NCI 10147: A Phase II Randomized Study of Topotecan/Carboplatin With or Without Veliparib in Advanced Myeloproliferative Disorders and Chronic Myelomonocytic Leukemia (CMML)
Phase: PHASE2
Conditions: Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Atypical Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Essential Thrombocythemia, Myelodysplastic/Myeloproliferative Neoplasm, Myelofibrosis, Polycythemia Vera, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
i 
SUMMARY OF CHANGES – Protocol 
 
To: 
CTEP Protocol and Information Office 
From: 
, MD 
Branch: Investigational Drug Branch, CTEP, DCTD, NCI 
Date: 
09/26/2019 
Re: 
Review of Amendment #05 of Protocol #10147: “A Phase II Randomized Study of 
Topotecan/Carboplatin with or Without Veliparib in Advanced Myeloproliferative Disorders and 
Chronic Myelomonocytic Leukemia (CMML)” 
 
I. Recommendations: 
 
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Section 
Comments 
1. 
4.1 
Please delete the information within this subsection and replace with the 
following language, in accordance with the new protocol language template. 
 
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 Program (CTEP) Identity and Access Management 
(IAM) account at https://ctepcore.nci.nih.gov/iam.  In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to Oncology 
Patient Enrollment Network (OPEN), Rave, or acting as a primary site contact) 
must complete their annual registration using CTEP’s web-based Registration and 
Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
 IVR:  MD, DO, or international equivalent, 
 NPIVR:  advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD), 
 AP:  clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System [RUMS], OPEN, 
Rave,), 
 Associate (A):  other clinical site staff involved in the conduct of NCI-
sponsored trials, and 
 Associate Basic (AB):  individuals (e.g., pharmaceutical company 
employees) with limited access to NCI-supported systems. 
 

NCI Protocol #: 10147 
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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). 
 
For trials that will include sites using their local IRB or REB as well as for a 
trial with non-U.S.-based NCTN and NCORP sites, include the following 
paragraph and the three associated bullet points:  
 
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: 
 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). 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
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PI Response: Information deleted and replaced. 
3. 
4.2.1 
Please delete the information within this subsection and replace with the 
following language, in accordance with the new protocol language template. 
 
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.  
 
 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-MD017, and protocol number 10147, 
 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 as described above.)  
 
PI Response: Information deleted and replaced.  
4. 
4.2.2 
Please delete the information within this subsection and replace with the 
following language, in accordance with the new protocol language template. 
 
4.2.2 Protocol Specific Requirements For 10147 Site Registration 
 
Upon site registration approval in RSS, the enrolling site may access OPEN to 
complete enrollments.  The enrolling site will select their credentialed provider 
treating the subject in the OPEN credentialing screen, and may need to answer 
additional questions related to treatment in the eligibility checklist.   
 
 A Site initiation visit (SIV) is required for each participating site prior to 
activation. The local site PI must participate on the call as well as their 
research nurse, study coordinator, and pharmacist. To schedule a SIV, 
please email the Protocol Liaison and crocc@jhmi.edu and reference the 
protocol in the subject line of the email.   
 Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each 
participating site will need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be 
submitted to the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual.  If an 
individual has previously completed the training for another ETCTN 

NCI Protocol #: 10147 
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requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
PI Response: Information deleted and replaced. 
7. 
4.3.2, 
4.3.3 
Please delete the information within these subsections and replace with the 
following language, in accordance with the new protocol language template. 
 
4.3.2 
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. 
 If a DTL is required for the study, 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.  If a DTL is required 
for the study, 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). 
 

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Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  Please print this confirmation for your 
records.  
 
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. 
 
PI Response: Information deleted and replaced.  
8. 
4 
As 10147 has been identified as a specimen tracking study, please create the 
following subsection. 
 
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. 
 
PI Response: Subsection added (4.3.5). 
 
9. 
7 
As this study has a CTEP-held IND, CTEP-AERS integration will be used. 
Please insert the following subsection into section 7. 
 
