Phase I Sequential Trial of Agents Against DNA Repair (STAR)
Phase: PHASE1
Conditions: Advanced Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, Refractory Malignant Solid Neoplasm, Unresectable Malignant Solid Neoplasm
Sponsor: National Cancer Institute (NCI)

 
i 
 To: 
CTEP Protocol and Information Office 
From:       Timothy Yap, M.D., Ph.D. 
Branch: 
Investigational Drug Branch, CTEP, DCTD, NCI  
Date: 
11/14/2022 
Re: 
Amendment #10 of Protocol #10329: “Phase I Sequential Trial of Agents Against 
DNA Repair (STAR)” 
 
 
I. 
PI-initiated Changes: 
# 
Section 
Comments 
 
 
1. 
Throughout 
and title 
page 
PI Response: The protocol version date was updated on the Title Page 
and throughout the document on the headers. 
 
Old Text: 
  February 21, 2022 
 
New Text: 
November 14, 2022 
 
 
 
2.  
5.7 
PI Response: The name of the RPPA Core Facility was updated in the 
Assay Laboratory and Lab PI table found in the biomarker plan. 
 
Old Text: RPPA Core Laboratory/MD Anderson 
 
New Text: Functional Proteomics RPPA Core Facility, MD Anderson Cancer 
Center (MDACC) 
 
 
3. 
5.7 
PI Response: The Assay Laboratory and Lab PI performing the WES, 
RNAseq, and ctDNA analysis were updated in the biomarker plan. 
 
Old Text:  
 
 
NCLN Genomics Laboratory 
Mickey Williams 
mickey.williams@nih.gov 
 
New Text: 
NCLN Genomics Laboratory or MoCha, Frederick National Laboratory for 
Cancer Research (FNLCR) 
Mickey Williams 
mickey.williams@nih.gov 

 
ii 
# 
Section 
Comments 
 
 
4. 
5.9.1.1 
PI Response: The instructions for specimen receipt and processing at the 
EET Biobank regarding RPPA analysis has been updated. 
 
Old Text: Frozen tissue for RPPA will be stored in liquid nitrogen vapor 
phase at the EET Biobank until batch shipping to Dr. Yiling Lu at the MD 
Anderson RPPA Core Laboratory. 
 
New Text: Frozen tissue for RPPA will be stored in liquid nitrogen vapor 
phase at the EET Biobank until batch shipping to Dr. Yiling Lu at the 
Functional Proteomics RPPA Core Facility, MD Anderson Cancer Center 
(MDACC).   
 
 
 
5. 
5.9.1.2 
PI Response: The name of the site performing the RPPA specimen 
analysis was updated.  
 
Old Text: This assay will be performed by Dr. Yiling Lu at the MD 
Anderson RPPA Core Laboratory. 
 
New Text: This assay will be performed by Dr. Yiling Lu at the Functional 
Proteomics RPPA Core Facility, MD Anderson Cancer Center (MDACC). 
 
6. 
5.9.1.3 
PI Response: Instructions regarding the shipment of specimens from the 
EET Biobank to the site performing the RPPA specimen analysis was 
added. 
 
5.9.1.4 
PI Response: Contant information for the site performing the RPPA 
specimen analysis was added. 
 
 
 
8. 
5.10.1.2 
PI Response: The site performing WES analysis was updated. 
 
Old Text: WES will be conducted in the NCLN Genomics Laboratory under 
the leadership of Mickey Williams, Ph.D. 
 
New Text: WES will be conducted in the NCLN Genomics Laboratory or 
MoCha, Frederick National Laboratory for Cancer Research (FNLCR) under 
the leadership of Mickey Williams, Ph.D.   
 
9. 
5.10.1.3 
PI Response: Instructions regarding the shipment of specimens from the 
EET biobank to the site performing WES analysis was added. 
 
7. 

 
iii 
# 
Section 
Comments 
10. 
5.10.1.4 
PI Response: Contact information for the lab performing WES analysis 
was added. 
 
 
 
 
11. 
5.10.3.2 
PI Response: The site performing the correlative studies for γH2AX and 
pRAD50 IHC and cycIF/mIHC was updated.  
 
Old Text: γH2AX and pRAD50 IHC and cycIF/mIHC will be performed by 
Dr. Gordon Mills at Oregon Health & Science University (ATTN: Dong 
Zhang, Oregon Health & Science University, 2730 S. Moody Ave., KCRB 
Mills Lab 2001.14, Portland, OR 97201). 
 
New Text: γH2AX and pRAD50 IHC and cycIF/mIHC will be performed by 
Dr. Gordon Mills at Oregon Health & Science University. 
 
 
12. 
5.10.3.3 
PI Response: The shipping address to send specimens from the EET 
biobank to the site performing γH2AX and pRAD50 IHC and 
cycIF/mIHC analysis was added. 
 
13. 
5.10.3.4 
PI Response: The contact information for the site performing γH2AX 
and pRAD50 IHC and cycIF/mIHC analysis was added. 
 
 
14. 
5.10.4.3 
PI Response: The shipping address to send specimens from the EET 
biobank to the site performing scRNAseq was added. 
 
 
15. 
5.10.4.4 
PI Response: The contact information for the site performing scRNAseq 
analysis was added. 
 
 
 
 
16. 
5.10.5.2 
PI Response: The lab performing the ctDNA analysis was updated.  
 
Old Text: ctDNA Analysis will be conducted in the NCLN Genomics 
Laboratory under the leadership of Mickey Williams, Ph.D. 
 
New Text: ctDNA Analysis will be conducted in the NCLN Genomics 
Laboratory or MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR)under the leadership of Mickey Williams, Ph.D. 
 
17. 
5.10.5.3 
PI Response: The shipping address to send specimens from the EET 
biobank to the site performing ctDNA analysis was added. 
 
18. 
5.10.5.4 
PI Response: The contact information for the lab performing the ctDNA 
analysis was added.  
 
 

NCI Protocol #:  10329 
Version Date: November 14, 2022  
 
1 
 
 
NCI Protocol #: 
10329 
 
Local Protocol #: 
TBD 
 
ClinicalTrials.gov Identifier:  NCT04197713 
 
TITLE:  Phase I Sequential Trial of Agents Against DNA Repair (STAR) 
 
Corresponding Organization: LAO-TX035 / University of Texas MD Anderson Cancer 
Center LAO 
 
Principal Investigator: 
Timothy A. Yap 
Department of Investigational Cancer Therapeutics 
University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 455 
Houston, TX  77030, USA 
(T):  713-563-1784 
(F):  713-794-4130 
tyap@mdanderson.org 
 
Translational PI: 
Gordon Mills 
 
Department of Precision Oncology 
 
Oregon Health & Science University Knight Cancer Institute 
 
3181 S.W. Sam Jackson Park Rd. 
 
Portland, OR 97239-3098, USA 
 
 
 
Dose Escalation Phase Participating Organizations  
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
Restricted to: 
TX035 / MD Anderson Cancer Center 
 
Dose Expansion Phase Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 

NCI Protocol #:  10329 
Version Date: November 14, 2022  
 
2 
LAO-NCI / National Cancer Institute LAO 
 
Interventional Radiologist: 
Ravi Murthy 
Department of Interventional 
Radiology 
University of Texas MD Anderson 
Cancer Center 
1515 Holcombe Blvd. 
Houston, TX  77030 USA 
(T):  713-745-0856 
rmurthy@mdanderson.org 
 
Statistician: 
Ying Yuan 
Department of Biostatistics 
University of Texas MD Anderson 
Cancer Center 
1515 Holcombe Blvd., Unit 1411 
Houston, TX  77030 USA 
(T):  713-563-4271  
(F):  713-563-4243 
yyuan@mdanderson.org 
Study Coordinator: 
Sandra Montez 
Department of Investigational Cancer 
Therapeutics 
University of Texas MD Anderson 
Cancer Center 
1515 Holcombe Blvd., Unit 455 
Houston, TX  77030, USA 
(T):  713-745-6274 
(F):  713-563-4002 
smontez@mdanderson.org 
 
Responsible Research Nurse: 
Sandra Montez 
Department of Investigational Cancer 
Therapeutics 
University of Texas MD Anderson 
Cancer Center 
1515 Holcombe Blvd., Unit 455 
Houston, TX  77030, USA 
(T):  713-745-6274 
(F):  713-563-4002 
smontez@mdanderson.org 
 
Responsible Data Manager: 
Chelsey Beer 
Department of Investigational Cancer 
Therapeutics 
University of Texas MD Anderson 
Cancer Center 
1515 Holcombe Blvd., Unit 455 
Houston, TX  77030, USA 
(T):  713.745.5303 
(F):  713-563-4002 
cnbeer@mdanderson.org 
 
 
 
 
NCI-Supplied Agents:  AZD1775 (adavosertib, NSC 751084) and olaparib (AZD2281, NSC 
747856) 
 
 

NCI Protocol #:  10329 
Version Date: November 14, 2022  
 
3 
IND #:  
 
 
IND Sponsor:  DTCD, NCI 
 
Protocol Type / Version # / Version Date: 
 
Original / May 7, 2019 
 
 
 
 
 
Revision 1 / August 20, 2019 
 
 
 
 
 
Revision 2 / September 26, 2019 
 
 
 
 
 
Revision 3 / November 13, 2019 
 
 
 
 
 
Revision 4a / January 22, 2020 
 
 
 
 
 
Revision 5 / February 14, 2020 
 
 
 
 
 
Amendment 1 / May 22, 2020 
 
 
 
 
 
Amendment 4/ October 5, 2020 
 
 
 
 
 
Amendment 5/ March 24, 2021 
 
 
 
 
 
Amendment 6/May 10, 2021 
 
 
 
 
 
Amendment 7/August 26, 2021 
 
 
 
 
 
Amendment 8/September 28, 2021 
 
 
 
 
 
Amendment 9/February 21, 2022 
 
 
 
 
 
Amendment 10/November 14, 2022 

NCI Protocol #:  10329 
Version Date: November 14, 2022  
 
4 
SCHEMA 
 
 
 
Dose Level 
Treatment 
MTD/RP2D expansion in 2 cohorts: 
• 
Patients with BRCA1/2 mutant advanced solid tumors treated with PARP inhibitors who had 
disease progression per RECIST at 1st re-staging (intrinsic resistance). 
• 
Patients with DDR aberrant advanced solid tumors treated with PARP inhibitors who had 
complete/partial response followed by disease progression per RECIST (acquired resistance). 
One cycle = 28 days 
2 
Olaparib 300 mg BID Days 1-5 and 15-19, AZD1775 300 mg QD Days 8-12 and 22-
26. 
1* 
Olaparib 300 mg BID Days 1-5 and 15-19, AZD1775 250 mg QD Days 8-12 and 22-
26. 
-1** 
Olaparib 200 mg BID Days 1-5 and 15-19, AZD1775 200 mg QD Days 8-12 and 22-
26. 
*Starting dose level 
**Either or both olaparib or AZD1775 may be reduced to 200mg BID or 200mg QD, respectively 
BID = twice a day 
QD = once a day 

NCI Protocol #:  10329 
Version Date: November 14, 2022  
 
5 
TABLE OF CONTENTS 
Title Page .........................................................................................................................................1 
SCHEMA .........................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives ...................................................................................................8 
1.2 
Secondary Objectives ...............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Study Disease ...........................................................................................................8 
2.2 
CTEP IND Agents ...................................................................................................9 
2.3 
Rationale ................................................................................................................16 
2.4 
Correlative Studies Background ............................................................................25 
3. 
PATIENT SELECTION ....................................................................................................26 
3.1 
Eligibility Criteria ..................................................................................................26 
3.2 
Exclusion Criteria ..................................................................................................31 
3.3 
Inclusion of Women and Minorities ......................................................................33 
4. 
REGISTRATION PROCEDURES ...................................................................................33 
4.1 
Investigator and Research Associate Registration with CTEP ..............................33 
4.2 
Site Registration .....................................................................................................35 
4.3 
Patient Registration ................................................................................................38 
4.4 
General Guidelines .................................................................................................39 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................40 
5.1 
Summary Table for Specimen Collection ..............................................................40 
5.2 
Summary Table(s) for Interventional Radiologist for Research Biopsies .............40 
5.3 
Specimen Procurement Kits and Scheduling .........................................................41 
5.4 
Specimen Tracking System Instructions ................................................................42 
5.5 
Specimen Collection ..............................................................................................46 
5.6 
Shipping Specimens to the EET Biobank ..............................................................48 
5.7 
Biomarker Plan ......................................................................................................53 
5.8 
Integral Correlative Studies ...................................................................................56 
5.9 
Integrated Correlative Studies ................................................................................56 
5.10 
Exploratory/Ancillary Correlative Studies ............................................................57 
6. 
TREATMENT PLAN ........................................................................................................61 
6.1 
Agent Administration .............................................................................................61 
6.2 
Definition of Dose-Limiting Toxicity ....................................................................62 
6.3 
Dose Expansion Cohorts ........................................................................................63 
6.4 
General Concomitant Medication and Supportive Care Guidelines ......................64 
6.5 
Duration of Therapy ...............................................................................................68 
6.6 
Duration of Follow-Up ..........................................................................................69 

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6 
7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................69 
7.1 
Olaparib..................................................................................................................69 
7.2 
AZD1775 ...............................................................................................................74 
8. 
PHARMACEUTICAL INFORMATION FOR CTEP IND AGENTS .............................77 
8.1 
Olaparib (NSC 747856) .........................................................................................77 
8.2 
AZD1775 (NSC 751084) .......................................................................................79 
8.3 
CTEP IND Agents – General Information .............................................................80 
9. 
STATISTICAL CONSIDERATIONS...............................................................................82 
9.1 
Study Design/Endpoints.........................................................................................82 
9.2 
Analysis of Secondary Endpoints ..........................................................................86 
9.3 
Sample Size/Accrual Rate ......................................................................................86 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................87 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................87 
10.2 
Adverse Event Characteristics ...............................................................................93 
10.3 
Expedited Adverse Event Reporting ......................................................................94 
10.4 
Routine Adverse Event Reporting .........................................................................97 
10.5 
Pregnancy ...............................................................................................................97 
10.6 
Secondary Malignancy ...........................................................................................97 
10.7 
Second Malignancy ................................................................................................98 
11. 
STUDY CALENDAR .......................................................................................................98 
11.1 
Calendar (each cycle is 28 days) ............................................................................99 
11.2 
Laboratory Assessments ......................................................................................101 
11.3 
ECG......................................................................................................................102 
12. 
MEASUREMENT OF EFFECT......................................................................................102 
12.1 
Antitumor Effect – Solid Tumors ........................................................................102 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................108 
13.1 
Study Oversight ...................................................................................................108 
13.2 
Data Reporting .....................................................................................................109 
13.3 
Data Quality Portal ..............................................................................................111 
13.4 
Collaborative Agreements Language ...................................................................112 
13.5 
Genomic Data Sharing Plan .................................................................................113 
13.6 
Incidental/Secondary Findings Disclosure Procedure .........................................114 
14. 
REFERENCES ................................................................................................................115 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................118 
APPENDIX B 
PRE-BIOPSY ASSESSMENT ................................................................119 
APPENDIX C 
FROZEN BIOPSY SPECIMEN BATCH RECORD ..............................120 

NCI Protocol #:  10329 
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7 
APPENDIX D 
PATIENT MEDICATION DIARIES – OLAPARIB AND 
AZD1775 
..................................................................................................................122 
APPENDIX E 
PATIENT DRUG INTERACTIONS HANDOUT AND 
WALLET CARD – AZD1775 .........................................................................................126 
APPENDIX F 
PATIENT CLINICAL TRIAL WALLET CARD – 
OLAPARIB AND azd 1775 ............................................................................................128 
APPENDIX G 
ACTIONS REQUIRED IN CASES OF COMBINED 
INCREASE OF AMINOTRANSFERASE AND TOTAL BILIRUBIN – 
HY’S LAW 
..................................................................................................................129 
APPENDIX H  
TISSUE BIOPSY VERFIFICATION FORM………………………….129 
 

NCI Protocol #:  10329 
Version Date: November 14, 2022  
 
9 
potentially avoid the development of drug resistance through sustained pressure on a specific 
target (Yap et al., 2013). 
 
