30 minutes 
On days 2, 9, and 16. 
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AZD1775 100 mg PO per day should be taken 
approximately 24 hours after the last dose. 
NOTE: 
Anti-emetics such as neurokinin-1 (NK-1) 
receptor inhibitor (e.g., aprepitant or 
fosaprepitant) are not allowed due to drug-
drug interactions with AZD1775. See 
Supportive Care (Section 5.7) for anti-emetic 
recommendations.  
NOTE: 
For drug-drug interaction, see Appendix VI for 
list of medications. 
5.1.3.3 
Arm C 
On days 1, 8 and 15: 
CBC and platelet count to be checked prior to drug 
administration 
Palenosetron 0.25 mg IV/Dexamethasone 16 mg IV over 
15 minutes and premedications (see Section 5.7) will be 
given followed by 
AZD1775 125 mg PO per day. AZD1775 should be 
administered concomitantly or just prior to the start of 
chemotherapy. 
Nab-Paclitaxel 100 mg/m2 IV given first over 30 minutes 
followed by 
Gemcitabine 750 mg/m2 IV over 30 minutes  
On days 2, 9, and 16. 
AZD1775 125 mg PO per day should be taken 
approximately 24 hours after the last dose. 
NOTE: 
Anti-emetics such as neurokinin-1 (NK-1) 
receptor inhibitor (e.g., aprepitant or 
fosaprepitant) are not allowed due to drug-
drug interactions with AZD1775. See 
Supportive Care (Section 5.7) for anti-emetic 
recommendations. 
NOTE: 
For drug-drug interaction, see Appendix VI for 
list of medications. 
5.1.3.4 
Arm D 
On days 1, 8 and 15: 
CBC and platelet count to be checked prior to drug 
administration 
Palenosetron 0.25 mg IV/Dexamethasone 16 mg IV over 
15 minutes and premedications (see Section 5.7) will be 
given followed by 
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AZD1775 150 mg PO per day. AZD1775 should be 
administered concomitantly or just prior to the start of 
chemotherapy. 
Nab-Paclitaxel 100 mg/m2 IV given first over 30 minutes 
followed by 
Gemcitabine 750 mg/m2 IV over 30 minutes. 
On Days 2, 9 and 16: 
AZD1775 150 mg PO per day should be taken 
approximately 24 hours after the last dose. 
NOTE: 
Anti-emetics such as neurokinin-1 (NK-1) 
receptor inhibitor (e.g., aprepitant or 
fosaprepitant) are not allowed due to drug-
drug interactions with AZD1775. See 
Supportive Care (Section 5.7) for anti-emetic 
recommendations. 
NOTE:  
For drug-drug interaction, see Appendix VI for 
list of medications. 
5.1.3.5 
Arm E 
On days 1, 8 and 15: 
CBC and platelet count to be checked prior to drug 
administration 
Palenosetron 0.25 mg IV/Dexamethasone 16 mg IV over 
15 minutes and premedications (see Section 5.7) will be 
given followed by 
AZD1775 175 mg PO per day. AZD1775 should be 
administered concomitantly or just prior to the start of 
chemotherapy. 
Nab-Paclitaxel 100 mg/m2 IV given first over 30 minutes 
followed by 
Gemcitabine 750 mg/m2 IV over 30 minutes. 
On Days 2, 9 and 16: 
AZD1775 175 mg PO per day should be taken 
approximately 24 hours after the last dose. 
NOTE: 
Anti-emetics such as neurokinin-1 (NK-1) 
receptor inhibitor (e.g., aprepitant or 
fosaprepitant) are not allowed due to drug-
drug interactions with AZD1775. See 
Supportive Care (Section 5.7) for anti-emetic 
recommendations. 
NOTE:  
For drug-drug interaction, see Appendix VI for 
list of medications. 
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5.1.3.6 
Arm F 
On days 1, 8 and 15: 
CBC and platelet count to be checked prior to drug 
administration 
Palenosetron 0.25 mg IV/Dexamethasone 16 mg IV over 
15 minutes and premedications (see Section 5.7) will be 
given followed by 
If 175 mg of AZD1775 was tolerated in Arm E: 
AZD1775 175 mg PO per day. AZD1775 should be 
administered concomitantly or just prior to the start of 
chemotherapy. 
Nab-Paclitaxel 125 mg/m2 IV given first over 30 minutes 
followed by 
Gemcitabine 750 mg/m2 IV over 30 minutes. 
On Days 2, 9 and 16: 
AZD1775 175 mg PO per day should be taken 
approximately 24 hours after the last dose. 
NOTE: 
Anti-emetics such as neurokinin-1 (NK-1) 
receptor inhibitor (e.g., aprepitant or 
fosaprepitant) are not allowed due to drug-
drug interactions with AZD1775. See 
Supportive Care (Section 5.7) for anti-emetic 
recommendations. 
NOTE:  
For drug-drug interaction, see Appendix VI for 
list of medications. 
5.1.3.7 
Arm G 
On days 1, 8 and 15: 
CBC and platelet count to be checked prior to drug 
administration 
Palenosetron 0.25 mg IV/Dexamethasone 16 mg IV over 
15 minutes and premedications (see Section 5.7) will be 
given followed by 
If 175 mg of AZD1775 was tolerated in Arm E 
AZD1775 175 mg PO per day. AZD1775 should be 
administered concomitantly or just prior to the start of 
chemotherapy. 
Nab-Paclitaxel 125 mg/m2 IV given first over 30 minutes 
followed by 
Gemcitabine 1000 mg/m2 IV over 30 minutes. 
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AZD1775 175 mg PO per day should be taken 
approximately 24 hours after the last dose. 
NOTE: 
Anti-emetics such as neurokinin-1 (NK-1) 
receptor inhibitor (e.g., aprepitant or 
fosaprepitant) are not allowed due to drug-
drug interactions with AZD1775. See 
Supportive Care (Section 5.7) for anti-emetic 
recommendations. 
NOTE:  
For drug-drug interaction, see Appendix VI for 
list of medications. 
If 175 mg of AZD1775 was NOT tolerated in Arm E 
AZD1775 150 mg PO per day. AZD1775 should be 
administered concomitantly or just prior to the start of 
chemotherapy. 
Nab-Paclitaxel 125 mg/m2 IV given first over 30 minutes 
followed by 
Gemcitabine 1000 mg/m2 IV over 30 minutes. 
On Days 2, 9 and 16: 
AZD1775 150 mg PO per day should be taken 
approximately 24 hours after the last dose. 
NOTE: 
Anti-emetics such as neurokinin-1 (NK-1) 
receptor inhibitor (e.g., aprepitant or 
fosaprepitant) are not allowed due to drug-
drug interactions with AZD1775. See 
Supportive Care (Section 5.7) for anti-emetic 
recommendations. 
NOTE:  
For drug-drug interaction, see Appendix VI for 
list of medications. 
5.1.4 
Evaluation for Adverse Events – Phase I 
Patients must be evaluated for adverse events on a weekly basis 
during the first cycle of treatment (4 weeks). 
Any patient who receives any study agent will be evaluable for 
adverse events. 
Any patient who experiences a dose-limiting toxicity (DLT) during 
Cycle 1 observation is considered fully evaluable for adverse events. 
Assessment of AZD1775 requires 3 patients at a time per cohort, and 
a total of 6 patients per cohort are required to confirm the MTD for 
AZD1775 when given in combination with Nab-Paclitaxel and 
gemcitabine. 
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5.1.5 
Dose-Limiting Toxicity (DLT) – Phase I 
A DLT is defined by the occurrence of any of the following toxicities 
(CTCAE v.4) possibly, probably, or definitely related to study drug(s) 
within first cycle (28 days). 
• 
Grade 4 neutropenia for more than 7 days 
• 
Grade 3-4 febrile neutropenia of any duration 
• 
Grade 4 anemia of any duration 
• 
Grade 3 thrombocytopenia in the presence of bleeding of any 
duration 
• 
Grade 4 thrombocytopenia of any duration 
• 
Any observed hematologic adverse event (of any grade) if it 
results in treatment delay of more than 14 days, except 
lymphopenia 
• 
Grade 4 nausea, vomiting or diarrhea of any duration 
• 
Grade 3-4 GGT, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), or bilirubin of any duration 
• 
Grade 4 creatinine of any duration 
• 
Grade 3 creatinine lasting longer than 72 hours despite hydration 
• 
Grade 4 hyperglycemia lasting longer than 24 hours despite active 
management or any duration with life-threatening consequence 
• 
Grade 3-4 hypokalemia, hypomagnesemia, hyponatremia or 
hypophosphatemia lasting longer than 72 hours despite active 
replacement 
• 
Grade 4 hypokalemia, hypomagnesemia, hyponatremia or 
hypophosphatemia of any duration with life-threatening 
consequence 
• 
≥ Grade 3 non-hematological toxicity of any duration, except: 
o Grade 3 nausea, vomiting or diarrhea will be considered a DLT 
only if it occurs for more than 72 hours despite optimal medical 
management 
o Alopecia (any grade)  
o Reversible laboratory abnormalities with no clinical sequelae 
and/or no clinical significance in the opinion of Investigator 
• 
Receipt of less than 66.7% of the planned dose of any study agent 
for reasons related to side effects or toxicity from study treatment. 
NOTE: 
If patient experiences DLT during Cycle 1, treatment must 
be discontinued. 
NOTE: 
As the primary safety concern relates to potential 
exacerbation of the expected hematologic toxicity of the 
Nab-Paclitaxel/gemcitabine regimen with the addition of 
AZD1775, any observed hematologic toxicity except 
lymphopenia will be considered a DLT if it results in 
treatment delay of more than 14 days. 
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NOTE: 
Growth factor support is allowed on cycle 1. See Sections 
5.6.1.2.1 and 5.7.2 for further information. 
5.2 
Phase II (Arms H and I) 
5.2.1 
Treatment – Phase II (Arms H and I) 
1 Cycle = 4 weeks (28 days) 
NOTE: 
Doses associated with the Nab-Paclitaxel and gemcitabine 
regimen will be based on actual body weight. Change the 
dose of Nab-Paclitaxel and gemcitabine if the calculated 
dose changes by > 10%. 
5.2.2 
Administration Schedule – Phase II (Arm H) 
1 Cycle = 4 weeks (28 days) 
Treatment will continue until development of progressive disease (as 
defined by Section 6.1.4) or unacceptable toxicity 
5.2.2.1 
Arm H 
On days 1, 8 and 15: 
CBC and platelet count to be checked prior to drug 
administration 
Palenosetron 0.25 mg IV/Dexamethasone 16 mg IV over 
15 minutes and premedications (see Section 5.7) will be 
given followed by 
Nab-Paclitaxel 125 mg/m2 IV given first over 30 minutes 
followed by 
Gemcitabine 1000 mg/m2 IV over 30 minutes 
5.2.3 
Administration Schedule – Phase II (Arm I) 
1 Cycle = 4 weeks (28 days) 
Treatment will continue until development of progressive disease (as 
defined by Section 6.1.4) or unacceptable toxicity. 
• 
AZD1775 will be supplied as both 100 mg and 25 mg capsules. 
• 
AZD1775 must be administered orally one hour prior to or two 
hours after a meal. 
• 
AZD1775 capsules should be swallowed whole and they cannot 
be crushed. 
• 
A missed or vomited dose of AZD1775 should not be replaced. 
The patient should be instructed to take the next scheduled dose 
at the regularly scheduled time. 
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5.2.3.1 
Arm I 
On days 1, 8 and 15: 
CBC and platelet count to be checked prior to drug 
administration 
Palenosetron 0.25 mg IV/Dexamethasone 16 mg IV over 
15 minutes and premedications (see Section 5.7) will be 
given followed by 
AZD1775 RP2D PO per day. AZD1775 should be 
administered concomitantly or just prior to the start of 
chemotherapy. 
Nab-Paclitaxel RP2D IV given first over 30 minutes 
followed by 
Gemcitabine RP2D IV over 30 minutes 
On days 2, 9, and 16. 
AZD1775 RP2D mg PO per day should be taken 
approximately 24 hours after the last dose. 
NOTE: 
Anti-emetics such as neurokinin-1 (NK-1) 
receptor inhibitor (e.g., aprepitant or 
fosaprepitant) are not allowed due to drug-
drug interactions with AZD1775. See 
Supportive Care (Section 5.7) for anti-emetic 
recommendations. 
NOTE:  
For drug-drug interaction, see Appendix VI for 
list of medications. 
5.3 
Adverse Event Reporting Requirements 
5.3.1 
Purpose  
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
• 
Routine reporting:  Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave.   
• 
Expedited reporting:  In addition to routine reporting, certain 
adverse events must be reported in an expedited manner via 
CTEP-AERS for timelier monitoring of patient safety and care. The 
following sections provide information and instructions regarding 
expedited adverse event reporting. 
5.3.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans (or with FLT or FDG 
imaging agents administered in the EA2131 imaging sub-studies), 
whether or not considered drug related. Therefore, an AE can be 
ANY unfavorable and unintended sign (including an abnormal 


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laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
• 
Attribution:  An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
Unlikely 
The AE is doubtfully related to treatment 
Possible 
The AE may be related to treatment 
Probable 
The AE is likely related to treatment 
Definite 
The AE is clearly related to treatment 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List):  An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND.  Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.   
• 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.  
• 
Dose Limiting Toxicity (DLT):  The appearance of side effects 
during the first cycle of treatment that are possibly severe enough 
to prevent further increase in dosage or strength of treatment 
agent, or to prevent continuation of treatment at any dosage level.  
Any adverse event that meets the EA2131 definition of DLT must 
be reported via CTEP-AERS. 
• 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred.   
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a serious when, based upon medical judgment, 


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they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
• 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting):  A subset of AEs within the CAEPR that contains list 
of events that are protocol specific exceptions to expedited 
reporting.  If an AE meets the reporting requirements of the 
protocol, and it is listed on the SPEER, it should ONLY be 
reported via CTEP-AERS if the grade being reported exceeds the 
grade listed in the parentheses next to the event. 
5.3.3 
Reporting procedure 
This study requires that expedited adverse event reporting use the 
CTEP’s Adverse Event Reporting System (CTEP-AERS). The NCI’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) 
• 
the NCI (301-897-7497)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours.  In addition, supporting or follow 
up documentation must be faxed to the NCI (301- 230-0159) in the 
same timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.3.4 
Determination of reporting requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
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• 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
• 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol EA2131 and outline 
the specific expedited adverse event reporting requirements for 
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5.3.5 
Steps to determine if an adverse event is to be reported in an 
expedited manner – Arms A (CLOSED), B, C, D, E, F, G, H and I 
5.3.5.1 
Guidelines for adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the 
last administration of the investigational agent(s). 
 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the 
six criteria in the top portion of the 
table below in Section 5.3.6 
Yes 
No 
Identify the type and 
grade of the event 
using CTCAE v4.0 
Determine if the patient was 
hospitalized for ≥ 24 hours 
for the event 
With this information, 
review the chart in Section 
5.3.6 to determine if event 
is reportable via CTEP-
Refer to Section 5.3.7 to 
determine if the event 
meets the protocol 
specific reporting 
requirements for this 
study. If so, report the 
Refer to Section 5.3.7 to 
determine if the event meets the 
protocol specific reporting 
requirements for this study. If 
so, report the event via CTEP-
Is the event 
reportable? 
No 
Yes 
Rev. 4/16 
Refer to section 5.3.7 to determine if the 
event meets the criteria as an exception 
to reporting on this protocol.  If it does 
not, report the event via CTEP-AERS. 


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5.3.5.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.3.6, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 3, 4 and Grade 5 AEs  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported via CTEP-AERS even if the patient 
is off study 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
5.3.6 
Expedited Reporting Requirements for Arms A (CLOSED), B, C, D, E, 
F, G, H and I on protocol EA2131 
Investigational Agents: AZD1775 
Commercial Agents: Nab-Paclitaxel, Gemcitabine 
When an investigational agent(s) is used in combination with a 
commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events follow the 
guidelines for investigational agents.   
Phase 1 and Early Phase 2 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
of investigational agent/intervention. 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE: Protocol-specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
• 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
• 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
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5.3.7 
Additional instructions, requirements and exceptions for protocol 
EA2131 
Additional Instructions: 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
birth defect events via CTEP-AERS, please contact the AEMD Help 
Desk at aemd@tech-res.com  or 301-897-7497.  This will need to 
be discussed on a case-by-case basis. 
 
EA2131 specific expedited reporting requirements: 
• 
Dose Limiting Toxicities (DLTs) – Phase I (All Arms): The 
following events require expedited reporting via CTEP-AERS. 
NOTE: 
In order to avoid unnecessary queries and delays 
in meeting reporting deadlines, please be sure to 
state that you are reporting a DLT and include all 
relevant details in the ‘Description of Event’ 
and/or ‘Abnormal or Relevant Normal Lab values’ 
sections of the CTEP-AERS report so that the 
ECOG-ACRIN Operations Office - Boston can 
document that the adverse event meets the 
definitions of DLT below (i.e.: duration, grade, 
relevant lab values, etc). 
A DLT is defined by the occurrence of any of the 
following toxicities (CTCAE v.4) possibly, probably, 
or definitely related to study drug(s) within first cycle 
(28 days): 
• 
Grade 4 neutropenia for more than 7 days 
• 
Grade 3-4 febrile neutropenia of any duration  
• 
Grade 4 anemia of any duration 
• 
Grade 3 thrombocytopenia in the presence of 
bleeding of any duration 
• 
Grade 4 thrombocytopenia of any duration 
• 
Any observed hematologic adverse event (of any 
grade) if it results in treatment delay of more than 
14 days, except lymphopenia 
• 
Grade 4 nausea, vomiting or diarrhea of any 
duration 
• 
Grade 3-4 GGT, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), or bilirubin of 
any duration 
• 
Grade 4 creatinine of any duration 
 
• 
Grade 3 creatinine lasting longer than 72 hours 
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• 
Grade 4 hyperglycemia lasting longer than 24 
hours despite active management or any 
duration with life-threatening consequence 
• 
Grade 3-4 hypokalemia, hypomagnesemia, 
hyponatremia or hypophosphatemia lasting 
longer than 72 hours despite active replacement  
• 
Grade 4 hypokalemia, hypomagnesemia, 
hyponatremia or hypophosphatemia of any 
duration with life-threatening consequence 
• 
≥ Grade 3 non-hematological toxicity of any 
duration, except: 
o 
Grade 3 nausea, or vomiting or diarrhea will 
be considered a DLT only if it occurs for more 
than 72 hours despite optimal medical 
management 
o 
Alopecia (any grade)  
o 
Reversible laboratory abnormalities with no 
clinical sequelae and/or no clinical 
significance in the opinion of Investigator. 
• 
Receipt of less than 66.7% of the planned dose 
of any study agent for reasons related to side 
effects or toxicity from study treatment. 
• 
FLT-PET Imaging Adverse Events (Arm H and I only): 
No adverse events have been attributed to Positron-
Emission Tomography (PET) imaging/diagnostic 
administration of [3'-deoxy-3'-[F-18]fluorothymidine (FLT) at 
the levels described in the Investigators Brochure.  
Therefore, no adverse events are expected as a result of 
the intravenous (IV) administration of FLT for typical PET 
imaging applications.  However, AE evaluation must be 
performed (in person or by phone) at 24 hours (± 4 hours) 
after each FDG-PET/CT and FLT-PET/CT imaging scan 
and any event that meets the criteria in Section 5.3.6 must 
be reported as an adverse event via CTEP-AERS. 
• 
Pregnancy  
Pregnancies and suspected pregnancies (including a 
positive or inconclusive pregnancy test regardless of age or 
disease state) occurring while the subject is on AZD1775, or 
within 28 days of the subject’s last dose of AZD1775, are 
considered immediately reportable events. The pregnancy, 
suspected pregnancy, or positive/inclusive pregnancy 
test must be reported via CTEP-AERS within 24 hours 
of the Investigator’s knowledge. Please refer to 
Appendix XIII for detailed instructions on how to report 
the occurrence of a pregnancy as well as the outcome 
of all pregnancies. 
 


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EA2131 specific expedited reporting exceptions: 
For study arms H and I (phase II only), the adverse events listed 
below do not require expedited reporting via CTEP-AERS: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS 
if the grade being reported exceeds the grade listed in the 
parentheses next to the event. 
5.3.8 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional AE information requested 
by ECOG-ACRIN MUST be submitted to BOTH the NCI and ECOG-
ACRIN. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.3.9 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave. 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
• 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
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61 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the ECOG-ACRIN 
Second Primary Form 


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5.4 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for AZD1775 
(NSC 751084) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold 
and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS 
(except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 299 patients. 
Below is the CAEPR for AZD1775. 
NOTE: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS if 
the grade being reported exceeds the grade listed in the parentheses 
next to the event in the SPEER. 
NOTE: 
The SPEER should ONLY be used for the Phase II portion of this 
study.  
Version 2.4, August 3, 20161 
 
 Adverse Events with Possible  
 Relationship to AZD1775 (MK-1775) 
 (CTCAE 4.0 Term) 
[n= 299] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
  
CARDIAC DISORDERS 
  
 
 
Atrial fibrillation 
  
 
 
Supraventricular tachycardia   
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
  
 
Tinnitus 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 2) 
Constipation 
 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
  
 
Flatulence 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Oral pain 
 
  
Vomiting 
 
 
 Vomiting (Gr 2) 
Rev. 7/14 
Rev. 11/16 
Rev. 4/16 


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 Adverse Events with Possible  
 Relationship to AZD1775 (MK-1775) 
 (CTCAE 4.0 Term) 
[n= 299] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
Fever 
 
 
 Fever (Gr 2) 
 
Flu like symptoms 
 
  
 
Malaise 
 
  
 
Non-cardiac chest pain 
 
  
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - 
Other (hepatitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
  
INFECTIONS AND INFESTATIONS 
  
Infection2 
 
 
 Infection2 (Gr 3) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
 
Blood bilirubin increased 
 
  
 
Creatinine increased 
 
  
 
Lymphocyte count 
decreased 
 
  
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased 
(Gr 4) 
Platelet count decreased  
 
 Platelet count decreased 
(Gr 4) 
 
Weight loss 
 
  
 
White blood cell decreased 
 
 White blood cell decreased 
(Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
Hypoalbuminemia 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
 Hypokalemia (Gr 2) 
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
  
 
Hypophosphatemia 
 
  


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 Adverse Events with Possible  
 Relationship to AZD1775 (MK-1775) 
 (CTCAE 4.0 Term) 
[n= 299] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Musculoskeletal and 
connective tissue disorder - 
Other (muscle spasms) 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
 
 
Intracranial hemorrhage 
  
 
Paresthesia 
 
  
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury3 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
  
 
Hiccups 
 
  
 
 
Hypoxia 
  
 
Voice alteration 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Hyperhidrosis 
 
  
 
Pruritus 
 
  
 
Rash4 
 
 Rash4 (Gr 2) 
VASCULAR DISORDERS 
  
 
 
Phlebitis 
  
 
Thromboembolic event 
 
  
1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3 Acute kidney injury includes renal impairment and acute renal insufficiency. 
4 Rash may include rash, erythema, eczema, and rash maculo-papular. 
5 Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory neuropathy. 
Adverse events reported on AZD1775 (MK-1775) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that AZD1775 (MK-1775) 
caused the adverse event: 


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BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (pancytopenia); Blood and lymphatic system disorders - Other (thrombocytosis); 
Leukocytosis 
CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (cardiomegaly); 
Chest pain - cardiac; Myocardial infarction; Palpitations; Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain 
EYE DISORDERS - Blurred vision; Cataract; Conjunctivitis; Eye disorders - Other (eye 
swelling); Eye disorders - Other (visual impairment); Eye pain; Keratitis; Photophobia; Scleral 
disorder; Watering eyes 
GASTROINTESTINAL DISORDERS - Anal pain; Ascites; Bloating; Cheilitis; Colitis; Dry mouth; 
Duodenal ulcer; Dysphagia; Gastric ulcer; Gastritis; Gastrointestinal disorders - Other 
(duodenitis); Gastrointestinal disorders - Other (eructation); Hemorrhoids; Lower gastrointestinal 
hemorrhage; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Gait 
disturbance; General disorders and administration site conditions - Other (catheter site pain); 
Infusion site extravasation 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and 
procedural complications - Other (excoriation); Injury, poisoning and procedural complications - 
Other (ligament sprain) 
INVESTIGATIONS - Electrocardiogram QT corrected interval prolonged; GGT increased; 
Investigations - Other (blood urea increased); Lymphocyte count increased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperkalemia; Hyperuricemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Bone pain; Flank 
pain; Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and 
connective tissue disorder - Other (groin pain); Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (carcinoid tumor); 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Dysesthesia; Encephalopathy; 
Lethargy; Nervous system disorders - Other (hemiparesis); Peripheral neuropathy5; 
Presyncope; Somnolence; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression 
RENAL AND URINARY DISORDERS - Hematuria; Urinary frequency; Urinary incontinence; 
Urinary retention; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Female genital tract fistula; Genital 
edema 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Bronchopulmonary hemorrhage; Nasal congestion; Pleural effusion; Pneumonitis; Pulmonary 
hypertension; Respiratory, thoracic and mediastinal disorders - Other (diaphragmalgia); 
Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin; Pain of 
skin; Palmar-plantar erythrodysesthesia syndrome; Purpura; Rash acneiform; Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypertension; Hypotension 


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NOTE: 
AZD1775 (MK-1775) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 


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5.5 
Comprehensive  Adverse Events & Potential Risks Lists (CAEPRs) for 3'-deoxy-
3'-[F-18]fluorothymidine (NSC 743144) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold 
and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS 
(except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. The CAEPR does not provide frequency data; 
refer to the Investigator’s Brochure for that information. 
NOTE: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS if 
the grade being reported exceeds the grade listed in the parentheses 
next to the event in the SPEER.    
Version 1.0, July 1, 2010 1 
 
Category 
(Body 
System) 
 
 
Adverse Events2 with Possible 
Relationship to 3'-deoxy-3'-[F-
18]fluorothymidine 
(CTCAE v4.0 Term) 
 
 
EXPECTED AEs FOR CTEP-AERS 
REPORTING  
 
Agent Specific Adverse Event List 
(ASAEL) 
 
 
 
No AEs reported in human studies2,3. 
 