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.    
 

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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: 
 
 Study specific documents:  Protocols > Documents > Education and 
Promotion, and   

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 Expedited Safety Reporting Rules Evaluation user guide:  
Resources > CTSU Operations Information > User Guides. 
 
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_application
s/docs/aeguidelines.pdf. 
 
PI Response: Subsection added.  
10. 12.2 
Please delete the information within the “Data Reporting” subsection and 
replace with the following language, in accordance with the new protocol 
language template. 
 
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.  To access Rave via iMedidata: 
 
 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account, and  
 
Assigned one of the following Rave roles on the relevant Lead Protocol 
Organization (LPO) or Participating Organization roster at the enrolling 
site:  Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or 
Rave Investigator.  Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must 
hold a minimum of an AP registration type, 
o To hold Rave Investigator role, the individual must be registered as 
an NPIVR or IVR, and 
o To hold Rave Read Only role, site staff must hold an Associates (A) 
registration type. 
 
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 

NCI Protocol #: 10147 
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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 Rave 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.   
 
PI Response: Information deleted and replaced. 
 
11. 12.2.1 
Verify if 10147 will be using Central Monitoring, and add the following 
language if applicable. 
 
Central Monitoring (CM) Review is required for this protocol.  CM allows 
Lead Protocol Organizations (LPOs) to remotely compare data entered in 
Rave to source documentation to ensure that sites are adhering to the 
protocol and central monitoring plan as well as accurately transcribing data 
from patients’ charts (i.e., source data verification).  
 
Sites can upload source documents required for CM Review as 
documented in the central monitoring plan using the Source Document 
Portal (SDP).  This application is available on the CTSU members’ website 
under Auditing & Monitoring and may also be accessed using a direct link 
within Rave on the CM Alert form.  Site staff with the CRA or Investigator 
roles in Rave can view and upload source documents.  Prior to saving 
source documents on the SDP, each site is responsible for removing or 
redacting any Personally Identifiable Information (PII) (note that 
functionality to do this redaction exists within the SDP itself).  Designated 
LPO staff will review each document after it has been loaded on the SDP 
to ensure the appropriate documents have been uploaded and to ensure PII 
is redacted. 
 
Additional information on the SDP is available on the CTSU members’ 
website under Auditing & Monitoring > Source Document Portal in the 
Help Topics button or by contacting the CTSU Help Desk (1-888-823-
5923 or ctsucontact@westat.com).   
 
PI Response: Study is reviewed by CTMS (Clinical Trials Monitoring 
System).  
 

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12. 12 
Please add the following subsection to section 12. 
2. 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. 
 
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.  
 
PI Response: Subsection added.  
 
II. Additional Changes  
 

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1. 
Title 
Page 
Protocol version date updated to reflect current changes.  
2. 
Title 
Page  
 added as Co-Investigator. 
3.  
Title 
Page 
Principal Investigator information updated.  
4. 
N/A 
Formatting and editorial changes were made throughout the protocol (e.g., page numbers) 
 