2.2 
CTEP IND Agents 
 
2.2.1 Olaparib (AZD2281) 
 
In December 2014, the European Commission approved olaparib capsules as a maintenance 
treatment for platinum-sensitive, relapsed, high grade serious epithelial ovarian, fallopian tube, 
or primary peritoneal cancer in adult patients with breast cancer (BRCA) mutations (germline 
[gBRCAm] and/or somatic [sBRCAm]) who are in a CR or PR to platinum-based chemotherapy.  
In December 2014, the Food and Drug Administration (FDA) approved olaparib capsules as 
monotherapy for advanced ovarian cancer in patients with deleterious or suspected gBRCAm 
who have been treated with three or more prior lines of chemotherapy.  In August 2017, the FDA 
approved the tablet formulation of olaparib for the maintenance treatment of adult patients with 
recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a CR or PR 
to platinum-based chemotherapy; olaparib tablets were also approved for the December 2014 
indication.  On January 12, 2018, the FDA granted regular approval to olaparib tablets for the 
treatment of patients with deleterious or suspected deleterious germline gBRCAm, human 
epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been 
treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting.  In 
December 2018, the FDA granted approval to olaparib as a 1st line maintenance therapy for adult 
patients deleterious or suspected deleterious germline or somatic BRCA-mutated advanced 
epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial 
response to 1st-line platinum-based chemotherapy. 
 
2.2.1.1 Mechanism of Action 
 
Olaparib inhibits PARP, a protein that repairs single-strand breaks (SSBs) via base excision 
repair (BER), a backup repair system to homologous recombination (HR) repair (Farmer et al.,; 
Olaparib Investigator’s Brochure, 2019).  Olaparib potently inhibits PARP1 (IC50=5 nM), 
PARP2 (IC50=1 nM), and PARP3 (IC50=4 nM) in vitro (Olaparib Investigator’s Brochure, 2019).  
The inhibition of PARP and disruption of BER via olaparib treatment leads to accumulation of 
double-strand breaks (DSBs); in tumors with defective components of HR repair, these DSBs 
cannot be accurately repaired, resulting in genomic instability and induction of synthetic lethality 
(Olaparib Investigator’s Brochure, 2019).  Cultures of cells deficient in HR repair factors, 
notably BRCA1 and BRCA2, are particularly sensitive to treatment with olaparib (Olaparib 
Investigator’s Brochure, 2019).  Furthermore, olaparib may enhance the effects of DNA damage 
caused by ionizing radiation and chemotherapy. 
 
2.2.1.2 Overview of Clinical Pharmacology  
 
Single PO dosing of olaparib tablets was rapidly absorbed with peak plasma concentrations 
typically observed at 1.5 hours (Olaparib Investigator’s Brochure, 2019).  A population PK 
analysis characterized the absorption phase of olaparib as a sequential zero- and first-order 
absorption and showed a significant impact of olaparib tablet strength on the absorption rate 

NCI Protocol #:  10329 
Version Date: November 14, 2022  
 
10 
constant.  Once tmax was reached, plasma concentrations of olaparib declined in a biphasic 
manner with an average t1/2 of 14.9 hours (standard deviation [StD]: 8.2 hours).  The mean 
apparent clearance (CL) after a single dose of olaparib tablets at 300 mg PO was approximately 
7.4 L/h (StD: 3.9 L/h).  Olaparib exhibited a mean volume of distribution (Vd) of 158 L (StD: 
136 L), indicating distribution into the tissues.  The plasma protein binding in vitro was moderate 
and showed evidence of concentration dependence (81.9% at 10 mcg/ml).   
 
Multiple-dose PK was reasonably well predicted from single-dose data, and accumulation on 
multiple dosing was not extensive (Olaparib Investigator’s Brochure, 2019).  At a 300 mg BID 
dose, olaparib PK appeared to be slightly time dependent with a temporal change parameter 
(TCP; AUC at steady state/AUC following a single dose) of approximately 1.45 (StD: 0.6).  
Exposure (measured by AUC from zero to 12 hours [AUC0-12]) increased approximately 
proportionally with olaparib tablets at 25-450 mg; Cmax increased slightly less than 
proportionally for the dose range.  The estimated geometric mean (Gmean) maximum steady 
state plasma concentration (Cmax ss), AUC0-12, and minimum plasma concentration (Cmin) after 
dosing with 300 mg tablet BID were 9.13 mcg/mL, 57.9 mcg.h/mL and 1.76 mcg/mL:  
equivalent to unbound concentrations of 1.65 mcg/mL, 10.5 mcg.h/mL and 0.318 mcg.h/mL, 
respectively.  The inter-individual variability was moderate to high (36% for Cmax ss, 49% for 
AUC0-12, and 104% for the minimum steady state plasma concentration [Cmin ss]).  After 
administration of a radiolabeled dose of olaparib capsules (100 mg BID) in study D0810C00010, 
unchanged drug accounted for approximately 70% of the circulating material in the plasma with 
the remainder accounted for by three other components (each approximately 10% of the 
material), all of which were also present in the excreta.  Drug-related material was eliminated in 
the urine (approximately 44% of the dose) and in the feces (approximately 42% of the dose) 
predominantly as metabolites.  Metabolism was extensive.  The metabolites produced were 
predominantly a consequence of oxidation of the piperazine carboxycyclopropyl, the 
fluorophenyl, and phthalazinone ring systems.  The pharmacological activity of the three 
circulating metabolites is not known.   
 
Although based on limited data, there was no evidence of any marked ethnic difference in the PK 
of olaparib tablets between Japanese, Chinese, and Caucasian patients for the olaparib tablet 
formulation (Olaparib Investigator’s Brochure, 2019).  In a population analysis, age, body 
weight, and gender covariates were not found to be predictors of olaparib plasma exposure.   
 
Data from a renal impairment study (D0816C00006) showed that olaparib tablets (300 mg BID) 
mean Cmax and AUC were approximately 15% and 24% higher, respectively, in patients with 
mild renal impairment (creatinine CL determined by Cockcroft-Gault: 51-80 mL/min; N=14), 
and olaparib mean Cmax and AUC were 26% and 44% higher, respectively, in patients with 
moderate renal impairment (creatinine CL determined by Cockcroft-Gault: 31-50 mL/min; 
N=14) (Olaparib Investigator’s Brochure, 2019).   
 
2.2.1.3 Overview of Safety 
 
As of December 15, 2017, approximately 8,319 patients are estimated to have received olaparib 
in the clinical program including AstraZeneca-sponsored studies (4575 patients), a MAP (810 
patients), investigator-sponsored studies (ISS), and collaborative group studies (2934 patients) 

NCI Protocol #:  10329 
Version Date: November 14, 2022  
 
11 
(Olaparib Investigator’s Brochure, 2019).  Since 2012/2013, most new clinical studies have 
utilized the tablet formulation which was designed to deliver the therapeutic dose of olaparib in 
fewer dose units than the capsule.  Of the 4575 patients in AstraZeneca-sponsored, interventional 
studies, 1512 received the capsule formulation, 3038 received the tablet formulation, and 25 
received both capsule and tablet.  The recommended olaparib monotherapy capsule dose is 400 
mg BID.  The recommended olaparib monotherapy tablet dose is 300 mg BID.  Olaparib 
monotherapy appears to be generally well tolerated across studies up to and including these 
doses.   
 
Toxicities considered to be associated with administration of olaparib include hematological 
effects (anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, mean corpuscular 
volume [MCV] elevation), decreased appetite, nausea and vomiting, diarrhea, dyspepsia, 
stomatitis, upper abdominal pain, dysgeusia, fatigue (including asthenia), increase in blood 
creatinine, headache, dizziness, hypersensitivity, rash, dermatitis, and cough (Olaparib 
Investigator’s Brochure, 2019).  Anemia was the most common CTCAE Grade ≥3 adverse 
reaction reported in clinical studies.  Median time to first onset of anemia was approximately 4 
weeks (approximately 7 weeks for CTCAE Grade ≥3 events).  An exposure-response 
relationship between olaparib and decreases in hemoglobin has been demonstrated.  In clinical 
studies with olaparib, the incidence of CTCAE Grade ≥2 shifts (decreases) from baseline in 
hemoglobin was 20%, absolute neutrophils 15%, platelets 5%, lymphocytes 30% and leukocytes 
20% (all % approximate) and the incidence of CTCAE Grade ≥2 shifts (elevations) from 
baseline in blood creatinine was approximately 15%.   
 
In a small number of patients, pneumonitis, myelodysplastic syndrome (MDS)/AML and new 
primary malignancies have been reported (Olaparib Investigator’s Brochure, 2019).  The 
incidence of MDS/AML in patients treated in clinical trials with olaparib monotherapy, 
including long-term survival follow-up, was <1.5%, and the majority of events had a fatal 
outcome.  All patients had potential contributing factors for the development of MDS/AML, 
having received previous chemotherapy with platinum agents.  SOLO2 and OlympiAD safety 
data provide additional supportive evidence that a causal relationship has not been established 
between olaparib treatment and the development of these AEs.  New primary malignancies other 
than MDS/AML have been reported in <1% of patients.  Pneumonitis has been reported in 
<1.0% patients treated with olaparib monotherapy in clinical studies.  Reports of pneumonitis 
had no consistent clinical pattern and were confounded by a number of pre-disposing factors 
(cancer and/or metastases in lungs, underlying pulmonary disease, smoking history, and/or 
previous chemotherapy and radiotherapy).   
 
Data from Phase 1 dose escalation studies of olaparib in combination with various chemotherapy 
agents indicated an increase in bone marrow toxicity (anemia, neutropenia, thrombocytopenia) 
greater than expected if the agents had been administered alone.  However, tolerable regimens 
combining olaparib with paclitaxel, attenuated dosed liposomal doxorubicin, and attenuated 
dosed carboplatin/paclitaxel have been established, supporting studies in the combination setting. 
 
 
 

NCI Protocol #:  10329 
Version Date: November 14, 2022  
 
27 
3.1.3 Subjects must have RECIST measureable disease and a tumor that is safely 
accessible for biopsy and must be willing to undergo biopsy.   
 
3.1.4 Subjects must have received at least one line of systemic therapy in the 
advanced/metastatic setting.  Subjects with diseases without known effective 
options, and subject who have declined standard of care therapy prior to study 
introduction are also eligible. 
 
3.1.5 Any prior palliative radiation therapy must have been completed at least 14 days 
prior to the start of study drugs, and patients must have recovered from any acute 
adverse effects prior to the start of study treatment. 
 
3.1.6 HIV-infected (HIV1/2 antibody-positive) patients may participate if they meet all 
the following eligibility requirements:  
• They must be on an anti-retroviral regimen with evidence of at least two 
undetectable viral loads within the past 6 months on this same regimen; the 
most recent undetectable viral load must be within the past 12 weeks.   
• They must have a CD4 count ≥250 cells/µL over the past 6 months on this 
same anti-retroviral regimen and must not have had a CD4 count <200 cells/µl 
over the past 2 years, unless it was deemed related to the cancer and/or 
chemotherapy-induced bone marrow suppression.  For patients who have 
received chemotherapy in the past 6 months, a CD4 count <250 cells/µl 
during chemotherapy is permitted as long as viral loads were undetectable 
during this same chemotherapy.   
• They must have an undetectable viral load and a CD4 count ≥250 cells/µL 
within 7 days of enrolment.   
• They must not be currently receiving prophylactic therapy for an opportunistic 
infection and must not have had an opportunistic infection within the past 6 
months.  Monitoring for HIV-infected patients should include:   
o Viral load and CD4 count q12w.   
o If CD4 count drops to less than 200 cells/µl while on study, initiate 
viral load test.  If viral load proves undetectable at this time, continue 
CD4 and viral load checks q8w.  If 2 consecutive viral load tests are 
undetectable, revert to q12w testing for CD4 and viral load testing.   
o If an opportunistic infection occurs with a CD4 count of <200 cells/µl, 
hold study treatment. Initiate treatment of the infection and continue to 
hold study treatment; once clinically stable, CD4 count is >200 cells/µl 
and viral load has remained undetectable, reinitiate study treatment. 
 
3.1.7 Patients with a past or resolved hepatitis B virus (HBV) infection (defined as the 
presence of hepatitis B core antibody and absence of HBsAg) are eligible.  Active 
HBV is defined by a known positive HBV surface antigen (HBsAg) result.  
Patients positive for hepatitis C virus (HBC) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA.  Patients with known 
active HBV or HBC infection are ineligible.   
 

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28 
3.1.8 Patients with treated brain metastases are eligible if follow-up brain imaging 
after central nervous system (CNS)-directed therapy shows no evidence of 
progression within 28 days. 
 
3.1.9 Patients with new or progressive brain metastases (active brain metastases) or 
leptomeningeal disease are eligible if the treating physician determines that 
immediate CNS specific treatment is not required and is unlikely to be required 
during the first cycle of therapy. 
 
3.1.10 Patients must have adequate organ and marrow function within 7 days of study 
drugs initiation, as defined by the following baseline laboratory values: 
 
• 
ANC ≥1500/µL 
• 
Hemoglobin (Hgb) ≥10g/dL with no blood transfusion in the past 28 days 
• 
Platelets ≥100,000/µL 
• 
Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic 
Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic 
Pyruvate Transaminase (SGPT) ≤ 2.5X upper limit of normal (ULN), unless 
liver metastases are present in which case they must be ≤ 5x ULN 
• 
Serum bilirubin within normal limits (WNL) or ≤1.5X ULN in patients with 
liver metastases, or total bilirubin ≤3X ULN with direct bilirubin WNL in 
patients with well-documented Gilbert’s Syndrome 
• 
Serum creatinine ≤1.5X ULN.  If elevated, check creatinine clearance (CrCl) 
with cut off ≥ 51mL/min as calculated by the Cockcroft-Gault method or 
based on a 24-hour urine test (confirmation of creatinine clearance is only 
required when serum creatinine is >1.5X institutional ULN). 
• 
Estimated CrCl (glomerular filtration rate [GFR]) = (140-age [years]) x 
(weight [kg]) x Fa (72 x serum creatinine mg/dL)  (a where F = 0.85 for 
females and F = 1 for males) 
 

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29 
3.1.11 The effects of AZD1775 and olaparib on the developing human fetus are either 
unclear or are known to be teratogenic, women of childbearing potential and their 
partners, who are sexually active, must agree to the use of TWO highly effective 
forms of contraception in combination.  This should be started from the signing of 
the informed consent and continue throughout the period of taking study 
treatment and for at least 1 month after last dose of study drug(s), or they must 
totally/truly abstain from any form of sexual intercourse.  Male patients must use 
a condom during treatment and for 3 months after the last dose of study drug 
when having sexual intercourse with a pregnant woman or with a woman of 
childbearing potential.  Female partners of male patients should also use a highly 
effective form of contraception if they are of childbearing potential.  Male 
patients should not donate sperm throughout the period of taking study drugs and 
for 3 months following the last dose of study drugs.    
 