1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol, and the agent should 
be included in the e-mail. 
2 No adverse events have been attributed to Positron-Emission Tomography (PET) imaging/diagnostic 
administration of[3'-deoxy-3'-[F-18]fluorothymidine at the levels described in the Investigators Brochure. 
Therefore, no adverse events are expected as a result of the intravenous (IV) administration of 3'-deoxy-
3'-[F-18]fluorothymidine for typical PET imaging applications. 
3 As with many intravenously administered agents, 3'-deoxy-3'-[F-18]fluorothymidine could cause an 
allergic reaction that could potentially pose a threat to life (anaphylaxis). This has not been observed in 
limited human exposure to date. Reasonable precautions should be taken, consistent with normal 
radiologic and clinical facility practice. The patient should be monitored until the PET procedure is 
completed, and trained personnel and emergency equipment should be available per facility standards. 
For purposes of informed consent regarding reasonably foreseeable risks to 
subjects in trials utilizing 3’-deoxy-3’-[F-18]fluorothymidine, the following potential 
adverse events are considered extremely rare: 
• 
Injection-related risks that may include infection, or accidental 
extravasation of the dose that may lead to discomfort, localized pain, or 
infection.  
• 
Risks related to allergic reaction/anaphylaxis that may be life 
threatening. 


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NOTE: 
As with all PET imaging agents, 3'-deoxy-3'-[F-18]fluorothymidine is a 
radiopharmaceutical that decays with positron emission. As such, it 
poses an intrinsic radiation exposure risk. However, when 
administered in accordance with the Investigator’s Brochure as a PET 
imaging agent, this risk is felt to be extremely small.  The organ and 
total body doses associated with FLT PET imaging are comparable to 
or lower than those associated with other widely used clinical nuclear 
medicine procedures. 
NOTE: 
3'-deoxy-3'-[F-18]fluorothymidine in combination with other agents 
could cause an exacerbation of any adverse event currently known to 
be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 


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5.6 
Dose Modifications  
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.6.1 
Phase I (Arms B, C, D, E, F and G) Dose Modification 
The following general rules apply: 
• 
For individual subjects, dose modifications will be based on 
hematologic or non-hematologic toxicity, laboratory test results, 
and clinical assessment on the day of treatment and during the 
previous cycle. 
• 
CBC with differential and platelet count must be drawn on Day 1, 
Day 8, and Day 15, and results known prior to treatment 
administration on Day 1, Day 8, and Day 15, respectively. 
• 
If more than one toxicity requiring dose reduction occurs, use 
lowest dose level required.   
• 
If multiple toxicities are seen, the dose administered in 
subsequent cycle should be based on the most severe toxicity 
experienced in the current cycle.  
• 
When a dose reduction is required, no dose re-escalation will be 
permitted for the duration of study treatment unless otherwise 
specified in the Dose Modification for Hematologic Toxicity tables 
below. 
• 
If patient experiences study drug-related toxicity that requires a 
delay in scheduled gemcitabine dosing for >14 days, the patient 
must discontinue all protocol therapy.  
• 
Patients who require discontinuation of both Nab-Paclitaxel and 
gemcitabine for toxicity will discontinue all protocol therapy. 
• 
Patients who discontinue Nab-Paclitaxel may continue to receive 
gemcitabine and AZD1775. This is expected to be common since 
the cumulative neurotoxicity of Nab-Paclitaxel often requires its 
cessation after 4-6 months. 
• 
Patients experiencing peripheral neuropathy that requires a delay 
in scheduled Nab-Paclitaxel dosing for ≥ 14 days will discontinue 
all protocol therapy. 
• 
If AZD1775 is held or discontinued for toxicities solely related to 
AZD1775, Nab-Paclitaxel and gemcitabine therapy should be 
continued. 
• 
Please refer to the respective tables for dose modifications related 
to protocol treatment. 
• 
The study chair or study chair liaison should be contacted for dose 
delays and modifications for all other toxicities not listed in this 
section. 
Rev. 4/16 


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Dose levels for Nab-Paclitaxel, gemcitabine and AZD1775: 
Arm A 
Closed to Accrual 
Arm B 
Dose Level 
Nab-Paclitaxel 
(mg/m2)a 
Gemcitabine 
(mg/m2)a 
AZD1775 (mg) 
Starting dose 
100 
750 
100 
-1 
75 
600 
75 
-2b 
50 
500 
50 
Arm C 
Dose Level 
Nab-Paclitaxel 
(mg/m2)a 
Gemcitabine 
(mg/m2)a 
AZD1775 (mg) 
Starting dose 
100 
750 
125 
-1 
75 
600 
100 
-2b 
50 
500 
75 
Arm D 
Dose Level 
Nab-Paclitaxel 
(mg/m2)a 
Gemcitabine 
(mg/m2)a 
AZD1775 (mg) 
Starting dose 
100 
750 
150 
-1 
75 
600 
125 
-2b 
50 
500 
100 
Arm E 
Dose Level 
Nab-Paclitaxel 
(mg/m2)a 
Gemcitabine 
(mg/m2)a 
AZD1775 (mg) 
Starting dose 
100 
750 
175 
-1 
75 
600 
150 
-2b 
50 
500 
125 
Arm F 
Dose Level 
Nab-Paclitaxel 
(mg/m2)a 
Gemcitabine 
(mg/m2)a 
AZD1775 (mg) 
Starting dose 
125 
750 
150/175* 
-1 
100 
600 
125/150 
-2b 
75 
500 
100/125 
* Dose reduction based on starting dose of AZD1775, see Section 5.1. 
Rev. 4/16 


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Arm G 
Dose Level 
Nab-Paclitaxel 
(mg/m2)a 
Gemcitabine 
(mg/m2)a 
AZD1775 (mg) 
Starting dose 
125 
1000 
150/175 
-1 
100 
750 
125/150 
-2b 
75 
600 
100/125 
* Dose reduction based on starting dose of AZD1775, see Section 5.1. 
a. Dose reductions may or may not be concomitant. Please refer to Section 
5.6.1.1 for specific recommendations regarding dose modifications for Day 1 
of each cycle for hematologic and non-hematologic toxicity. Please refer to 
Section 5.6.1.2 for specific recommendations regarding dose modifications 
within a cycle for hematologic and non-hematologic toxicities, respectively. 
b. A maximum of 2 dose level reductions are allowed.   
5.6.1.1 
Phase I (Arms B, C, D, E, F and G) Dose Modifications at 
Day 1 
In the event dose modifications are required at the 
beginning of a cycle due to AEs or hematologic toxicities, 
doses of Nab-Paclitaxel, gemcitabine and AZD1775 may 
be adjusted as detailed below: 
Phase I Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity) 
Phase I (Arms B, C, D, E, F and G): Treatment day counts and toxicity 
ANC 
 
Platelets 
Timing 
 1,500/mm3 
And 
 
100,000/mm3 
Treat on time 
< 1,500/mm3  
Or 
< 
100,000/mm3 
Delay by 1 week intervals until recovery and decrease Nab-
Paclitaxel, gemcitabine, and AZD1775 by one dose level. 
Abbreviation: ANC = Absolute neutrophil count.
Rev. 4/16 
Rev. 4/16 


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Phase I Dose Modifications for Day 1 of Each Cycle (Non-Hematologic Toxicity) 
Category 
Grade 
Nab-Paclitaxel 
Gemcitabine 
AZD1775 
Tinnitus 
1 
No dose modification 
No dose modification 
No dose modification 
2 
No dose modification 
No dose modification 
Hold until ≤ grade 1, then 
reduce by one dose level  
3 
No dose modification 
No dose modification 
Hold until ≤ grade 1, then 
reduce by one dose level  
Fatigue 
(lethargy, 
malaise, 
asthenia) 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 2, 
then reduce by one 
dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
Peripheral 
sensory 
neuropathya 
1 
No dose modification 
No dose modification 
No dose modification 
2 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
No dose modification 
No dose modification 
3-4 
Discontinue 
May continue. No dose 
modification.  
May continue. No dose 
modification. 
Cutaneous 
toxicity 
1-2 
No dose modification 
No dose modification 
No dose modification 
3 
Hold until ≤ grade 2, 
then reduce by one 
dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
4 
Discontinue 
Discontinue 
Discontinue 
Diarrhea 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 2, 
then reduce by one 
dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
Mucositis oral 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
Vomiting  
 
(All patients 
should receive 
prophylaxis) 
1 
No dose modification 
No dose modification 
No dose modification 
2 
Hold until ≤ grade 1, 
then maintain dose 
level and intensify anti-
emetics 
Hold until ≤ grade 1, then 
maintain dose level and 
intensify anti-emetics 
Hold until ≤ grade 1, then 
maintain dose level and 
intensify anti-emetics 
3 
Hold until ≤ grade 1, 
then reduce by one 
dose level and intensify 
anti-emetics 
Hold until ≤ grade 1, then 
reduce by one dose level 
and intensify anti-emetics 
Hold until ≤ grade 1, then 
reduce by one dose level 
and intensify anti-emetics 
4 
Hold until ≤ grade 2, 
then reduce by one 
dose level and intensify 
anti-emetics 
Hold until ≤ grade 2, then 
reduce by one dose level 
and intensify anti-emetics 
Hold until ≤ grade 2, then 
reduce by one dose level 
and intensify anti-emetics 
AST and/or ALT 
Bilirubin 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hepatic failure 
3-4 
Discontinue 
Discontinue 
Discontinue 


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Category 
Grade 
Nab-Paclitaxel 
Gemcitabine 
AZD1775 
All Other Non-
Hematologic 
Toxicitiesb, c 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
a Nab-Paclitaxel treatment should be withheld in patients who experience ≥ Grade 3 peripheral 
neuropathy. Gemcitabine and AZD1775 administration can continue during this period. Nab-Paclitaxel 
treatment may be resumed at the next lower dose level in subsequent cycles after the peripheral 
neuropathy improves to ≤ Grade 1. Patients experiencing peripheral neuropathy that requires a delay in 
scheduled Nab-Paclitaxel dosing for ≥ 14 days will discontinue study treatment. The time to resolution to 
Grade ≤ 1 should be the adverse event duration used for adverse event reporting. 
b Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will be exempt 
from this requirement. Asymptomatic or clinically mild pulmonary embolism can be treated with standard 
anti-coagulation (see Section 5.7.3) without interruption of therapy.  Moderate to severe pulmonary 
embolism will require permanent discontinuation of treatment. 
c Dose reduce if investigator deems appropriate and clinically necessary 
5.6.1.2 
Phase I (Arms B, C, D, E, F and G) Dose Modifications 
within a Treatment Cycle 
In the event that patients must have treatment delayed 
within a treatment cycle due to toxicities, those doses held 
during a cycle will not be made up.   
Dose modifications due to hematologic toxicity (as 
represented by the blood counts and toxicities, below) 
within a treatment cycle should be adjusted as outlined in 
Section 5.6.1.2.1. Dose modifications may also be made 
for non-hematological toxicity within a cycle as specified in 
Section 5.6.1.2.2. 
Rev. 4/16 


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5.6.1.2.1 
Phase I Dose Modifications for Hematologic Toxicity within a Cycle  
Day 8 Blood 
Counts 
Day 8 Nab-
Paclitaxel 
Day 8 
Gemcitabine 
Day 8, 9 
AZD1775 
Day 15 Blood 
Counts 
Day 15 Nab-
Paclitaxel 
Day 15 
Gemcitabine 
Day 15, 16 
AZD1775 
Any Day Nab-
Paclitaxel 
Any Day 
Gemcitabine 
Any Day 
AZD1775 
ANC ≥ 
1000/mm3  
and 
Platelets ≥ 
75,000/mm3 
100% 
100% 
100% 
ANC ≥ 
1000/mm3  
and 
Platelets 
≥ 75,000/mm3 
100% 
100% 
100% 
 
 
 
ANC 500-
999/mm3 
or 
Platelets 
50,000-
74,999/mm3 
Full Dose 
(treat on 
time)  
+ G-CSFa 
Full Dose 
(treat on 
time)  
+ G-CSFa 
Full Dose 
(treat on 
time)  
+ G-CSFa 
 
 
 
ANC < 500/mm3 
or 
Platelets  
< 50,000/mm3 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
 
 
 
ANC 500-
999/mm3 
or 
Platelets 
50,000-
74,999/mm3 
Decrease 
dose by 1 
level (treat 
on time) 
Decrease 
dose by 1 
level (treat on 
time 
Decrease 
dose by 1 
level (treat 
on time) 
ANC ≥ 
1000/mm3  
and 
Platelets  
≥ 75,000/mm3 
Return to 
Previous 
Dose level 
(treat on 
time) + G 
CSFa 
Return to 
Previous 
Dose level 
(treat on 
time) + G 
CSFa 
Return to 
Previous 
Dose level 
(treat on 
time) + 
G-CSFa 
 
 
 
ANC 500-
999/mm3 
or 
Platelets 
50,000-
74,999/mm3 
Same Dose 
(as Day 8, 
treat on 
time) + 
G-CSFa 
Same Dose 
(as Day 8, 
treat on 
time) + 
G-CSFa 
Same Dose 
(as Day 8, 
treat on 
time) + 
G-CSFa 
 
 
 
ANC < 500/mm3 
or 
Platelets  
< 50,000/mm3 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
 
 
 
 


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Day 8 Blood 
Counts 
Day 8 Nab-
Paclitaxel 
Day 8 
Gemcitabine 
Day 8, 9 
AZD1775 
Day 15 Blood 
Counts 
Day 15 Nab-
Paclitaxel 
Day 15 
Gemcitabine 
Day 15, 16 
AZD1775 
Any Day Nab-
Paclitaxel 
Any Day 
Gemcitabine 
Any Day 
AZD1775 
ANC < 
500/mm3  
or Platelets  
< 50,000/mm3 
Hold 
Hold 
Hold 
ANC ≥ 
1000/mm3  
and 
Platelets  
≥ 75,000/mm3 
Decrease 
Day 8 dose 
by 1 level 
(treat on time) 
+ G-CSFa 
Decrease 
Day 8 dose 
by 1 level 
(treat on 
time) + 
G-CSFa 
Decrease 
Day 8 dose 
by 1 level 
(treat on 
time) + 
G-CSFa 
 
 
 
ANC 
500-999/mm3 
or 
Platelets 
50,000-
74,999/mm3 
Decrease 
Day 8 dose 
by 1 level 
(treat on time) 
+ G-CSFa 
Decrease 
Day 8 dose 
by 1 level 
(treat on 
time) + 
G-CSFa 
Decrease 
Day 8 dose 
by 1 level 
(treat on 
time) + 
G-CSFa 
 
 
 
ANC < 500/mm3 
or 
Platelets  
< 50,000/mm3 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
 
 
 
Febrile 
Neutropenia 
(Grade 3 or 4) 
 
 
 
 
 
 
 
Hold.  Upon 
resuming 
dosing, 
decrease to 
next lower 
level and do 
not 
re-escalate 
throughout 
the rest of 
treatment. 
Hold.  Upon 
resuming 
dosing, 
decrease to 
next lower 
level and 
do not 
re-escalate 
throughout 
the rest of 
treatment. 
Hold.  Upon 
resuming 
dosing, 
decrease to 
next lower 
level and 
do not 
re-escalate 
throughout 
the rest of 
treatment. 
Recurrent 
Febrile 
Neutropenia 
(Grade 3 or 4)b 
 
 
 
 
 
 
 
Decrease to 
next lower 
dose level 
and do not 
re-escalate 
throughout 
the rest of 
treatment. 
Decrease 
to next 
lower dose 
level and 
do not 
re-escalate 
throughout 
the rest of 
treatment 
Decrease 
to next 
lower dose 
level and 
do not 
re-escalate 
throughout 
the rest of 
treatment 
Abbreviations:  ANC = Absolute neutrophil count; G-CSF = Granulocyte colony stimulating factor. 
a 
G-CSF is optional if descent only affects platelets. .For the prevention of neutropenia or febrile neutropenia, granulocyte colony stimulating 
factors (G-CSF) may be administered throughout the study, including during cycle 1, in order to maintain adequate blood counts. If G-CSF is 


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used for the prevention of neutropenia or febrile neutropenia, it may be administered from days 10-13 (total of 4 days) and/or days 17-20 (total of 
4 days) after the most recent systemic therapy. G-CSF is not permitted within 48 hours prior to or following any systemic therapy. Pegfilgrastim 
(Neulasta) is not permitted in this study. G-CSF may be given according to institutional guidelines for the treatment of neutropenic fever or 
infections associated with neutropenia. Patients not experiencing resolution of neutropenia within 14 days, despite uninterrupted G-CSF 
treatment, will discontinue study treatment. The use of G-CSF and the associated dose and scheduling is entirely per the discretion of the 
treating physician. 
b 
If patients do not experience resolution of neutropenia within 14 days, despite uninterrupted G-CSF treatment, study treatment will be 
discontinued. 
c 
Patients with grade 4 fever (regardless of neutrophil count) should have their chemotherapy treatment interrupted. A full sepsis diagnostic work-
up should be performed while continuing broad spectrum antibiotics. If cultures are positive, the antibiotic may or may not be changed, 
depending on the sensitivity profile of the isolated organism. Patients with persisting fever after 2 weeks, despite uninterrupted antibiotic 
treatment, will discontinue study treatment.  Febrile neutropenic patients can also receive G-CSF, in addition to antibiotic treatment, to hasten 
the resolution of their febrile neutropenia (following current institutional guidelines). In all cases, blood counts must have returned to baseline 
levels before resuming chemotherapy treatment. 


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5.6.1.2.2 
Phase I Dose Modifications for Non-
Hematologic Toxicity Within a Cycle 
Category 
Grade 
Nab-Paclitaxel 
Gemcitabine 
AZD1775 
Tinnitus 
1 
No dose modification 
No dose modification 
No dose modification 
2 
No dose modification 
No dose modification 
Hold until ≤ grade 1, then reduce 
by one dose level  
3 
No dose modification 
No dose modification 
Hold until ≤ grade 1, then reduce 
by one dose level  
Fatigue 
(lethargy, 
malaise, 
asthenia) 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 2, 
then reduce by one 
dose level 
Hold until ≤ grade 2, 
then reduce by one 
dose level 
Hold until ≤ grade 2, then reduce 
by one dose level 
Peripheral 
sensory 
neuropathya 
1 
No dose modification 
No dose modification 
No dose modification 
2 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
No dose modification 
No dose modification 
3-4 
Discontinue 
May continue. No 
dose modification.  
May continue. No dose 
modification. 
Cutaneous 
toxicity 
1-2 
No dose modification 
No dose modification 
No dose modification 
3 
Hold until ≤ grade 2, 
then reduce by one 
dose level 
Hold until ≤ grade 2, 
then reduce by one 
dose level 
Hold until ≤ grade 2, then reduce 
by one dose level 
4 
Discontinue 
Discontinue 
Discontinue 
Diarrhea 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 2, 
then reduce by one 
dose level 
Hold until ≤ grade 2, 
then reduce by one 
dose level 
Hold until ≤ grade 2, then reduce 
by one dose level 
Mucositis oral 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
Hold until ≤ grade 1, then reduce 
by one dose level 
Vomiting  
 
(All patients 
should receive 
prophylaxis) 
1 
No dose modification 
No dose modification 
No dose modification 
2 
Hold until ≤ grade 1, 
then maintain dose 
level and intensify 
anti-emetics 
Hold until ≤ grade 1, 
then maintain dose 
level and intensify 
anti-emetics 
Hold until ≤ grade 1, then 
maintain dose level and intensify 
anti-emetics 
3 
Hold until ≤ grade 1, 
then reduce by one 
dose level and 
intensify anti-emetics 
Hold until ≤ grade 1, 
then reduce by one 
dose level and 
intensify anti-emetics 
Hold until ≤ grade 1, then reduce 
by one dose level and intensify 
anti-emetics 
4 
Hold until ≤ grade 2, 
then reduce by one 
dose level and 
intensify anti-emetics 
Hold until ≤ grade 2, 
then reduce by one 
dose level and 
intensify anti-emetics 
Hold until ≤ grade 2, then reduce 
by one dose level and intensify 
anti-emetics 
AST and/or ALT 
Bilirubin 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
Hold until ≤ grade 1, then reduce 
by one dose level 


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Category 
Grade 
Nab-Paclitaxel 
Gemcitabine 
AZD1775 
Hepatic failure 
3-4 
Discontinue 
Discontinue 
Discontinue 
All Other Non-
Hematologic 
Toxicitiesb, c 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
Hold until ≤ grade 1, 
then reduce by one 
dose level 
Hold until ≤ grade 1, then reduce 
by one dose level 
a Nab-Paclitaxel treatment should be withheld in patients who experience ≥ Grade 3 peripheral 
neuropathy. Gemcitabine and AZD1775 administration can continue during this period. Nab-Paclitaxel 
treatment may be resumed at the next lower dose level in subsequent cycles after the peripheral 
neuropathy improves to ≤ Grade 1. Patients experiencing peripheral neuropathy that requires a delay in 
scheduled Nab-Paclitaxel dosing for ≥ 14 days will discontinue study treatment. The time to resolution to 
Grade ≤ 1 should be the adverse event duration used for adverse event reporting. 
b Pulmonary embolism if mild or asymptomatic, will be exempt from this requirement. Asymptomatic or 
clinically mild pulmonary embolism can be treated with standard anti-coagulation (see Section 5.7.3) 
without interruption of therapy.  Moderate to severe pulmonary embolism will require permanent 
discontinuation of treatment. 
5.6.2 
Phase II (Arms H and I) Dose Modifications 
The following general rules apply: 
• 
For individual subjects, dose modifications will be based on 
hematologic or non-hematologic toxicity, laboratory test results, 
and clinical assessment on the day of treatment and during the 
previous cycle.  
• 
Laboratory tests must be performed within 3 working days prior to 
treatment administration Day 1 of each cycle. CBC with differential 
and platelet count must be drawn on Day 1, Day 8, and Day 15, 
and results known prior to treatment administration on Day 1, Day 
8, and Day 15, respectively. 
• 
If patient experiences study drug-related toxicities that require a 
delay in scheduled gemcitabine dosing for > 14 days, the patient 
must discontinue all protocol treatment.  
• 
When a dose reduction is required, no dose re-escalation will be 
permitted for the duration of study treatment unless otherwise 
specified in the Dose Modification for Hematologic Toxicity tables 
below. 
• 
If more than one toxicity requiring dose reduction occurs, use 
lowest dose level required.   
• 
If multiple toxicities are seen, the dose administered in 
subsequent cycle should be based on the most severe toxicity 
experienced in the current cycle.  
• 
Patients who require discontinuation of both Nab-Paclitaxel and 
gemcitabine for toxicity will discontinue all protocol therapy. 
• 
Patients who discontinue Nab-Paclitaxel may continue to receive 
gemcitabine and AZD1775. This is expected to be common since 
the cumulative neurotoxicity of Nab-Paclitaxel often requires its 
cessation after 4-6 months. 
Rev. 4/16 


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• 
Patients experiencing peripheral neuropathy that requires a delay 
in scheduled Nab-Paclitaxel dosing for ≥ 14 days will discontinue 
all protocol therapy. 
• 
If AZD1775 is held or discontinued for toxicities solely related to 
AZD1775, Nab-Paclitaxel and gemcitabine therapy should be 
continued. 
• 
Please refer to the respective tables for dose modifications related 
to protocol treatment. 
• 
The study chair or study chair liaison should be contacted for dose 
delays and modifications for all other toxicities not listed in this 
section. 
Dose levels for Nab-Paclitaxel, gemcitabine & AZD1775: 
Dose Level 
Nab-Paclitaxel 
(mg/m2)a 
Gemcitabine 
(mg/m2)a 
AZD1775(mg) 
0 
RP2D 
RP2D 
RP2D 
-1 
TBD 
TBD 
TBD 
-2b 
TBD 
TBD 
TBD 
a. Dose reductions may or may not be concomitant. Please refer to Section 
5.6.2.1 for specific recommendations regarding dose modifications for 
Day 1 of each cycle for hematologic and non-hematologic toxicity, 
respectively. Please refer to Section 5.6.2.2 for specific 
recommendations regarding dose modifications within a cycle for 
hematologic and non-hematologic toxicities, respectively.   
b. A maximum of 2 dose level reductions are allowed.   
5.6.2.1 
Phase II Dose Modifications at Day 1 
In the event dose modifications are required at the 
beginning of a cycle due to AEs or hematologic toxicities, 
doses of Nab-Paclitaxel, gemcitabine and AZD1775 may 
be adjusted as detailed below: 
5.6.2.1.1 
Dose Modifications for Day 1 of Each Cycle 
(Hematologic Toxicity) 
Hematologic nadir (complicated or 
otherwise) anytime in the cycle should be 
used to decide on dose reduction for the 
next cycle. 
Phase II Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity) 
ANC 
 
Platelets 
Timing 
 1,500/mm3 
And 
 100,000/mm3 
Treat on time 
< 1,500/mm3 
Or 
< 100,000/mm3 
Delay by 1 week intervals until recovery 
Key: ANC = Absolute neutrophil count. 
Rev. 4/16 


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5.6.2.1.2 
Dose Modifications for Day 1 of Each Cycle 
(Non-Hematologic Toxicity) 
If more than one grade 4 non-hematologic 
toxicity is seen concurrently as a result of 
therapy patients should be taken off study, 
unless continuation is approved by the 
study chair. 
Phase II Dose Modifications for Day 1 of Each Cycle (Non-Hematologic Toxicity) 
Toxicity/dose 
held 
Nab-Paclitaxel+Gemcitabine+AZD1775 dose this cycle 
Grade 0, 1 or 2 
toxicity 
Same as Day 1 of previous cycle  
Grade 3 toxicity 
Decrease Nab-Paclitaxel, gemcitabine and AZD1775  to next lower 
dose levela 
Grade 4 toxicitya, b 
Off protocol treatmentb 
a. If the toxicity only affects neuropathy, then only Nab-Paclitaxel should be reduced. 
b.  Pulmonary embolism, if mild or asymptomatic, will be exempt from this requirement. 
5.6.2.2 
Phase II Dose Modifications within a Treatment Cycle 
In the event that patients must have treatment delayed 
within a treatment cycle due to toxicities, those doses held 
during a cycle will not be made up.   
Dose modifications due to hematologic toxicity (as 
represented by the blood counts and toxicities, below) 
within a treatment cycle should be adjusted as outlined in 
Section 5.6.2.2.1. Dose modifications due to non-
hematologic toxicity within a treatment cycle should be 
adjusted as outlined in Section 5.6.2.2.2. 