(Please retain the section break below, so that the Title Page is page “1” of the document.) 
 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1.  OBJECTIVES ...........................................................................................................................6 
1.1  Primary Objectives ......................................................................................................6 
1.2  Secondary Objectives ..................................................................................................6 
2.  BACKGROUND ......................................................................................................................7 
2.1  Myeloproliferative neoplasms and CMML .................................................................7 
2.2  Veliparib(ABT-888) ...................................................................................................7 
2.3  Topotecan & Carboplatin ............................................................................................8 
2.4  Rationale .....................................................................................................................8 
2.5  Correlative Studies Background .................................................................................9 
3.  PATIENT SELECTION .........................................................................................................12 
3.1  Pre-Registration Eligibility Criteria ..........................................................................12 
3.2    Randomization Eligibility Criteria  ...........................................................................13 
3.3  Exclusion Criteria .....................................................................................................13 
3.4  Inclusion of Women and Minorities .........................................................................14 
4.  REGISTRATION PROCEDURES ........................................................................................15 
4.1  Investigator and Research Associate Registration with CTEP .................................15 
4.2  Site Registration ........................................................................................................16 
4.3  Patient Registration ...................................................................................................19 
4.4  General Guidelines ....................................................................................................21 
5.  TREATMENT PLAN .............................................................................................................22 
5.1  Agent Administration ................................................................................................22 
5.2  General Concomitant Medication and Supportive Care Guidelines .........................23 
5.3  Duration of Therapy ..................................................................................................24 
5.4  Duration of Follow Up ..............................................................................................25 
6.  DOSING DELAYS/DOSE MODIFICATIONS.....................................................................26 
7.  ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .................................27 
7.1  Comprehensive Adverse Events and Potential Risks List (CAEPR) ........................28 
7.2  Adverse Event Characteristics ..................................................................................31 
7.3  Expedited Adverse Event Reporting .........................................................................31 
7.4  Routine Adverse Event Reporting ............................................................................34 
7.5  Pregnancy ..................................................................................................................34 
7.6  Secondary Malignancy ..............................................................................................34 
7.7  Second Malignancy ...................................................................................................35 
8.  PHARMACEUTICAL INFORMATION ...............................................................................36 
8.1  CTEP IND Agent(s) ..................................................................................................36 

NCI Protocol #: 10147 
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8.2  Commercial Agent(s) Topotecan hydrochloride (Hycamptin) .................................39 
8.3  Carboplatin ................................................................................................................39 
9.  BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .............................................40 
9.1  Laboratory Correlative Studies .................................................................................40 
9.2  Integrated Correlative Studies ...................................................................................41 
9.3  Exploratory/Ancillary Correlative Studies ...............................................................44 
10.  STUDY CALENDAR ..........................................................................................................49 
11.  MEASUREMENT OF EFFECT...........................................................................................51 
11.1  Antitumor Effect – Hematologic Tumors ...............................................................51 
11.2  Other Response Parameters ....................................................................................53 
12.  STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................59 
12.1  Study Oversight ......................................................................................................59 
12.2  Data Reporting ........................................................................................................60 
12.3  CTEP Multicenter Guidelines .................................................................................62 
12.4  Collaborative Agreements Language ......................................................................62 
12.5  Genomic Data Sharing Plan ....................................................................................64 
13.  STATISTICAL CONSIDERATIONS..................................................................................65 
13.1  Study Design/Endpoints..........................................................................................65 
13.2  Sample Size/Accrual Rate .......................................................................................65 
13.3  Stratification Factors ...............................................................................................66 
13.4  Early Stopping Guidelines ......................................................................................66 
13.5  Analysis of Endpoints .............................................................................................68 
13.6  Analysis of Secondary Endpoints ...........................................................................69 
13.7  Reporting and Exclusions .......................................................................................70 
REFERENCES ..............................................................................................................................71 
APPENDIX A  PERFORMANCE STATUS CRITERIA ...........................................................75 
APPENDIX B  PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD ...............................................................................................................76 
APPENDIX C 
BIOASSAY TEMPLATES ................................................................................78 
 
 
 

NCI Protocol #: 10147 
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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To estimate and compare the Complete Response/Complete Response with incomplete recovery 
(CR/CRi) rate of induction therapy with Topotecan/Carboplatin (T/C) with or without Veliparib 
(V) in myeloproliferative disorder associated leukemias and CMML. 
 