Acceptable non-hormonal birth control methods include: 
• Total/True abstinence: When the patient refrains from any form of sexual 
intercourse and this is in line with their usual and/or preferred lifestyle; this must 
continue for the total duration of the trial and for at least 1 month after the last 
dose of study drug for women of child bearing potential.  For male patients, 3 
months after last dose. [Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods, or declaration of abstinence solely for 
the duration of a trial) and withdrawal are not acceptable methods of 
contraception.]  
• Vasectomised sexual partner PLUS male condom.  With participant assurance 
that partner received post-vasectomy confirmation of azoospermia. 
• Tubal occlusion PLUS male condom. 
• IUD PLUS male condom.  Provided coils are copper-banded. 

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Acceptable hormonal methods: 
• Normal and low dose combined oral pills PLUS male condom. 
• Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only 
highly efficacious progesterone based pill. 
• Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom. 
• Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom. 
• Norelgestromin / EE transdermal system PLUS male condom. 
• Intrauterine system [IUS] device (e.g., levonorgestrel releasing IUS -Mirena®) 
PLUS male condom. 
• Intravaginal device (e.g., EE and etonogestrel) PLUS male condom. 
• In the case of use of oral contraception, women should be stable on the same pill 
before taking study treatment. 
• Note: oral contraceptives are allowed but should be used in conjunction with a 
barrier method of contraception due to unknown effect of drug-drug interaction.  
Women are considered post-menopausal and not of childbearing potential if they 
have had 12 or more months of natural (spontaneous) amenorrhea following 
cessation of exogenous hormonal treatment with an appropriate clinical profile 
(e.g.  age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy).  In the case of 
oophorectomy alone, she will be considered not of childbearing potential only 
when her reproductive status has been confirmed by follow up hormone level 
assessment.   
• Male patients will be advised to arrange for the freezing of sperm samples prior to 
the start of the study should they wish to father children while on study drugs or 
during the 3 months after stopping study drugs. 
 
3.1.12 Male or female patient ≥18 years of age.  Because no dosing or adverse event data 
are currently available on the use of AZD1775 in combination with olaparib in 
patients <18 years of age, children are excluded from this study, but will be 
eligible for future pediatric trials.   
 
3.1.13 Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 
0-1 (Karnofsky ≥70%, see Appendix A). 
 
3.1.14 Ability to understand and the willingness to sign a written informed consent 
document.  Participants with impaired decision-making capacity (IDMC) who 
have a legally-authorized representative (LAR) and/or family member available 
will also be eligible.  Has read and understands the informed consent form (ICF) 
and has given written informed consent (IC) prior to any study procedures. 
 

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3.1.15 Willingness and ability to comply with study and follow-up procedures. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to AZD1775 or olaparib. 
 
 
3.2.2 Use of anti-cancer treatment drug ≤28 days or 5 half-lives (whichever is shorter) 
prior to the first dose of study treatment.  For drugs for which 5 half-lives is ≤21 
days, a minimum of 10 days between termination of the prior treatment and 
administration of study treatment is required. 
 
3.2.3 Use of radiotherapy (except for palliative reasons) within ≤28 days prior to study 
treatment. 
 
3.2.4 No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal 
anticancer therapy radiotherapy), biological therapy or other novel agent is to be 
permitted while the patient is receiving study medication.  Patients with 
castration-resistant prostate cancer on luteinizing hormone-releasing hormone 
(LHRH) analogue treatment for more than 6 months are allowed entry into the 
study and may continue at the discretion of the investigator. 
 
3.2.5 Concomitant use of CYP3A inducers/inhibitors:   
• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, 
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or 
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, 
verapamil). The required washout period prior to starting olaparib is 2 weeks. 
• Concomitant use of known strong (e.g., phenobarbital, enzalutamide, 
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St 
John’s Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, 
modafinil). The required washout period prior to starting study treatment is 5 
weeks for enzalutamide or phenobarbital and 3 weeks for other agents. 
 
3.2.6 Major surgical procedures ≤28 days of beginning study treatment, or minor 
surgical procedures ≤7 days.  Patients must have recovered from any of the effects 
of any major surgery.  No waiting period required following port-a-cath 
placement or other central venous access placement. 
 
3.2.7 Known malignant central nervous system (CNS) disease other than neurologically 
stable, treated brain metastases – defined as metastasis having no evidence of 
progression or hemorrhage for at least 2 weeks after treatment (including brain 
radiotherapy).  Must be off any systemic corticosteroids for the treatment of brain 
metastases for at least 14 days prior to enrollment.  Subjects with brain metastases 

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32 
must have completed treatment, either surgery or radiation, and be stable for at 
least 28 days off steroid prior to screening.  A brain MRI demonstrating there is 
no current evidence or progressive brain metastases is required in subjects with 
previous brain metastasis.  Patients with breast tissue expanders may have brain 
CT for assessment. 
 
3.2.8 Patients with either previous or current myelodysplastic syndrome (MDS)/acute 
myeloid leukemia (AML) or features suggestive of MDS/AML (e.g., persistent 
anemia or other blood dyscrasias) are excluded because olaparib and AZD1775 
are agents with the potential to induce MDS/AML. 
 
3.2.9 AZD1775 should not be given to patients who have a history of Torsades de 
pointes (TdP) unless all risk factors that contributed to TdP have been corrected. 
 
3.2.10 Any of the following cardiac diseases currently or within the last 6 months: 
o Unstable angina pectoris 
o Acute myocardial infarction 
o Congestive heart failure ≥ Class 2 (as defined by New York Heart Association 
(NYHA)) 
o Conduction abnormality not controlled with pacemaker or medication 
o Significant ventricular or supraventricular arrhythmias (patients with chronic rate-
controlled atrial fibrillation in the absence of other cardiac abnormalities are 
eligible) 
 
3.2.11 Participants with a mean resting corrected QT interval (QTc) ≥ 480msec at study 
entry, as calculated by the Frederica formula (QTcF) by institutional standards 
obtained from an electrocardiogram (ECG) or congenital long QT syndrome.  
(Note: if one ECG demonstrates a QTcF >480 msec, then a mean QTcF of ≤ 480 
msec obtained from 3 ECGs 2-5 minutes apart is required at study entry.   
 
3.2.12 Patients considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease or active, uncontrolled infection.  
Examples include, but are not limited to, uncontrolled ventricular arrhythmia, 
recent (within 3 months) myocardial infarction, uncontrolled major seizure 
disorder, unstable spinal cord compression, superior vena cava syndrome, 
extensive interstitial bilateral lung disease on High Resolution Computed 
Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining 
informed consent.. 
 
3.2.13 Patients with uncontrolled intercurrent illness. 
 
3.2.14 Patients with psychiatric illness/social situations, or other psychological, familial, 
sociological, or geographical conditions that would limit compliance with study 
requirements. 
 

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33 
3.2.15 Persistent grade >1 toxicity from prior cancer therapy (except alopecia). 
 
3.2.16 Patients with previous allogeneic, bone marrow, or double umbilical cord blood 
transplants are not allowed. 
 
3.2.17 Consumption of grapefruit juice while on study drugs. 
 
3.2.18 Involvement in the planning and/or conduct of the study. 
 
3.2.19 Patients unable to swallow orally administered medications and patients with 
gastrointestinal disorders likely to interfere with absorption of the study 
medication. 
 
3.2.20 Pregnant or breastfeeding women are excluded from this study because AZD1775 
and olaparib are agents with the potential for teratogenic or abortifacient effects.  
Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with AZD1775 and olaparib, 
breastfeeding should be discontinued if the mother is treated with AZD1775 and 
olaparib. 
 
3.2.21 Other malignancy unless curatively treated with no evidence of disease for ≥5 
years exept: adequalty treated non-melanoma skin cancer, curatively treated in 
situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 
endometrial carcinoma.   
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 

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35 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval.  
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
In addition, all investigators act as the Site-Protocol PI (Investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the Clinical Investigator (CI) on 
the DTL must be rostered at the enrolling site with a participating organization. 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval   
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website.  
Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation, 
• IRB-signed CTSU IRB Certification Form, and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 

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36 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Regulatory Documents 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment.  To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Participating 
Organization on the protocol. One way to search for a protocol is listed below. 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-TX035, and 
protocol number 10329, 
• Click on Documents, select Site Registration, and download and complete the forms 
provided.  (Note:  For sites under the CIRB initiative, IRB data will load automatically to 
the CTSU.)  
 
4.2.2 Requirements For 10329 Site Registration 
 
 
• Specimen Tracking  System Training Requirement: 
• All data entry users (Clinical Research Associate role) at each participating site 
will need to complete the Theradex-led training. 
• Theradex will provide a certificate of completion, which will need to be submitted 
to the CTSU through the Regulatory Submission Portal. 

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37 
• The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU.  However, new versions of the Specimen Tracking 
system may require new training. 
•  This training will need to be completed before the first patient enrollment at a 
given site. 
• Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com, Theradex phone: 609-799-7580)   
 
4.2.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to the 
Regulatory section, and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application in the Delegation 
Log section on the CTSU members’ website.  The Clinical Investigator (CI) is required to review 
and electronically sign the DTL prior to the site receiving an Approved site registration status 
and enrolling patients to the study.  To maintain an approved site registration status the CI must 
re-sign the DTL at least annually and when a new version of the DTL is released; and activate 
new task assignments requiring CI sign-off.  Any individual at the enrolling site on a 
participating roster may initiate the site DTL.  Once the DTL is submitted for CI approval, only 
the designated DTL Administrators or the CI may update the DTL.  Instructions on completing 
the DTL are available in the Help Topics button in the DTL application and include a Master 
Task List, which describes DTL task assignments, CI signature, and CTEP registration 
requirements. 
 
4.2.4 Checking Site Registration Status 
You can verify your site’s registration status on the members’ side of the CTSU website.  
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration  
• Enter your 5-character CTEP Institution Code and click on Go 

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38 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined above.  It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
Requirements for OPEN access:   
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar.  
Registrars must hold a minimum of an AP registration type. 
• The registrar(s) must hold the OPEN Registrar task on the DTL for the site. 
• Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  The IVR or NPIVR must be assigned the appropriate OPEN-related 
tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  IWRS system also sends an email confirmation of the registration. Please 
print this confirmation for your records.  

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Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on 
the protocol is available to the patient.  Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study.  
 
4.3.2 Special Instructions for Patient Enrollment 
 
This Study will use the ETCTN Specimen Tracking System (STS).  
 
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   
• The system is accessed through special Rave user roles:  “CRA Specimen Tracking” for 
data entry at the treating institutions and “Biorepository” for users receiving the 
specimens for processing and storage at reference labs and the Biorepository.   
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website under the Rave/DQP tab. 
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Detailed instructions can be found in Section 5.4. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11.  This link to the Theradex website is also on the CTSU website OPEN 
tab.  For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
609-619-7862 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 8 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 

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41 
4 
Exploratory 
scRNAseq 
>50% 
Snap Frozen 
 
 
Biopsy #:  2 
Trial Time Point:  Cycle 1, Day 12 
IR Biopsy Definition:  Research – No Clinical Impact 
Core 
Priority 
Use in the Trial 
Biomarker Name(s) 
Tumor Content 
Required 
Post-Biopsy 
Processing 
1 
Integrated 
Proteomic Analysis 
>50%  
Snap Frozen 
2 
Exploratory 
WES/RNAseq 
>50% 
Snap Frozen 
3 
Exploratory 
γH2AX and pRAD50 
IHC and cycIF/mIHC 
>50%  
FFPE 
3 
Exploratory 
scRNAseq 
>50% 
Snap Frozen 
 
 
Biopsy #:  3 
Trial Time Point:  Disease Progression (optional biopsy) 
IR Biopsy Definition:  Research – No Clinical Impact 
Core 
Priority 
Use in the Trial 
Biomarker Name(s) 
Tumor Content 
Required 
Post-Biopsy 
Processing 
1 
Integrated 
Proteomic Analysis 
>50%  
Snap Frozen 
2 
Exploratory 
WES/RNAseq 
>50% 
Snap Frozen 
3 
Exploratory 
γH2AX and pRAD50 
IHC and cycIF/mIHC 
>50%  
FFPE 
3 
Exploratory 
scRNAseq 
>50% 
Snap Frozen 
 
Note:  Pre-biopsy assessments will be reported and tracked through a trial-specific CRF within 
the CTEP Medidata Rave system (see Appendix B).   
 
5.3 
Specimen Procurement Kits and Scheduling 
 
5.3.1 Specimen Procurement Kits  
 
Kits for the collection and shipment of blood in Streck cfDNA tubes to the EET Biobank can be 
ordered online via the Kit Management system: 
(https://ricapps.nationwidechildrens.org/KitManagement).   
 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit.  Please note that protocol may include more than 
one type of kit.  Each user may order two kit types per protocol per day (daily max = 6 kits).  
Kits are shipped ground, so please allow 5-7 days for receipt.  A complete list of kit contents for 
each kit type is located on the Kit Management system website. 
 
5.3.2 Scheduling of Specimen Collections 
 

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5.3.3 Specimen Collections at the EET Biobank 
 
Please adhere to the following guidelines when scheduling procedures to collect samples:  
 
• Tumor tissue specimens collected during biopsy procedures and paraffin embedded and 
fixed in formalin must be shipped on the same day of collection. FFPE tissue can be 
collected Monday through Wednesday and shipped overnight for arrival on Tuesday 
through Thursday at the EET Biobank at Nationwide Children’s Hospital. 
 
• Frozen Tissue:  Tumor tissue submitted frozen can be collected on any day but must be 
stored frozen and shipped to the EET Biobank on Monday through Thursday.  In the 
event that frozen specimens cannot be shipped immediately, they must be maintained in a 
-70°C to -80°C freezer. 
 
• Fresh Blood:  Fresh blood specimens may be collected and shipped Monday through 
Friday.   
 
• FFPE Tumor Cores: Tumor tissue specimens collected during biopsy procedures fixed in 
formalin and paraffin embedded can be collected on any day but must be shipped to the 
EET Biobank on Monday through Thursday. 
 
 
5.4 
Specimen Tracking System Instructions 
 
5.4.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this or any other protocol that uses the ETCTN Specimen Tracking 
System.  The UPID contains no information or link to the treatment protocol.  IWRS will 
maintain an association between the UPID for ETCTN biobanking and molecular 
characterization and any treatment protocols the patient participates in, thereby allowing analysis 
of the molecular characterization results with the clinical data.   
 

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Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave.  Important:  Remove any personally identifying 
information, including, but not limited to, the patient’s name, date of birth, initials, medical 
record number, and patient contact information from the institutional pathology report 
prior to submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com.  
 
The Shipping List must be included with all sample submissions. 
 
5.4.2 Specimen Labeling 
 
5.4.2.1 Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood) 
• Collection date (to be added by hand) 
 
5.4.2.2 Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers:  
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., formalin-fixed paraffin-embedded [FFPE] Block, Frozen Tissue) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number   (if applicable) 
• Block number from the corresponding pathology report (archival only) 
• Collection date (to be added by hand) 
 
5.4.2.3 Example of Specimen Label Generated by STS 
 

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STS includes a label printing facility, accessed va the Print Label CRF in the All Specimens 
folder. A generated PDF is emailed to the user as a result of saving that form. 
 
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide. 
 
 
 
 
The QR code in the above example is for the Specimen ID shown on the second line.   
 