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5.6.2.2.1 
Phase II Dose Modifications for Hematologic Toxicity within a Cycle 
Day 8 Blood 
Counts 
Day 8 
Nab-
Paclitaxel 
Day 8 
Gemcitabine 
Day 8, 9 
AZD1775 
Day 15 Blood 
Counts 
Day 15 Nab-
Paclitaxel 
Day 15 
Gemcitabine 
Day 15, 16 
AZD1775  
Any Day Nab-
Paclitaxel 
Any Day 
Gemcitabine 
Any Day 
AZD1775 
ANC ≥ 
1000/mm3  
and 
Platelets 
≥75,000/mm3 
100% 
100% 
100% 
ANC ≥ 
1000/mm3  
and 
Platelets  
≥ 75,000/mm3 
100% 
100% 
100% 
 
 
 
ANC 500-999 
or 
Platelets 
50,000-
74,999 
Full Dose 
(treat on time) 
+ G-CSFa 
Full Dose 
(treat on time) 
+ G-CSFa 
Full Dose 
(treat on time) 
+ G-CSFa 
 
 
 
ANC < 
500/mm3 
or 
Platelets  
< 50,000/mm3 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
 
 
 
ANC 500-
999/mm3 
or 
Platelets 
50,000-
74,999/mm3 
Decrease 
dose by 1 
level (treat 
on time) 
Decrease 
dose by 1 
level (treat on 
time) 
Decrease 
dose by 1 
level (treat 
on time) 
ANC ≥ 
1000/mm3  
and 
Platelets  
≥ 75,000 
Return to 
Previous 
Dose level 
(treat on time) 
+ G-CSFa 
Return to 
Previous 
Dose level 
(treat on time) 
+ G-CSFa 
Return to 
Previous Dose
level (treat on 
time) + 
G-CSFa 
 
 
 
ANC 500-
999/mm3 
or 
Platelets 
50,000-
74,999/mm3 
Same Dose 
(as Day 8, 
treat on time) 
+ G-CSFa 
Same Dose 
(as Day 8, 
treat on time) 
+ G-CSFa 
Same Dose 
(as Day 8, 
treat on time) 
+ G-CSFa 
 
 
 
ANC < 
500/mm3 
or 
Platelets  
< 50,000/mm3 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
 
 
 


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Day 8 Blood
Counts 
Day 8 
Nab-
Paclitaxel 
Day 8 
Gemcitabine 
Day 8, 9 
AZD1775 
Day 15 Blood 
Counts 
Day 15 Nab-
Paclitaxel 
Day 15 
Gemcitabine 
Day 15, 16 
AZD1775 
Any Day Nab-
Paclitaxel 
Any Day 
Gemcitabine 
Any Day 
AZD1775 
ANC < 
500/mm3 
or 
Platelets  
< 
50,000/mm3 
Hold 
Hold 
Hold 
ANC ≥ 
1000/mm3  
and 
Platelets  
≥ 75,000/mm3 
Decrease 
Day 8 dose 
by 1 level 
(treat on 
time) + 
G-CSFa 
Decrease 
Day 8 dose 
by 1 level 
(treat on 
time) + 
G-CSFa 
Decrease 
Day 8 dose 
by 1 level 
(treat on 
time) + 
G-CSFa 
 
 
 
500-999/mm3 
or 
Platelets 
50,000-
74,999/mm3 
Decrease 
Day 8 dose 
by 1 level 
(treat on 
time) + 
G-CSFa 
Decrease 
Day 8 dose 
by 1 level 
(treat on 
time) + 
G-CSFa 
Decrease 
Day 8 dose 
by 1 level 
(treat on 
time) + 
G-CSFa 
 
 
 
ANC < 
500/mm3 or 
Platelets  
< 50,000/mm3 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
Hold + 
G-CSFa 
 
 
 
Febrile 
Neutropenia
(Grade 3 or 
4) 
 
 
 
 
 
 
 
Hold. Upon 
resuming 
dosing, 
decrease to 
next lower level 
and do not 
re-escalate 
throughout the 
rest of 
treatment. 
Hold. Upon 
resuming 
dosing, 
decrease to 
next lower level 
and do not 
re-escalate 
throughout the 
rest of 
treatment. 
Hold.  Upon 
resuming 
dosing, 
decrease to 
next lower level 
and do not 
re-escalate 
throughout the 
rest of 
treatment. 
Recurrent  
Febrile 
Neutropenia 
(Grade 3 or 
4)b 
 
 
 
 
 
 
 
Decrease to 
next lower 
dose level and 
do not 
re-escalate 
throughout the 
rest of 
treatment. 
Decrease to 
next lower 
dose level and 
do not 
re-escalate 
throughout the 
rest of 
treatment 
Decrease to 
next lower 
dose level and 
do not 
re-escalate 
throughout the 
rest of 
treatment 
Abbreviations:  ANC = Absolute neutrophil count; G-CSF = Granulocyte colony stimulating factor. 
a G-CSF is optional if descent only affects platelets. For the prevention of neutropenia or febrile neutropenia, granulocyte colony stimulating factors 
(G-CSF) may be administered throughout the study, in order to maintain adequate blood counts. If G-CSF is used for the prevention of 
neutropenia or febrile neutropenia, it may be administered from days 10-13 (total of 4 days) and/or days 17-20 (total of 4 days) after the most 


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Version Date: October 18, 2016 
 
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83 
recent systemic therapy. G-CSF is not permitted within 48 hours prior to or following any systemic therapy. Pegfilgrastim (Neulasta) is not 
permitted in this study. G-CSF may be given according to institutional guidelines for the treatment of neutropenic fever or infections associated 
with neutropenia. Patients not experiencing resolution of neutropenia within 14 days, despite uninterrupted G-CSF treatment, will discontinue 
study treatment. The use of G-CSF and the associated dose and schduleing is entirely per the discretion of the treating physican. 
b If patients do not experience resolution of neutropenia within 14 days, despite uninterrupted G-CSF treatment, study treatment will be 
discontinued. 
c Patients with Grade 4 fever (regardless of neutrophil count) should have their chemotherapy treatment interrupted. A full sepsis diagnostic work-
up should be performed while continuing broad spectrum antibiotics. If cultures are positive, the antibiotic may or may not be changed, depending 
on the sensitivity profile of the isolated organism. Patients with persisting fever after 3 weeks, despite uninterrupted antibiotic treatment, will 
discontinue study treatment. Febrile neutropenic patients can also receive G-CSF, in addition to antibiotic treatment, to hasten the resolution of 
their febrile neutropenia (following current institutional guidelines).  In all cases, blood counts must have returned to baseline levels before 
resuming chemotherapy treatment. 


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84 
5.6.2.2.2 
Dose Modification for Non-Hematologic 
Toxicity Within a Cycle 
Category 
Grade 
Nab-Paclitaxel 
Gemcitabine 
AZD1775 
Tinnitus 
1 
No dose modification 
No dose modification 
No dose modification 
2-3 
No dose modification 
No dose modification 
Hold until ≤ grade 1, then 
reduce by one dose level  
Fatigue 
(lethargy, 
malaise, 
asthenia) 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 2, then 
reduce by one dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
Peripheral 
sensory 
neuropathya 
1 
No dose modification 
No dose modification 
No dose modification 
2 
Hold until ≤ grade 1, then 
reduce by one dose level 
No dose modification 
No dose modification 
3-4 
Discontinue 
May continue. No dose 
modification.  
May continue. No dose 
modification. 
Cutaneous 
toxicity 
1-2 
No dose modification 
No dose modification 
No dose modification 
3 
Hold until ≤ grade 2, then 
reduce by one dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
4 
Discontinue 
Discontinue 
Discontinue 
Diarrhea 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 2, then 
reduce by one dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
Hold until ≤ grade 2, then 
reduce by one dose level 
Mucositis 
oral 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
Vomiting  
(All patients 
should 
receive 
prophylaxis) 
1 
No dose modification 
No dose modification 
No dose modification 
2 
Hold until ≤ grade 1, then 
maintain dose level and 
intensify anti-emetics 
Hold until ≤ grade 1, then 
maintain dose level and 
intensify anti-emetics 
Hold until ≤ grade 1, then 
maintain dose level and 
intensify anti-emetics 
3 
Hold until ≤ grade 1, then 
reduce by one dose level 
and intensify anti-emetics 
Hold until ≤ grade 1, then 
reduce by one dose level 
and intensify anti-emetics 
Hold until ≤ grade 1, then 
reduce by one dose level 
and intensify anti-emetics 
4 
Hold until ≤ grade 2, then 
reduce by one dose level 
and intensify anti-emetics 
Hold until ≤ grade 2, then 
reduce by one dose level 
and intensify anti-emetics 
Hold until ≤ grade 2, then 
reduce by one dose level 
and intensify anti-emetics 
AST and/or 
ALT 
Bilirubin 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hepatic 
failure 
3-4 
Discontinue 
Discontinue 
Discontinue 
All Other 
Non-
Hematologic 
Toxicitiesb, c 
1-2 
No dose modification 
No dose modification 
No dose modification 
3-4 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
Hold until ≤ grade 1, then 
reduce by one dose level 
a Nab-Paclitaxel treatment should be withheld in patients who experience ≥ Grade 3 peripheral neuropathy.  
Gemcitabine and AZD1775 administration can continue during this period. Nab-Paclitaxel treatment may be 


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Version Date: October 18, 2016 
 
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resumed at the next lower dose level in subsequent cycles after the peripheral neuropathy improves to ≤ Grade 1. 
Patients experiencing peripheral neuropathy that requires a delay in scheduled Nab-Paclitaxel dosing for ≥ 14 days 
will discontinue study treatment. The time to resolution to Grade ≤ 1 should be the adverse event duration used for 
adverse event reporting. 
b Pulmonary embolism , if mild or asymptomatic, will be exempt from this requirement. Asymptomatic or clinically 
mild pulmonary embolism can be treated with standard anti-coagulation (see Section 5.7.3) without interruption 
of therapy.  Moderate to severe pulmonary embolism will require permanent discontinuation of treatment. 
5.7 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
Information on possible interactions with other agents for patients and their 
caregivers and non-study health care team is provided in Appendix VIII. 
Anxiolytics and analgesics may be provided at treating physician's discretion. 
5.7.1 
Anti-emetics: 
• 
Patients must be premedicated for nausea with palenosetron 0.25 
mg/Dexamethasone 16 mg IV over 15 minutes. The anti-emetic 
regimen may substitute ondansetron for palenosetron per the 
treating physician’s discretion. 
• 
Coadministration with administration with NK-1 antagonists (e.g. 
aprepitant or fosaprepitant) must be avoided due to possible drug-
drug interaction with AZD1775. 
5.7.2 
Growth Factors 
• 
For low white blood cell counts, G-CSF (filgrastim, Neupogen) 
may be used, however, routine prophylactic use of G-CSF is not 
recommended. Due to the treatment schedule, G-CSF (filgrastim, 
Neupogen) is preferred (see dose modification guidelines, Section 
5.6) Pegfilgrastim (Neulasta) is not permitted in this study. ASCO 
guidelines should be followed. Therapeutic G-CSF use in patients 
with serious neutropenic complications such as tissue infections, 
sepsis syndrome, fungal infection, etc., may be given at the 
investigator’s discretion and should follow ASCO Guidelines for G-
CSF use. The use of G-CSF and the associated dose and 
scheduling is entirely per the discretion of the treating physician. 
• 
Erythropoietin Stimulating Agents (ESA): Please follow ASCO 
guidelines for the use of ESA in patients diagnosed with cancer. 
5.7.3 
Anticoagulant Use 
• 
Prophylactic anticoagulation will be allowed during therapy 
provided the activity of the agent used is reflected in either INR or 
PPT and that those parameters remain as follows: INR < 1.5 or 
PTT within normal limits 
• 
Anticoagulation for therapeutic use of treatment of DVT or PE is 
allowed. 
5.7.4 
Prohibited Treatments 
• 
NK-1 antagonists (e.g. aprepitant or fosaprepitant) 
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• 
Any concurrent anticancer therapy including but not limited to 
chemotherapy, radiotherapy, hormonal therapy (except megestrol 
acetate as supportive care), immunotherapy, locoregional therapy, 
other investigational agents, or immunosuppressive therapies. 
• 
Medications that may cause QTc prolongation are prohibited. See 
Appendix VII. 
5.7.5 
CYP3A4 inhibitors and CYP3A4 substrates 
Drugs known to be moderate or potent inhibitors or inducers of 
CYP3A4 or sensitive CYP3A4 substrates or substrates of CYP3A4 
with narrow therapeutic window which cannot be discontinued two 
weeks prior to Day 1 dosing, and withheld throughout the study until 2 
weeks after the last dose of AZD1775 are prohibited. See Appendix 
VI.  
5.7.6 
CYP2C19 substrates 
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. See 
Appendix VI.  
5.7.7 
P-glycoprotein (P-gp) inhibitors and substrates 
Avoiding concomitant use are inhibitors or substrates of P-
glycoprotein should be strongly considered. AZD1775 is a substrate of 
P-gp. See Appendix VI. 
5.7.8 
BRCP inhibitors 
The use of Atoravastatin is prohibited in the current study. Other 
drugs where the disposition is mediated via BCRP should be 
administered with caution. See Appendix VI. 
5.7.9 
Substrates of CYP2C8 
Caution should be exercised with concomitant administration of 
AZD1775 and agents that are sensitive substrates of CYP2C8, or 
substrates of this enzyme with narrow therapeutic range. See 
Appendix VI. 
5.7.10 
Substrates of CYP2C9 
Caution should be exercised with concomitant administration of 
AZD1775 and agents that are sensitive substrates of CYP2C9, or 
substrates of this enzyme with narrow therapeutic range. See 
Appendix VI. 
5.7.11 
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. Subjects should stop using these herbal medications 7 days 
prior to first dose of AZD1775. 


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5.8 
Duration of Therapy – Phase I and Phase II 
Patients will receive protocol treatment unless: 
5.8.1 
Patient has disease progression per Section 6.1.4. 
5.8.2 
Patient experiences unacceptable toxicity or DLT. 
5.8.3 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued.  
5.8.4 
Patient withdraws consent. 
5.8.5 
Patient receives any non-protocol therapies. 
5.9 
Duration of Follow-up – Phase I and Phase II 
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated and for survival for 2 years from the date of registration/randomization. 
All patients must also be followed through completion of all protocol therapy. 


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6. 
Measurement of Effect  
6.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients must be re-evaluated for response every 
8 weeks. 
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before registration. 
2. All measurements should be recorded in metric notation by use of a ruler or 
calipers. 
3. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up. 
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the 
definitions stated below.  (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered 
evaluable.) 
Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but 
do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target lesion assessment. The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 
with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE:  
Tumor lesions that are situated in a previously irradiated 
area are not considered measurable. 


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Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE:  
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum 
of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
disease 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of 


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these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up. 
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than 4 weeks before registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm 
in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung. However, 
CT is preferable. 
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up must 
be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
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PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next.  If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.   
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor 
has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 


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6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progression, See Section 
6.1.4.3). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 8 weeks. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase. 


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When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy.      
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it: 
a) increases in size to ≥ 15 mm in the short axis, or  
b) there is new pathological confirmation that it is disease 
(regardless of size). 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). The 
patient’s best response assignment will depend on the 
achievement of both measurement and confirmation 
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Table 6.1: Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not 
evaluated 
No 
PR 
SD 
Non-PD***/not 
evaluated 
No 
SD 
Documented at least once 
≥ 8 wks. from study entry 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease (Section 6.1.4.2) for further explanation. 
NOTE:  Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 8 weeks 


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7. 
Study Parameters 
7.1 
Phase I Therapeutic Parameters  
1. To be completed within 5 days before registration: 
• 
Pregnancy test 
2. To be completed within 14 days before registration: 
• 
Pre-study labs including CBC (with differential and platelet count) and chemistries, unless otherwise specified  
3. To be completed within 28 days before registration: 
• 
CT of chest  
• 
CT and/or MRI of abdomen and pelvis 
 
Baseline 
requirements1 
Day 1 of each 
cycle 
Days 8 and 15 of 
each cycle 
Every 2 cycles 
(every 8 weeks) 
Post Treatment8 
Tests & Observations 
 
 
 
 
 
History & Progress Notes2 
X 
X 
 
 
X 
Physical Examination2 
X 
X 
 
 
X 
Pulse, Blood Pressure2 
X 
X 
 
 
 
Height 
X 
 
 
 
 
Weight/BSA2 
X 
X 
 
 
 
Performance Status2 
X 
X 
 
 
 
Tumor Measurements2 
X 
 
 
X 
X 
Adverse Events Assessment2 
 
X 
  X10 
 
  X11 
Capsule Diary 
 
X 
 
 
 
EKG9 
X 
 
 
X 
X 
Laboratory Studies 
 
 
 
 
 
CBC with Differential, Platelets3 
X 
 X3 
 X3 
 
 
Serum Electrolytes2,4 
X 
X 
 
 
 
Other Serum Chemistry2,5 
X 
X 
 
 
 
CA 19-92 
X 
 
 
X 
 
Serum or Urine Pregnancy Test 7 
X 
 
 
 
 
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Radiographic Studies2,6 
X 
 
 
X 
X 
1. Baseline requirements must be assessed prior to registration as outlined in Section 3. Blood tests must be performed ≤ 2 weeks prior to 
registration. CT and/or MRI must be performed ≤ 4 weeks prior to registration.  
2. After Cycle 2, the following assessments may be scheduled with a +/- 3 day leeway. History and Progress Notes, including Physical 
Examination; Pulse, Blood Pressure; Weight/BSA; Performance Status; Adverse Events Assessment, Serum Electrolytes; Other Serum 
Chemistry, CA-19-9; Radiographic Studies; and Tumor Measurements. 
3. CBC with differential and platelet count required prior to each dose of gemcitabine (days 1, 8, and 15) and should be checked on the day of 
study treatment. For cycle 1 only: CBC with differential and platelet count should be checked on days 1, 8, 15 and 22. 
4. Serum electrolytes: Glucose, Na+, K+, bicarbonate, BUN, Cl, creatinine – every cycle 
5. Other serum chemistries: Albumin, total protein, alkaline phosphatase, SGOT(AST), SGPT(ALT), total bilirubin; Ca++, Mg++, phosphorus - 
every cycle. 
6. CT of chest, abdomen and pelvis. If only MRI of the abdomen and/or pelvis is available, this can be substituted, for CT of abdomen and/or 
pelvis, but CT of chest should still be obtained. Contrast agents should be administered.   
7. For women of childbearing potential. Must be done ≤ 5 days prior to registration. 
8. After completion of protocol treatment, monitor for survival, adverse events, and scans every 3 months until patient is 2 years from registration. 
Follow-up is no longer required after patient is more than 2 years from registration. Once the patient progresses, adverse event assessments 
and scans no longer need to be performed. 
9. EKG to be performed at baseline for phase I study (Arm B, C, D, E, F and G) only. Additional EKGs will be collected prior to and approximately 
2 hours after study drug AZD1775 (matching PK time points) on Cylce 1 Day 1 and Cycle 1 Day 16. Starting with Cycle 3, EKGs will be 
collected every 2 cycles prior to treatment and at end of protocol treatment. All EKGs should be performed in triplicate. 
10. Cycle 1 only. Patients must be evaluated for adverse events on a weekly basis during the first cycle of treatment (4 weeks total). See 
Section 5.1.3.6. 
11. Adverse Events Assessment is required 30 days after last dose of protocol therapy. 
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7.1.1 
Phase I Biospecimen Submissions 
The collection and submission of pharmacokinetic blood samples is 
MANDATORY. Guidelines for sample submissions are outlined in 
Section 11. 
All samples must be logged and tracked via the ECOG-ACRIN Sample 
Tracking System (STS). All times are relative to time of administration of 
AZD1775. 
 
 
 
Time pt 
abbreviation 
Time point of draw 3 mL EDTA vacutainer 
Process and submit PLASMA 
Visit: Cycle 1 Day 1 
1 
C1D1-0h 
Cycle 1, Day 1, Prior to AZD1775 administration 
2 
C1D1-1h 
Cycle 1, Day 1, 1 hour 
3 
C1D1-2h 
Cycle 1, Day 1, 2 hours 
4 
C1D1-4h 
Cycle 1, Day 1, 4 hours 
5 
C1D1-6h 
Cycle 1, Day 1, 6 hours 
6 
C1D1-8h 
Cycle 1, Day 1, 8 hours 
7 
C1D1-24h 
Cycle 1, Day 2, 24 hours after Day 1 AZD1775 administration (prior to day 
2 administration of AZD1775) 
Visit: Cycle 1 Day 16 
8 
C1D16-0h 
Cycle 1, Day 16, Prior to AZD1775 administration 
9 
C1D16-1h 
Cycle 1, Day 16, 1 hour 
10 
C1D16-2h 
Cycle 1, Day 16, 2 hours 
11 
C1D16-4h 
Cycle 1, Day 16, 4 hours 
12 
C1D16-6h 
Cycle 1, Day 16, 6 hours 
13 
C1D16-8h 
Cycle 1, Day 16, 8 hours 
14 
C1D16-24h 
Cycle 1, Day 17 (24 hours after Day 16 AZD1775 administration) – 
strongly encouraged but not required 


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7.2 
Phase II Therapeutic Parameters  
1. To be completed within 5 days before randomization: 
• 
Pregnancy test 
2. To be completed within 14 days before randomization: 
• 
Prestudy labs including CBC (with differential and platelet count) and chemistries, unless otherwise specified.  
3. To be completed within 28 days before randomization: 
• 
CT of chest  
• 
CT or MRI of abdomen and pelvis 
 
Baseline1 
Day 1 of each 
cycle 
Days 8 and 15 of 
each cycle 
Every 2 cycles (every 
8 weeks) 
Post 
Treatment8 
Tests & Observations 
 
 
 
 
 
History & Progress Notes2 
X 
X 
 
 
X 
Physical Examination2 
X 
X 
 
 
X 
Pulse, Blood Pressure2 
X 
X 
 
 
 
Height 
X 
 
 
 
 
Weight/BSA2 
X 
X 
 
 
 
Performance Status2 
X 
X 
 
 
 
Tumor Measurements2 
X 
 
 
X 
X 
Adverse Events Assessment2 
 
X 
 
 
 X9 
Capsule Diary 
 
X 
 
 
 
Laboratory Studies 
 
 
 
 
 
CBC with Differential, Platelets 
X 
 X3 
X 
 
 
Serum Electrolytes2,4 
X 
X 
 
 
 
Other Serum Chemistry2,5 
X 
X 
 
 
 
CA 19-92 
X 
 
 
X 
 
Serum or Urine Pregnancy Test 7 
X 
 
 
 
 
Radiographic Studies2,6 
X 
 
 
X 
X 


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1. Baseline requirements must be assessed prior to randomization as outlined in Section 3. Blood tests must be performed ≤ 2 weeks prior to 
randomization. CT and/or MRI must be performed ≤ 4 weeks prior to randomization.  
2. After Cycle 1, the following assessments may be scheduled with a +/- 3 day leeway. History and Progress Notes, including Physical 
Examination; Pulse, Blood Pressure; Weight/BSA; Performance Status; Adverse Events Assessment, Serum Electrolytes; Other Serum 
Chemistry, CA-19-9; Radiographic Studies; and Tumor Measurements. 
3. CBC with differential and platelet count required prior to each dose of gemcitabine (days 1, 8, and 15) and should be checked on the day of 
study treatment.  
4. Serum electrolytes: Glucose, Na+, K+, bicarbonate, BUN, Cl, creatinine – every cycle 
5. Other serum chemistries: Albumin, total protein, alkaline phosphatase, SGOT(AST), SGPT(ALT), total bilirubin; Ca++, Mg++, phosphorus - 
every cycle. 
6. CT of chest, abdomen and pelvis. If only MRI of the abdomen and/or pelvis is available, this can be substituted, for CT of abdomen and/or 
pelvis, but CT of chest should still be obtained. Contrast agents should be administered.   
7. For women of childbearing potential. Must be done within 5 days prior to randomization. 
8. After completion of protocol treatment, monitor for survival, adverse events, and scans every 3 months until patient is 2 years from registration. 
Follow-up is no longer required after patient is more than 2 years from registration. Once the patient progresses, adverse event assessments 
and scans no longer need to be performed.. 
9. Adverse Events Assessment is required 30 days after last dose of protocol therapy. 


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7.2.1 
Phase II Submissions for Central Review and Ancillary Studies  
Imaging studies guidelines are provided in Section 10. 
Specimens are to be submitted as outlined in Section 12. All samples 
submitted must be entered and tracked via the online ECOG-ACRIN 
Sample Tracking System (STS). 
 
Baseline 
Cycle 1 day 
2 
Cycle 1, day 25 ± 3 days 
(prior to start of Cycle 2 
Treatment) 
Submit to: 
Specimen submissions (Section 12): Submit from patients who answer “Yes” to “I agree to have 
my samples collected and I agree that my samples and related information may be used for the 
laboratory studies described above.” 
Tumor Tissue – 
FFPE2 
X 
 
 
CBPF 
Hair follicles in 
NBF1  
X 
X 
 
Imaging Studies - Limited Institution: Patients from ACRIN-qualified participating sites who are 
participating in either or both imaging studies. Patients may participate in only one of the imaging 
substudies, and to do so must consent to participate in the relevant imaging study and must meet 
the appropriate eligibility criteria as outlined in Section 3.2.26. Patients participating in an imaging 
study must have laboratory values and adverse events monitored as outlined in Section 10.4, 
including Table 10.1 and related footnotes.  
FLT-PET3,5 
X 
X 
 
ACRIN 
FDG-PET4,5 
X 
 
X 
1. Time of specimen collection AND time of administration of treatment (if applicable) must be reported 
with the sample submission.  
2. Representative tumor tissue block from previous biopsy or surgery. Pathology reports and completed 
ECOG-ACRIN Generic Specimen Submission Form (#2981)must accompany all tissue submissions. 
3. FLT-PET to be performed pre-treatment (within 2 weeks prior to randomization), and again at day 2 
(20-24 hours) after initiation of cycle 1. A limited number of sites will perform the FLT-PET studies. 
FLT-PET study consent language will be included in local IRB reviews and approvals only at qualified 
participating sites. 
4. FDG-PET to be performed pre-treatment (within 2 weeks prior to randomization) and again at day 25 
± 3 days after initiation of cycle 1 only (prior to the start of cycle 2). FDG-PET sub-study qualification 
through the ACR Imaging Core Laboratory will be open to all ECOG-ACRIN membership sites for 
participation. Similarly, FDG-PET study consent language will be included in local IRB reviews and 
approvals only at qualified participating sites. 
5. Patients on FDG-PET study will not be enrolled in the FLT-PET study and vice versa. 
 