1.2 
Secondary Objectives 
1. 
To evaluate and compare the toxicities of T/C/V vs. T/C 
2. 
To compare the 2-year disease-free survival (DFS) and overall survival (OS) in 
response to T/C/V vs. T/C 
3. 
To detect and compare the presence of minimal residual disease (MRD) remaining 
after T/C/V vs. T/C 
4. 
Evaluate predictive biomarkers of response via assessment of pretreatment impaired 
homologous recombination via assessment of: 
a. NGS panel for genes mutated in myeloid malignancies done as standard of care per 
institution.  The Johns Hopkins assay assesses mutations in ABL1, ASXL1, ATM, 
ATRX, BCOR, BCORL1, BRAF, CALR, CBL, CBLB, CDKN2A, CEBPA, 
CSF3R, DNMT31, EP300, ERBB2, ETV6, EZH2, FLT3, GATA1, GATA2, 
GNAS, IDH1, IDH2, IKZF1, JAK2, KDM2B, KDM6A, KIT, KRAS, KMT2D, 
KMT2C, MPL, NF1, NLRP1, NOTCH1, NOTCH2, NPM1, NRAS, NSD1, 
NUP98, PDGFRA, PIK3CA, PHF6, PIGA, PTEN, PTPN11, RAD50, RECQL4, 
RUNX1, SETBP1, SF3BA, SRSF2, STAG2, STAT3, TET2, TP53, U2AF1, WT1 
and ZRSR2 genes.   
b. Functional impairment of DNA damage response via assessment of pretreatment 
samples for radiation-induced RAD51 foci. 
c. Topotecan-induced stabilization of topoisomerase I-DNA covalent complexes, 
which has recently been observed to be a critical predictor of response to 
combination of a topoisomerase I poison and PARP inhibitor in xenografts 
 
5. 
To evaluate veliparib exposure and contribution to response (efficacy and toxicity) 

NCI Protocol #: 10147 
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2. BACKGROUND 
 
2.1 
Myeloproliferative neoplasms and CMML 
 
Myeloproliferative neoplasms (MPNs) represent a heterogeneous group of clonal 
diseases with a common propensity to progress to acute leukemia.1-4 Essential 
Thrombocythemia (ET), Polycythemia Vera (PV), and Primary Myelofibrosis (MF), as well 
as mixed myelodysplastic/myeloproliferative neoplasms such as Chronic Myelomonocytic 
Leukemia (CMML) are all clonal neoplasms derived from aberrant early hematopoietic 
precursors but have varied clinical manifestations. Upon progression, they are uniformly 
refractory to standard acute leukemia therapies, with median survival less than six months.    
 
One common mutation in MPNs, an activating V617F point mutation in the tyrosine 
kinase JAK2, is found in greater than 80% of cases of PV,5 40% of cases of ET, and 30% of 
cases of MF,6 JAK2 mutation and overexpression have been associated with increased 
homologous recombination (HR) and genomic instability.7-9 Other alterations conferring an 
MPN-like phenotype, such as BCR/ABL translocations in CML, FIP1L1-PDGFR 
rearrangements in eosinophilic leukemias, and FLT3 mutations in acute myeloid leukemia, 
have also been associated with changes in the DNA repair pathways leading to increased 
genomic instability and drug resistance.9,10 For example, even though early studies indicated 
that RAD51, a critical component of the homologous recombination (HR) pathway, is 
upregulated in BCR/ABL-positive CML cells,11 subsequent studies demonstrated that repair 
in these cells is error-prone and leads to mutations and large deletions or insertions.12  
Further analysis traced this genomic instability to several changes, including (i) enhanced 
tyrosine phosphorylation of RAD51, leading to its aberrant function;13 (ii) downregulation of 
BRCA1;14 (iii) stimulation of single-strand annealing, an error-prone DNA repair pathway;15 
and (iv) other changes in the Fanconi anemia/BRCA pathway that can be reverted by ectopic 
BRCA1 expression.16  
 