Labels may be printed on a special purpose label printer, one label at a time, or on a standard 
laser printer, multiple labels per page. Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers: 
https://www.labtag.com/shop/product/cryo-laser-labels-1-28-x-0-5-cl-23-colors-available/ 
 
The last line item on the label includes the following data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. An alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
Space is provided at the bottom of the label for the handwritten date and optional time. The 
last line on the example label is for the handwritten date and optional time. 
 
5.4.3 Overview of Process at Treating Site 
 
5.4.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system.  OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments.  If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  

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1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.4.3.2 Rave Specimen Tracking Process Steps 
 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate participant. 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies.  Enter the 
initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded).  CRF generates unique 
Specimen ID.   
 
Step 2:  Print labels using the Print Labels CRF located in the All Specimens folder, then 
collect specimen. 
• Label specimen containers and write collection date on each label. 
• After collection, store labeled specimens as described in Section 5.4.2. 
• Apply an extra specimen label to each report before scanning.  Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
4), Surgical (or Operative) reports and Tissue Biopsy Verification form (when 
applicable).  Return to Specimen Tracking Enrollment CRF to upload any molecular 
report (one per specimen) and/or specimen specific pathology or related report (one per 
specimen).  Uploaded reports should have protected health information (PHI) data, like 
name, date of birth, mailing address, medical record number or social security number 
(SSN), redacted.  Do not redact SPID, block number , diagnosis or relevant dates, and 
include the UPID and patient study ID on each document.   
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form:  Enter collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, recipient, 
number of containers and ship date once for the first specimen in a shipment. 
• Copy Shipping CRF:  In the specimen folders for additional specimens (if any) that will 
be shipped with the initial specimen, please use the Copy Shipping form to derive 
common data into the additional Shipping Status forms. A few unique fields will still 
need to be entered in Shipping Status.  

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Step 5:  Print shipping list report and prepare to ship.   
• Shipping List report is available at the site level. 
• Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
• Print pathology or other required reports to include in the box.  Be sure the printed copy 
includes the specimen label. 
 
Step 6:  Send email notification.   
• For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 
Step 8: Monitor the Receiving Status form located in each specimen folder for acknowledgment 
of receipt and adequacy. 
 
5.5 
Specimen Collection  
 
5.5.1 Core Needle Biopsy (CNB) and Other Small Biopsy Specimens  
 
A maximum number of 3 cores (1 cm in length) or small biopsies (3 mm diameter) will be 
obtained from the procedure.  The number of specimens obtained will be affected by the 
patient’s clinical condition at the time of biopsy and determined by the specialist performing the 
procedure.  Core biopsy should be performed using a 16-18-gauge needle, condition permitting.   
• Number of Cores: Two cores (1 cm in length) or small biopsies (3 mm diameter) should 
be obtained for proteomic RPPA analysis and nucleic acid analysis (WES and RNAseq) 
at the MD Anderson RPPA Core Laboratory and the NCLN Genomics Laboratory, 
respectively.  One core (1 cm in length) or small biopsy (3 mm diameter) should be 
obtained for γH2AX/pRAD50 IHC and cycIF/mIHC  and one core (1 cm in length) or 
small biopsy (3 mm diameter) should be obtained for scRNAseq at Oregon Health & 
Science University (Dr. Gordon Mills). Alternating passes: First obtain 1 core for RPPA 
(snap freezing), followed by 1 core for WES and RNAseq (snap freezing), followed by 1 
core for γH2AX/pRAD50 IHC and cycIF/mIHC (FFPE), followed by 1 core for 
scRNAseq (snap freezing). 
 
 
5.5.1.1 Formalin-Fixed Paraffin-Embedded (FFPE)Tumor Biopsies 
 
At each time point, one core should be fixed in formalin for 12-24 hours and then embedded in 
paraffin. 
 
See Section 5.4.2 for labeling instructions. 
 

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5.5.1.2 Collection of Snap-Frozen Biopsies for WES and RNAseq 
 
1. Tissue should be frozen as soon as possible.  Optimally, freeze within 30 minutes from 
resection. 
2. Label cryovial(s) according to instructions in Section 5.4.2.  
3. Using clean forceps, place the tissue in a cryovial and freeze the tube in either vapor phase 
liquid nitrogen, on dry ice, or by immediate placement in a -70 to -80°C freezer.  
Keep frozen until shipment to the EET Biobank. 
 
5.5.1.3 Collection of Snap-Frozen Core Needle Biopsies for RPPA  
 
 
1.    Label collection tubes according to instructions in section 5.4.2. 
1. Arrive at the biopsy collection site early enough to allow sufficient time to set up 
laboratory supplies, collect relevant clinical information, and ensure rapid transport of 
specimens to the laboratory for placement at -80ºC (or lower) after collection.  
2. Bring all necessary lab supplies including: disposable tweezers, a minimum of two 
1.5-mL Sarstedt tubes (one for each whole biopsy core) pre-cooled on liquid nitrogen 
or dry ice/ethanol in an insulated bucket, and one pre-printed specimen label (see 
Section 5.4.1.1) to give to the research nurse for the patient record. 
Note:  Pre-chill additional 1.5-mL Sarstedt tubes for specimen collection in case the 
interventional radiologist collects additional passes, or one of the other tubes is 
compromised prior to collection. 
3. The total time elapsed between biopsy collection and placement into the pre-chilled 
tube is of key importance to biomarker analysis; biopsies should be frozen within 2 
min of collection.  The interventional radiologist will eject the biopsy onto a sterile 
slide (for optimal analyte recovery the slide should be pre-chilled).  Start a stop watch 
(or note the time) at this point (Appendix C, Biopsy Collection) and immediately 
walk the slide to the sample preparation table.  
Note:  The preferred method of collection, when whole biopsies are collected, is for 
the interventional radiologist to eject the biopsy directly into the pre-chilled tube 
(next step). This minimizes the time between collection and fixation of analytes. 
4. Indicate if a full or halved biopsy is prepared in the Batch Record (Appendix C, 
Biopsy Collection).  
a. For whole biopsies:  Uncap an empty, prechilled 1.5-mL Sarstedt tube and 
using disposable tweezers, pick up the freshly collected needle biopsy with the 
tweezers at one end, and touch the opposite end of the biopsy to the inner 
surface of the prechilled 1.5-mL Sarstedt tube.  This should attach the tissue to 
the tube, allowing it to be dropped into the tube while releasing the tissue 
from the tweezers without sticking.  Dispose of the tweezers in the appropriate 
biohazardous waste container(s).  
b. For halved biopsies:  Use 1-2 disposable tweezers and cut/shear the biopsy in 
half cross-wise while it is on the slide (do not pull or stretch the biopsy 
longitudinally).  Use the tweezers to transfer the halved biopsies to sterile pre-
chilled tubes as indicated above.  

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5. Immediately snap freeze the biopsy by placing the tube in liquid nitrogen or a dry 
ice/ethanol bath. 
6. Calculate the total time elapsed from biopsy collection to biopsy freezing and record 
the total number of minutes and seconds elapsed in the Batch Record (Appendix C, 
Biopsy Collection). 
7. If biopsy procedure details can be obtained from the interventional radiologist or 
research nurse, record them in the Batch Record (Appendix C, Biopsy Procedure 
Details).  Some information may not be available until a later time from the clinical 
staff. 
8. Transfer the frozen biopsy specimen(s) to -80ºC (or lower) for storage until shipment 
to the EET Biobank.  Record the date and time specimens are placed at -80ºC (or 
lower; Appendix C, Biopsy Storage). 
9. Review and finalize the Batch Record and document ANY and ALL deviations in the 
Batch Record (Appendix C, Notes). 
10. The appropriate laboratory personnel should review the Batch Record and sign to 
affirm the data contained within are correct (Appendix C, Review of Batch Record). 
 
5.5.2 Collection of Blood in cfDNA Streck Tube 
 
1. Label two 10 mL cfDNA Streck tube according to the instructions in Section 5.4.2.   
2. Collect 20 mL of blood into the pre-labeled tube and gently invert to mix.  Note:  
blood must be thoroughly mixed to ensure preservation of specimen.  Heparin should 
be avoided in pre-collection flush procedures.  If therapeutic heparin dosing 
contamination is a possibility, then venipuncture is recommended as a first choice 
collection method.  If a cfDNA Streck tube immediately follows a heparin tube in the 
draw order, then collecting an EDTA tube as a waste tube prior to collection in the 
Streck Cell-Free DNA BCT is recommended. 
3. After collection, blood in cfDNA Streck tubes should never be refrigerated, as 
this will compromise the specimen.  Blood collected in cfDNA Streck tubes is stable 
at room temperature.   
 
 
5.6 
Shipping Specimens to the EET Biobank  
 
5.6.1 General Shipping Information 
 
Core biopsies that are fixed in formalin and paraffin embedded and fresh blood should be 
shipped as one shipment at ambient temperature, whenever possible.  The same box sent with 
Streck cfDNA tubes should be used to ship blood to the EET Biobank.  Frozen cores are shipped 
frozen on dry ice in a container provided by the institution. FFPE tissue is shipped ambient in a 
container provided by the institution. 
 
For tissue from biopsies, if the corresponding anatomical pathology report is not available at the 
time of shipment, then the surgical and/or radiology reports from the tissue removal procedure 
and the diagnostic anatomic pathology report and Tissue Biopsy Verification Form (Appendix 
H) must be included in the package, or the specimen will not be processed.  Once completed, 

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upload the corresponding pathology report to the ETCTN specimen trackind system and send a 
copu to the EET Biobank. 
  
 
5.6.2 Specimen Shipping Instructions 
 
• FFPE tissue must be shipped on Monday through Thursday. 
• Frozen specimens may be shipped on Monday through Thursday.   
• Fresh blood may be shipped on Monday through Friday.  Please select “Saturday 
Delivery” when shipping fresh blood on a Friday.   
 
5.6.2.1 Shipping of FFPE Blocks 
1. Before packaging blocks, verify that each specimen is labeled according to Section 5.4.2.2. 
2. Blocks should be placed in a hard-sided container, preferably a special block holder, to protect 
the specimen.  
3. Place the blocks in a reinforced cardboard shipping box with appropriate packaging filler to 
minimize the movement of specimens within the shipping box. 
4. Include a copy of the forms listed above and a shipping manifest from the Specimen Tracking 
System with each shipment. 
5. Please include a cold pack when shipping on hot days and extra insulation on cold days. 
6. Ship specimens to the address listed below. FedEx Priority Overnight is strongly 
recommended to prevent delays in package receipt. 
 
5.6.2.2 Shipping Blood in an Ambient Shipper 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed.   
2. Prepare the SAF-T-TEMP Gel Pak for shipment.  Note: If contents of the Pak are 
crunchy, place Pak in a warm water bath until gel is smooth.  Do not refrigerate, freeze, 
or microwave.   
3. Place the SAF-T-TEMP Pak in bottom of insulated chest.  Note:  The insulated chest 
must be shipped inside the provided cardboard box(es).   
4. Place the blood collection tubes in zip-lock bags.   
5. Next, place blood into a biohazard envelope with absorbent material.  Expel as much air 
as possible and seal the envelope securely.   
6. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 
7. Place packaged blood collection tube(s) and a copy of the shipping manifest from the 
Sample Tracking System on top of SAF-T-TEMP Pak.   
8.  Place the lid on the insulated chest.   
9. Close the outer flaps of the shipping box and tape shut. 
10. Attach a shipping label to the top of the shipping container.   
11. Attach an Exempt Human Specimen sticker to the side of the box. 
12. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.   

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5.6.2.3 Shipping Frozen Specimens in an Insulated Shipping Container 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are tightly 
sealed.   
2. Place the specimens in zip-lock bags.  Use a separate zip-lock bag for each specimen type 
and time point.   
3. Place the zip-lock bags in the biohazard envelope containing absorbent material.  Expel 
as much air as possible and seal securely.   
4. Put the secondary envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely.   
5. Place frozen specimens in an insulated shipping container with dry ice.  Layer the bottom 
of the container with dry ice until it is approximately one-third full.  Place the frozen 
specimens on top of the dry ice.  Cover the specimens with the dry ice until the 
compartment is almost completely full.  When packaging specimens, ensure that you 
leave enough room to include at least 5 pounds of dry ice in the shipment.   
6. Insert a copy of the required forms into a plastic bag and place in the shipping container. 
7. Place the lid on top to secure specimens during shipment.   
8. Close the flaps of the outer box and tape it shut with durable sealing tape.  Do not 
completely seal the container. 
9. Complete a FedEx air bill and attach to top of shipping container. 
10. Complete a dry ice label. 
11. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
12. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.   
 
5.6.2.4 Shipping Frozen and Ambient Specimens in a Dual-Chamber Kit 
 
The Dual-Chambered Specimen Procurement Kit is constructed to allow the shipment of 
frozen (on dry ice) and ambient (room temperature) specimens in the same container.  Dry 
ice may be placed in either compartment of the kit but should not be put in both.  The 
dual chambered kit is only used for shipments that contain both frozen and ambient 
specimens.  If formalin-fixed tissue is shipped separately (not in the same shipment as frozen 
specimens), then it must be shipped using institutional shipping supplies.    
 
• Frozen specimens may be shipped on Monday through Thursday.  Ensure that sufficient 
dry ice is included to completely encase the specimens to maintain specimen integrity 
during shipment.   
• FFPE tissue may only be shipped on Monday through Wednesday. 
 
1. 
Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are 

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tightly sealed.  If included in the shipment, formalin jar lids should be wrapped in 
parafilm. 
2. 
Pre-fill one of the kit chambers about 1/3 with dry ice. 
3. 
Place the specimens in zip-lock bags.  Use a separate zip-lock bag for each 
specimen type. 
4. 
Two biohazard envelopes are provided so that ambient and frozen specimens can 
be packaged separately.   
• Place the zip-lock bags containing room temperature specimens in a biohazard 
envelope with absorbent material.  Expel as much air as possible and seal the 
envelope securely.   
• Place the zip-lock bags containing frozen specimens into the other biohazard 
envelope containing absorbent material.  Expel as much air as possible and seal 
securely.   
5. 
Put each secondary envelope into a Tyvek envelope.  Expel as much air as 
possible and seal each envelope securely.   
6. 
Quickly place the Tyvek envelope containing frozen specimens (e.g., frozen 
tumor, serum, etc.) in the kit compartment that is pre-filled with dry ice.  Place the 
Tyvek envelope on top of the dry ice.  Cover the specimens with additional dry 
ice until the compartment is almost completely full.   
7. 
Place the Styrofoam lid on top to secure specimens during shipment.  Do not tape 
the inner chamber shut. 
8. 
Place the Tyvek envelope containing ambient temperature specimens (e.g., 
formalin-fixed tissue) in the other kit compartment at room temperature.   
9. 
Insert a copy of the required forms into a plastic bag and place in the kit chamber 
with the ambient specimens. 
10. Place the Styrofoam lid on top of the kit compartment to secure specimens during 
shipment.  Do not tape the inner chamber shut. 
11. Close the outer lid of the Specimen Procurement Kit and tape it shut with durable 
sealing tape.  Do not completely seal the container. 
12. Complete a FedEx air bill and attach to top of shipping container. 
13. Complete a dry ice label. 
14. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
15. Ship specimens via overnight courier to the address below.  FedEx Priority 
Overnight is strongly recommended to prevent delays in package receipt.   
 
5.6.3 Shipping Address 
 
Ship to the address below.  Ship formalin-fixed and fresh blood specimens the same day 
of specimen collection.  Do not ship specimens the day before a holiday. 
 