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8. 
Drug Formulation and Procurement 
Availability 
Drug Ordering: NCI supplied agents may be requested by the Principal Investigator (or 
their authorized designee) at each participating institution. Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where the 
patient is to be treated. PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained.) The CTEP assigned protocol number must 
be used for ordering all CTEP supplied investigational agents. The responsible 
investigator at each participating institution must be registered with CTEP, DCTD 
through an annual submission of FDA form 1572 (Statement of Investigator), Curriculum 
Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  
If there are several participating investigators at one institution, CTEP supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application: https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx.  
Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of 
an “active” account status and a “current” password. For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
NCI Supplied Agents – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time. 
Drug Returns: Only undispensed drug supplies (no partial bottles) should be returned to 
the PMB. When it is necessary to return study drug (e.g., sealed vials remaining when a 
patient permanently discontinues protocol treatment, expired vials recalled by the PMB), 
investigators must return the study drug to the PMB using the NCI Return Agent Form 
available on the NCI home page (http://ctep.cancer.gov) or by calling the PMB at (240) 
276-6575. 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of all 
drugs received from the PMB using the NCI Investigational Agent Accountability Record 
available on the NCI home page (http://ctep.cancer.gov) or by calling the PMB at (240) 
276-6575. These forms will be reviewed for accuracy and completeness during NCI 
cooperative group quality assurance audits. 
8.1 
Nab-Paclitaxel 
8.1.1 
Other Names  
ABI-007, nab-paclitaxel, paclitaxel protein-bound particles for 
injectable suspension 
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8.1.2 
Classification  
Antimicrotubular, Taxane Derivative 
8.1.3 
Mode of Action  
Nab-Paclitaxel is a biologically interactive albumin-bound paclitaxel 
combining a protein with a chemotherapeutic agent in the particle 
form. This composition provides a novel approach of increasing intra-
tumoral concentrations of the drug by a receptor-mediated transport 
process allowing transcytosis across the endothelial cell. This 
albumin-specific receptor mediated process involves the binding of 
albumin to a specific receptor (gp60) on the intralumminal endothelial 
cell membrane, resulting in activation of a protein (caveolin-1), which 
initiates an internalization process in the endothelial cell through the 
formation of caveolae, with transport of the intact albumin-bound 
chemotherapeutic complex via these caveolae to the underlying tumor 
interstitium (Desai et al, 2004). A protein specifically secreted by the 
tumor (SPARC) binds albumin, allowing release of the hydrophobic 
drug to the tumor cell membrane (Desai et al, 2004). Nab-Paclitaxel is 
the first biologically interactive nanoparticle product leveraging this gp-
60/caveolin-1/caveolae/SPARC pathway to increase intra-tumoral 
concentration of the drug and reducing toxic effects in normal tissue. 
8.1.4 
Storage and Stability  
Storage: 
Store the vials in original cartons at 20º C to 25º C (68º F 
to 77ºF). Retain in the original package to protect from 
bright light.  
Stability: 
Unopened vials of Nab-Paclitaxel are stable until the date 
indicated on the package when stored between 20ºC to 
25ºC (68ºF to 77ºF), in the original package. Neither 
freezing nor refrigeration adversely affects the stability of 
the product. 
Stability of Reconstituted Suspension in the Vial  
Reconstituted Nab-Paclitaxel should be used immediately, but may be 
refrigerated at 2ºC to 8ºC (36ºF to 46ºF) for a maximum of 8 hours if 
necessary. If not used immediately, each vial of reconstituted 
suspension should be replaced in the original carton to protect it from 
bright light. Discard any unused portion. 
Stability of Reconstituted Suspension in the Infusion Bag  
The suspension for infusion prepared as recommended in an infusion 
bag should be used immediately, but may be stored at ambient 
temperature (approximately 25º C) and lighting conditions for up to 8 
hours.  
8.1.5 
Dose Specifics  
100-125 mg/m2 IV over 30 minutes on days 1, 8, and 15 of each cycle 
as outlined in Administration Schedule (Sections 5.1.3 and 5.2.2). The 
use of an in-line filter is not recommended. 
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8.1.6 
Reconstitution and use of Nab-Paclitaxel 
1. Calculate the patient’s body surface area at the beginning of the 
study and if the weight changes by > 10% by using the Mosteller 
formula. 
2. Calculate the total dose (in mg) to be administered by:  
• 
Total Dose (mg) = BSA x (study dose mg/m2 ) 
3. Calculate the total number of vials required by: 
Total Number of Vials = Total Dose (mg) 
 
100 (mg/vial) 
Round up the number of vials to be reconstituted to the next 
higher whole number when a fractional number of vials is obtained 
by the above formula (e.g., if the total number of vials = 4.05 or 
4.5, then 5 vials would be reconstituted).  
4. Using sterile technique, prepare the vials for reconstitution. 
5. Swab the rubber stoppers with alcohol. 
6. Aseptically, reconstitute each Nab-Paclitaxel vial by injecting 20 mL 
of 0.9% Sodium Chloride Injection, USP. 
• 
Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, 
USP, over a minimum of 1 minute, using the sterile syringe 
directing the solution flow onto the inside wall of the vial. 
• 
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP 
solution directly onto the lyophilized cake as this will result in 
foaming. 
• 
Once the injection is complete, allow the vial to sit for a 
minimum of 5 (five) minutes to ensure proper wetting of the 
lyophilized cake/powder.   
• 
Gently swirl and/or invert the vial slowly for at least 2 
minutes until complete dissolution of any cake/powder occurs.  
Avoid generation of foam.  Rapid agitation or shaking will 
result in foaming. 
• 
If foaming or clumping occurs, stand solution for at least 15 
minutes until foam subsides. 
• 
Each ml of reconstituted product will contain 5 mg of 
paclitaxel. 
7. Calculate the exact total dosing volume of 5 mg/ml suspension 
required for the patient: 
• 
Dosing volume (ml) = Total dose (mg) / 5 (mg/ml) 
8. The reconstituted suspension should be milky and homogeneous 
without visible particulates. If particulates or settling are visible, 
the vial should be gently inverted again to ensure complete 
resuspension prior to use. Discard the reconstituted suspension if 
precipitates are observed.  
9. Once the exact volume of reconstituted Nab-Paclitaxel has been 
withdrawn from the vials, discard any excess solution left over in 
accordance with standard operating procedures. 


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10. Further dilution is not necessary. Inject the calculated dosing 
volume of reconstituted Nab-Paclitaxel suspension into an empty 
sterile, standard PVC IV bag using an injection port. Inject 
perpendicularly into the center of the injection port to avoid 
dislodging plastic material into the IV bag. 
11. Administer the calculated dosing volume of reconstituted Nab-
Paclitaxel suspension by IV infusion over 30 minutes.  The use of 
in-line filters is not recommended because the reconstituted 
solution may clog the filter. 
8.1.7 
Route of Administration  
IV infusion 
8.1.8 
Availability 
Nab-Paclitaxel is commercially available.  
8.1.9 
Side Effects  
Hematologic Effects 
Neutropenia was dose dependent and reversible. Among patients with 
metastatic breast cancer in the randomized trial, neutrophil counts 
declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated 
with a dose of 260 mg/m2 compared to 22% in patients receiving 
paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been 
observed in clinical trials. 
Infections 
Infectious episodes were reported in 24% of the patients treated with 
Nab-Paclitaxel. Oral candidiasis, respiratory tract infections and 
pneumonia were the most frequently reported infectious 
complications. 
Hypersensitivity Reactions (HSRs) 
Grade 1 or 2 HSRs occurred on the day of Nab-Paclitaxel 
administration and consisted of dyspnea (1%) and flushing, 
hypotension, chest pain, and arrhythmia (all < 1%). The use of Nab-
Paclitaxel in patients previously exhibiting hypersensitivity to paclitaxel 
injection or human albumin has not been studied. 
Cardiovascular 
Hypotension, during the 30-minute infusion, occurred in 5% of 
patients. Bradycardia, during the 30-minute infusion, occurred in < 1% 
of patients. These vital sign changes most often caused no symptoms 
and required neither specific therapy nor treatment discontinuation. 
Severe cardiovascular events possibly related to single-agent Nab-
Paclitaxel occurred in approximately 3% of patients. These events 
included cardiac ischemia/infarction, chest pain, cardiac arrest, 
supraventricular tachycardia, edema, thrombosis, pulmonary 
thromboembolism, pulmonary emboli, and hypertension. Cases of 
cerebrovascular attacks (strokes) and transient ischemic attacks have 
been reported. Electrocardiogram (ECG) abnormalities were common 


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among patients at baseline. ECG abnormalities on study did not 
usually result in symptoms, were not dose-limiting, and required no 
intervention. ECG abnormalities were noted in 60% of patients. 
Among patients with a normal ECG prior to study entry, 35% of all 
patients developed an abnormal tracing while on study. The most 
frequently reported ECG modifications were non-specific 
repolarization abnormalities, sinus bradycardia, and sinus 
tachycardia. 
Respiratory 
Dyspnea (12%), cough (7%), and pneumothorax (< 1%) were 
reported after treatment with Nab-Paclitaxel. 
Neurologic 
The frequency and severity of sensory neuropathy increased with 
cumulative dose. Sensory neuropathy was the cause of Nab-
Paclitaxel discontinuation in 7/229 (3%) patients. Twenty-four patients 
(10%) treated with Nab-Paclitaxel developed Grade 3 peripheral 
neuropathy; of these patients, 14 had documented improvement after 
a median of 22 days; 10 patients resumed treatment at a reduced 
dose of Nab-Paclitaxel and 2 discontinued due to peripheral 
neuropathy. Of the 10 patients without documented improvement, 4 
discontinued the study due to peripheral neuropathy. No Grade 4 
sensory neuropathies were reported. Only one incident of motor 
neuropathy (Grade 2) was observed in either arm of the controlled 
trial. 
Vision Disorders 
Ocular/visual disturbances occurred in 13% of all patients (n=366) 
treated with Nab-Paclitaxel and 1% were severe. The severe cases 
(keratitis and blurred vision) were reported in patients who received 
higher doses than those recommended (300 or 375 mg/m2). These 
effects generally have been reversible. 
Arthralgia/Myalgia 
The symptoms were usually transient, occurred two or three days 
after Nab-Paclitaxel administration, and resolved within a few days. 
Hepatic 
Grade 3 or 4 elevations in GGT were reported for 14% of patients 
treated with Nab-Paclitaxel and 10% of patients treated with paclitaxel 
injection in the randomized trial. 
Renal 
Overall 11% of patients experienced creatinine elevation, 1% severe. 
No discontinuations, dose reductions, or dose delays were caused by 
renal toxicities. 
Other Clinical Events 


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Nail changes (changes in pigmentation or discoloration of nail bed) 
have been reported. Edema occurred in 10% of patients; no patients 
had severe edema. Dehydration and pyrexia were also reported. 
8.1.10 
Nursing/Patient Implications  
Nab-Paclitaxel is injected into a vein [intravenous (I.V.) infusion] over 
30 minutes. The use of an in-line liter is not recommended. 
8.1.11 
References  
FDA approved package insert. 
8.2 
Gemcitabine 
8.2.1 
Other Names  
2'-Deoxy-2',2'-difluorocytidine monohydrochloride, Gemzar 
8.2.2 
Classification  
Antimetabolite (nucleoside pyrimidine analogue) 
8.2.3 
Mode of Action  
Gemcitabine exhibits cell phase specificity, primarily killing cells 
undergoing DNA synthesis (S phase) and also blocking the 
progression of cells through the G1/S phase boundary. Gemcitabine 
is metabolized intracellularly by nucleoside kinases to the active 
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The 
cytotoxic effect of gemcitabine is attributed to a combination of two 
actions of the diphosphate and the triphosphate nucleosides, which 
leads to inhibition of DNA synthesis. First, gemcitabine diphosphate 
inhibits ribonucleotide reductase, which is responsible for catalyzing 
the reactions that generate the deoxynucleoside triphosphates for 
DNA synthesis. Inhibition of this enzyme by the diphosphate 
nucleoside causes a reduction in the concentrations of 
deoxynucleotides, including dCTP. Second, gemcitabine triphosphate 
competes with dCTP for incorporation into DNA. The reduction in the 
intracellular concentration of dCTP (by the action of the diphosphate) 
enhances the incorporation of gemcitabine triphosphate into DNA 
(self-potentiation). After the gemcitabine nucleotide is incorporated 
into DNA, only one additional nucleotide is added to the growing DNA 
strands. After this addition, there is inhibition of further DNA synthesis. 
DNA polymerase epsilon is unable to remove the gemcitabine 
nucleotide and repair the growing DNA strands (masked chain 
termination). In CEM T lymphoblastoid cells, gemcitabine induces 
internucleosomal DNA fragmentation, one of the characteristics of 
programmed cell 
8.2.4 
Storage and Stability 
Unreconstituted drug vials are stored at controlled room temperature 
(15ºC to 30ºC, 59ºF to 86ºF). Reconstituted solution should be stored 
at controlled room temperature and used within 24 hours. Solutions of 
gemcitabine should not be refrigerated; as crystallization may occur. 
The unused portion should be discarded. 


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8.2.5 
Dose Specifics  
750-1000 mg/m2 IV over 30 minutes on days 1, 8, and 15 of each 
cycle as outlined in Administration Schedule (Sections 5.1.3 and 
Error! Reference source not found.). 
8.2.6 
Preparation  
Gemcitabine may be further diluted with normal saline as per 
institutional standards. 
8.2.7 
Route of Administration  
IV infusion. 
8.2.8 
Availability  
Gemcitabine is commercially available in 200 mg and 1 gm vials 
8.2.9 
Side Effects  
8.2.9.1 
Hematologic: Neutropenia, anemia, thrombocytopenia, and 
leukopenia are reported. 
8.2.9.2 
Dermatologic: A rash is seen in about 25% of patients and 
is associated with pruritus in about 10% of patients. The 
rash is usually mild, not dose-limiting, and responds to 
local therapy. Desquamation, vesiculation, and ulceration 
have been reported rarely. Alopecia is usually minimal. 
Injection-site reactions. 
8.2.9.3 
Gastrointestinal: Nausea and vomiting are reported in 
about two-thirds of patients and requires therapy in about 
20% of patients. It is rarely dose limiting, and is easily 
manageable with standard antiemetics. Diarrhea, 
constipation, mucositis. 
8.2.9.4 
Hepatic: Abnormalities of hepatic transaminase enzymes 
occur in two-thirds of patients, but they are usually mild, 
non-progressive, and rarely necessitate stopping 
treatment. However, gemcitabine should be used with 
caution in patients with impaired hepatic function. 
8.2.9.5 
Pulmonary: Bronchospasm and/or dyspnea within a few 
hours of infusion of the drug, cough, rhinitis, pneumonitis. 
8.2.9.6 
Neurologic: Somnolence, insomnia, paresthesia, pain. 
8.2.9.7 
Cardiovascular: A few cases of hypotension were reported. 
Some cases of myocardial infarction, congestive heart 
failure, and arrhythmias have been reported. Peripheral 
edema is reported in about 30% of patients. 
Some cases of facial edema have also been reported. 
Edema is usually mild to moderate, rarely dose-limiting, 
sometimes painful, and reversible after stopping 
gemcitabine treatment. 
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8.2.9.8 
Other: Flu-like symptoms are reported for about 20% of 
patients. This includes fever, headache, back pain, chills, 
myalgia, asthenia, and anorexia. Malaise and sweating are 
reported. 
8.2.10 
Nursing/Patient Implications 
If the patient reports burning at the injection site, slow down rate to 
allow the dose to run in over 1 hour. 
Rash can be treated with topical therapy or the administration of 
diphenhydramine prior to administration. 
Flu-like symptoms can be treated with acetaminophen. 
8.2.11 
Reference 
FDA-approved package insert. 
8.3 
AZD1775 (NSC 751084)  
8.3.1 
Chemical Name  
2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-
methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-
d]pyrimidin-3-one 
8.3.2 
Other Names  
MK-1775 
8.3.3 
Molecular Formula 
C27H32N8O2·H2O M.W.: 518.623 
8.3.4 
Description 
AZD1775 is a crystalline, non-hygroscopic, monohydrate of the 
neutral drug. It dehydrates upon heating leading to formation of a 
crystalline anhydrate. 
8.3.5 
Classification  
Highly selective, adenosine-triphosphate (ATP) competitive, small 
molecule inhibitor of Wee1 kinase. 
8.3.6 
Mode of Action  
AZD1775 is an inhibitor of the Wee1-kinase. Wee1 is a tyrosine 
kinase upstream of CDC2 thereby involved in regulation of cell cycle 
checkpoints, particularly the G2 checkpoint. As the majority of human 
cancers harbor abnormalities in the p53 pathway they become more 
dependent on S- and G2-phase checkpoints. In preclinical models, 
AZD1775 selectively enhanced chemotherapy-induced death of cells 
deficient in p53 signaling. 
8.3.7 
Storage and Stability 
Store bottles at controlled room temperature, not to exceed 30° C.  
Shelf life studies of AZD1775 are on-going. 
Rev. 4/16 


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8.3.8 
Dose Specifics  
100-175 mg 
8.3.9 
Route of Administration  
Oral administration on days 1, 2, 8, 9, 15, and 16 of each cycle. Take 
AZD1775 one hour prior to or two hours after a meal. 
8.3.10 
Availability  
AZD1775 25 mg capsules and 100 mg capsules are supplied by 
Merck Corp and AstraZeneca and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI as yellow, size 2 gelatin 
capsules. The capsules consist of a roller compacted granule of 
agent, lactose, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. Each high density polyethylene (HDPE) bottle 
contains 20 capsules. 
The pharmaceutical collaborator does not have stability data to 
support repackaging AZD1775 capsules in any container other than 
what is provided. 
8.3.11 
Side Effects  
See Section 5.4 for side effects. 
8.3.12 
Agent Ordering 
NCI-supplied agents may be requested by the Principal Investigator 
(or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that agent 
be shipped directly to the institution where the patient is to be treated.  
PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained). The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied 
investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA Form 1572 (Statement of Investigator), 
Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF). If there are several participating 
investigators at one institution, CTEP-supplied investigational agents 
for the study should be ordered under the name of one lead 
investigator at that institution. 
Active CTEP-registered investigators and investigator-designated 
shipping designees and ordering designees can submit agent 
requests through the PMB Online Agent Order Processing (OAOP) 
application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). 
Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account (https://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password. For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday 
through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
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8.3.13 
Agent Inventory Records 
Agent Accountability: 
The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition 
and return of all drugs received by the PMB using the Drug 
Accountability Record Form available on the NCI home page 
(http://ctep.cancer.gov). 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF. A 
separate NCI Drug Accountability Record Form must be maintained 
for each patient ID number (e.g., “088-xxx”) on this protocol. The 
combination Julian date / order number in the upper right hand corner 
of the patient-specific bottle label (e.g., 12365-9999) should be 
recorded as the lot number. 
Agent Returns:  
Only undispensed drug supplies (no partial bottles) should be 
returned to the PMB. When it is necessary to return study drug (e.g., 
sealed vials remaining when expired vials are recalled by the PMB), 
investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov).   
Agent Transfers:  
Bottles may NOT be transferred from one patient to another patient or 
from one protocol to another protocol. All other transfers (e.g., a 
patient moves from one participating clinical site to another 
participating clinical site, the registering investigator for a given patient 
changes) must be approved in advance by the PMB. To obtain an 
approval for transfer, investigators should complete and submit to the 
PMB (fax number 240-276-7893) a Transfer Investigational Agent 
Form available on the CTEP home page (http://ctep.cancer.gov).  
For questions about drug orders, transfers, returns, or accountability, 
call 240-276-6575 Monday through Friday between 8:30 am and 4:30 
pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
8.3.14 
Nursing/Patient Implications 
Do not open capsules. Wash the exposed area with soap and water 
immediately after direct contact with the drug. 
Patients will be required to record dose of capsules in diary and return 
capsules, bottles and diary with each cycle.  
8.3.14.1 
Potential Drug Interactions: In human liver microsomes, 
AZD1775 is primarily metabolized by CYP450 3A4, so 
exercise caution in patients taking 3A4 inhibitors and 
inducers. It is also a weak reversible inhibitor of CYP2C8, 
2C9, 2C19 and 3A4. Avoid concomitant medications with a 
narrow therapeutic window that are substrates for these 
isoforms. AZD1775 is a p-glycoprotein substrate. 


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8.3.14.2 
Contraindications: Treatment with AZD1775 is 
contraindicated in subjects with hypersensitivity to any 
component of the drug. Developmental and reproductive 
toxicity studies of AZD1775 have not been performed. 
AZD1775 is not to be given to women who are pregnant or 
breast feeding. Women of child-bearing potential and men 
participating in clinical studies of AZD1775 must use 
appropriate contraception throughout the study including 
abstinence and double barrier methods throughout 
treatment.  Contraception use must continue for 3 months 
after the last dose of study treatment. 
8.3.15 
References 
AZD1775 Investigator Brochure 
8.4 
3'-deoxy-3'-[F-18]fluorothymidine (FLT)-PET  
For complete information, please refer to the Investigator’s Brochure: 
“3'-deoxy-3'-[F-18]fluorothymidine: [F-18]FLT, An Investigational Positron 
Emission Tomography (PET) Radiopharmaceutical for Injection and intended for 
use as an in vivo diagnostic for imaging active cellular proliferation of malignant 
tumors”, Edition Number 7, Edition date 2009. 
8.4.1 
Pharmacology and Toxicology 
The pharmacology of FLT is based on its action as an inhibitor of DNA 
synthesis.36-38  Intracellular metabolism of FLT produces nucleotides 
that inhibit endogenous DNA polymerases because they lack a 3'-
hydroxyl substituent. This results in premature chain termination of 
DNA synthesis.39, 40 These biochemical properties can account for 
FLT's prominent hematological and liver toxicity.40-42  The 
pharmacology of FLT closely parallels that of the widely used 
prescription HIV-antiviral drug azidothymidine (AZT).43, 44  Both FLT 
and AZT are 3'-deoxythymidine analogs that act as inhibitors of DNA 
synthesis and are cleared from the body in the same way. However, 
FLT is significantly more cytotoxic than AZT in test cell lines.42 Cellular 
uptake of FLT and thymidine is greater than that of AZT.  Transport of 
FLT and thymidine across cell membranes occurs by active transport 
and passive diffusion.44 
8.4.2 
Toxicity of FLT in Humans 
FLT was investigated as an anti-AIDS drug in humans.41  Toxic effects 
and death were reported for some subjects who received FLT during 
randomized concentration-controlled trials during a 16-week treatment 
of oral multi-dosing. Doses of 0.125 mg/kg every 12h produced a 
mean cumulated drug exposure (AUC12: area under curve) of 417 
ng-h/mL. At this level, serious (grade 3) hematologic toxicity occurred 
in 6 of 10 subjects. At 300 ng-h/mL, grade 2 or greater (fall in 
hemoglobin to < 9.4 g/dL) developed within 4 weeks in 9 of 12 
subjects. At 200 ng-h/mL almost no clinically significant anemia 
developed, but dose-limiting granulocytopenia (< 750 
granulocytes/mm3) occurred in 5 of 15 subjects. Mild peripheral 


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neuropathy occurred in 2 of 10 subjects at 50 ng-h/mL, but was not 
dose- limiting.  FLT drug trials were terminated after the unexpected 
death of 2 subjects of hepatic failure.  One patient assigned to 200 ng-
h/mL developed progressive liver failure and died after 12 weeks of 
FLT therapy.  A second subject, who received a fixed dose of 10 
mg/day, developed progressive liver failure and died at about the 
same time.  All surviving subjects were followed closely for 4 weeks 
after stopping FLT and none had evidence of clinically significant liver 
disease or other adverse effects. Overall, 25 of the 44 subjects 
receiving at least two doses of FLT completed the 16 week study 
without clinically significant adverse effects. 
FLT (Alovudine) was withdrawn from development for several years, 
and then reinvestigated for multi-drug resistant HIV infection.  Fifteen 
patients with multi-drug resistance HIV received 7.5 mg each day for 
28 days along with their ongoing therapy.72 No serious adverse events 
were observed. In a randomized, double-blind, placebo-controlled 
study by the same group, 51 patients received 0.5 mg, 1.0 mg, or 2.0 
mg daily for 28 days in addition to their routine therapy; 21 patients 
received placebo.73 No unexpected adverse events were observed, 
and no serious AEs were attributed to the study drug. 
8.4.3 
Dosimetry 
The dose of FLT to be administered in this imaging trial is 1400-fold 
lower than the dose that led to serious toxicity in the studies described 
above. A summary of the relevant human dosimetry for 2 different 
voiding scenarios from the investigator’s brochure. 
Table 8.1. Human dosimetry estimates 
Organ of Interest 
  Men    mGy/MBq   (mrad/mCi) 
Women mGy/MBq   (mrad/mCi) 
Total Body Dose 
Scenario 1     1.23E-02      (46)  
Scenario 2     1.26 E-02     (47)       
Scenario 1    1.56E-02        (58)  
Scenario 2    1.59 E-02       (59)       
Bladder 
Scenario 1     1.79E-01     (662) 
Scenario 2     7.91E-02     (293)  
Scenario 1    1.74E-01       (646) 
Scenario 2    7.76E-02       (287)  
Liver 
Scenario 1     4.51E-02     (167) 
Scenario 2     4.54 E-02    (168) 
Scenario 1    6.42E-02       (238) 
Scenario 2    6.45 E-02      (239) 
Scenario 1:  Single bladder voiding at 6 h after FLT administration 
with a 10% post-voiding bladder residual decayed to infinity.  This 
scenario assumed no urine reaccumulation after 6 h.   
Scenario 2:  First bladder voiding at 2 h after FLT administration with 
a 10% post-voiding residual; urine reaccumulation between 2 and 6 h 
at a rate determined by the bladder curve fit; second bladder voiding 
at 6 h with a 10% post-voiding residual decayed to infinity.  This 
scenario assumed no urine reaccumulation after 6 h.  The first 
scenario is conservative, whereas the second has a more realistic 
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8.4.4 
FLT Administered Dose 
The administered dose will be 0.07 mCi/kg with a maximum of 5 mCi. 
A ± 20% allowance for dose modification is allowable at the discretion 
of the site PI. The drug solution is stored at room temperature in a 
gray butyl septum sealed, sterile, pyrogen-free glass vial and has an 
expiration time of 8 hours. The injectable dose of  FLT for most 
studies will be ≤ 0.07 mCi/kg of fluorine 18, not to exceed 5 mCi with a 
specific activity greater than 200 Ci/mmol at the time of injection.  In 
the dose of FLT, only a small fraction of the FLT molecules are 
radioactive.  The amount of injected drug is ≤ 6.1 µg (≤ 25 nmol per 
dose) of FLT. FLT is administered to subjects by intravenous injection 
of ≤ 10 mL. There is no evidence that nonradioactive and radioactive 
FLT molecules display different biochemical behavior. 
8.4.5 
Quality Assurance, Quality Control, and Storage 
In accordance with regulations, the radioisotope vendor conducts 
several quality control tests on the FLT product prior to release for 
human administration. Once delivered to the participating institution, 
doses will be stored in the appropriate storage area in the nuclear 
medicine facility until they are administered to the patient. 
8.4.6 
Supplier of FLT 
Drug Ordering: FLT will be purchased from a commercial vendor of 
radioisotopes in most cases. The vendor must be authorized within 
the NCI IND. The investigator or the investigator-designee will order 
patient doses of FLT; orders must be made a minimum of 2 calendar 
days prior to the scheduled FLT-PET/CT imaging study. The 
investigative radiopharmaceutical FLT solution will be shipped to the 
site the same day the participant is to be injected. 
The investigational pharmacist or qualified nuclear medicine 
technologist at the participating institution will be the responsible party 
designated by the investigator.  
FLT can only be synthesized on site if the chemistry manufacturing 
and control procedures are filed within the NCI IND.  
Drug Returns: If for any reason the study imaging is unable to be 
completed, sites will allow the radioactivity of the [18F]FLT solution to 
decay and then discard it appropriately per site’s policies and 
procedures.  A copy of the policy should be available upon request. 
Drug Accountability: The investigator or the investigator-designee 
must maintain a detailed record of receipt, disposition, and destruction 
dates of FLT solution, using the Drug Accountability Record form 
available on the ACRIN web site.  
[18F]FLT will be synthesized according to the standard operating 
procedures provided by the NCI.  A summary of the synthesis 
procedure and associated quality control can be found in the 
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[18F]FLT will be administered in the PET imaging suite under 
physician supervision. The imaging technologist or nurse will 
administer the [18F]FLT by intravenous infusion over one minute, 
followed by a saline flush.  A fully equipped emergency cart and ACLS 
certified personnel will be available. Reported adverse events and 
potential risks are described in Section 5.5.  The infusion and imaging 
procedure will be terminated in any patient who exhibits anaphylaxis, 
chest pain, dyspnea, or grand mal seizure. 


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8.4.7 
FLT Imaging IND Agent Estimated Effective Dose from Isotope and Scans 
Table 8.2 Estimated Effective Dose from Isotope and Scans  
(Sponsor: Cancer Imaging program, NCI, NIH) 
Scans 
Eligible 
Patients 
PET 
Agent 
Dose 
ED for 
maximu
m dose 
of 
isotope 
(mSv) 
Equipmen
t Type 
PET/CT 
Image 
Acquisition 
Attenuation 
(Transmission) 
Scan 
ED from 
CT scan 
(mSv) 
(mean) 
ED from 
CT scan 
(mSv) 
(Max) 
ED from 
transmission 
scan (mSv) 
(max) 
Total 
ED 
(mSv) 
(likely) 
Total 
ED 
(mSv) 
(max) 
ED (mSv) 
with 
transmission 
scan 
FLT-1 
prior to 
therapy 
(baseline, 
Day 1, 
Cycle 1) 
All 
2.6 
MBq/kg 
(0.07 
mCi/kg) 
maximu
m 185 
MBq (5 
mCi) 
4.8 
PET/CT  
or PET 
Torso 
Scan 60 
minutes 
dynamic  
post 
injection 
low-dose CT 
scan or 
transmission 
6.4 
8.6 
0.2 
11.2 
13.4 
5 
FLT-2 
(early-
treatment, 
~Day 4, 
Cycle 1) 
All 
2.6 
MBq/kg 
(0.07 
mCi/kg) 
maximu
m 185 
MBq (5 
mCi) 
4.8 
PET/CT  
or PET 
Torso 
Scan 60 
minutes 
dynamic  
post 
injection 
low-dose CT 
scan or 
transmission 
6.4 
8.6 
0.2 
11.2 
13.4 
5 
2 FLT 
Scans 
Arms H 
and I 
≤ 10 mCi 
9.6 
 
 
 
12.8 
17.2 
0.4 
22.4 
26.8 
10 
ED = Estimated Effective Dose in mSv 
Likely dose = radionuclide + mean from CT scan 
 


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9. 
Statistical Considerations 
9.1 
Endpoints 
The definitions of primary and secondary endpoints are described in Sections 2 
and 9.2. 
Phase I (Open-label study) 
Maximum tolerated-dose (MTD) 
Phase II (Randomized study)  
Primary endpoint: Progression free survival (PFS) 
Secondary endpoints: Overall survival (OS), response rate (CR+PR), and 
disease control rate (CR+PR+SD) 
9.2 
Sample Size With Power Justification 
A maximum total of 109 patients will be needed for the entire trial that consists of 
Phase I and Phase II. 
9.2.1 
Phase I 
Assuming a roughly 5% dropout rate, a maximum of 50 patients will 
be needed to accrue a maximum of 48 eligible patients in the 3+3 
dose escalation design described in Section 9.3. 
9.2.2 
Phase II 
A total of 84 patients will be in Phase II. The study seeks to establish 
an improvement in the primary endpoint, which is defined as a 66.6% 
increase in median progression free survival (PFS) from 6 months in 
the control arm (Arm H) to 10 months in the experimental arm (Arm I) 
assuming exponential failure. The study is designed to have 85% 
power for a hazard ratio of 0.6 with 69 PFS events (as total 
information) which are expected to occur with 14 months of accrual at 
6 patients per month and 13 additional months of follow-up, using a 
log-rank test at a one–sided significance level of 0.15. The sample 
size was computed using seqopr6 (part of the study design library at 
the ECOG-ACRIN Statistical Office). 
9.3 
Analysis Plan Including Plans for Formal Interim Analysis 
9.3.1 
Phase I 
The MTD of all three agents, gemcitabine, Nab-Paclitaxel and 
AZD1775 when given as a combination will be determined using a 
3+3 dose escalation design with escalating doses of gemcitabine, 
Nab-Paclitaxel and AZD1775 and six patients treated at the proposed 
MTD. The dose escalation strategy is as follows: 
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Arm 
Gemcitabine 
(mg/m2) days 1, 8 
and 15 
Nab-Paclitaxel 
(mg/m2) days 1, 8 
and 15 
AZD1775  
(mg) days 1, 2, 8, 
9, 15 and 16 
Arm A (CLOSED TO ACCRUAL) 
Arm B 
750 
100 
100 
Arm C 
750 
100 
125 
Arm D 
750 
100 
150 
Arm E 
750 
100 
175 
Arm F 
750 
125 
*see footnote 
Arm G 
1000 
125 
*see footnote 
* If AZD1775 150 mg is the highest achievable dose—Arm D—(DLTs 
observed in Arm E), proceed to Arm F and continue with dose escalation of 
gemcitabine and Nab-Paclitaxel using the highest tolerated AZD1775 dose. 
* If AZD1775 175 mg is achievable in Arm E, proceed to Arm F and continue 
with dose escalation of gemcitabine and Nab-Paclitaxel using AZD1775 175 
mg. If unacceptable toxicity is observed with AZD1775 175 mg in either Arm 
F or Arm G, each/either of these dose levels may be reassessed (Arm F150, 
Arm G150) using AZD1775 150 mg. 
Enrollment to the phase I component will be within limited participating 
institutions. In the dose escalation design, 3 patients will be initially 
treated at the lowest dose level. If more than one patient experience 
DLT at this dose, accrual will stop and the regimen will be 
reconsidered as the MTD will have been exceeded. If no DLT occurs 
in the first 3 patients, accrual to the next dose level will begin, again 
with 3 patients. If at either dose one DLT occurs in the first 3 patients, 
3 additional patients will be treated at that dose level and the dose 
either escalated or deemed the MTD if none of the additional 3 
patients experiences DLT. If one or more of the additional 3 patients 
experiences DLT, the MTD will have been exceeded and the MTD will 
be defined to be the lower dose. If at any time 2 or more patients 
experience DLT at a dose level, the MTD will have been exceeded. 
With the escalation strategy, the table below gives the probability of 
escalation as a function of the true underlying DLT rate for a variety of 
true rates. The definition of DLT is given in Section 5.1.5. There will 
be 6 patients treated at the MTD before moving to the phase II 
component of the study. That is, if the second dose is deemed too 
toxic and only 3 patients had been treated at the first dose, a second 
cohort of 3 patients will be treated at the first dose. If the dose 
escalates and three patients are treated at the second dose with no 
DLTs, a second cohort of 3 patients will be treated at the second dose 
in order to study a total of 6 patients at the proposed MTD and further 
define the adverse event profile. 
In addition, we have also stipulated that if a patient receives less than 
66.7% of the planned doses of any study agent for reasons at least 
possibly related to side effects or toxicity from the study treatment 
during their first cycle on the phase I study, the patient will be counted 
as having had a DLT. Information about the dose intensity (or percent 


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of planned dose received) and any toxicity experienced will be 
reviewed and reported for each patient on the Phase I portion of the 
study. The dose intensity and toxicity information will be reviewed at 
each decision point in the Phase I dose escalation study and will be 
included in the evaluation of the recommended Phase II dose. 
True rate of DLT 
10% 
20% 
30% 
40% 
50% 60% 70% 
Probability of escalation 
.91 
.71 
.49 
.31 
.17 
.08 
.03 
9.3.2 
Phase II 
Once the MTD of gemcitabine, Nab-Paclitaxel and AZD1775 has 
been determined, the study will move to Phase II defined as a 
randomized, Phase II study in patients with PS 0-1 and metastatic 
adenocarcinoma of the pancreas who are equally randomized 
between gemcitabine/Nab-Paclitaxel (Arm H) or gemcitabine/Nab-
Paclitaxel/AZD1775 (Arm I). Stratification factors on randomization 
are ECOG PS and intent to participate in an imaging study (see 
Section 4.2.5) and these factors will not be used in analysis. The 
primary analysis set will be an intent-to-treat (ITT) set that includes all 
randomized patients. 
A total of 84 patients will be randomized in the Phase II component of 
the study. The study seeks to establish an improvement in the primary 
endpoint, progression free survival (PFS), which is defined as a 
66.6% increase in median PFS from 6 months in the control arm (Arm 
H) to 10 months in the experimental arm (Arm I), a hazard ratio of 
0.60. Progression free survival (PFS) is defined as time from 
randomization to documented progression or death without 
progression. Disease progression will be evaluated using evaluation 
criteria defined in Section 6. Patients without documented progression 
or death reported will be censored at the time of the last documented 
disease evaluation. The study is designed to have 85% power for the 
target hazard ratio of 0.60 with 84 patients and 69 PFS events at full 
information, which are expected to occur at 27 months post activation 
(assuming 14 months of accrual at 6 patients per month and 13 
additional months of follow-up). The primary analysis will be via a 
stratified log rank test at a one-sided significance level of 0.15. 
The study will be monitored for potential efficacy stopping using an 
early look at PFS after approximately 50% of the planned full 
information (35 PFS events) has been observed. A one-sided 
stratified log rank test for PFS will be performed for the monitoring 
analysis. To preserve the overall type I error at 0.15, a critical value at 
the interim analysis will be determined using the O’Brien-Fleming 
boundary. Under the planned accrual schedule with six patients per 
month, the monitoring analysis is projected to occur at 13 months 
following the start of accrual, a time point that should be close to the 
end of accrual. If the true control median PFS is 6 months and the 
true experimental median PFS is 10 months, there will be 41% 
probability of crossing the upper efficacy boundary (1.72).  


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This study will also be monitored for futility using a rule that the study 
will be stopped early for lack of benefit if the estimated hazard ratio for 
experimental/control ≥ 1 at 50% of the planned full information. 
Overall survival, overall objective response, disease control rate and 
toxicity will be important secondary endpoints of this phase II trial. 
Overall survival is defined as time from randomization to death from 
any cause, censoring cases who are alive at the date of last contact. 
PFS and OS by arm will be compared using one-sided log-rank tests. 
Cox’s proportional hazards models will be used to estimate hazard 
ratios. Response rate (complete response or partial response) and 
disease control rate (complete response, partial response, or stable 
disease) are also secondary endpoints which will be analyzed using 
Fisher’s exact tests at a one–sided significance level of 0.15. 
Furthermore, we will perform subset analyses within baseline p53 
status (wild type and mutated prior to cycle 1) for each endpoint in an 
exploratory fashion. The ratio of p53 wild type to p53 mutation is 
expected to be 50:50. Patient demographics and disease 
characteristics will be compared using two-sample t-tests or Fisher’s 
exact tests as appropriate. 
Interim analyses of toxicity are performed twice yearly for all ECOG-
ACRIN studies. Expedited reporting of certain adverse events is 
required. With 42 patients per arm, phase II will have sufficient 
precision to provide 90% confidence interval on toxicity that will be no 
wider than 27.1%. For rare toxicities with 3% true probability, there will 
be at least 72% probability of observing one or more toxicities in either 
arm. For rare toxicities with 4% true probability, there will be at least 
82% probability of observing one or more toxicities on either treatment 
arm. Formal comparison of toxicity rates between the arms is not a 
goal in phase II of this trial and the sample size will provide sufficient 
power for detecting only relatively large differences in adverse events. 
With the limited sample size, comparisons of overall survival will also 
be limited in statistical nature. 
9.4 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office - Boston. 


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9.5 
Gender and Ethnicity 
The sample size for the phase I component is unknown as it is based on the 
dose escalation rules; therefore the accrual projection table below is based on 
the phase II component sample size of 84 patients. Based on previous data from 
past pancreas trials, the anticipated accrual in subgroups defined by gender and 
race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
1 
3 
Not Hispanic or Latino 
35 
46 
81 
Ethnic Category: Total of all subjects 
37 
47 
84 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
1 
2 
Black or African American 
3 
3 
6 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
33 
43 
76 
Racial Category: Total of all subjects 
37 
47 
84 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
9.6 
Statistical Analysis for Advanced Imaging Studies 
9.6.1 
To evaluate the change in tumor FDG uptake (SUVmax) between 
baseline FDG-PET and week 4 FDG-PET as a predictor of response 
using RECIST as the reference standard for response in patients with 
metastatic pancreatic cancer. 
A total of 60 patients (30 patients each from Arm H and I) will undergo 
FDG-PET imaging and provide data for the FDG-PET imaging 
analysis. This sample size provides 86.9% power for a two-sided test 
to determine whether the area under the ROC curve (AUC) for the 
prediction of RECIST response is above 0.7, assuming that the actual 
area is 0.9 and 1/3 of the patients (20 out of 60) will have complete or 
partial response as assessed by RECIST at 8 weeks. 
SUVmax is defined as the highest single-pixel SUV in a volume of 
interest (VOI). In the primary analysis for this objective we will 
estimate the AUC of the change in SUVmax (treated as a continuous 
variable) with a binary RECIST assessment of response at 8 weeks 
as the reference standard. The RECIST response status will be 
categorized as “positive” if response is classified as complete or 
partial and “negative” otherwise. The analysis will be carried out using 
the pooled data across both arms of the trial. In an elaboration of this 
analysis we will consider regression modeling with indicators of 
treatment arm as covariates.37 In a secondary exploratory analysis we 
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will dichotomize the SUVmax response using a 25% threshold (< -25% 
versus ≥ -25%) discussed in the literature38 and compute the 
sensitivity and specificity of the dichotomized variable with RECIST 
response defining the reference standard.  
9.6.2 
To evaluate the accuracy of change in tumor FDG update (SUVmax) 
between baseline FDG-PET and week 4 FDG-PET as a predictor of 
overall survival in patients with metastatic pancreatic cancer. 
Overall survival (OS) is defined as time from randomization to 
documented death. Patients without documented death will be 
censored at the time of the last documented disease evaluation.  
In the primary analysis for this objective, we will use time-dependent 
ROC methodology to assess the ability of SUVmax change to predict 
OS39. This type of ROC analysis in needed in order to account for the 
censoring in the OS variable defining the reference standard 
information. We will derive time-specific estimates of the ROC curve 
and its area at clinically relevant time-points (e.g. 1 year). We will also 
estimate the time-averaged AUC as a measure of overall accuracy. In 
secondary analyses we will examine the performance of SUVmax as an 
independent predicator of OS using Cox-regression modeling. 
9.6.3 
To evaluate the accuracy of change in tumor FDG uptake (SUVmax) 
between baseline FDG-PET and week 4 FDG-PET as a predictor of 
progression-free survival in patients with metastatic pancreatic 
cancer. 
Progression-free survival (PFS) is defined as time from randomization 
to documented progression or death without progression. Patients 
without documented progression or reported death will be censored at 
the time of the last documented disease evaluation.   
In the primary analysis for this objective, we will use time-dependent 
ROC methodology to assess the ability of SUVmax change to predict 
PFS.39 This type of ROC analysis is needed in order to account for the 
censoring in the PFS variable defining the reference standard 
information. We will derive time-specific estimates of the ROC curve 
and its area at clinically relevant time-points (e.g. 6 months) and we 
will also estimate the time-averaged AUC as a measure of overall 
accuracy. In secondary analyses we will examine the performance of 
SUVmax as an independent predictor of PFS using Cox-regression 
modeling.  
9.6.4 
To compare the change in tumor FDG uptake (SUVmax) between 
baseline FDG-PET and week 4 FDG-PET between the patients from 
treatment arms F and G. 
The change in SUVmax will be compared between Arm H vs. I only as 
a continuous variable using Wilcoxon test and as binary variable 
(defined as summed SUVmax change from baseline < -25% versus ≥ -
25%) using Fisher’s exact tests. 
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9.6.5 
To evaluate if an early increase in tumor FLT uptake (FLT-flare) is 
observed within 24 hours after initiation of treatment with Nab-
Paclitaxel/gemcitabine. 
9.6.6 
To evaluate if an early (within 24 h) increase in tumor FLT uptake 
(FLT-flare) is abrogated after initiation of treatment with Nab-
Paclitaxel/gemcitabine/AZD1775. 
9.6.7 
To compare the change in tumor FLT uptake (SUVmax) from baseline 
to 24 hours after initiation of treatment between the patients from 
treatment arms H and I. 
The analysis for the FLT-PET imaging is exploratory and will be based 
on data collected on a total of 10 patients (5 patients from Arm H and 
I, respectively). We will tabulate descriptive statistics on summed 
SUVmax change of the 5 hottest lesions from baseline to Day 2 post-
treatment by arm. The change in SUVmax will be compared between 
Arm H vs. I only as a continuous variable using Wilcoxon test and as 
binary variable (defined as summed SUVmax change from baseline  
< -25% versus ≥ -25%) using Fisher’s exact tests. 
9.7 
Statistical analysis of laboratory biomarkers 
9.7.1 
Correlational analyses 
patients in the Phase II portion of this study. Treating both the 
changes in biomarker expression from baseline to 24-hours post-
treatment in cycle 1 and tumor response at 8 weeks defined by 
RECIST (complete response, partial response, stable, and 
progression of disease) as cross-sectional predictors for progression-
free endpoint, their correlations will be determined using Spearman 
correlation coefficients (ρ). We will apply Evan’s decision criteria for ρ: 
0.19=very weak correlation, 0.20-0.39=weak correlation, 0.40-
0.59=moderate correlation, 0.60-0.79=strong correlation, >0.80=very 
strong correlation in each arm. Assuming that 10% of 42 patients per 
arm in Phase II of the study will not have laboratory samples, there 
will be at least 80% power to distinguish between the null hypothesis 
correlation of 0.59 and the alternative hypothesis correlation of 0.80 
using a one-sided Fisher’s Z-test with a significance level of 0.15. 
9.7.2 
Analyses of p53 
For analyses of p53 as a prognostic marker, there is at least 80% 
power to detect a PFS hazard ratio of at least 1.66 using a one-sided 
0.05 level log rank test, using the assumptions above that roughly 
90% of the patients will have usable biologic samples (n=108) and 
that roughly half of patients will be mutated. Power for p53 as a 
predictive marker will be more limited. There will be at least 80% 
power for an interaction effect (ratio of hazard ratios) of 2.9 in a Cox 
proportional hazards model with a one-sided 0.05 significance level 
using a partial likelihood test. Hence power is fairly limited in this 
phase II study for looking at p53 as a predictive marker but the 
calculations here are fairly conservative. Power may be higher if a 
larger number of samples are available. Power is also computed 
under the assumption of 16 months of follow-up to coincide with the 
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statistical considerations of the clinical endpoints; if more follow-up is 
possible due to the timing of completing the laboratory analyses 
interaction effects smaller than 2.9 may be detectable. 
Analyses of pharmacodynamic biomarkers 
The biomarkers described in Section 12.2 (Phospho-Cdc2Tyr15, 
Cyclin A2, etc; 5 primary biomarkers total listed in Section 12.1) can 
be considered quantitative as they result from assays providing 
percent of cells or averages of scored components. This section will 
therefore focus on power for two-sample equal variances t-tests 
comparing pharmacodynamic biomarker values between the 
treatment arms for either individual markers measured at pre-
treatment (tumor measurements) or change in biomarkers post-
treatment minus pre-treatment (hair follicle measurements) and again 
assuming that 90% of patients will provide data for these analyses 
(n=76) total or 38 patients per arm). Power will be expressed in terms 
of detectable effect size since preliminary measures of variability of 
each marker are not available. For each biomarker, testing will be 
done strictly at a significance level of 0.05 two-sided but no other type 
I error control will be used to maximize power for these largely 
exploratory analyses. If raw distributions or log-transformed values 
are in violation of normality assumptions, non-parametric Wilcoxon 
tests will be used. In those cases, power may be somewhat lower 
than that quoted here. For each marker, a two-sided t-test will have at 
least 80% power to detect an effect size of 0.67 assuming equal 
variances. If the variance ratio is large (>/= 4), there is 80% power for 
an effect size of 1.08 using an unequal variances t-test (using the 
smaller variance to compute the effect size, and assuming that the 
larger variance occurs in the group with the higher mean, which is 
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10. 
Imaging Studies 
The background for the research imaging studies is outlined in Section 1.7. A limited 
number of ECOG-ACRIN membership institutions will participate in the ACRIN imaging 
sub-studies. These institutions will need to complete ACRIN qualification requirements 
prior to consenting and enrolling participants to the ACRIN imaging sub-studies. Once 
the site is ACRIN-qualified, all imaging-eligible patients enrolling to the EA2131 parent 
therapeutic trial must be asked to participate in the optional imaging sub-study. 
Qualification procedures are provided in the EA2131 Imaging Manual, posted on the 
ACRIN web site at www.acrin.org/EA2131_imagingmaterials.aspx. 
The target patient populations are: 
a. FDG-PET cohort: 60 patients total, recruited from phase II Arms H and I 
b. FLT-PET cohort: 10 patients total, recruited from phase II Arms H and I 
** Patients in the FDG-PET cohort may not enroll in the FLT-PET sub-study and vice 
versa.** 
10.1 
Research Objectives: 
10.1.1 
To evaluate the change in tumor FDG uptake (SUVmax) between 
baseline FDG-PET and week 4 FDG-PET as a predictor of response 
using RECIST as the reference standard for response.  
10.1.2 
To evaluate the change in tumor FDG update (SUVmax) between 
baseline FDG-PET and week 4 FDG-PET as a predictor of overall 
survival. 
10.1.3 
To evaluate the change in tumor FDG uptake (SUVmax) between 
baseline FDG-PET and week 4 FDG-PET as a predictor of 
progression-free survival. 
10.1.4 
To compare the change in tumor FDG uptake (SUVmax) between 
baseline FDG-PET and week 4 FDG-PET between the patients from 
treatment arms H and I. 
10.1.5 
To evaluate if an early increase in tumor FLT uptake (FLT-flare) is 
observed within 24 hours after initiation of treatment with Nab-
Paclitaxel/gemcitabine. 
10.1.6 
To evaluate if an early (within 24 h) increase in tumor FLT uptake 
(FLT-flare) is abrogated after initiation of treatment with Nab-
Paclitaxel/gemcitabine/AZD1775 
10.1.7 
To compare the change in tumor FLT uptake (SUVmax) from baseline 
to 24 hours after initiation of treatment between the patients from 
treatment arms H and I. 
10.2 
Imaging Sub-Study Site Review and Qualification 
ECOG-ACRIN member institutions interested in participating in the FLT-PET 
and/or FDG-PET ACRIN imaging sub-studies must meet site review and 
qualification procedures prior to enrolling patients onto either of the imaging sub-
studies: 
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• 
For sites participating in the FLT-PET imaging sub-study, a radiologist site PI 
must be identified and provide the FDA Form 1572 to ACRIN for delivery to 
the NCI Cancer Imaging Program (CIP); 
• 
The site must complete an ACRIN protocol-specific application (PSA), which 
will be posted to the ACRIN web site (www.acrin.org), that requires: logistical 
plan for identifying and consenting patients to the ACRIN imaging sub-study 
and logistical plan for tracking receipt, storage, and use of the IND FLT 
imaging agent; 
• 
A copy of the IRB approval letter and the IRB-approved, institutional study-
specific informed consent must be delivered to the ACRIN trial monitor to 
review and to keep on file at ACRIN Headquarters (fax: 215-717-0936, ATTN: 
Protocol Development and Regulatory Compliance Department); 
Parameters for the FDG-PET and FLT-PET imaging protocols are available in 
the EA2131 Imaging Manual (www.acrin.org/EA2131_imagingmaterials.aspx). 
The imaging manual should be printed and made available to imaging 
technologists at participating, ACRIN-qualified sites to ensure adherence to the 
research imaging protocols, including quality control procedures as outlined by 
the manufacturer and ACRIN for PET (see 
www.acrin.org/CORELABS/PETCORELABORATORY/PETQUALIFICATION/tabi
d/485/Default.aspx). Sites will be informed when the imaging manual is updated; 
the most-current version will be made available online. 
Qualification at sites comprises: completion of an application including 
information about local QC procedures; uniform phantom imaging that verifies 
both quantification (SUV) and uniformity (Normalization); two test cases to 
validate scanner functionality and image quality and to verify images are properly 
formatted.  Annual renewal with phantom assessment of research machine(s) will 
follow. 
A dedicated PET scan unit or hybrid PET/CT scanner is mandatory. The PET 
scanner must be capable of performing both emission and transmission images 
in order to allow for attenuation-corrected PET scan images. The ability to 
calculate standardized uptake values (SUVs) also is mandatory. All sequential 
imaging sessions will be performed on an identical or technically equivalent 
PET/CT scanner. 
10.3 
ACRIN Regulatory Oversight 
The investigator and the investigator-designated research staff must follow 
OHRP-approved consent procedures (Title 45, Part 46 Code of Federal 
Regulations), as well as those set by the local IRB at the institution. Site 
investigators will provide a copy(s) of IRB approval letter(s) for any 
amendment(s), and copy(s) of annual renewal(s). The ACRIN Biostatistics and 
Data Management Committee (BDMC) and the ACRIN Steering Committee will 
regularly review the sub-study accrual and may request information about the 
sub-study’s accrual performance to better understand general accrual barriers or 
issues. Accrual and safety information will be presented to the ACRIN Data and 
Safety Monitoring Committee (DSMC) at regularly scheduled meetings thereof; 
the DSMC may, at its discretion, re-evaluate the study with respect to feasibility 
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10.4 
Imaging Sub-Study Time Points and Procedures: FDG and FLT Cohorts 
Site Quality Control: A daily quality control (QC) check must be performed at 
the beginning of the day prior to scheduled imaging, including PET scanner and 
dose calibrator, in accordance with the manufacturer recommendations. If any of 
the QC results are outside of the manufacturer’s guidelines, the study must be 
rescheduled and the problem rectified before scanning any patients. 
Participants must be scanned on ACRIN-qualified scanners that are quality 
controlled per instructions provided in the EA2131 Imaging Manual: 
www.acrin.org/EA2131_imagingmaterials.aspx 
10.4.1 
FDG Cohort Procedures 
The FDG Cohort will comprise a total of 60 participants, from study 
Arms F and G, undergoing FDG-PET/CT at limited institutions that 
have been ACRIN-qualified for participation in the ACRIN imaging 
sub-study. Patients enrolled in the EA2131 trial must be eligible for 
the FDG cohort, including a post-consent evaluation of standard 
imaging to identify evaluable lesion (either primary pancreas mass or 
metastasis) of > 2 cm in size. AE-reporting requirements, including 
those for the imaging sub-studies, are outlined in Sections 5.3- 5.5. 
FDG-PET scans will be obtained at two (2) time points: 
1. Pre-treatment FDG-1 (at baseline, defined as after consent and 
standard imaging assessment for eligibility, but before treatment 
initiation on Day 1 of Cycle 1); and  
2. Pre-Cycle 2 FDG-2 (at Day 25 [± 3 days] after Cycle 1 
initiation/before Cycle 2 initiation).  
Blood Glucose and FDG Administration: The participant’s blood 
glucose level must be checked before FDG injection. Blood sugar 
(measured by glucometer) must be less than 200 mg/dL at the time of 
FDG administration. If the blood glucose level is greater than 200 
mg/dL, the FDG-PET scan should be rescheduled for within 7 working 
days after the first attempt. If the blood glucose level still exceeds 200 
mg/dL on the following scheduled day for PET scanning, the patient 
will not be included in the trial. Insulin administration immediately 
before the FDG-PET study to reduce the glucose levels is not 
allowed. Patients with diabetes should continue to adhere to their oral 
agents or insulin routines. These medications should not be 
administered near the FDG injection time. In insulin-dependent 
patients, insulin should be administered at least 5 hours prior to the 
FDG injection. Patients with diabetes who are on oral diabetic 
medication should take their medication 4 to 5 hours prior to the FDG-
PET. 
10.4.1.1 
VISIT 1: Eligibility/Registration 
• 
Determine patient’s eligibility to participate in the 
imaging sub-study. 
• 
Obtain a signed informed consent form for the imaging 
sub-study prior to performing any sub-study 
procedures. For sites which will be performing both 
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FDG- and FLT-PET scans, allow the participant to 
choose the cohort to join if eligible for either.  
• 
Schedule the baseline imaging scan for VISIT 2, FDG-
1.  
10.4.1.2 
VISIT 2 FDG-1: Baseline FDG-PET/CT Imaging Scan 
The baseline FDG PET/CT (FDG-1) scan will take place 
prior to chemotherapy on Day 1 of Cycle 1. 
• 
Assess pregnancy status for all women of childbearing 
potential, per the institution’s general practice and 
standard of care prior to performing any imaging scans 
using contrast. 
• 
Check glucose level prior to administration of FDG 
(must be less than 200 mg/dL; see additional 
instructions above).  
• 
Specific image acquisition and reconstruction protocols 
can be found on the ACRIN web site at 
www.acrin.org/EA2131_imagingmaterials.aspx. 
• 
An adverse event evaluation will be performed at 24 
hours (+/- 4 hours) after the imaging study is 
completed.  
10.4.1.3 
VISIT 3 FDG-2: Pre-Cycle 2 FDG-PET/CT Imaging Scan  
The pre-cycle 2 FDG PET/CT (FDG-2) scan will take place 
prior to chemotherapy on Day 25 (± 3 days) of Cycle 
1/prior to initiation of Cycle 2. 
• 
Assess pregnancy status for all women of childbearing 
potential, per the institution’s general practice and 
standard of care prior to performing any imaging scans 
using contrast. 
• 
Check glucose level prior to administration of FDG 
(must be less than 200 mg/dL; see additional 
instructions above).  
• 
Specific image acquisition and reconstruction protocols 
can be found on the ACRIN web site at 
www.acrin.org/EA2131_imagingmaterials.aspx.  
• 
An adverse event evaluation will be performed at 24 
hours (+/- 4 hours) after the imaging study is 
completed. 
10.4.2 
FLT Cohort Procedures 
The FLT Cohort will comprise a total of 10 participants, 5 each from 
Arms H and I, undergoing FLT-PET/CT at limited institutions that have 
been ACRIN-qualified for participation in the ACRIN imaging sub-
study. Patients enrolled in the EA2131 trial must be eligible for FLT 
cohort, including a post-consent evaluation of standard imaging to 
identify evaluable lesion in the pancreas (likely to have primary 
adenocarcinoma of the pancreas) > 2 cm in size that is not primarily 
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fibrotic or mucinous in nature. AE-reporting requirements, including 
those for the imaging sub-studies, are outlined in Section 5.3. The 
CAEPR for FLT and radiation exposure associated with the imaging 
sub-studies are available in Section 5.5. 
The FLT agent will need to be ordered a minimum of 2 calendar 
days prior to the scheduled FLT-PET/CT study. 
FLT-PET/CT scans will be obtained at two (2) time points:  
1. Pre-treatment FLT-1 (baseline, defined as after consent and 
standard imaging assessment for eligibility, but before treatment 
initiation on Day 1 of Cycle 1);  
2. Early-Cycle 1 FLT-2 (defined as Day 2 [20 to 24 hours] after Cycle 
1 initiation) 
See Section 8.4 for FLT IND Administration Information. 
10.4.2.1 
VISIT 1: Eligibility/Registration 
• 
Determine patient’s eligibility to participate in the 
imaging sub-study. 
• 
Obtain a signed informed consent form for the imaging 
sub-study prior to performing any sub-study 
procedures. For sites which will be performing both 
FDG- and FLT-PET scans, allow the participant to 
choose the cohort to join if eligible for either.  
• 
Schedule the baseline imaging scan for VISIT 2, FLT-
1.  
10.4.2.2 
VISIT 2 FLT-1: Baseline FLT-PET/CT Imaging Scan  
The baseline FLT PET/CT (FLT-1) scan will take place 
prior to chemotherapy on Day 1 of Cycle 1. 
• 
Assess pregnancy status for all women of childbearing 
potential, per the institution’s general practice and 
standard of care prior to performing any imaging scans 
using contrast. 
• 
Specific image acquisition and reconstruction protocols 
can be found on the ACRIN web site at 
www.acrin.org/EA2131_imagingmaterials.aspx.  
• 
An adverse event evaluation will be performed at 24 
hours (+/- 4 hours) after the imaging study is 
completed.  
10.4.2.3 
VISIT 3 FLT-2: Early-Cycle 1 FLT-PET/CT Imaging Scan  
The early-cycle 1 FLT PET/CT (FLT-2) scan will take place 
after chemotherapy on Day 2 (20 to 24 hours after cycle 1 
initiation and at least 2 hours after AZD1775 is 
administered on day 2) of Cycle 1. 
• 
Assess pregnancy status for all women of childbearing 
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standard of care prior to performing any imaging scans 
using contrast. 
• 
Specific image acquisition and reconstruction protocols 
can be found on the ACRIN web site at 
www.acrin.org/EA2131_imagingmaterials.aspx.  
• 
An adverse event evaluation will be performed at 24 
hours (+/- 4 hours) after the imaging study is 
completed. 
Table 10.1: Time points for FDG- and FLT-PET/CT Scans 
 