EET Biobank 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive, WA1340 
Columbus, Ohio 43205 
PH: (614) 722-2865 

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FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.   
 
NOTE:  The EET Biobank FedEx Account will not be provided to submitting 
institutions. 
 
5.6.4 Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
EET Biobank  
Toll-free Phone:  (800) 347-2486 
E-mail:  BPCBank@nationwidechildrens.org 

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5.8 
Integral Correlative Studies 
 
5.8.1 BRCA Mutations 
 
BRCA mutation status will be evaluated prior to registration.  Eligibility for the dose expansion 
Cohort A (with intrinsic resistance) will be based on the presence of germline or somatic 
mutations in BRCA1 or BRCA2.  All alterations will be reviewed by MD Anderson’s Precision 
Oncology Decision Support (PODS) team.  No VUS will be allowed as the qualifying genetic 
mutation .   
 
5.8.1.1 Specimen Receipt and Processing  
 
Local labs should process these samples per institutional SOPs as part of standard of care. 
 
 
5.8.1.2 Site Performing Correlative Study 
 
A local CLIA-certified laboratory or Dr. Timothy Yap at MD Anderson will analyze samples. 
 
5.8.2 DDR Mutations 
 
DDR mutation status will be evaluated prior to registration.  Eligibility for the dose expansion 
Cohort B (with acquired resistance) will be based on the presence of any of the following DDR 
genes: BRCA1, BRCA2, BRIP1, FANCA, PALB2, or the non-DDR gene marker Cyclin E 
amplification, or other genes at the discretion of the principal investigator.  All alterations will be 
reviewed by MD Anderson’s Precision Oncology Decision Support (PODS) team.  No VUS will 
be allowed as the qualifying genetic mutation.   
 
5.8.2.1 Specimen Receipt and Processing  
 
Local labs should process these samples per institutional SOPs as part of standard of care. 
 
5.8.2.2 Site Performing Correlative Study 
 
A local CLIA-certified laboratory or Dr. Timothy Yap at MD Anderson will analyze samples. 
 
5.9 
Integrated Correlative Studies 
 
5.9.1 Proteomic Analysis via Reverse Phase Protein Array (RPPA) 
 
RPPA-based proteomic analysis will be performed using 181 high-quality antibodies that target 
total (n=128), cleaved (n=1), acetylated (n=1) and phosphorylated forms (n=51) of proteins in 
patient samples.  The function space covered by the antibodies used in the RPPA analysis 
encompasses major functional and signaling pathways of relevance to human cancer.  Different 
batches of RPPA data will be merged using an algorithm, called Replicates Based Normalization 

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(RBN), which mitigates batch effects facilitating creation of a single protein dataset merging 
samples across different batches.  Two-way unsupervised hierarchical clustering analysis will be 
used to discover the groups of biological objects sharing common characteristics, and a two-
dimensional heat map to visualize protein expression patterns.  To detect the discriminating 
biomarkers for each cluster (obtained by hierarchical clustering using the RPPA data normalized 
by RBN), LIMMA will be used to select biomarkers by comparing samples in each cluster with 
samples in all the other clusters together.  In addition, pathway activity scores will be computed 
using a series of pathway predictors developed based on member proteins selected by literature 
review. 
 
5.9.1.1 Specimen Receipt and Processing at the EET Biobank 
 
Frozen tissue for RPPA will be stored in liquid nitrogen vapor phase at the EET Biobank until 
batch shipping to Dr. Yiling Lu at the Functional Proteomics RPPA Core Facility, MD Anderson 
Cancer Center (MDACC).   
 
5.9.1.2 Site Performing Correlative Study 
 
This assay will be performed by Dr. Yiling Lu at the Functional Proteomics RPPA Core Facility, 
MD Anderson Cancer Center (MDACC). 
 
5.9.1.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Prior to shipping specimens, set up an account with the Functional Proteomics RPPA Core 
Facility at MDACC at https://mdanderson.ilabsolutions.com. After an account has been set up, 
proceed to the RPPA Core iLab Page to submit a service request. The Functional Proteomics 
RPPA Core facility will review and approve all requests before the specimen is shipped to the 
address below: 
 
Functional Proteomics RPPA Core Facility 
Attn: Doris Siwak, PhD 
6565 MD Anderson Blvd., Room Z4.2040 
Houston, TX 77030 
  
5.9.1.4 Contact information for Notification of Specimen Shipment 
 
Yiling Lu (yilinglu@mdanderson.org) 
 
 
5.10 
Exploratory/Ancillary Correlative Studies 
 
5.10.1 Genomic Analysis via Whole Exome Sequencing (WES) 
 
5.10.1.1 
Specimen Receipt and Processing at the EET Biobank 
 

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Frozen tissue specimens received from the collection site should be stored in liquid nitrogen 
vapor phase.  DNA and RNA will be co-extracted from tumor tissue.  The nucleic acids will be 
analyzed to determine concentration and quality.  Aliquots of DNA and RNA will be shipped to 
the central sequencing laboratory for analysis. 
 
At baseline, whole blood collected in Streck cfDNA tubes will be processed for plasma. DNA 
will be extracted from the blood following plasma removal. DNA and plasma will be stored at - 
80ºC until distribution for testing. 
 
5.10.1.2 
Site Performing Correlative Study   
 
WES will be conducted in the NCLN Genomics Laboratory or MoCha, Frederick National 
Laboratory for Cancer Research (FNLCR) under the leadership of Mickey Williams, Ph.D.   
 
5.10.1.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to one of the laboratories designated in 
Section 5.10.1.2. 
 
5.10.1.4 Contact information for Notification of Specimen Shipment 
 
Thomas Forbes (NCLNGenomicsReceiving@nih.gov) 
 
 
5.10.2 Gene Expression Analysis via RNA Sequencing (RNAseq) 
 
5.10.2.1 
Specimen Receipt and Processing at the EET Biobank 
 
Please see Section 5.10.1.1. 
 
5.10.2.2 
Site Performing Correlative Study   
RNAseq will be conducted in the NCLN Genomics Laboratory or MoCha, Frederick National 
Laboratory for Cancer Research (FNLCR) under the leadership of Mickey Williams, Ph.D.   
 
5.10.2.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to one of the laboratories designated in 
Section 5.10.2.2. 
 
5.10.2.4 Contact information for Notification of Specimen Shipment 
 
Thomas Forbes (NCLNGenomicsReceiving@nih.gov) 
 
 

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5.10.3 γH2AX and pRAD50 IHC and cycIF/mIHC 
cycIF will assess the composition and molecular states of tumor cells and the microenvironment 
in which they live. Using the process of staining and registration, we will stain 48 proteins on 
FFPE sections using a cycIF analysis that proceeds through successive rounds of 5 color 
fluorescence staining (DAPI plus 4 immunofluorescence markers), imaging using Zeiss 
Axioscan, and hydrogen peroxide bleaching. We will assess over 150 proteins selected from 107 
validated antibodies that interrogate aspects of differentiation, DNA damage repair, proliferation, 
architecture, immune cell composition, and aspects of the stroma and vasculature. Quantitative 
features are extracted by segmentation of each individual cell in the tissue, followed by 
measurement of its protein expression profile. Spatial information is distilled by relating 
neighboring cell-cell interactions, and identifying architectural patterns, such as tumor nests and 
islanda of resistance. This results in a high dimensional single-cell based feature space for each 
tissue and unsupervised clustering methods will be used to reduce the complexity and allow 
exploration of the molecular consequences of cell-cell interactions. 
 
mIHC is a 36-plex IHC procedure that proceeds through repeated rounds of IHC staining, 
detection with AEC (3-amino-9-ethylcarbazole) chromagen, image acquisition using an Aperio 
scanner, removal of AEC with ethanol, and heating to strip antibodies. The panel of 17 distinct 
epitopes allows phenotyping of lymphoid and myeloid lineage cells and functional status of T 
cells. 
 
5.10.3.1 Specimen Receipt and Processing at the EET Biobank 
Upon receipt, FFPE tissue will be accessioned, barcoded, and stored at room temperature until 
distribution.  
 
5.10.3.2 
Site Performing Correlative Study 
γH2AX and pRAD50 IHC and cycIF/mIHC will be performed by Dr. Gordon Mills at Oregon 
Health & Science University. 
 
 
5.10.3.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
ATTN: Dong Zhang 
Oregon Health & Science University 
2730 S. Moody Ave. 
KCRB Mills Lab 2001.14 
Portland, OR 97201 
 
5.10.3.4 Contact information for Notification of Specimen Shipment 
 
Gordon Mills (millsg@ohsu.edu) 
 
 

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5.10.4 scRNAseq 
scRNA-seq will be used to assay transcriptomes of several thousand cells from each tumor 
biopsy. The scRNASeq technology provides us with a unique tool to dissect the heterogeneous 
response in individual tumor cells to PARPinhibitor and WEE1 inhibitor treatment. Samples will 
be dissociated using standard single-cell nuclei extraction protocols, and scRNAseq performed 
using the 10x Chromium platform. Initial analysis will identify constituent cellular subtypes 
using unsupervised UMAP clustering algorithms. Transcriptome information will then be 
analyzed to identify key molecular pathways predominant in each cellular subtype and track 
changes in these pathways as they evolve in response to therapeutic stress at a single-cell level. 
 
5.10.4.1 Specimen Receipt and Processing at the EET Biobank 
Frozen tissue will be accessioned, barcoded, and stored in a liquid nitrogen freezer until 
distribution.  
 
5.10.4.2 
Site Performing Correlative Study 
scRNAseq will be performed by Dr. Gordon Mills at Oregon Health & Science University.  
 
5.10.4.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
ATTN: Dong Zhang 
Oregon Health & Science University 
2730 S. Moody Ave. 
KCRB Mills Lab 2001.14 
Portland, OR 97201 
 
5.10.4.4 Contact information for Notification of Specimen Shipment 
 
Gordon Mills (millsg@ohsu.edu) 
 
 
5.10.5 Circulating Tumor DNA (ctDNA) Analysis via Next Generation Sequencing (NGS) 
 
5.10.5.1 
Specimen Receipt and Processing at the EET Biobank 
 
Whole blood collected in Streck cfDNA tubes will be centrifuged to separate plasma. At 
baseline, residual blood will be processed for DNA; at other time points buffy coat will be 
processed and banked. Plasma and buffy coat aliquots will be stored in a -80°C freezer. 
 
5.10.5.2 
Site Performing Correlative Study   
 
ctDNA Analysis will be conducted in the NCLN Genomics Laboratory or MoCha, Frederick 
National Laboratory for Cancer Research (FNLCR)under the leadership of Mickey Williams, 
Ph.D. 
 
5.10.5.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 

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Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions.  Repeat dose interruptions are allowed as required, 
for a maximum of 4 weeks on each occasion.  If the interruption is any longer, the study team 
must be informed.  Study treatment can be dose reduced to 200 mg twice daily. If the reduced 
dose of 200 mg twice daily is not tolerable, no further dose reduction is allowed and study 
treatment should be discontinued.   
Once dose is reduced, escalation is not permitted. 
 
Olaparib dose reductions for study treatment 
Initial Olaparib Dose 
Following re-challenge post 
interruption: Dose reduction 1 
 
300 mg BID 
200 mg BID 
 
 
 
7.1.1 Dose Reduction/Discontinuation for Organ Dysfunction 
 
7.1.1.1 Hepatic Impairment 
 
The effect of mild or moderate hepatic impairment (Child-Pugh classification A or B) on single 
dose PK of olaparib has been characterized and no olaparib dose adjustment in patients with mild 
or moderate hepatic impairment is required. 
 
Olaparib is not recommended for use in patients with severe hepatic impairment as the PK and 
safety of olaparib in patients with severe hepatic impairment has not been studied. 
 
7.1.1.2 Renal Impairment 
 
If, subsequent to study entry and while still on study therapy, a patient’s Cockcroft-Gault 
estimated CrCl falls below the threshold for study inclusion (≥51 mL/min), retesting should be 
performed promptly.   
 
A dose reduction is recommended for patients who develop moderate renal impairment (CrCl 
between 31 and 50 mL/min, as estimated by Cockcroft-Gault or based on a 24-hour urine test) 
for any reason during the course of the study: the dose of olaparib should be reduced to 200 mg 
BID. 
 
Because the CrCl determination is only an estimate of renal function, in instances where the CrCl 
falls to between 31 and 50 mL/min, the investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted. 
 
The effect of mild and moderate renal impairment on the single dose PK of olaparib has been 
evaluated in a formal renal impairment study.  Olaparib has not been studied in patients with 
severe renal impairment (CrCl ≤30 mL/min) or end-stage renal disease; if patients develop 
severe impairment or end stage disease, is it recommended that olaparib be discontinued. 

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Olaparib dose reduction if patient develops moderate renal impairment 
Initial Olaparib Dose 
Moderate renal impairment (calculated creatinine clearance by 
Cockcroft-Gault equation or based on a 24 hour urine test 
between 31 and 50 mL/min): Dose reduction  
 
300 mg BID 
200 mg BID 
 
     
7.1.2 Management of Hematological Toxicity 
 
7.1.2.1 Management of Anemia 
 
Management of Anemia 
Hemoglobin (Hb) 
Action to be taken 
Hb <10 but ≥8 g/dL 
(CTCAE Grade 2) 
First occurrence: 
Give appropriate supportive treatment and investigate causality.   
Investigator judgement to continue olaparib with supportive treatment 
(e.g.  transfusion) or interrupt dose for a maximum of 2 weeks.  Study 
treatment can be restarted if Hb has recovered to >9 g/dL.   
Subsequent occurrences: 
If Hb <10 but ≥9 g/dL, investigator judgement to continue olaparib with 
supporting treatment (e.g.  transfusion) and dose reduction may be 
considered (to 200 mg twice daily). 
If  Hb <9 but ≥8 g/dL, dose reduction (to 200 mg twice) until Hb ≥9 g/dL. 
Hb <8 g/dL 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g.  transfusion) and investigate 
causality.   
Interrupt olaparib for a maximum of 2 weeks until improved to Hb ≥9 
g/dL. 
Upon recovery dose reduce to 200 mg twice daily in the case of repeat Hb 
decrease. 
 
Common treatable causes of anemia (e.g., iron, vitamin B12, or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases, management 
of anemia may require blood transfusions.  For cases where patients develop prolonged 
hematological toxicity (warranting ≥2 week interruption/delay in study treatment due to CTCAE 
grade 3 or worse anemia and/or development of blood transfusion dependence), refer to Section 
7.1.3.3 for the management of this.   
 
7.1.2.2 Management of Neutropenia, Leukopenia and Thrombocytopenia 
 

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Management of Neutropenia, Leukopenia and Thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grade 1-2 
Investigator judgement to continue treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment 
and causality investigation 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE grade 1 or better for a 
maximum of 4 weeks.  If repeat CTCAE grade 3-4 occurrence, dose 
reduce olaparib to 200 mg twice daily  
 
AEs of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow-up and interruption of study drug if CTCAE grade 3 or worse 
neutropenia occurs. 
 
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not recommended; 
however, if a patient develops febrile neutropenia, study treatment should be stopped and 
appropriate management including G-CSF should be given according to local hospital 
guidelines.  Please note that study drug should not be administered within 24 hours of G-CSF (7 
days for pegylated G-CSF). 
 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
 
For cases where patients develop prolonged hematological toxicity (≥2 week interruption/delay 
in study treatment due to CTCAE grade 3 or worse), refer to the next section.   
 