Baseline1 
(Day 1, Cycle 1, Prior to 
Chemotherapy Administration) 
Early-Cycle 1 
(Day 2, Cycle 1) 
Pre-Cycle 2 
(Day 25 ± 3 Days, Cycle 
1/Before Cycle 2 Initiation) 
FDG-PET/CT2 
X3  
– 
X3 
FLT-PET/CT 
X 
X 
 
AE evaluation4  
X 
X 
X 
1. Must be scheduled for the same day as/prior to chemotherapy initiation.  
2. Insulin administration immediately before the FDG-PET/CT study to reduce the glucose levels is not 
allowed. Patients with diabetes should continue to adhere to their oral agents or insulin routines. 
These medications should not be administered near the FDG injection time. In insulin-dependent 
patients, insulin should be administered at least 5 hours prior to the FDG injection. Patients with 
diabetes who are on oral diabetic medication should take their medication 4 to 5 hours prior to the 
FDG-PET/CT. 
3. Blood glucose level should be checked before FDG injection. Blood sugar (measured by glucometer) 
must be less than 200 mg/dL at the time of the FDG-PET study. If the blood glucose level is greater 
than 200 mg/dL, the FDG-PET imaging should be rescheduled. If the blood glucose level still exceeds 
200 mg/dL on the following scheduled day for PET scanning, the patient will not be included in the 
trial. 
4. AE evaluation must be performed (in person or by phone) at 24 hours (± 4 hours) after each FDG-
PET/CT and FLT-PET/CT imaging scan. See Sections 5.3 and 5.5 for AE reporting requirements of 
the imaging sub-studies.  
10.4.3 
FDG-PET/CT Analysis Description 
Analysis will determine the degree of change in summed SUVmax, and 
its correlation with tumor response by standard RECIST criteria and 
PFS. The percentage change in the sum of SUVmax of the 5 hottest 
lesions at baseline will be determined. The same lesions will be 
measured pre- and post-treatment. The change in SUVmax will be 
used in the primary analysis as a continuous variable. In secondary 
analysis, the change will be categorized into 2 groups – summed 
SUVmax change from baseline ≥ -25% vs. summed SUVmax change 
from baseline < -25%. We hypothesize that the larger SUVmax change 
will predict better tumor response with standard imaging at 8 weeks 
and have improved outcomes as assessed by PFS. The change in 
SUVmax between Arms H and I will also be compared. 
10.4.4 
FLT-PET/CT Analysis Overview and Release of Results 
The percentage change in the sum of SUVmax of the 5 hottest lesions 
at baseline will be determined. The same lesions will be measured 
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pre- and post-treatment. We hypothesize the early-FLT flare will be 
induced by gemcitabine-based chemotherapy and that early-FLT flare 
will be abrogated by the addition of AZD1775 to gemcitabine-based 
chemotherapy. The final results of the FLT-PET study will be shared 
with the participating centers at the completion of the entire study. 
With agreement between the patient and the treating physician, and at 
the discretion of the participating center, the treating physician may 
share the experimental results of the FLT imaging scans with the 
participant. The sharing of the informal results should be done with 
caution, as the FLT-PET is still experimental and the significance of 
these results is unknown. The results from the FLT-PET scans should 
not be part of the patient’s medical record and should not be used to 
direct or change therapy. We emphasize that sharing of imaging 
results with patients remains optional and at the discretion of the 
participating center, the patient and the treating physician. 
10.4.5 
Off-Imaging Criteria 
Participants who do not complete baseline FDG-PET or FLT-PET 
imaging scans will not continue on-study for the imaging sub-studies 
to complete the second protocol-defined imaging study. Additional 
participants will be recruited until target accrual is reached, as long as 
study funds and overall trial recruitment timelines allow. 
10.5 
Imaging Submissions for Quality Control and Central Reader Study 
10.5.1 
Imaging Submission Instructions 
For TRIAD Submission: The preferred image transfer method is via 
TRIAD, a software application that ACRIN provides for installation on 
a site’s PC. One or several computers of choice within the institutional 
“firewall” and on the institutional network may be equipped with 
TRIAD software; Internet access is also required. The TRIAD 
application can then be configured as a DICOM destination on either 
scanner(s) and/or PACS system for direct network transfer of study 
related images into the TRIAD directory. When properly configured, 
the TRIAD software anonymizes, encrypts, and performs a lossless 
compression of the images before they are transferred to the ACRIN 
image archive in Philadelphia. Once equipment-readiness has been 
determined, imaging personnel from ACRIN will coordinate installation 
and training for the software. 
For more information, contact: TRIAD-support@phila.acr.org or call 
215-940-8820. 
An Image Transmittal Worksheet (ITW) must accompany all media 
submissions and should be delivered via email or fax (to: 
imagearchive@acr.org or 215-923-1737).  


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Images may be mailed to: 
American College of Radiology Imaging Network 
ACR Imaging Core Laboratory 
Attn: ECOG-ACRIN EA2131 
1818 Market Street 16th floor 
Philadelphia, PA 19103 
10.5.2 
Quality Control (QC) Review 
First imaging studies from each site must be submitted within 48 
hours after acquisition for a review of adherence to study protocol. 
Local review of imaging studies for completeness, DICOM content, 
and dose correction, for example, is encouraged prior to submission 
to the core lab. QC review will be performed on all FDG-PET/CT and 
FLT-PET/CT image submissions to the ACR Imaging Core Lab. 
ACRIN’s imaging specialists will provide feedback to participating 
sites, especially during early submissions, in response to QC 
assessments. 
10.5.3 
Central Reader Study  
A central review and analysis of all FDG-PET and FLT-PET scans will 
be performed by ACRIN at the ACR Imaging Core Laboratory. The 
centralized imaging analysis will be used for secondary endpoint 
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11. 
Phase I Biospecimen Submissions and Research Studies 
Plasma specimens for pharmacokinetics studies are REQUIRED from all patients 
enrolled on the Phase I aspect of the trial.  
Kits are requested from and samples submitted to Covance Laboratories, Inc. for 
assessment of the AZD1775 pharmacokinetics. 
11.1 
Sample submissions 
Submission of plasma samples are MANDATORY.  All times are relative to 
the administration of AZD1775 administration.  
Collection and shipping kit request form is in Appendix XI. Each kit will contain 
the materials (vacutainers, cryovials, labels, and shippers) for the collection and 
submission of samples for a single patient for all required time points. Two kits 
may be requested by the Phase I participating site upon IRB approval of the 
Phase I aspect of the trial. 
The date and time of AZD1775 administration, the start time of 
chemotherapy (for day 1), and actual draw times must be entered into the 
ECOG-ACRIN Samples tracking system and must be provided in the 
documentation submitted with the blood samples. 
LABELING: All samples are to be labeled with the ECOG-ACRIN protocol 
number EA2131, the ECOG-ACRIN patient ID number, date, time point (e.g. 
C1D1-0) of collection, and type of material (plasma EDTA). Pre-printed labels, 
provided in the kits, with a unique Custom ID will be used on all sample and 
aliquot tubes.  
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. 
11.1.1 
Submission Schedule  
Sample submission schedule is outlined in table format in 
Section 7.1.1. 
Blood samples will be collected into 2 mLvacutainers containing 
EDTA and processed to isolate the plasma at: 
• 
Cycle 1, Day 1: Time points will be at 0 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 
hr and 24 hrs (Day 2, 0 min) from the time of first AZD1775 
administration. Patients are to bring their day 2 dosage to take 
AFTER the 24 hour draw.    
• 
Cycle 1, Day 16: Time points will be at 0 min, 1 hr, 2 hr, 4 hr, 6 hr, 
8 hr and 24 hrs (Day 17) from the administration of first AZD1775 
administration. Note, the 24 hour (day 17) draw is strongly 
encouraged but not required. Patients are to arrive at the clinic 
prior to time they are to take their day 16 dose. 
The collected plasma samples are to be batched at ≤ -70°C and 
shipped on dry ice at the end of cycle 1, upon collection of all samples 
from a single patient. 
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11.1.2 
Preparation and Shipping Guidelines 
Blood samples are to be processed within 30 minutes of the draw and 
the collected plasma placed in the freezer (≤ -70°C) as quickly as 
possible.  
Please label and track the collection of these samples carefully, as the 
collection times will impact assessment of the samples.  
Time of administration of AZD1775, start of first chemotherapy IV (day 
1 only) and actual draw time for each sample must be indicated in the 
Sample Tracking System. 
• 
Draw 2 mL of peripheral blood into the EDTA (purple top) 
vacutainer tube provided in the kit provided by Covance. Gently 
invert tube 10 times. 
• 
Place the vacutainer in ice bath immediately. Within 30 minutes of 
collection, separate plasma in a centrifuge at refrigerated (~ 4°C) 
at 1500 g for 10 min. 
• 
Pipette roughly equal amounts of plasma into two properly labeled 
plastic cryogenic tubes and freeze at -20°C or less until shipped. 
Packaging instructions: 
• 
DO NOT SPLIT THE SAMPLES FROM A SINGLE PATIENT 
ACROSS MULTIPLE SHIPMENTS.  
• 
All samples must be labeled. No unlabeled samples are to be 
shipped. 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 of the cryovial as possible, but do 
not adhere the label to the cap of the tube. Do not cover any 
written information with the label. 
• 
It is strongly recommended that Day 1 and Day 16 samples from a 
single patient be in separate biohazard bags.  
• 
Do not ship samples from multiple patients together.  
• 
Each biohazard bag within the shipment must be clearly labeled 
with the protocol number, patient case ID, and day of collection 
(C1D1 or C1D16).  
• 
MUST be shipped on dry ice (sufficient quantity to ensure they 
remain frozen for at least 72 hours) overnight MONDAY through 
THURSDAY only. Do not ship on the day before a weekend or 
holiday.   
• 
Samples must be securely packed in boxes to avoid breakage 
during transit and double-bagged to contain leaks. 
• 
Ship using the courier shipping label provided in the kit. 
• 
A fax of the completed COVANCE Specimen Shipment Pre-
Alert Form (Appendix XII) : 
o Fax:  1-800-335-1462  
o Email:  SMSpecialHandlingIndy@Covance.com 
o Email: Phyllis.Sellars@Covance.com 


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o Email: Gaelle.Legaud@Covance.com   
on the day of sample shipment.  The samples being shipped to 
CCLS should be shipped using the Covance-supplied kit supplies 
and labeled with the original CCLS barcode label for identification 
purposes.  Place the purple label, if provided, on the outside of the 
shipper.  The samples should be accompanied with a specimen 
packing list to allow sample reconciliation upon receipt at CCLS.   
An STS-generated shipping manifest must be submitted with 
every shipment and an electronic copy of the manifest should be 
emailed directly to the email addresses above. 
Ship to Covance Laboratories at: 
Covance Central Laboratory Services 
Attn:  Phyllis Sellars – Special Handling 
8211 SciCor Drive 
Indianapolis, Indiana 46214 
Phone:  317-271-1200 
11.2 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked using 
the ECOG-ACRIN Sample Tracking System (STS). The software will allow the 
use of either 1) an ECOG user-name and password previously assigned (for 
those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst 
Important: Any case reimbursements associated with specimen submissions may 
not be captured if specimens are not logged into STS. Additionally, please note 
that the STS software creates pop-up windows, so you will need to enable pop-
ups within your web browser while using the software. A user manual and 
interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated shipping manifest should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
Study Specific Notes 
The date and time of AZD1775 administration, start time of chemotherapy, 
and actual draw time of each sample must be entered into the ECOG-
ACRIN Samples tracking system, and be provided with the documentation 
submitted with the blood samples. 
Generic Specimen Submission Form (#2981)  will be used in the event that STS 
is unavailable at time of sample submission as a substitute for the STS-shipping 
manifest.  Indicate the appropriate Lab on the submission form: 
• 
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Retroactively enter all specimen collection and shipping information when STS is 
available. 
11.3 
Storage for Future Research 
Residual material from the Phase I pharmacokinetic specimens submitted will not 
be retained for future research. Specimens will be held until specimen and data 
analyses are completed and then destroyed. 
11.4 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory.  
Inventories of specimens forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office - Boston. 
11.5 
Lab Data Transfer Guidelines  
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. The quarterly 
cut-off dates are March 31, June 30, September 30, and December 31. Data is 
due at the ECOG-ACRIN Operations Office - Boston 1 week after these cut-off 
dates. 
 


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12. 
Phase II Biospecimen Submissions and Research Studies 
Sample submissions apply to patients in the Phase II Study (Arms H and I) only. 
Specimens are to be submitted from patients on either treatment arm who consent “Yes” 
to “ I agree to have my samples collected and I agree that my samples and related 
information may be used for the laboratory studies described above” for the research 
studies outlined in Section 12.1. 
It is required that all samples submitted on this trial be entered and tracked using the 
ECOG-ACRIN Sample Tracking System (STS). An STS shipping manifest is to be 
included with every submission to any receiving laboratory.  
All samples and aliquots must be labeled with the protocol number (EA2131), ECOG-
ACRIN patient ID number, patient initials, date of collection and sample type. 
12.1 
Specimen Collection and Submission  
12.1.1 
Schedule 
Specimens must be labeled with the protocol number, ECOG-ACRIN 
patient sequence number, date AND TIME of collection, and 
specimen type. 
Order form for collection/shipping kits is located in Appendix XIII. 
Starter kits are NOT available. 
Samples are to be submitted as follows: 
• 
Pre-trial diagnostic pathology materials are to be submitted within 
2 weeks following randomization.  See Section 12.1.2 
• 
Scalp punch biopsy samples (hair follicles) are to be submitted as 
outlined in Section 12.1.3 upon collection and processing of the 
day 2 sample. Samples are to be collected at the following 
timepoints:  
• 
prior to start of protocol treatment,  
• 
Cycle 1 Day 2 
12.1.2 
Submission Tissue 
Submitting pathologist and clinical research associate may refer to 
Appendix I which also outlines the Pathology Submission Guidelines.  
The tissue samples are to be labeled with the pathology ID specimen 
ID as well as containing the information above. 
12.1.2.1 
Required Materials 
Forms: Must be submitted with all tissue submissions. 
• 
STS generated shipping manifest. 
• 
Copy of the surgical pathology report. 
Biological Material Submission: 
• 
Representative diagnostic or surgical tumor tissue 
block 
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NOTE: 
If a block is unavailable for submission, 
cores and slides are to be submitted, all 
cores and slides must be adequately 
labeled, with slides number sequentially in 
the order cut. Alternative submission 
requirement: 
• 
One (1) H&E, and  
• 
Twenty (20) 4 µm unstained air-dried plus slides, 
and 
• 
One (1) or more core punches (minimum of 4mm). 
If core punch tool is unavailable, request core 
punch kit from the ECOG-ACRIN CBPF (844-744-
2420). Adequately label every slide and core 
submitted. 
12.1.2.2 
Shipping Procedures 
Access to the shipping account for specimen shipments to 
the ECOG-ACRIN CBPF at MD Anderson Cancer Center 
can now only be obtained by logging into fedex.com with 
an account issued by the ECOG-ACRIN CBPF. For 
security reasons, the account number will no longer be 
given out in protocols, over the phone, or via email. This 
account is used for all shipment to the ECOG-ACRIN 
CBPF for any ECOG-ACRIN trial. If your site needs to 
have an account created, please contact the ECOG-
ACRIN CBPF by email at eacbpf@mdanderson.org. 
Pathology materials are to be shipped at ambient 
temperature within 2 weeks of patient randomization.   
Ship to the E-A CBPF at: 
MD Anderson Cancer Center 
Department of Pathology 
Tissue Qualification Laboratory for ECOG-ACRIN 
Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Tel: 844-744-2420 
Fax: 713-563-6505 
Email: eacbpf@mdanderson.org 
12.1.3 
Submissions of Scalp Biopsies 
Questions regarding shipments are to be directed to the ECOG-
ACRIN CBPF. Questions regarding performance of the scalp biopsies 
are to be directed to Erin Hohler at (216) 286-3889 / (216) 386-3890. 
Samples are to be collected prior to start of protocol treatment and 
Cycle 1, Day 2 of treatment. 


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12.1.3.1 
Specimen preparation 
Hair Follicles (Scalp Punch Biopsy) 
Patient is to be instructed not to apply any topical agents to 
the biopsy area within 72 hours prior to the procedure 
(local anesthetic is allowed). Make sure the processing set-
up is complete before collecting the scalp punch biopsy. 
• 
Complete and adhere the labels provided on all 
collection vials with date of specimen collection and 
patient identifiers.   
• 
Obtain the biopsy from the scalp area 2 inches behind 
the ears between the top of the ear to middle of the 
ear. 
• 
Prepare the site with an alcohol wipe or alcohol swab. 
• 
OPTIONAL: If local anesthetic is needed, inject the site 
of biopsy with 1% lidocaine with 1:100,000 epinephrine 
as local anesthetic. 
• 
Using the thumb and forefinger of your nondominant 
hand, stretch the skin at the biopsy site. 
• 
Use a 4-mm skin punch biopsy instrument to push 
vertically into the biopsy site and then rotate the 
instrument to cut through the skin into the 
subcutaneous fat. As you go through the skin into the 
fat, a decrease in resistance will be felt. 
• 
Push down with your fingers around the biopsy site and 
the biopsy specimen should lift up. Carefully grasp the 
biopsy specimen with forceps and lift up. Use sharp 
tissue scissors to cut the subcutaneous base of the 
biopsy specimen. 
• 
Apply direct pressure to the biopsy site to achieve 
hemostasis and then close the site with steristrips or a 
sterile adhesive dressing. Have a suture kit available in 
case a suture needs to be placed to close the wound. 
Load needle driver with 5-0 prolene and place 1-2 
sutures. Cut sutures about 5 mm from skin surface 
• 
Place the biopsy specimen into 10% neutral buffered 
formalin (NBF). Transfer the recently obtained skin 
punch biopsy to the container of 10% NBF as soon as 
possible (0-30 min of removal). The formalin solution 
should be at least 10 times the volume of the 
specimen. Seal with parafilm and place in a biohazard 
bag. 
• 
Store at room temperature until shipping. DO NOT 
FREEZE. 
• 
Samples for an individual patient are to be batched and 
shipped together for pre-treatment and post-treatment 
(Cycle 1, Day 2) samples. 


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• 
Adequately label every specimen submitted.  
12.1.3.2 
Shipping procedures 
Access to the shipping account for specimen shipments to 
the ECOG-ACRIN CBPF at MD Anderson Cancer Center 
can now only be obtained by logging into fedex.com with 
an account issued by the ECOG-ACRIN CBPF. For 
security reasons, the account number will no longer be 
given out in protocols, over the phone, or via email. This 
account is used for all shipment to the ECOG-ACRIN 
CBPF for any ECOG-ACRIN trial. If your site needs to 
have an account created, please contact the ECOG-
ACRIN CBPF by email at eacbpf@mdanderson.org. 
Ship the scalp punch biopsy samples at ambient 
temperature with the STS-generated shipping manifest 
MONDAY through THURSDAY only, via overnight courier 
o the E-A CBPF at: 
MD Anderson Cancer Center 
Department of Pathology 
Tissue Qualification Laboratory for ECOG-ACRIN 
Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Tel: 844-744-2420 
Fax: 713-563-6505 
Email: eacbpf@mdanderson.org 
12.1.4 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and 
tracked using the ECOG-ACRIN Sample Tracking System (STS). The 
software will allow the use of either 1) an ECOG-ACRIN user-name 
and password previously assigned (for those already using STS), or 
2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the 
samples required for this study, please access the Sample Tracking 
System software by clicking https://webapps.ecog.org/Tst 
Important: Any case reimbursements associated with specimen 
submissions may not be captured if specimens are not logged into 
STS. Additionally, please note that the STS software creates pop-up 
windows, so you will need to enable pop-ups within your web browser 
while using the software.  A user manual and interactive demo are 
available by clicking this link: http://www.ecog.org/general/stsinfo.html 
Please take a moment to familiarize yourself with the software prior to 
using the system. 
An STS generated shipping manifest should be shipped with all 
specimen submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 


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Study Specific Notes 
Generic Specimen Submission Form (#2981v2) will be required only if 
STS is unavailable at time of sample submission. Notify the laboratory 
of the shipment by faxing a copy of the completed form to the 
laboratory. Indicate the appropriate Lab on the submission form: 
• 
ECOG-ACRIN CBPF 
Retroactively enter all submissions when STS is available. 
12.1.5 
Use of Specimens in Research 
Specimens will be distributed for the research studies defined in 
Section 12.2 per patient consent. 
Specimens from patients who consented to allow their specimens to 
be used for future approved research studies, including residuals from 
the currently defined research studies, will be retained in an ECOG-
designated central repository. For this trial, specimens will be retained 
at the ECOG-ACRIN Central Biorepository and Pathology Facility 
Specimens submitted will be processed to maximize their utility for 
current and future research projects and may include, but are not 
limited to, extradition of plasma, serum, DNA and RNA. 
If future use is denied or withdrawn by the patient, the samples will be 
removed from consideration for use in any future study. Pathology 
materials may be retained for documentation purposes or returned to 
the site. All other specimens will be destroyed per guidelines of the 
respective repository. 
12.2 
Phase II Research Studies 
We propose a comprehensive approach to predict efficacy of Nab-Paclitaxel, 
gemcitabine and AZD1775. Subjects in the phase II portion of the study will have 
tumor tissue and scalp punch biopsies collected. An initial panel of biomarkers, 
described briefly below, is planned and additional markers will be added as they 
are identified. 
Priority of tissue use: 
1. p53 mutational analysis 
2. Pharmacodynamic biomarkers for AZD1775 
12.2.1 
Evaluation of p53 mutation status by DNA sequencing 
As discussed in Section 1.6.1, p53 status will be assessed on pre-
treatment tumor tissue of patients in Arms H and I as studies have 
suggested preferential killing of p53-deficient cells with S-/G2-
checkpoint inhibitors.27 However, some studies have also suggested 
p53-proficient tumors are killed with S-/G2-checkpoint inhibitors.28-31 
Combination of AZD1775 and gemcitabine potentiates the efficacy of 
gemcitabine in established human pancreatic cancer xenografts.23 
Nine individual patient-derived low passage pancreatic cancer 
xenografts (3 with wild-type p53 and 6 with deficient p53 [mutant]) 
were implanted in athymic mice. Five of 9 xenografts treated with 
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gemcitabine and AZD1775 produced complete tumor growth inhibition 
resulting in tumor shrinkage.23  Combination treatment caused greater 
than 50% regression in tumor size in 4 of 6 xenografts with p53-
deficient tumors (Figure 5).23 The p53 pathway can also be inactivated 
by genetic or epigenetic events that occur upstream or downstream of 
p53.32 Therefore, it is important to assess the integrity of the p53 
pathway to determine optimal timing of administration of S-/G2-
checkpoint inhibitors and for correlations to be drawn between p53 
functional status and tumor response.32 
Figure 5: Combination of AZD1775 and gemcitabine potentiates the efficacy 
of gemcitabine in established human pancreatic cancer xenografts. Tumor 
growth inhibition was observed in the p53-wild type tumors treated with 
AZD1775 and gemcitabine compared to control; however, combination 
treatment caused greater than 50% regression in tumor size in 4 of 6 
xenografts with p53-deficient tumors.23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The discrepancies between preferential killing of p53-deficient vs. -proficient 
tumors with S/G2 checkpoint inhibitors may be explained by dosing schedules 
and the integrity of the p53 pathway in the cell lines being treated.32 In models of 
Chk1, loss of viability is observed when cells knocked down for Chk1 are 
exposed to antimetabolites to activate S-phase checkpoint and then released 
from the S-phase block. This response is independent of p53 status and 
suggests that p53-proficient tumors could potentially be targeted by concurrent 
administration of an antimetabolite and a Chk1 inhibitor.29,32 The differential 
response of p53 proficient- vs. p53-deficient tumors to combination therapy is 
most readily observed when cells treated with a DNA-damaging agent are given 
time to arrest at the G2-checkpoint and then exposed to Chk inhibitors. Under 
these conditions only p53-deficient cells are observed to enter a lethal 
mitosis.32,101 The p53 pathway can also be inactivated by genetic or epigenetic 
events that occur upstream or downstream of p53.32 We would expect similar 
Figure 5 


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changes using a Wee1 inhibitor such as AZD1775. Therefore, it is important to 
assess the integrity of the p53 pathway to determine optimal timing of 
administration of S-/G2-checkpoint inhibitors and for correlations to be drawn 
between p53 functional status and tumor response.32 
p53 mutational analysis will be performed using the Ion AmpliSeqTM Cancer 
Hotspot Panel v2 (Ion Torrent/Life Technologies) as described.102,103 This cancer 
panel targets 50 oncogenes and tumor suppressor genes, including the TP53 
gene. The test uses 207 primer pairs in a single reaction, requiring only 10ng of 
input DNA from FFPE samples.  Briefly, Amplicons averaging 154 bp will be 
purified (Agencourt AMPure XP, Beckman Coulter), quantified (2100 Bioanalyzer 
DNA 7500, Agilent Technologies), prepared and enriched for sequencing on the 
Ion Sphere Particles™ (ISPs) using the Ion OneTouch™ 200 Template Kit v2 
(Life Technologies) in the Ion OneTouch™ 2 System (Life Technologies). 
Templated ISPs will be quantified (Qubit 2.0, Life Technologies) and loaded 
into an Ion 318™ Chip (Life Technologies) to be sequenced on the Ion PGM™ 
using the Ion PGM™ Sequencing 200 Kit v2 (Life Technologies). Signal 
processing and base calling will be performed with Torrent Analysis Suite version 
3.4.2. FASTQ files generated from the Ion Torrent PGM™ Server will be aligned 
to the Hg19 version of the human genome (The Broad Institute bundle download 
2.5) using the Burroughs-Wheeler Alignment algorithm as implemented in the 
BWA software package v.0.7.5a104. MuTect v.1.1.4105 and the Ion Reporter™ 
Software (Life Technologies) will be used to identify somatic point mutations in 
aligned reads.  Genetic variants will be functionally annotated using ANNOVAR 
v.2013Jul28106 and proprietary software developed by GenomOncology 
(www.genomoncology.com). Variants will be filtered dynamically to focus on 
features of biological interest, including (i) filtering out all variations present in 
dbSNP, (ii) only showing variations that alter protein function, (iii) only showing 
variations in genes found in the COSMIC cancer gene database, in a subset of 
COSMIC by cancer type, in a subset of the Gene Ontology, in a subset of 
pathways from the NCI/Nature pathway set, or any combination of these 
parameters. 
These studies will be performed at the University Hospitals Translational 
Laboratory (UHTL), a CLIA/CAP accredited laboratory specialized in deep 
sequencing assays at University Hospitals Case Medical Center/Case Western 
Reserve University.  
12.2.2 
Evaluation of pharmacodynamic biomarkers of AZD1775 
In response to DNA damage, cells undergo cell cycle arrest due to the 
presence of cell cycle checkpoints, mainly in the G1 and G2 phases. 
Checkpoint pathways operating at the G1 phase are frequently lost in 
cancer cells due to mutation of the p53 tumor suppressor gene, which 
is common in pancreatic cancer. Cells lacking functional p53 would 
not be anticipated to arrest at the G1 checkpoint and would depend on 
the G2 checkpoint to permit DNA repair prior to undergoing mitosis. 
Thus, G2 checkpoint abrogation should preferentially kill p53-deficient 
cancer cells by removing the only checkpoint that protects these cells 
from premature entry into mitosis in response to DNA damage. Pre-
clinical data using gemcitabine and AZD1775 pancreatic cancer 
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Wee1 is the major kinase phosphorylating the Tyr-15 site of Cdc2 and 
Wee1-dependent phosphorylation of Cdc2 maintains the Cdc2/cyclin 
B1 complex in an inert form. Cdc2 initiates mitosis, which is the 
ultimate target of DNA replication and repair checkpoints. 23 It has 
been demonstrated that AZD1775 treatment strongly inhibited 
phosphorylation of Tyr-15 of Cdc2, the primary substrate of Wee1. 23 
Tumor cells treated with gemcitabine induces G2 arrest, which 
correlates with an increased Cdc2 inhibitory phosphorylation at Tyr-15 
and prevents mitotic entry as evidenced by decreased phospho-
histone H3Ser10 (p-HH3Ser10)23 However, the decreased Cdc2 inhibitory 
phosphorylation at Tyr-15 caused by AZD1775 treatment indicates 
that AZD1775 has the ability to abrogate the G2 arrest induced by 
gemcitabine and promote mitotic entry as demonstrated by enhanced 
p-HH3Ser10. 23 Loss of Cyclin B1, a marker of G2 phase in combination 
AZD1775 and gemcitabine treatment compared to control and 
gemcitabine-treated pancreatic tumors, indicate the exit from G2 
phase arrest.23.  The levels of phospho-H2AXSer139 (γ-H2AX) were 
used as a surrogate for unrepaired DNA damage.107 γ-H2AX 
expression was clearly elevated in the combination AZD1775 and 
gemcitabine treatment group compared to gemcitabine-treated 
tumors, indicating the persistence of unrepaired DNA damage in the 
tumors.23 Therefore, the pre-clinical observations provide mechanistic 
support to the potential biomarkers which will be investigated in this 
study. 
Immunohistochemistry (IHC) to biomarkers in the Wee1 signaling 
pathway will be performed in pre-treatment tumor tissue and pre- and 
post-treatment hair follicles from scalp punch biopsies to determine 
the treatment effects and target engagement of AZD1775. A summary 
of the markers of interest that will be investigated are as follows: 
Biomarker 
Purpose 
Phospho-Cdc2Tyr15 (p-
Cdc2Tyr15) 
Primary substrate of Wee1 and indicates target 
engagement by AZD1775. 
Phospho-histone H3Ser10 
(p-HH3Ser10) 
Measure of mitotic entry 
Cyclin A2 
Marker of S-, G2- and prophase cells. 
Phospho-Chk1 (p-Chk1) 
Phospho-H2AXSer139 (γ-
H2AX) 
Measure of DNA damage 
Cleaved caspase 3 
Measure of cell death 
We would expect that the addition of AZD1775 to gemcitabine and 
Nab-Paclitaxel will: decrease p-Cdc2Tyr15 expression indicating 
abrogation of G2 arrest, increase p-HH3Ser10 and decrease in cyclin A2 
expression as the cells enter mitosis, increase p-Chk1 and γ-H2AX 
reflecting the presence of unrepaired DNA damage and increase 
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Additional information on the markers of interest: 
• 
Phospho-Cdc2Tyr15 (p-Cdc2Tyr15) - This should provide a direct 
indication of drug activity, if drug is on board at the time of 
sampling. 
• 
Phospho-histone H3Ser10 (p-HH3Ser10) - This is a mitotic marker that 
is increased >10 fold in mitotic cells. We expect that we can 
measure the mitotic index on H&E sections alone, but in the event 
that they are rare (e.g., in hair follicles), we will use this marker 
which detects all mitotic stages. 
• 
Cyclin A2 - This will mark S, G2, and prophase cells. If mitotic cells 
are rare in the hair follicle sections, the ratio of cyclin A2 positive 
to cyclin A2 negative cells in the follicle should provide a measure 
of cell cycle perturbation, which we expect both from gemcitabine 
and Nab-Paclitaxel and from AZD1775. 
• 
Phospho-Chk1 (p-Chk1) and Phospho-H2AXSer139 (γ-H2AX) - 
These are both measures of DNA damage. Phospho-Chk1 is an 
activation marker for cells that have an activated G2 checkpoint. It 
is possible that the activity of Chk1 could antagonize the activity of 
Wee1. Both in the normal cell cycle and in the DNA damage 
response, these two enzymes act in concert to delay entry to 
mitosis. In the presence of a Wee1 inhibitor, the activity of Chk1 
could prevent the intended action of Wee1 inhibition. Therefore, 
we will monitor individual patient activity of Chk1 Phospho-
H2AXSer139 is a direct measure of DNA damage downstream of 
ATR and ATM. This should be directly correlated with Chk1 
activation and related to the level of apoptosis. 
• 
Cleaved caspase 3 - This will be used to evaluate the extent of 
induced programmed cell death. 
12.2.3 
Immunohistochemistry (IHC) Method 
Formalin-fixed paraffin embedded (FFPE) tissues will be cut at 5um 
and mounted on charged slides for evaluation by IHC. Slides will be 
baked in an oven at 60° C to melt paraffin, remove underlying 
moisture, and keep tissue sections adhered to the slide. Further 
deparaffinization and rehydration of tissue sections will be carried out 
by immersion through xylenes, graded ethanols, and finally dH2O.  
Testing of antigen retrieval (AR) methods will include steamer (low 
heat), pressure cooker (high heat), and/or no retrieval, in addition to 
AR buffers with different chemistries (Citrate & Tris) and pHs (6 & 9). 
Endogenous peroxidase activity will be quenched by treating sections 
with a 3% H2O2 solution. Blocking of charged protein activity and 
reduction of non-specific background will be achieved by using a 
proprietary blocking reagent. Titration of individual antibodies will be 
performed according to dilution ranges specified on vendor 
datasheets as a starting basis. Additional titration will be performed 
when necessary. Horseradish peroxidase (HRP) conjugated 
secondary antibody polymers will be used to detect the target antigen-
antibody bound complexes. 3, 3’ diaminobenzidene (DAB) will be 


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used as the chromogen to visualize the target proteins under basic 
light microscopy. 
We plan on purchasing and validating the primary antibodies to 
phospho-Cdc2Tyr15 (Bioss Inc., Cell Signaling Technologies or BD 
Biosciences), phospho-histone H3Ser10 (Cell Signaling Technology), 
cyclin A2 (Novus Biologicals, Novacastra or BD Biosciences), 
phospho-Chk1 (Cell Signaling Technology), phospho-H2AXSer139 (Cell 
Signaling Technology or BD Biosciences) and cleaved caspase 3 
(Cell Signaling Technology, currently used at Case Western and 
validated).  
Assays for validation including appropriate tissue, cell and intracellular 
(localization) expression, specificity and antibody titration will be 
performed on known positive and negative control tissues based on 
manufacturer recommendations and published peer-reviewed 
literature. Hence, the antibodies may be subject to change based on 
the validation assays.  If available from researchers, known gene 
tested positive and negative cell line pellets can be included. Western 
blot analysis for single band expression can be performed if not 
already demonstrated by manufacturer, provided cell lysates are 
available. The Case Comprehensive Cancer Center IHC Core is not a 
CLIA regulated or certified facility. The tests performed in this facility 
are for research purposes only.  
Analysis of IHC evaluation 
• 
Tumor tissue 
Immunohistochemical markers will be evaluated in tumor tissue. 
Those proteins that may have both cytoplasmic and nuclear 
expression that are dependent on cell cycle and/or mutational 
alterations such as Chk-1 and Cyclin A2, will be scored and 
averaged for both components in a minimum of 3 (20x) fields for 
relative intensity (0-3+; representing respectively:  negative , low , 
moderate and strong) and approximate distribution in quartiles  
(< 25%, 26-50%, 51-75%, > 75%). Immunohistochemical stains 
that are confined to nuclear expression (p-Cdc2Tyr15, p-
HH3Ser10and γ-H2AX) are best enumerated (number of positive 
nuclei/ 5-10 HPF). Cleaved caspase 3 may be semiquantitatively 
evaluated as a number of apoptotic cells in 3 separate 0.4 mm 
linear basal layer hair follicle epithelium units, and expressed in 
quartiles as above. The number of fields may need to be adjusted 
due to the size of the biopsy specimens. 
• 
Hair follicles 
Immunohistochemical markers will be evaluated in hair follicle 
epithelium from scalp biopsies. Those proteins that may have both 
cytoplasmic and nuclear expression that are dependent on cell 
cycle and/or mutational alterations such as Chk-1 and Cyclin A2, 
will be scored and averaged for both components in a minimum of 
3 (20x) fields for relative intensity (0-3+; representing respectively: 
negative, low , moderate and strong) and approximate distribution 


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in quartiles (< 25%, 26-50%, 51-75%, > 75%) of basal layer 
keratinocytes. Immunohistochemical stains that are confined to 
nuclear expression (p-Cdc2Tyr15, p-HH3Ser10and γ-H2AX) are best 
enumerated (number of positive nuclei/ basal layer keratinocyte).  
Cleaved caspase 3 may be semiquantitatively evaluated as a 
number of apoptotic cells in 3 0.4 mm linear basal layer hair 
follicle epithelium units, and expressed in quartiles as above. The 
number of fields may need to be adjusted due to the size of the 
biopsy specimens. 
12.3 
Sample Inventory Submission Guidelines  
Inventories of all samples submitted, be tracked via the ECOG-ACRIN STS and 
receipt and usability verified by the receiving laboratory via STS. Inventories of 
specimens allocated, and used for any approved research studies will be 
submitted by the investigating laboratories to the ECOG-ACRIN Operations 
Office - Boston on a monthly basis in an electronic format defined by the ECOG-
ACRIN Operations Office - Boston  
12.4 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. The quarterly 
cut-off dates are March 31, June 30, September 30, and December 31. Data 
submitted quarterly is due at the ECOG-ACRIN Operations Office - Boston 1 
week after these cut-off dates. 


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13. 
Electronic Data Capture 
Please refer to the EA2131 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
14. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
15. 
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47. Vesselle H, Grierson J, Muzi M, et al. In vivo validation of 3'deoxy-3'-
[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: 
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immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res 
2002;8:3315-23. 
48. Dittmann H, Dohmen BM, Paulsen F, et al. [18F]FLT PET for diagnosis and 
staging of thoracic tumours. Eur J Nucl Med Mol Imaging 2003;30:1407-12. 
49. Buck AK, Halter G, Schirrmeister H, et al. Imaging proliferation in lung tumors with 
PET: 18F-FLT versus 18F-FDG. J Nucl Med 2003;44:1426-31. 
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67. Turcotte E, Wiens LW, Grierson JR, Peterson LM, Wener MH, Vesselle H. 
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72. Saga T, Kawashima H, Araki N, et al. Evaluation of primary brain tumors with FLT-
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79. Kenny LM, Vigushin DM, Al-Nahhas A, et al. Quantification of cellular proliferation 
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81. van Westreenen HL, Cobben DC, Jager PL, et al. Comparison of 18F-FLT PET 
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82. Buck AK, Hetzel M, Schirrmeister H, et al. Clinical relevance of imaging 
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83. Been LB, Elsinga PH, de Vries J, et al. Positron emission tomography in patients 
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84. Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumors with 
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85. Choi SJ, Kim JS, Kim JH, et al. [18F]3'-deoxy-3'-fluorothymidine PET for the 
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86. Buchmann I, Neumaier B, Schreckenberger M, Reske S. [18F]3'-deoxy-3'-
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87. Cobben DC, Elsinga PH, Hoekstra HJ, et al. Is 18F-3'-fluoro-3'-deoxy-L-thymidine 
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88. Halter G, Buck AK, Schirrmeister H, et al. [18F] 3-deoxy-3'-fluorothymidine positron 
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lesions? J Thorac Cardiovasc Surg 2004;127:1093-9. 
89. Smyczek-Gargya B, Fersis N, Dittmann H, et al. PET with [18F]fluorothymidine for 
imaging of primary breast cancer: a pilot study. Eur J Nucl Med Mol Imaging 
2004;31:720-4. 
90. Visvikis D, Francis D, Mulligan R, et al. Comparison of methodologies for the in 
vivo assessment of 18FLT utilisation in colorectal cancer. Eur J Nucl Med Mol 
Imaging 2004;31:169-78. 
91. Cobben DC, van der Laan BF, Maas B, et al. 18F-FLT PET for visualization of 
laryngeal cancer: comparison with 18F-FDG PET. J Nucl Med 2004;45:226-31. 
92. Cobben DC, Elsinga PH, Suurmeijer AJ, et al. Detection and grading of soft tissue 
sarcomas of the extremities with (18)F-3'-fluoro-3'-deoxy-L-thymidine. Clin Cancer 
Res 2004;10:1685-90. 
93. Wagner M, Seitz U, Buck A, et al. 3'-[18F]fluoro-3'-deoxythymidine ([18F]-FLT) as 
positron emission tomography tracer for imaging proliferation in a murine B-Cell 
lymphoma model and in the human disease. Cancer Res 2003;63:2681-7. 
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95. Francis DL, Visvikis D, Costa DC, et al. Potential impact of [18F]3'-deoxy-3'-
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A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or without 
AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. List of Required Materials for EA2131 
2. Instructional memo to submitting pathologists 
 
Rev. 4/16 


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List of Required Material 
EA2131: A Phase I and Randomized Phase II Study of Nab-
Paclitaxel/Gemcitabine with or without AZD1775 in Treatment-Naïve 
Metastatic Adenocarcinoma of the Pancreas 
The following materials are to be submitting within one month of registering the patient to 
the trial:  
1. Pathology specimens:  
Diagnostic tumor tissue block - open biopsy or core needle biopsy specimens 
preferred, although cytology cell blocks will be accepted. 
NOTE:  
Since blocks are being used for laboratory studies, in some cases the 
material may be depleted and, therefore, the block may not be returned. If 
blocks are not available, contact the ECOG-ACRIN Central Biorepository 
and Pathology Facility (CBPF) to obtain alternative submission 
guidelines. 
2. Forms and reports: 
The following items are to be included with the pathology materials: 
• 
Institutional Surgical Pathology Report 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981) completed 
• 
ECOG-ACRIN Sample Tracking System (STS) manifest. If STS is not available 
at time of submission, submit the completed ECOG-ACRIN Generic Specimen 
Submission Form (#2981) and retroactively enter the submission information in 
STS when available. 
NOTE:  
Adequate patient identifying information must be included with every 
submission. It is strongly recommended that full patient names be 
provided. The information will be used only to identify patient materials, 
will expedite any required communications with the institution (including 
site pathologists.) 
3. Mail pathology materials to the CBPF at: 
MD Anderson Cancer Center 
Department of Pathology 
Tissue Qualification Laboratory for ECOG-ACRIN 
Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate 
any problems in meeting the pathology material submission deadline of one 
month, contact the Pathology Coordinator at the ECOG-ACRIN Central 
Biorepository and Pathology Facility Office by telephone 844-744-2420 or by email 
at eacbpf@mdanderson.org. 
 


 
157 
MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EA2131:  A Phase I and 
Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or 
without AZD1775 in Treatment-Naïve Metastatic Adenocarcinoma of 
the Pancreas 
The patient named on the attached ECOG-ACRIN Generic Specimen Submission Form 
(#2981) has been entered onto an ECOG-ACRIN protocol by 
______________________________ (ECOG-ACRIN Investigator). This protocol 
requires the submission of pathology materials for research studies. 
Keep a copy for your records and return the completed Submission Form, the surgical 
pathology report(s), the slides and/or blocks and any other required material (see List of 
Required Material) to the Clinical Research Associate (CRA). The CRA will forward all 
required pathology material to the ECOG-ACRIN Central Biorepository and Pathology 
Facility. 
Blocks and slides submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies. Paraffin blocks will be returned upon written request for 
purposes of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the Central 
Biorepository and Pathology Facility at 844-744-2420 or by email at 
eacbpf@mdanderson.org 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 
 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
158 
A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or without 
AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas 
 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG-ACRIN web site at http://www.ecog.org. As this is a 
personal letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the help of people like you who participate in clinical 
trials, we will improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 
Rev. 4/16 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
159 
A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or without 
AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas 
 
Appendix III 
 
Patient Capsule Calendar 
 
 
Capsule Calendar Directions 
1. Take your scheduled dose of each capsule. 
2. If you forget, the missed capsules will not be taken later. 
3. Please bring the bottle, or any leftover capsules and your capsule calendar to your 
next clinic visit. 
Instructions for taking AZD1775: 
• 
Take AZD1775 one hour prior or two hours after a meal.  
• 
On days of chemotherapy, take AZD1775 at the same time or just before the start of 
chemotherapy.  
• 
On days when you do not have chemotherapy, take AZD1775 about 24 hours after 
your previous dose.  
• 
Swallow each capsule whole with a full glass of water.  
• 
Do not crush, chew or open the capsules. If capsule is broken and the powder of the 
capsules gets on skin, wash the exposed area with as much water as necessary. 
Inform investigator or nurse if that occurs. 
 