7.1.2.3 Management of Prolonged Hematological Toxicities While on Study Treatment 
 
If a patient develops prolonged hematological toxicity such as: 
• ≥2 week interruption/delay in study treatment due to CTCAE grade 3 or worse anemia 
and/or development of blood transfusion dependence 
• ≥2 week interruption/delay in study treatment due to CTCAE grade 3 or worse 
neutropenia (ANC <1×109/L) 
• ≥2 week interruption/delay in study treatment due to CTCAE grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (platelets 
<50×109/L) 
Check weekly differential blood counts including reticulocytes and peripheral blood smear.  
Study treatment should be discontinued if blood counts do not recover to CTCAE grade 1 or 
better within 4 weeks of dose interruption.  Refer to a hematologist. 
 
If any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the patient 
should be referred to hematologist for further investigations.  Patients with laboratory findings 
consistent with AML or MDS should receive a full work up as per the local standard of care for 
evaluation of a suspected hematological malignancy including, but not limited to, bone marrow 

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aspirate/smear, flow cytometric evaluation of the marrow, and evaluation of cytogenetics.  If it is 
not possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample. 
 
Development of a confirmed MDS, AML, or other clonal blood disorder should be reported as 
an SAE via CTEP-AERS and full reports must be provided by the investigator to the CTEP 
Medical Officer.  Olaparib treatment should be discontinued if the patient’s diagnosis of MDS 
and/or AML is confirmed. 
 
7.1.3 Management of Non-Hematological Toxicity 
 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion.  
If the interruption is longer than 4 weeks, the CTEP Medical Monitor must be informed.  Where 
toxicity reoccurs following re-challenge with study treatment, and where further dose 
interruptions are considered inadequate for management of toxicity, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment. 
 
Olaparib can be dose reduced to 200 mg BID.  Treatment must be interrupted if any NCI-
CTCAE grade 3 or 4 AE occurs which the investigator considers to be related to administration 
of study treatment. 
 
7.1.3.1 Management of New or Worsening Pulmonary Symptoms  
 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in 
the absence of a clear diagnosis, an interruption in study treatment dosing is recommended and 
further diagnostic workup (including a high-resolution CT scan) should be performed to exclude 
pneumonitis.   
 
Following investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, then study treatment can be restarted, if deemed appropriate by the investigator.  If 
significant pulmonary abnormalities are identified, these need to be discussed with the CTEP 
Medical Monitor. 
 
7.1.3.2 Management of Nausea and Vomiting 
 
Events of nausea and vomiting are known to be associated with olaparib treatment.  These events 
are generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent, and manageable on 
continued treatment.  The first onset generally occurs in the first month of treatment for nausea 
and within the first 6 months of treatment for vomiting.  For nausea, the incidence generally 
plateaus at around 9 months, and for vomiting at around 6 to 7 months. 
 
No routine prophylactic anti-emetic treatment is required at the start of study treatment; however, 
patients should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines.  Alternatively, 
olaparib tablets can be taken with a light meal/snack (i.e., two pieces of toast or a couple of 
cookies, crackers, or biscuits). 

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8. 
PHARMACEUTICAL INFORMATION FOR CTEP IND AGENTS 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 10.1. 
 
8.1 
Olaparib (NSC 747856) 
 
Chemical Name:  4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Other Names: AZD2281; KU-0059436; CO-CE 42; Lynparza 
 
Classification: PARP inhibitor 
 
CAS Registry Number: 763113-22-0 
 
Molecular Formula:  C24H23FN4O3  
M.W.: 434.46 
 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
Mode of Action:  Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5′ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3).  In tumors that are deficient in the 
homologous recombination DNA repair pathway (example, BRCA mutants), inhibition of PARP by 
olaparib causes accumulation of DNA double-strand breaks and genomic instability.  Olaparib may 
also enhance the effects of DNA damage caused by ionizing radiation and chemotherapy.   
 
Description: crystalline solid 
 
How Supplied:  AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, film-
coated tablets in 100 mg and 150 mg strengths.   
 
• 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 150 mg tablets are 14.5 mm x 7.25 mm oval-shaped 

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Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with child-
resistant closures.  Each bottle contains 32 tablets with desiccant.   
 
Tablet core components include active drug substance, copovidone, colloidal silicon dioxide, 
mannitol and sodium stearyl fumarate.  Film coating contains hydroxypropyl methylcellulose 
(hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, iron oxide yellow and 
iron oxide black. 
 
Storage: Store in a secure location below 30° C (86° F).   
 
If a storage temperature excursion is identified, promptly return olaparib (AZD2281) to room 
temperature and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.   
 
Stability:  Shelf-life studies are ongoing.  Sites are not permitted to re-package tablets.  Once the 
bottle is opened, olaparib tablets must be used within 3 months of the opening date; unused 
tablets should be discarded.  Instruct patients not to open a bottle until they are ready to use it. 
 
Route and Method of Administration:  Oral.  Take tablets without regard to meals.  Olaparib 
tablets should be taken at the same time each day, approximately 12 hours apart with one glass of 
water.  The tablets should be swallowed whole and not chewed, crushed, dissolved or divided.  If 
vomiting occurs, the dose should only be replaced if all of the intact tablets can be seen and 
counted.  Should a patient miss a scheduled dose (e.g., as a result of forgetting to take the tablets 
or vomiting), the patient will be allowed to take the scheduled dose up to a maximum of 2 hours 
after that scheduled dose time.  If greater than 2 hours have passed, the missed dose is skipped 
and the patient should take their allotted dose at the next scheduled time. 
 
Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans.  For this reason, avoid concomitant administration of strong 
and moderate CYP 3A4/5 inducers and inhibitors.  Consult the protocol document or study 
investigator prior to making any dose adjustments related to potential drug-drug interactions. 
 
In vitro data shows olaparib is a substrate for P-gp, but not for organic anion-transporting 
polypeptides (OATP1B1 and OATP1B3), OCT1, MRP-2 efflux transporter or BCRP.  
Administration of strong P-gp inhibitors and inducers should be avoided with concurrent olaparib.   
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and induces CYP 
1A2, 2B6, and 3A4.  Therefore, avoid concomitant administration of sensitive substrates, 
particularly those with narrow therapeutic ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an inhibitor of 
OATP1B3 or MRP-2.  In vitro studies suggest that olaparib may increase exposure of substrates of 

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these transport systems, although the clinical relevance is not clear.  The manufacturer recommends 
that statins, in particular, should be administered with caution when given concomitantly with 
olaparib. 
 
Patient Care Implications:  Pre-clinical data indicate that olaparib adversely affects embryofetal 
survival and development.  Therefore, women of child-bearing potential and their partners should 
agree to use two (2) highly effective forms of contraception throughout study participation and for 
at least six (6) months after the last dose of olaparib.  It is not known whether olaparib is found in 
seminal fluid, so as a precaution, male study participants must use a condom during treatment and 
for three (3) months after the last dose and should avoid fathering a child or donating sperm during 
this same time period.  The study investigator should discuss the most appropriate forms of highly 
effective contraceptive methods for each patient.   
 
Lactation is a protocol exclusion criterion and not advised since there is potential for serious adverse 
reactions in breastfed infants.  Advise lactating women to not breastfeed during study treatment and 
for one (1) month after receiving the last dose of olaparib.   
 
Because the adverse events related to olaparib may include asthenia, fatigue and dizziness, 
patients should be advised to use caution while driving or using machinery. 
 
There are no data on the effect of olaparib on wound healing, therefore as a precaution, olaparib 
treatment should be stopped at least 3 days prior to planned surgery.  After surgery olaparib can 
be restarted when the wound has healed.  No stoppage of olaparib is required for any needle 
biopsy procedure. 
  
Availability:  Olaparib is an investigational agent supplied to investigators by the DCTD, NCI.  
Olaparib is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 13.4). 
 
8.2 
AZD1775 (NSC 751084) 
 
Chemical Name: 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[4-(4-methylpiperazin-1-
yl)anilino]pyrazolo[3,4-d]pyrimidin-3-one hemihydrate 
 
Other Names: Adavosertib; MK-1775 
 
Classification: inhibitor of WEE1 kinase 
 
CAS: 1277170-60-1 
 
Molecular Formula:  C27H32N8O2·0.5H2O  
M.W.: 500.6 
 
Mode of Action: AZD1775 inhibits WEE1 which phosphorylates and inhibits cyclin-dependent 
kinases 1 (CDK1) and 2 (CDK2), and is involved in regulation of the intra-S and G2 cell cycle 
checkpoints.  In in vitro and in vivo preclinical models, AZD1775 selectively enhanced 
chemotherapy induced death of cells deficient in p53 signaling. 

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Description: AZD1775 is a crystalline, hemihydrate form of the drug substance. 
 
How Supplied: AZD1775 is supplied by AstraZeneca and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI as capsules available in 25 mg (yellow color, size 2 gelatin 
capsule) and 100 mg (orange color, size 2 gelatin capsule) strengths.  The dry-filled capsules consist 
of a roller-compacted granule of drug substance, lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, and magnesium stearate.  Each high density polypropylene (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. 
 
Storage: Store at 2 to 30˚C (36 to 86˚F).  Do not freeze.  If a storage temperature excursion is 
identified, promptly return AZD1775 to between 2-30°C and quarantine the supplies.  Provide a 
detailed report of the excursion (including documentation of temperature monitoring and duration of 
the excursion) to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Shelf-life stability studies of AZD1775 capsules are ongoing. 
 
Route of Administration: Oral administration.  Capsules should not be opened. 
 
Potential Drug Interactions: AZD1775 is primarily metabolized by CYP3A4 and is a weak, 
time-dependent inhibitor of CYP3A4.  Avoid concomitant CYP3A4 moderate or strong 
inhibitors/inducers, and sensitive substrates with a narrow therapeutic index.  AZD1775 is also a 
weak inhibitor of CYP2C19.  Caution should be exercised with concomitant administration of 
sensitive substrates or substrates with a narrow therapeutic index. 
 
In vitro transporter studies have shown that AZD1775 was an inhibitor of OATP1B1, OATP1B3, 
MATE1, MATE2K, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), and a 
substrate for P-gp and BCRP.  The PK parameters of AZD1775 could be altered if AZD1775 is 
coadministered with P-gp and BCRP inhibitors/inducers, and there is potential for drug-drug 
interactions when coadministered with OATP1B1, OATP1B3, MATE1, MATE2K, P-gp and 
BCRP substrates.  This finding is particularly relevant for drugs administered orally where 
exposure is normally limited by BCRP-mediated efflux, in particular some statins.  Modelling 
has predicted a substantial increase in the exposure of atorvastatin when coadministered with 
AZD1775 and the use of atorvastatin is therefore prohibited. 
 
Availability:  AZD1775 is an investigational agent supplied to investigators by the DCTD, NCI.  
AZD1775 is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 13.4). 
 
8.3 
CTEP IND Agents – General Information 
 
8.3.1 Agent Ordering  
 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol number must be used 

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for ordering all CTEP-supplied investigational agents.  The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for enrollment 
onto the study. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management.   
 
8.3.2 Agent Accountability and Inventory Records 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
8.3.3 Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.3.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 

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9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
In this trial olaparib (300 mg) will be combined with AZD1775 at a maximum dose of 300 mg in 
a sequential alternating dosing schedule. This treatment combination will assess 2 separate 
cohorts of patients: 1) those with BRCA1/2 mutant cancers that have been treated with PARP 
inhibitors who had disease progression per RECIST at 1st re-staging (intrinsic resistance) 2) 
those with DDR aberrant advanced solid tumors treated with PARP inhibitors who had 
complete/partial response followed by disease progression per RECIST (acquired resistance). 
Mandatory tumor biopsies and blood sampling will be undertaken at baseline and on C1D12.  
 
Please refer to “SCHEMA” section for study design. 
 
1. Primary Endpoints:  
• 
Identify the incidence and severity of dose-limiting toxicities. 
• 
Determine the causality of each adverse event to the sequential treatment of olaparib 
and AZD1775 and grade severity according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
 
2. Secondary Endpoints: objective response (OR) rate (CR+PR); clinical benefit rate 
(OR+SD>6 months); progression free survival; overall survival 
 
3. Correlative Endpoints:  
• 
Correlation of molecular alterations in the DDR pathway (BRCA1/2, DDR 
mutation) with objective response to the sequential alternating combination of 
olaparib with AZD1775. 
• 
Correlation of change in expression of pharmacodynamics markers downstream of 
DDR inhibition and change in expression of genes involved in DNA repair 
pathways with objective response to treatment. 
• 
Correlation of mutations not associated with DDR pathway with presence and 
absence of objective response to treatment.  
 
Safety and toxicity data from the dose escalation phase (n ≤30) has been formally reviewed by 
and discussed with the study team and CTEP, and Dose Level 2 was established as the MTD and 
RP2D and schedule for use in the dose expansion phase.  Any treatment-related deaths will be 
carefully discussed in specially-convened ad hoc Safety Management Committee (SMC) meeting 
(including the PI and NCI CTEP medical monitor) to review the trial drug related toxicities, 
clinical management of patient, and the SMC recommendation for the dose/schedule for the 
drug.  The protocol has been amended to open the trial to the ETCTN network during the dose 
expansion phase upon establishement of the MTD.  The dose expansion phase will enroll a 
maximum of 12 patients per cohort to verify toxicity and perform correlative studies.   

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After the trial is completed, select the MTD based on isotonic regression as specified in Liu and 
Yuan (2015).  This computation is implemented by the shiny app "BOIN" available at 
http://www.trialdesign.org.  Specifically, select as the MTD the dose for which the isotonic 
estimate of the toxicity rate is closest to the target toxicity rate.  If there are ties, select the higher 
dose level when the isotonic estimate is lower than the target toxicity rate and select the lower 
dose level when the isotonic estimate is greater than or equal to the target toxicity rate. 
Expansion Phase:  Once we determine the MTD, an additional 12 patients will be enrolled for 
additional experience with safety and efficacy in each of 2 cohorts.  Dose Level 2 was 
established as the MTD and RP2D and schedule for use in the dose expansion phase. We will use 
the elimination boundaries in the dose escalation/de-escalation rule for the BOIN Design Table 
for toxicity monitoring during this phase. 
Operation Characteristics:  The operating characteristics of the BOIN Design for the 
combinations tables below shows the operating characteristics of the trial design based on 1000 
simulations of the trial using shiny app "BOIN" available at http://www.trialdesign.org.  The 
operating characteristics show that the design selects the true MTD, if any, with high probability 
and allocates more patients to the dose levels with the DLT rate closest to the target of 0.25. The 
actual average sample size for dose escalation phase is about 20 or less, depending on the 
scenario. 
 
Operating characteristics of the BOIN Design 
  
Dose Level 
Number of 
Patients 
% Early 
Stopping 
  
-1 
1 
2 
Scenario 1 
True DLT Rate 
0.25 
0.42 
0.59 
16.26 
26.8 
Selection % 
51.7 
21.1 
0.4 
# Pts Treated 
8.0 
7.1 
1.2 
Scenario 2 
True DLT Rate 
0.10 
0.25 
0.40 
19.25 
2.1 
Selection % 
20.7 
61.4 
15.8 
# Pts Treated 
5.0 
10.0 
4.3 
Scenario 4 
True DLT Rate 
0.05 
0.12 
0.25 
19.04 
0.1 
Selection % 
1.8 
34.1 
64.0 

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# Pts Treated 
1.8 
8.5 
8.7 
 
 
9.2 
Analysis of Secondary Endpoints 
 
Secondary endpoints are two-fold:  
 
1. Correlate antitumor activity of the sequentially-administered combination of olaparib and 
AZD1775 with the detection of putative predictive biomarkers of response and resistance.   
2. Assess if an MTD can be safely established using sequentially-administered combination 
olaparib and AZD1775. 
 
To evaluate the capacity of our biomarkers to predict response, we will assess: 
• ORR (Complete Response [CR] + Partial Response [PR])  
• Duration of Response (DOR) 
• Progression-Free Survival (PFS) 
• Overall Survival (OS)   
 
We will estimate ORR with 95% confidence intervals (CI).  Inferences and estimation are based 
on the exact binomial test.  With 12 patients, the 95% CI for an observed ORR of 25% would 
extend from 5% to 57%.  A treatment will be declared worthy of further study if we see at least 
2 patients (17%) out of 12 with ORR; the probability of doing so would be 12% if the true OR 
rate was 5% and would be 73% if the true ORR was 20%.  We will use the Kaplan-Meier 
method to estimate DOR, PFS, and OS in these distributions. 
 
For correlative studies, we will assess changes using paired t-tests or Wilcoxon signed rank tests.  
With 12 patients, we would have 80% power to detect an effect size (mean difference divided by 
standard deviation of differences) = 0.90 assuming Normal data with two-sided 5% alpha.  We 
will assess associations between marker levels and response using receiver operating 
characteristic (ROC) curve analysis, graphical analysis and logistic regression analysis as 
appropriate.  If success rate is 50%, then we would have 80% power to detect an area under the 
ROC curve of 0.82 as statistically different from the null value of 0.50 assuming a 20% alpha 
and 12 patients with data. 
 
9.3 
Sample Size/Accrual Rate 
 
Planned accrual rate is 3-4 patients per month for the dose escalation phase of the study, and 5-
10 patients per month for the dose expansion phase of the study.  We plan to enroll up to 54 
evaluable patients. 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 

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- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 Rave CTEP-AERS Integration 
The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting, and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting.    
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to 
collect AEs that start during the period or persist from the previous reporting period.  The 
Clinical Research Associate (CRA) will enter AEs that occur prior to the start of 
treatment on a baseline form that is not included in the Rave-CTEP-AERS integration.  
AEs that occur prior to enrollment must begin and end on the baseline Adverse Event 
form and should not be included on the standard Adverse Events form that is available at 
treatment unless there has been an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-free 
(fields added to the form during study build do not need to be query-free for the 
integration call with CTEP-AERS to be a success). 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements.  The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the deep link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 

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• Study specific documents:  Protocols > Documents > Education and Promotion, 
and   
• Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU 
Operations Information > User Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf. 
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.   
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality as long as the death occurred less than 30 days after the last administration of the 
investigational agent.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.   
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
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.   

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Otherwise, after study treatment completion (i.e. after any scheduled post treatment follow-up 
period has ended) there is no obligation to actively report information on new AEs or SAEs 
occurring in former study patients. This includes new AEs/SAEs in patients still being followed 
up for survival but who have completed the post treatment follow up period (30 days). 
Overdose:  There is currently no specific treatment in the event of overdose with olaparib and 
possible symptoms of overdose are not established. Olaparib must only be used in accordance 
with the dosing recommendations in this protocol. Any dose or frequency of dosing that exceeds 
the dosing regimen specified in this protocol should be reported as an overdose. The Maximum 
Tolerated Dose is 300 mg twice daily (tablet). 
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately. 
 
10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via Medidata Rave.  Three options are available to 
describe the event:  

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1. Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
2. Myelodysplastic syndrome (MDS)  
3. Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 

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a – Treatments dosed as assigned. 
b – A fresh tumor sample from Baseline can be used if archival tissue is not available. 
c – Tumor biopsies are mandatory at Baseline and Cycle 1 Day 12.   
d – Blood collections will occur at baseline, C1D12, each restaging, and disease progression.  
e – Radiologic scans to occur at the start of the study, then every 2nd cycle beginning with a scan at the end of Cycle 2 (i.e., every 8 weeks).  Radiologic documentation must be provided for patients 
removed from the study for disease progression. 
f – Physical exam to include vital signs, weight, and performance status. 
• 
Vital signs, weight, and performance status to be evaluated at Baseline, every other week during Cycles 1 and (Days 1 and 15), then Day 1 of every cycle thereafter, at disease progression, 
and at the 30-Day Follow-Up Visit.  
• 
Height to be recorded only at Baseline and as clinically indicated thereafter. 
g – If screening laboratory assessments are performed within 3 days prior to Day 1, they do not need to be repeated at Day 1.  General assessments to occur at pre-study, weekly during Cycle 1, twice 
during Cycle 2, Day 1 of each subsequent cycle, at disease progression, and at the 30-Day Follow-Up Visit, or as clinically indicated.  The frequency of the hematology, serum chemistry and liver 
function test testing may need to be increased to every two weeks, depending on clinical need.  These assessments are to include: 
• 
CBC with differential and platelets. 
• 
urinalysis: to include hemoglobin/erythrocytes/blood, protein/albumin, and glucose.  To be conducted at pre-study, Cycle 1 Day 1, Cycle 2 Day 1, and as clinically indicated. 
• 
comprehensive chemistry panel:  including albumin, alkaline phosphatase, amylase, total bilirubin, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, LDH, 
lipase, phosphorus, potassium, total protein, SGOT (AST), SGPT (ALT), and sodium.  Gamma glutamyl transferase to be tested at pre-study, Day 1 of each cycle, and as clinically indicated. 
• 
coagulation factors:  aPTT, INR; required at pre-study and as clinically indicated.  Patients receiving warfarin must also be assessed weekly for aPTT and INR during the first month of the 
study; if the INR is stable, coagulation factor assessments may be performed on a monthly basis.  Each coagulation test result will be recorded in the CRF. 
• 
pregnancy test for women of childbearing potential.  Pregnancy tests on blood or urine samples will be performed for women of childbearing potential within 28 days prior to the start of 
study treatment, on Day 1 of the study prior to commencing treatment and at each subsequent visit during study treatment and at the 30 day follow up visit.  Tests will be performed by the 
hospital’s local laboratory.  If pregnancy results are positive the patient is ineligible/must be discontinued from study treatment immediately.  Details of the pregnancy tests must be recorded 
in the patient’s medical records. 
h – Single 12-lead ECG to be performed at spre-study,  at D1 of C2 and higher, at end of study/progression, and when clinically indicated. Triplicate ECGs will be performed for patients whose QTcF 
is >480 msec on the initial screening ECG.  
i – Optional collection. 
j – Should occur on C1D12 unless documented as unavoidable. 
 
 
 

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11.2 Laboratory Assessments 
 
Full hematology assessments for safety (hemoglobin, red blood cells [RBC], platelets, mean cell 
volume [MCV], mean cell hemoglobin concentration [MCHC], mean cell hemoglobin [MCH], 
white blood cells [WBC], absolute differential white cell count (neutrophils, lymphocytes, 
monocytes, eosinophils and basophils) and absolute neutrophil count or segmented neutrophil 
count and band forms should be performed at pre-study, at each visit, and when clinically 
indicated.  If absolute differentials are not available, please provide % differentials.   
 
Serum biochemistry assessments for safety include sodium, potassium, calcium, magnesium, 
fasting glucose, creatinine, total bilirubin, gamma glutamyltransferase (GGT), alkaline 
phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), urea or blood 
urea nitrogen (BUN), total protein, albumin, amylase, lipase, and lactic dehydrogenase (LDH).  
These assessments should be performed at pre-study, at every clinic visit, and when clinically 
indicated.  Gamma glutamyltransferase (GGT) testing is to be performed at pre-study, Day 1 of 
each cycle, and as clinically indicated. 
 
Coagulation (activated partial thromboplastin time [aPTT] and INR) will be performed at pre-
study and if clinically indicated unless the patient is receiving warfarin.  Patients taking warfarin 
may participate in this study; however, it is recommended that prothrombin time (INR and 
aPTT) be monitored carefully at least once per week for the first month, then monthly if the INR 
is stable.  Each coagulation test result will be recorded in the CRF. 
 
Urinalysis by dipstick should be performed at pre-study and only if clinically indicated 
thereafter.  Microscopic analysis should be performed by the hospital’s local laboratory if 
required. 
 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities as defined in Section 7.1.3. 
 
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic analysis 
and flow cytometry, and a core biopsy for bone marrow cellularity.  If it is not possible to 
conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then attempts 
should be made to carry out the tests on a blood sample.  Full reports must be provided by the 
investigator for documentation on the Patient Safety database.  These data are not required to be 
entered into CRF. 
 
These tests will be performed by the hospital’s local laboratory.  Additional analyses may be 
performed if clinically indicated. 
 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. 
 
In case a patient shows an AST or ALT ≥3×ULN or total bilirubin ≥2×ULN, please refer to 
Appendix G, “Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law”, for further instructions.   

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11.3 ECG 
 
Single 12-lead ECG will be performed at pre-study, at Day 1 of Cycle 2 and higher, at end of 
study/progression, and when clinically indicated.  Triplicate ECGs will be performed for patients 
whose QTcF is >480 msec on the initial screening ECG. 
 
Twelve-lead ECGs will be obtained after the patient has been rested in a supine position for at 
least 5 minutes in each case.  The investigator or designated physician will review the paper 
copies of each of the timed 12-lead ECGs on each of the study days when they are collected. 
ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the investigator as to 
whether they are clinically significantly abnormal/not clinically significantly abnormal.  If there 
is a clinically significant abnormal finding, the Investigator will record it as an AE on the eCRF.  
The original ECG traces must be stored in the patient medical record as source data. 
 
 
12. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of these drug has not yet been established, the intent of offering this 
treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability.  Patients 
with measurable disease will be assessed by standard criteria.  
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained at least 4 (not less than 4) 
weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (Eisenhauer et al., 2009).  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
• Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with olaparib. 
• 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.) 

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• 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 disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.   
 
12.1.2 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 (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  Tumor lesions that are situated in a previously irradiated area may be 
considered measurable if they have progressed by RECIST since being irradiated.    
• Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  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 [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic 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 

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reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
• Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.   
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
• Clinical lesions.  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) 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.  CT should be diagnostic quality with IV and oral contrast, if 
possible.  This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice 
thickness greater than 5 mm (0.5 cm), 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 should be the same as was used at baseline and the lesions should be 

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measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
• PET-CT.  PET-CT is not an acceptable imaging method.     
• 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.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
• 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. 
• FDG-PET.  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
o Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
o No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 

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is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
o FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.1.4 Response Criteria 
 
12.1.4.1 
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 (<1 
cm). 
• 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 (0.5 cm).  (Note:  the appearance 
of one or more new lesions is also considered progressions). 
• Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
• Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] 
short axis). 
o Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 

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• Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
• Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not 
a single lesion increase. 
o 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). 
 
12.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks.  Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks.  Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not 
evaluated 
No 
PR 
SD 
Non-PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks.  from baseline** 
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. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 

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Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.1.5 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.   
 
• Patients who withdraw from treatment will be regarded as censored.  
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.  Patients who withdraw from treatment will be regarded as censored. 
 
12.1.7 Overall Survival 
 
OS is defined as the duration of time from start of treatment to time of death.  Patients who 
withdraw from treatment will be regarded as censored. 
 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 

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This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
All decisions regarding dose escalation/expansion/de-escalation require sign-off by the Protocol 
Principal Investigator through the CTMS/IWRS.  In addition, the Protocol Principal Investigator 
will have at least monthly, or more frequently, conference calls with the Study Investigators and 
the CTEP Medical Officer(s) to review accrual, progress, and adverse events and unanticipated 
problems.   
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.   
Requirements to access Rave via iMedidata: 
• 
A valid account, and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  Rave role 
requirements: 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an Associate Plus (AP) registration type, 
o To hold Rave Investigator role, the individual must be registered as an Non-
Physician Investigator (NPIVR) or Investigator (IVR), and 
o To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 
• 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 

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Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the CTSU 
website in the Data Management section under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance).  Additional information on iMedidata/Rave is 
available on the CTSU members’ website in the Data Management > Rave section at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com.  
 
13.2.1 Monitoring Method:  CTMS Comprehensive 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 

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Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will be 
included when appropriate to meet unique study requirements.  The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm). 
 
13.3 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports.  Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website.  Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 

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Note:  Some Rave protocols may not have delinquent form details or reports specified on 
the DQP.  A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP.  Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.  
13.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 

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113 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R.  Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13.5 
Genomic Data Sharing Plan 
 
The investigators and statistician and/or bioinformaticians for a study will have access to all data 
on mutations and variants stored in the Theradex Data Base and the GDC.  This information will 
be sequestered from access throughout the study until it is analyzed for purposes of reporting and 
publishing of the study results.  As specified in the CRADA for the agents used in the clinical 
study, the pharmaceutical collaborator will have at least 6 months, longer if needed for a 
regulatory filing, to review the data and or receive copies of the data once the study is completed 
and analyzed, or sooner, if specified for purposes of generating Intellectual Property.  Once these 
timeframes have been exceeded, the data will be available through a Data Access Committee 
(DAC) in the GDC following NCI and Collaborator review of the proposals.   
 

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114 
13.6 
Incidental/Secondary Findings Disclosure Procedure 
 
Given the potential clinical implications conferred by detecting a germline and/or somatic 
mutation in one of the proven cancer susceptibility genes, this protocol will use the following 
disclosure procedure, consistent with the recommendations of the American College of Medical 
and Genomics [ACMG] (Green et al., 2013 and Kalia et al., 2016): 
 
The NCI Molecular Characterization Laboratory will review the mutations/variants once at the 
time of initial specimen evaluation according to the most recent version of the ACMG guidance 
on variants.  The NCI Molecular Characterization Laboratory will not re-review all specimens 
received if a new version of the ACMG guidance is published after the initial review. 
 
For each participant with a pathogenic or likely pathogenic germline and/or somatic variant 
detected in the WES of blood (as defined in the ACMG guidance), the NCI Molecular 
Characterization Laboratory will report to the Program Director or Scientific Officer the UPID 
and variant(s) identified.  The Program Director or Scientific Officer will contact Theradex to 
obtain the name of the protocol, investigator treating the patient, and the Principal Investigator of 
the grant.  The treating physician will be contacted by phone and in writing to ask the patient 
whether he or she is interested in learning more about the finding. 
 
If the patient wants to know more, the physician should contact the Program Director for more 
information about the mutation/variant.  The treating physician and a medical genetics counselor 
should meet with the patient to discuss the importance and meaning of the finding, but not the 
finding itself, and notify the patient that this research finding must be confirmed by Sanger 
sequencing at the patient’s/patient insurer’s expense in a Clinical Laboratory Improvement 
Amendments (CLIA)-approved laboratory.  The treating physician and genetic counselor should 
inform the patient of the confirmed result and its meaning and significance to the patient.  If 
desired, the patient may elect to undergo genetic counseling and confirmatory CLIA-approved 
clinical testing on his or her own.  Neither the research laboratory nor the National Cancer 
Institute will be responsible for the costs incurred for any confirmatory genetic testing or 
counseling.  

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designs.  Clin Cancer Res.  DOI: 10.1158/1078-0432.CCR-18-0168.

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 

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APPENDIX B 
PRE-BIOPSY ASSESSMENT 
 
A pre-biopsy lesion assessment can increase trial safety and efficiency.  By agreement between 
all investigators, an attempt at biopsy will be made if the clinical trial team determines that a 
biopsy poses minimal relative risk, provides potential clinical gain to the participant, and will 
likely yield sufficient tissue for analysis.   
 