 
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Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
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Patient Capsule Calendar 
ECOG-ACRIN patient no.: ________________ 
Patient’s Initials: ________________ 
Agent name: AZD1775, 25 mg capsules, by mouth, taken on days 1, 2, 8, 9, 15 & 16 
Take AZD1775 one hour prior or two hours after a meal. 
Day 
Date 
# of 100 
mg pills 
taken 
# of 25  mg 
pills taken 
Use the space below to make notes about things 
you would like to tell the doctor (including 
unusual symptoms you experience, other 
medicine you have taken and anything else you 
think would be of interest.) 
Month 
Day 
Year 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
Signature of patient or the person administering the oral medication: 
________________________________ 
 
Date: ___________ 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
161 
A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or without 
AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas 
 
Appendix IV 
 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
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Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
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4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator’s 
confidential and proprietary data, in addition to Collaborator(s)’s intellectual property rights, 
are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also 
be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/ proprietary information. 
 
Rev. 4/16 


ECOG-ACRIN 
EA2131 
Cancer Research Group 
Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
163 
A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or without 
AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas 
 
Appendix V 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 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. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
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Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
164 
A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or without 
AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas 
 
Appendix VI 
 
Select CYP3A4, CYP2C8, CYP2C9, CYP2C19, P-gp Inhibitors or BCRP Inhibitors or 
Substrates With Narrow Therapeutic Range 
A. CYP3A4 
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 become available.  
The following is a list of CYP3A4 substrates with a narrow therapeutic range. This is NOT 
a complete list of medications that are potentially incompatible with treatment on this 
protocol. Please refer to the following websites for more information:  
As the lists of these agents are constantly changing, it is important to regularly consult a 
frequently updated medical reference. 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginterac
tionslabeling/ucm093664.htm 
CYP = Cytochrome p450. 
CYP3A Inhibitors 
Strong 
• 
Clarithromycin 
• 
Telithromycin 
• 
Ketoconazole 
• 
Itraconazole 
• 
Fluvoxamine 
• 
Nefazodone 
• 
Ritonavir 
• 
Indinavir 
• 
Nelfinavir 
• 
Saquinavir 
• 
Atazanavir 
• 
Amprenavir 
• 
Conivaptan 
• 
Fosamprenavir 
• 
Grapefruit Juice 
• 
Telaprevir 
• 
Troleandomycin 
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Moderate 
• 
Aprepitant *prohibited on study* 
• 
Cimetidine 
• 
Diltiazem 
• 
Erythromycin 
• 
Fluconazole 
• 
Nifedipine 
• 
Posaconazole 
• 
Seville oranges 
• 
Star fruit 
• 
Verapamil 
CYP3A Inducers (strong and moderate) 
• 
Barbutrates 
• 
Bosentan 
• 
Carbamazepine 
• 
Efavirenz 
• 
Etavirine 
• 
Nafcillin 
• 
Nevaripine 
• 
Pheonobarbitone 
• 
Phenytoin 
• 
Rifampin 
• 
St. John’s Wort 
CYP3A4 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 
• 
Alfentanil 
• 
Alfuzosin 
• 
Amiodarone 
• 
Bexaroine 
• 
Cyclophosporine 
• 
Dihydroergotamine 
• 
Disopyramide 
• 
Dofetilide 
• 
Ebastine 
• 
Eletriptan 
• 
Eplerenone 
• 
Ergotamine 
• 
Fentanyl 
• 
Halofantrine 
• 
Mosapride 


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Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
166 
• 
Pimozide 
• 
Propafenone 
• 
Propofol 
• 
Quinidine 
• 
Ranolazine 
• 
Romidepsin 
• 
Sirolimus 
• 
Tacrolimus 
• 
Theophylline 
• 
Thioridazine 
• 
Tretinoin 
B. CYP2C8 
Caution should be exercised with concomitant administration of AZD1775 and agents that 
are sensitive substrates of CYP2C8, or substrates of this enzyme with narrow therapeutic 
range. 
CYP2C8 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 
• 
Repaglinide 
C. CYP2C9 
Caution should be exercised with concomitant administration of AZD1775 and agents that 
are sensitive substrates of CYP2C9, or substrates of this enzyme with narrow therapeutic 
range. 
CYP2C9 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 
• 
Celecoxib 
• 
Warfarin 
• 
Phenytoin 
D. 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. 
CYP2C19 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 
• 
Phenytoin 
• 
S-mephenytoin 
E. 
P-glycoprotein (p-gp) 
Caution should be exercised when agents that are inhibitors or substrates of P-gp are 
administered concomitantly with AZD1775 
P-gp Substrates 
• 
Digoxin.  


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Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
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NOTE: 
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). 
P-gp Inhibitors (strong) 
• 
Quinidine 
• 
Valspodar 
F. 
BCRP 
AZD1775 is an inhibitor of BCRP. 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.  
BCRP Substrates 
• 
Atorvastatin *prohibited on study* 
• 
Fluvastatin 
• 
Rosuvastatin 
• 
Simvastatin 
• 
Topotecan 
 


ECOG-ACRIN 
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Version Date: October 18, 2016 
 
NCI Update Date: June 26, 2014 
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A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or without 
AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas 
 
Appendix VII 
 
Medications That May Cause QTc Prolongation 
The following table presents a list of drugs that may prolong the QTc. These drugs are 
prohibited during the study. AZD1775 may be administered after a 5 half-life washout period 
elapses following the use of these drugs. Washout period is based on roughly 5 half-lives 
and rounded to a convenient interval. 
Compound 
Compound Half Life 
Possible 
Washout  
Period - Hours 
Possible 
Washout 
Period - Days 
Alfuzocin 
~10 hours 
 
7 
Amantadine 
17 +/- 4 hours (10-25) 
 
4 
Amiodarone 
(cordarone) 
58 days (15-142) 
36 days (active metabolite) 
 
180 
Amitriptyline* 
> 24 hours, wide interpatient variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hr (26-64) 
 
10 
Chloral hydrate 
Readily converted to Trichloroethanol (active metabolite 
T1/2=7-10 hour) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30 +/- 7 hours 
 
7 
Cisapride 
6 – 12 hour, up to 20 hour 
60 
 
Clarithromycin 
Non linear PK3-4 hr (250mg Q12) 5-7 hr (500mg Q12) 
36 
 
Cloroquine 
6 to 60 days; mean 20 days 
 
 
Desipramine* 
> 24 hours, wide interpatient variability 
 
 
Disopyramide 
6.7 hr (4-10) 
36 
 
Dofetilide 
10 hr 
48 
 
Dolesetron 
8.1 hr 
 
 
Domperidone 
7-8 hr 
48 
 
Doxepin* 
> 24 hours, wide interpatient variability 
 
 
Droperidol 
2.2 hours 
10 
 
Erythromycin 
* Each salt form has different Half life* 
 
 
Felbamate 
20-23 hr 
 
5 
Flecainide 
20 hr (12-27) 
 
5 
Foscarnet  
87.5+/-41.8 hours *distribution and release from bone* 
 
20 
Fosphenytoin 
12-29 hr 
 
6 
Gatifloxacin 
7-14 hr 
48 
 
Gemifloxacin 
7 hours 
48 
 
Grepafloxacin 
16 hr 
 
3 
Halofantrine 
6-10 days ( variable among individual) 
 
45 
Haloperidol 
18 +/-5 hr 
 
5 
Ibutilide 
6 hours (2-12) * variable among subject* 
36 
 
Imipramine* 
> 24 hours, wide interpatient variability 
 
 
Indapamide 
14 hours (biphasic elimination) 
 
3 
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Compound 
Compound Half Life 
Possible 
Washout  
Period - Hours 
Possible 
Washout 
Period - Days 
Isradipine 
8 hours ( multiple metabolites) 
48 
 
Levofloxacin 
6-8 hours 
48 
 
Levomethadyl 
Multiple compartment PK with active metabolite 2.6 day for 
LAAM, 2 day for nor-LAAM, 4 day for dinor-LAAM 
 
20 
Lithium 
24 hour (10-50) 
 
7 
Mesoridazine 
24-48 hours ( animal study) 
 
10 
Methadone 
15-30 hours 
 
7 
Moexipril/HCTZ 
2-9 hour (include active metabolite) for moexipril; 5.6-14.8 
hours for HCTZ  
48 
 
Moxifloxacin 
12 +/-1.3 hours 
72 
 
Naratriptan 
6 hours 
36 
 
Nicardipine 
~ 2 hour post IV infusion 
12 
 
Nortriptyline* 
> 24 hours, wide interpatient variability 
 
 
Octreotide 
1.7 hours 
12 
 
Ofloxacin 
5 to 7.5 hours 
 
2 
Ondansetron 
4 hours (IV/IM); 3 hours (PO) 
 
1 to 3 
Pentamidine 
6.4+/-1.3 hours 
36 
 
Pimozide 
55 hours 
 
10 
Procainamide 
3-4 hour for PA and NAPA (active metabolite) 
24 
 
Protiptyline* 
> 24 hours, wide interpatient variability 
 
 
Quetiapine 
6 hours 
36 
 
Quinidine 
6-8 hours in adult; 3-4 hours in children 
36 
 
Quinine 
4-5 hours 
 
 
Risperidone 
3-20 hours (extensive to poor metabolizer) 9-
hydroxyrisperidone (active metabolite) T ½ =21-30 hours 
(extensive to poor metabolizer) 
 
4 
Salmeterol 
5.5 hours ( only one datum) 
36 
 
Sotalol 
12 hours 
72 
 
Sparfloxacin 
20 hours (16-30) 
 
4 
Sumatriptan 
2.5 hours 
12 
 
Tacrolimus 
~34 hours in healthy; ~19 hours in Kidney transplant 
 
7 
Tamoxifen 
5-7 days (biphasic) 
 
30 
Telithromycin 
2-3 hr 
24 
 
Thioridazine 
20-40 hours (Phenothiazines) 
 
7 
Tizanidine 
2.5 hours 
12 
 
Vardenifil 
4 to 5 hours 
 
 
Venlaflaxine 
5 +/-2 hours for parent comp. 11+-2 hours for OVD (active 
metabolite) 
60 
 
Voriconizole 
6 hours; dose dependent 
 
 
Ziprasidone 
7 hr 
36 
 
Zolmitriptan 
2.8-3.7 hours (higher in female) 
18 
 
* Weakly associated with Torsades de Pointes and/or QT prolongation but that are unlikely to be a risk for 
Torsades de Pointes when used in usual recommended dosages and in patients without other risk 
factors (e.g., concomitant QT prolonging drugs, bradycardia, electrolyte disturbances, congenital long 
QT syndrome, concomitant drugs that inhibit metabolism). 
References: 
1. Physician’s Desk Reference 2002 


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NCI Update Date: June 26, 2014 
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2. Facts and Comparisons (update to June 2005) 
3. The Pharmacological Basis of Therapeutics 9th Edition, 1996 


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A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or without 
AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas 
 
Appendix VIII 
 
Information On Possible Interactions With Other Agents For Patients And Their 
Caregivers And Non – Study Health Care Team 
 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to 
the patient at the time of enrollment.  Use or modify the text as appropriate for the study 
agent, so that the patient is aware of the risks and can communicate with their regular 
prescriber(s) and pharmacist.  A convenient wallet-sized information card is also included 
for the patient to clip out and retain at all times.] 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent AZD1775. This clinical trial is sponsored by the National Cancer 
Institute. This form is addressed to the patient, but includes important information for 
others who care for this patient.  
AZD1775 interacts with many drugs that are processed by your liver.  Because of this, it is 
very important to tell your study doctors about all of your medicine before you start this 
study.  It is also very important to tell them if you stop taking any regular medicine, or if 
you start taking a new medicine while you take part in this study.  When you talk about 
your medicine with your study doctor, include medicine you buy without a prescription at 
the drug store (over-the-counter remedy), or herbal supplements such as St. John’s wort.  
Many health care prescribers can write prescriptions. You must also tell your other 
prescribers (doctors, physicians’ assistants or nurse practitioners) that you are taking part 
in a clinical trial. Bring this paper with you and keep the attached information card in 
your wallet.  These are the things that you and they need to know:  
AZD1775 interacts with (a) certain specific enzyme(s) in your liver.  
• 
The enzyme in question is CYP450 3A4. AZD1775 is metabolized predominantly by 
3A4. It is also a weak inhibitor of CYP 3A4, 2C8, 2C9, 2C19. AZD1775 must be used 
very carefully with other medicines that need these liver enzymes to be effective or to 
be cleared from your system. 
• 
Other medicines may also affect the activity of the enzyme.   
• 
Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance of 
harmful side effects. 
• 
AZD1775 is considered a weak “inhibitor” of the enzyme, meaning that it can affect 
the levels of other drugs that are processed by that enzyme. This can lead to 
harmful side effects and/or reduce the effectiveness of those medications. 
• 
You and healthcare providers who prescribe drugs for you must be careful about 
adding or removing any drug in this category.  
• 
Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
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CYP450 3A4. 
• 
Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ or consult a medical reference to 
see if any medicine they want to prescribe is on a list of drugs to avoid. 
• 
Please be very careful! Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye. They also have a generic name—it’s usually small 
and located above or below the brand name, and printed in the ingredient list. Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   
• 
Be careful:  
• 
If you take acetaminophen regularly: If you are an adult under 65 years of age, you 
should not take more than 8 extra strength tablets a day or 12 regular strength 
tablets a day. If you are older than 65 years of age, you should not take more than 
4 extra strength tablets a day or 7 regular strength tables a day. Read labels 
carefully! Acetaminophen is an ingredient in many medicines for pain, flu, and cold. 
• 
If you drink grapefruit juice or eat grapefruit: Avoid these until the study is over.  
• 
If you take herbal medicine regularly: You should not take St. John’s wort while you 
are taking AZD1775. 
Other medicines can be a problem with your study drugs.  
• 
You should check with your doctor or pharmacist whenever you need to use an over-
the-counter medicine or herbal supplement.  
• 
Your regular prescriber should check a medical reference or call your study doctor 
before prescribing any new medicine for you. Your study doctor’s name is  
_____________________________________  
and he or she can be contacted at  
_____________________________________.  
AZD1775 interacts with a specific liver enzyme called 
CYP450 3A4, and must be used very carefully with other 
medicines that interact with this enzyme.  
➢ Before you start the study, your study doctor will work 
with your regular prescriber to switch any medicines 
that are considered “strong inducers/inhibitors or 
substrates of CYP450 3A4.” 
➢ Before prescribing new medicines, your regular 
prescribers should go to 
http://medicine.iupui.edu/clinpharm/ddis/table.asp for a 
list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is ______________ and can 
be contacted at ______________.  
INFORMATION ON POSSIBLE DRUG 
INTERACTIONS  
You are enrolled on a clinical trial using the 
experimental agent AZD1775.  This clinical trial is 
sponsored by the NCI.   
AZD1775 interacts with drugs that are processed by 
your liver.  Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular 
medicine or if you start taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ 
assistant, nurse practitioner, pharmacist) that you 
are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever 
you need to use an over-the-counter medicine or 
herbal supplement. 
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Appendix IX 
 
Information for Local Radiology Team – Quality Control for Images 
[Note to investigators and study coordinators:  This appendix describes the data 
necessary for the FDG- and FLT-PET/CT sub-studies. It consists of a procedural 
“checklist” to be kept on-hand in the radiology department for the study imaging 
technologist and radiologist to use in quality control review of images prior to submission 
to the American College of Radiology (ACR) Imaging Core Laboratory. Consideration of 
these procedures will reduce queries in imaging data submission and ensure data 
integrity. If you have questions, contact the core lab at 215-923-1737.] 
Checklist for PET/CT Image Quality Control 
Upon Participant Arrival (FDG-PET/CT Only) 
Have you checked participant fasting state and blood glucose levels prior to 
administration of fluorodeoxyglucose (FDG)?  
NOTE: Fasting and blood glucose measurements are not needed for FLT PET/CT 
scans. 
✓ Has it been confirmed and documented that the participant fasted for > 4 hours prior 
to arrival to the facility? 
✓ Was the serum glucose concentration < 200 mg/dL and documented? 
SUV Calculations 
Standard uptake values (SUVs) will be used as the quantitative measurement to define 
response to therapy in the imaging sub-studies. The following are necessary to ensure 
accurate SUV measures. 
✓ Time of Injection and Scan Start Time 
o Have the time of injection and the scan start time been properly recorded? If the 
PET scanner software performs decay correction for the time interval between 
injection and imaging, check whether the time of injection and the start time of 
the scanner have been correctly entered. 
✓ Injected Dose 
o Has the injected dose been correctly calculated and entered in the DICOM 
header of the PET data set? 
o Is the time between radiotracer injection and start of the PET emission scan 
within the specifications of the imaging protocol? NOTE: The time between 
injection of the radiotracer and PET emission scan start time should be targeted 
at 60 minutes with an acceptable window of 50 to 70 minutes. 
✓ Body Weight 
o Has the body weight of the participant been correctly recorded and entered into 
the DICOM header of the PET data set? NOTE: The patient’s height and weight 
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must be measured; verbal relay by the patient is not acceptable for this data 
element. 
Follow-up Scans 
The tracer uptake time for follow-up scans should be matched as closely as possible to 
the baseline scans with a targeted window of +/- 5 minutes (with an acceptable window 
of +/- 10 minutes). NOTE: The time between injection of the radiotracer and PET 
emission scan start time should be targeted at 60 minutes with an acceptable window of 
50 to 70 minutes. 
✓ FDG-PET/CT Follow-up Scans  
o Is the difference in mean liver SUV between the baseline and follow-up scan less 
than 1.0? (Check by placing a large circular region of interest [ROI, diameter ≥ 5 
cm] in normal liver tissue for mean SUV.) 
o Is the mean liver SUV between 1.5 and 4.0 (≥ 1.5 and ≤ 4.0)? 
o If mean liver SUV is < 1.5 or > 4.0, then check the scanner calibration and cross 
calibration of the dose calibrator and PET scanner. 
Review for Artifacts in Reconstructed Images 
✓ Did you check for beam hardening artifacts in the CT scan? Are there any metal 
implants or other structures with high density in the abdomen or pelvis? 
o Do the implants cause beam hardening artifacts in CT that are visible on the 
reconstructed PET emission images? 
o Are the beam hardening artifacts overlying the tumor region? 
Participant Movement 
✓ Is there any visible mis-registration between the CT scan and the reconstructed PET 
emission images? 
In addition to using quality control review findings to improve future imaging studies for 
the trial, issues found during review (artifacts, movement, reasons for outliers in SUV 
requirements, etc.) should be noted in the comments field on the PET Technical 
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Appendix X 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy test 
regardless of age or disease state) of a female patient while she is on AZD1775 or within 28 
days of the patient’s last dose of AZD1775 must be reported in an expeditious manner.  The 
outcome of the pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be reported 
via CTEP-AERS 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, followed 
by a complete expedited CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERS report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium and 
perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
• 
The start date of the pregnancy should be reported as the calculated date of conception. 
• 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the CTEP-AERS 
report.  
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female patient until completion of the pregnancy and must 
report the outcome of the pregnancy and neonatal status via CTEP-AERS.  
• 
The decision on whether an individual female patient can continue protocol treatment will be 
made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office - Boston. Please contact the ECOG-ACRIN Operations Office - Boston to 
ask for a conference call to be set up with the appropriate individuals. 
• 
It is recommended the female subject be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling.  
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How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERS 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself. However, if 
the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-AERS report 
should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the AEMD Help 
Desk at aemd@tech-res.com or 301-897-7497, for it will need to be discussed on a case by 
case basis. 
Reporting a Fetal Death 
A fetal death is defined in CTCAE as “A disorder characterized by death in utero; failure of the 
product of conception to show evidence of respiration, heartbeat, or definite movement of a 
voluntary muscle after expulsion from the uterus, without possibility of resuscitation.” 
It must be reported via CTEP-AERS as Grade 4 “Pregnancy, puerperium and perinatal 
conditions - Other (pregnancy loss)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions”.   
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERS recognizes 
this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A disorder characterized by cessation of life occurring 
during the first 28 days of life” that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention.  However, for this protocol, any neonatal death that occurs 
within 28 days of birth, without regard to causality, must be reported via CTEP-AERS AND any 
infant death after 28 days that is suspected of being related to the in utero exposure to 
AZD1775 must also be reported via CTEP-AERS. 
It must be reported via CTEP-AERS as Grade 4 “General disorders and administration - Other 
(neonatal loss)”under the System Organ Class (SOC) “General disorder and administration”.  
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERS reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any additional 
medical information to CTEP (301-230-0159).  This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  


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A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or without 
AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas 
 
Appendix XI 
 
Phase I AZD1775 Pharmacokinetic Collection and Shipping Kits 
Each kit will contain the materials (vacutainers, cryovials, shippers, shipping labels) for the 
collection and submission of samples for a single patient 
Two starter kits are to be ordered by the site upon site activation (IRB approval) of the Phase I 
aspect of the trial. Do not split contents from a single kit between patients. 
To order collection kits, complete the kit order form (page 2 of this appendix) and Fax to 
Zemotak as indicated on the form. 
Kits should be shipped to the site at the contact indicated below, unless otherwise notified. 
 
 
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PHASE I INSTITUTION CONTACT INFORMATION 
Site Address for Shipping Kits 
Case Comprehensive Cancer Center (Site # OH029) 
 
 
Investigator: Jennifer Eads, MD 
• 
(216) 844-6031  
• 
jennifer.eads@uhhospitals.org   
Nurses/CRA: Carol E. Smith RN, BSN, CCRP 
• 
(440) 816-6067, carol.smith@UHHospitals.org  
Lab Coordinator  for KITS: Erin Hohler 
• 
(216) 844-5562 
• 
Erin.hohler@UHhospitals.org 
Erin Hohler 
University Hospitals Seidman Cancer 
Center 
Translational Research Core 
11100 Euclid Avenue, Seidman 3608 
Cleveland, Ohio 44106-5061 
Fox Chase Cancer Center  
 
Investigator: Efrat Dotan, MD 
• 
(215) 728-8128, efrat.dotan@fccc.edu 
C. Rebecca Marlow RN, BSN, MBA, CCRP 
• 
(215) 214-1451, becky.marlow@fccc.edu 
Kit Contact: R. Katherine Alpaugh, PhD. 
• 
P: 215 214-1634, F: 215 214-1635, 
RK_Alpaugh@fccc.edu 
R. Katherine Alpaugh, PhD. 
Fox Chase Cancer Center 
Protocol Support Laboratory 
333 Cottman Avenue P2009 
Philadelphia, PA 19111 USA 
Northwestern University 
Investigator: Al B Benson III 
• 
(312) 926-3023, a-benson@northwestern.edu 
CRA: Erin Alonso 
• 
(312) 695-4168, erin.alonso@northwestern.edu  
Kit Contact:   
• 
Elena Ramos, Elena.ramos@northwestern.edu 
• 
312-503-3384, ecogpcorl@northwestern.edu 
Northwestern University (Site #: IL036) 
Path Core Facility/ Attn: Elena Ramos 
Robert H Lurie Comprehensive Cancer 
Center 
Northwestern University 
710 North Fairbanks Court, Olson 8421/31 
Chicago IL 60611 
University of Pennsylvania 
Investigator: Peter O’Dwyer, MD 
• 
(215) 662-7268, peter.odwyer@uphs.upenn.edu 
Nurses/CRA: Maryanne Redlinger, RN 
• 
(215) 662-7452, 
maryann.redlinger@uphs.upenn.edu 
 
Vanderbilt Ingram Cancer Center 
Investigator: Dana B. Cardin, MD 
• 
(615) 936-6925, dana.backlund@vanderbilt.edu 
Nurses/CRA: Shaunita A. Michael, RN, BSN 
• 
(615) 343-0798, shaunita.a.michael@vanderbilt.edu 
Lab Coordinator  for KITS:  Megan M. Cook 
• 
P: 615-936-3428, F: 615-936-7626 
• 
megan.m.cook@vanderbilt.edu 
Megan M. Cook 
Laboratory Manager – Biospecimen Team, 
CTSR 
Vanderbilt-Ingram Cancer Center 
634 PRB 
Nashville, TN  37232-5310 


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EA2131 PHASE I AZD1775 
Pharmacokinetic Collection and Shipping Kit Order Form 
Starter kits for two patients may be ordered by the site upon IRB approval. 
 
To request kits for the EA2131 PHASE I PK blood draws, shipping material or 
documents, the site/CRA can directly go to the online kit ordering:  
http://www.covance.com/kitordering 
or  
Contact the investigator support team: Phyllis.Sellars@Covance.com and 
Gaelle.Legaud@Covance.com  
 
 
 
 
Comments: 
Protocol specific notes: 
• 
Specimens will be submitted to Covance using the Covance-Provided Kits. 
• 
PK Collection time points from start of AZD1775 administration:  
o Cycle 1 Day 1 at 0 min, 1 hr, 2hr, 4hr, 6hr, 8hr, 24hr (Day 2 0min) 
o Cycle 1 Day 16 at 0 min, 1 hr, 2hr, 4hr, 6hr, 8hr, 24hr (Day 17) 
 


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Appendix XII 
 
Covance Specimen Shipment Pre-Alert Form 
Upon submission of samples to Covance, complete the form and Fax as instructed. 
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A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine with or without 
AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas 
 
Appendix XIII 
 
EA2131 PHASE II Collection and Shipping Kits Order Form 
Use this form to request kits for the EA2131 PHASE II specimen kits. Starter kits ARE 
NOT AVAILABLE.  Kits are to be ordered upon registration of the patient to the trial. 
FAX Completed form to Zemotak-International at (800) 815-4675. 
Date:   
 
Case ID of the Patient:  ______________________ 
Kit is to be shipped to: 
Institution Contact:  _______________________________________ 
Phone number for contact:  _________________________________ 
E-mail for contact:  ________________________________________ 
Institution Address: 
__________________________________________ 
__________________________________________ 
__________________________________________ 
NOTE: 
Questions are to be directed to the ECOG-ACRIN CBPF– at (844) 744-2420 or 
eacbpf@mdanderson.org 
Comments: 
Rev. 4/16