Pre-biopsy assessments will be reported and tracked through a trial-specific CRF within the 
CTEP Medidata Rave system.  Additional information can be found in the Investigational 
Radiology SOP available at:   
https://ctep.cancer.gov/initiativesPrograms/docs/ETCTN_IR_Research_Biopsy_SOP.pdf.   
 
Individual Patient Pre-Biopsy Assessment.  IR co-investigators are encouraged to apply this 
pre-biopsy scoring and correlation system to assist in the determination of biopsy 
appropriateness. 
 
• IR co-investigators assign a subjective score of 1-3 based on likelihood of success due to 
lesion characteristics.   
 
1.  Biopsy should not be done  
A. Due to safety concerns 
B. Due to lack of suitable lesion for biopsy 
 
2.  Uncertainty about success  
A. Due to access path to lesion 
B. Due to lesion characteristics  
 
3.  Likely successful  
 
• Lesion characteristics to be considered 
• 
Size (small) (<2 cm) 
• Location/path to lesion 
• Morphologic features (necrosis, sub-solid, sclerosis, ill-defined/infiltrative) 
• PET (+/-), avidity  
• Organ/site (sclerotic bone is low yield; fine needle aspiration to be used) 

 
120 
APPENDIX C 
FROZEN BIOPSY SPECIMEN BATCH RECORD 
 
Batch Record 
 
A separate Batch Record should be started for each patient sample.  
 
Facility / Clinic Collecting Specimens: ____________________________ 
 
NCI Protocol Number:  10329 
Patient ID:_________ 
 
 
1. Biopsy Collection 
 
 
 
2. Biopsy Procedure Details 
 
  
 

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3. Biopsy Storage 
 
 
 
4. Notes, including any deviations from this protocol 
 
______________________________________________________________________________ 
 
______________________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
5. Review of Batch Record 
 
 
 
Laboratory Personnel:  ______________________________ (Print) 
 
Laboratory Personnel:  ______________________________ (Sign) 
 
Date:  ___________________________________________ 
 

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APPENDIX E 
PATIENT DRUG INTERACTIONS HANDOUT AND WALLET 
CARD – AZD1775 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis:  
      
Trial #: 
      
Study 
Doctor: 
      
Study Doctor 
Phone #:  
      
Study 
Drug(s)
: 
      
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse 
practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the 
National Cancer Institute.  
 
These are the things that your healthcare providers need to know: 
AZD1775 (adavosertib) interacts with certain specific enzymes in the liver or other tissues like 
the gut and certain transport proteins that help move drugs in and out of cells. 
 
 
Explanation 
CYP 
isoenzymes 
The enzymes in question are CYP 3A4 and 2C19.  AZD1775 (adavosertib) is 
metabolized by CYP3A4 and may be affected by other drugs that inhibit or 
induce these enzymes.  AZD1775 (MK-1775) is an inhibitor of CYP 3A4 and 
2C19 and may affect the metabolism of other drugs. 
Protein 
transporters 
The proteins in question are P-gp, MATE1, MATE2K, and BCRP.  AZD1775 
(adavosertib) is a substrate of P-gp and BCRP and may be affected by other 
drugs that inhibit or induce these transporters.  AZD1775 (adavosertib) is an 
inhibitor of P-gp, MATE1, MATE2K, and BCRP and may affect transport of 
other drugs in and out of cells. 
 
These are the things that you need to know: 
The study drug AZD1775 (adavosertib), may interact with other drugs which can cause side 
effects. For this reason, it is very important to tell your doctors about all your medicines, 
including: (a) medicines you are taking before this clinical trial, (b) medicines you start or stop 
taking during this study, (c) medicines you buy without a prescription (over-the-counter remedy), 
(d) herbals or supplements (e.g. St. John’s Wort). It is helpful to bring your medication bottles or 
an updated medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health 
care providers to review any medicines and herbal supplements that are considered “strong 
inducers/inhibitors or substrates of CYP 3A4, 2C19, P-gp, MATE1, MATE2K, and BCRP.” 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  

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APPENDIX G 
ACTIONS REQUIRED IN CASES OF COMBINED INCREASE OF 
AMINOTRANSFERASE AND TOTAL BILIRUBIN – HY’S LAW 
 
Briefly, Hy’s Law cases have the following three components: 
 
• The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control 
drug or placebo 
• Among trial subjects showing such AT elevations, often with ATs much greater than 
3xULN, one or more also show elevation of serum TBL to >2xULN, without initial 
findings of cholestasis (elevated serum ALP) 
• No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury 
 
Finding one Hy’s Law case in the clinical trial database is worrisome; finding two is considered 
highly predictive that the drug has the potential to cause severe drug induced liver injury (DILI) 
when given to a larger population. 
 
The following actions are required in cases of combined increase of aminotransferase and total 
bilirubin: 
 
1. Confirmation 
 
In general, an increase of serum AST/A:T to >3xULN should be followed by repeat testing 
within 48 to 72 hours of all four of the usual serum measures (ALT, AST, ALP, and TBL) to 
confirm the abnormalities and to determine if they are increasing or decreasing. There also 
should be inquiry made about symptoms. Serum AT may rise and fall quite rapidly, and waiting 
a week or two before obtaining confirmation of elevations may lead to a false conclusion that the 
initially observed abnormality was spurious. Of greater concern, delay in retesting may allow 
progression to severe worsening if the initial abnormality was the herald of a severe reaction to 
follow. The need for prompt repeat testing is especially great if AST/ALT is much greater than 
3xULN and/or TBL is greater than 2xULN. For outpatient trials, or trials in which subjects are 
far away from the trial site, it may be difficult for the subjects to return to the trial site promptly. 
In this case, the subjects should be retested locally, but normal laboratory ranges should be 
recorded, results should be made available to trial investigators immediately, and the data should 
be included in the case reports. If symptoms persist or repeat testing shows AST/ALT >3xULN 
for subjects with normal baseline measures or 2-fold increases above baseline values for subjects 
with elevated values before drug exposure, it is appropriate to initiate close observation to 
determine whether the abnormalities are improving or worsening. If close monitoring is not 
possible, the drug should be discontinued. 
 
2. Close Observation 
 

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It is critical to initiate close observation immediately upon detection and confirmation of early 
signals of possible DILI, and not to wait until the next scheduled visit or monitoring interval. A 
threshold of aminotransferase levels greater than 3xULN seems reasonable, as lesser elevations 
are common and nonspecific. If additional testing, beyond that specified in the trial protocol, is 
carried out, it is important that the subject’s information be added to the case report forms and 
database. 
Close observation includes: 
 
Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the trial drug has been 
discontinued and the subject is asymptomatic. 
Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
Obtaining a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets. 
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease. 
Obtaining a history of exposure to environmental chemical agents. 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin). 
Considering gastroenterology or hepatology consultations. 
 
3. Decision to Stop Drug Administration 
 
It has been observed that de-challenge (stopping drug administration) does not always result in 
immediate improvement in abnormal lab values. Abnormal test values and symptoms may 
progress for several days or even weeks after discontinuation of the drug that caused the 
abnormality. For example, rising TBL usually follows serum AT increases by a few days to 
weeks. The primary goal of close observation is to determine as quickly as possible whether 
observed abnormal findings are transient and will resolve spontaneously or will progress. For 
most DILI, no specific antidotes are available (except N-acetylcysteine for acute acetaminophen 
overdose if given promptly, and, possibly, intravenous carnitine for valproic acid hepatotoxicity). 
 
Promptly stopping the offending drug usually is the only potentially effective therapy. 
 
Because transient fluctuations of ALT or AST are common, and progression to severe DILI or 
acute liver failure is uncommon, automatic discontinuation of trial drug upon finding a greater 
than 3xULN elevation of ALT or AST may be unnecessary. For most people, the liver appears 
capable of adapting to injury by foreign chemical substances, which may render a person tolerant 
to the drug despite continued exposure. Stopping a drug at the first hint of mild injury does not 
permit learning whether adaptation will occur, as it does for drugs such as tacrine, which cause 
liver injury but do not cause severe DILI. On the other hand, continuing drug appears 
unacceptably dangerous if there is marked serum aminotransferase elevation or evidence of 
functional impairment, as indicated by rising bilirubin or INR, which represent substantial liver 
injury. Although there is no published consensus on exactly when to stop a drug in the face of 
laboratory abnormalities and the decision will be affected by information on related drugs, the 
accumulating clinical experience, the clinical status of the patient, and many other factors, the 
following can be considered a basic guide. Discontinuation of treatment should be considered if: 

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ALT or AST >8xULN 
ALT or AST >5xULN for more than 2 weeks 
ALT or AST >3xULN and (TBL >2xULN or INR >1.5) 
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 
It should be noted that although these guidelines have not been evaluated systematically in a 
prospective fashion, they represent an approach that is similar to current practice. 
 
4. Evaluating Data for Alternative Causes 
 
An important purpose of close observation is to gather additional clinical information to seek 
other possible causes of the observed liver test abnormalities, such as one of the following 
common causes: 
 
Acute viral hepatitis. The usual onset of hepatocellular DILI is indistinguishable from acute viral 
hepatitis A or B. Hepatitis C is much less often acute in its onset and tends to be insidious, but it 
sometimes can resemble acute DILI. The presence of acute viral hepatitis A, B, and C should be 
evaluated by serological markers. Viral hepatitis D (requires concomitant hepatitis B infection) 
and E are relatively rare in the United States. Hepatitis E is more common in developing 
countries, including Southeast Asia, and should be considered in recent travelers to those 
countries and in patients in trials conducted in those countries. Also rare are hepatocellular liver 
injuries caused by Epstein-Barr virus, cytomegalovirus, herpes simplex virus, toxoplasmosis, 
varicella, and parvovirus, although these infections are seen more typically in immuno- 
suppressed individuals. Adolescent and young adult patients with possible DILI should be tested 
for Epstein-Barr virus. Hepatitis is common among transplant patients with cytomegalovirus 
disease. 
 
Alcoholic and autoimmune hepatitis. Acute alcoholic hepatitis usually is recurrent, with a history 
of binging exposure to alcohol preceding episodes, and it has some characteristic features, such 
as associated fever, leukocytosis, right upper quadrant pain and tenderness, hepatomegaly, and 
AST >ALT, that may help distinguish it from other causes of liver injury. Other features of the 
physical examination may include the presence of stigmata of cirrhosis, such as spider nevi, 
palmar erythema, estrogenic changes in males, and Dupuytren’s contractures. Alcoholic and 
autoimmune hepatitis should be assessed by history, physical examination, and laboratory 
testing, including serologic testing (e.g., antinuclear or other antibodies). 
 
Hepatobiliary disorders. Biliary tract disease, such as migration of gallstones or intrahepatic 
lesions, more often causes cholestatic injury initially and should be investigated with gall bladder 
and ductal imaging studies, especially if ALP is increased. Malignant interruption of the biliary 
tract also should be considered. 
 
Nonalcoholic steatohepatitis.  Nonalcoholic steatohepatitis may be seen in obese, 
hyperlipoproteinemic, and/or diabetic patients and may be associated with fluctuating 

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aminotransferase levels, and hepatic and sometimes splenic enlargement. It is sometimes 
associated with cirrhosis and portal hypertension. 
 
Cardiovascular causes. Cardiovascular disease, especially right heart failure and hypotension or 
any cause of impaired oxygenation of the liver, may cause acute centrilobular hypoxic cell 
necrosis (ischemic hepatitis) with rapid and sometimes spectacular increases of serum AT (e.g., 
AT >10,000 U/L). Cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure, should be assessed by physical examination and history. 
 
Concomitant treatments. It is critical to discover concomitant treatments, including exposure to 
nonprescription and dietary supplement products that might be responsible for injury. Many 
people take multiple drugs, perhaps less often in controlled clinical trials because of exclusion 
criteria, but subjects may not report taking disallowed drugs or other agents. The possible 
exposure to potentially toxic herbal or dietary supplement mixtures (sometimes of unknown 
composition), nonprescription medications such as acetaminophen, or to occupational chemical 
agents may not be volunteered unless subjects are specifically questioned. 
 
5. Follow-Up to Resolution 
 
All trial subjects showing possible DILI should be followed until all abnormalities return to 
normal or to the baseline state. DILI may develop or progress even after the causative drug  has 
been stopped. Results should be recorded on the case report form and in the database. Note that 
longer follow-up can sometimes reveal an off-drug repetition of what had appeared to be DILI, 
indicating that liver injury was related to underlying liver disease. 
 
6. Re-challenge 
 
Whether or not to re-challenge a subject who showed mild DILI is a difficult decision. Re- 
exposure may initiate a sometimes explosive and more severe reaction, as was observed with 
halothane several decades ago. Some cases of DILI show indicators of immunological reaction 
such as eosinophilia, rash, fever, or other symptoms or findings, and it is possible that such cases 
are more prone to recur with re-exposure. Re-challenge may not be considered negative unless 
the subject is exposed to and tolerates the same dose and treatment duration that preceded the 
original reaction. A negative re-challenge does not necessarily allow a conclusion that the drug 
did not cause the injury. Most people can adapt to xenobiotic substances, including new drugs, 
and develop tolerance for them. This has been observed even for drugs that can cause severe 
injury, such as isoniazid. The large majority of people showing hepatocellular injury while 
taking isoniazid recover fully or recover while continuing to take the drug, and some, but not all, 
can resume or continue taking the drug without further adverse consequence. If such tolerance 
has developed, the use of re-challenge to verify drug causation would give a false negative result. 
 
Generally, re-challenge of subjects with significant AT elevations (>5xULN) should not be 
attempted. If such subjects are re-challenged, they should be followed closely. Re-challenge can 
be considered if the subject has shown important benefit from the drug and other options are not 
available or if substantial accumulated data with the test drug do not show a potential for severe 

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injury. The subject should be made aware of the potential risk, and consent to the re-challenge, 
and the PI consulted. 

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APPENDIX H 
TISSUE BIOPSY VERIFICATION FORM 
 
 
A copy of the diagnostic pathology report must be shipped with all tissue specimens sent 
to the EET Biobank. 
 
If the corresponding pathology report is not available for the biopsy, then a copy of the radiology report 
or operative report from the biopsy procedure and the diagnostic pathology report must be sent to the EET 
Biobank. A completed copy of this appendix (i.e., Tissue Biopsy Verification) must also be submitted to 
the EET Biobank. 
Note: If this information is not provided with the biopsy specimen, then it will not be accepted by the EET 
Biobank. 
 
Please have the Clinician* responsible for signing out this patient’s case complete the 
following: 
 
ETCTN Universal Patient ID:  
 
 
ETCTN Patient Study ID:   
 
 
Date of Procedure (mm/dd/yyyy):   
 
 
Tissue Type (circle one): 
Primary 
Metastatic 
 
Time point (circle one):  Baseline  Cycle1, Day 12   Each Restag ing   Progression  
 
Site Tissue Taken From:   
 
 
Diagnosis:   
 
 
I agree that this tissue may be released for research purposes only and that the release 
of this tissue will not have any impact on the patient’s care. 
 
Clinician Signature 
 
 
 
 
Date 
  Clinician Printed Name 
 
*Note: For the purposes of this form, Clinician could include the Nurse Practitioner, Registered Nurse, Pathologist, 
Radiologist, Interventional Radiologist, Surgeon, Oncologist, Internist, or other medical professional responsible for 
the patient’s care.  

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Version: 1 
Effective Date: 9/2019