2.2 
Veliparib (ABT-888) 
 
Poly(ADP-ribose) polymerase (PARP) inhibitors are a class of antineoplastic agents being 
widely tested in solid tumors.17-22  These agents target PARP1, PARP2, and PARP3, three 
enzymes that contribute to various aspects of DNA repair.18,20,21,23-25  PARP inhibition not only 
diminishes base excision repair, but also impairs alternative end-joining26 and accelerates 
nonhomologous end-joining.27 In cells with diminished HR, these changes lead to error-prone 
DNA repair and cell death.18,20,28 In addition, PARP inhibition leads to trapping of PARP1 on 
DNA, preventing access of downstream repair proteins to sites of DNA damage29-31 and 
providing a potential mechanism for PARP inhibitor-induced killing in HR proficient cells that 
contain high levels of PARP1 protein. Importantly, chromosome 1q (including the PARP1 
locus at 1q42) is amplified in a subset of chronic phase MPNs and even more commonly in 
transformed MPNs,32,33 providing a potential opportunity for PARP1 trapping even in MPNs 
without HR defects. 
 
Veliparib (ABT-888) is an orally available, small molecule PARP inhibitor that enhances 
the cytotoxicity of diverse classes of DNA damaging agents, including ionizing radiation, 

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8 
alkylating agents, platinating agents and topoisomerase I (topo I) poisons.34-36 Studies in AML 
cell lines and clinical samples demonstrated that veliparib enhanced the antiproliferative and 
proapoptotic effects of topotecan in vitro, whereas no synergy was found with cytarabine or 
etoposide.37 Further analysis indicated that the synergy resulted from trapping of PARP1 on 
the damaged DNA, thereby inhibiting repair downstream of topo I-DNA covalent complex 
stabilization.37,38 
 
We previously compared the sensitivity of clinical isolates from several BCR/ABL-
negative chronic myeloid neoplasms, including CMML, ET, PV and PMF, to normal controls 
using two different PARP inhibitors in colony forming assays ex vivo.39 Results of this analysis 
demonstrated that myeloid progenitors from many patients with JAK2 wildtype MPNs and 
CMML exhibit enhanced PARP inhibitor sensitivity, which is greatest in those with defective 
formation of RAD51 foci after DNA damage. These observations support the further study of 
PARP inhibitors, alone or in combination with other therapies, in certain MPNs and CMML. 
 
2.3 
Topotecan & Carboplatin 
 
Topotecan and carboplatin induce synergistic cytotoxicity in acute leukemia cell lines and 
primary AML cells in vitro.40 This observation was the basis for a phase I study of topotecan + 
carboplatin by five-day intravenous continuous infusion (IV CI) in adults with relapsed or 
refractory acute leukemia.40 Oral and gastrointestinal (GI) mucositis were the dose limiting 
toxicities (DLTs) of this combination. Complete remissions (CRs) were observed at multiple dose 
levels, including 3 of 6 patients at the maximum tolerated dose (MTD) of topotecan 1.6 mg/m2/day 
and carboplatin 150 mg/m2/day simultaneously for 5 days.40 A subsequent ECOG Phase II trial of 
topotecan/carboplatin at this MTD resulted in CRs in 5 of 35 (14%) patients with relapsed and 
refractory AML, a response rate similar to a mitoxantrone/etoposide/cytarabine- (MEC-) based 
arm in the same trial.41 This Phase II trial of topotecan and carboplatin only studied the doses of 
1.6 mg/m2/day topotecan with 150 mg/m2/day of carboplatin combination.  In the phase I study of 
the combination, there were 21 evaluable patients in the doses below the 1.2 mg/m2/150 mg/m2 
combination and responses in 3 of these patients (14%). In the dose levels above 1.2/150, there 
were 14 patients treated with 6 responses (43%).  These data should be interpreted with caution, 
however, as these patients included a mixture of acute myeloid leukemia, acute lymphoid 
leukemia, myelodysplastic syndrome, and blast crisis CML. Of the 46 patients on this phase I 
study, only three had antecedent myeloproliferative disorders, which is the study population we 
are targeting with the present study. In the control ARM B we will use the recommended phase II dose 
of topotecan (1.6mg/m2/day) in combination with carboplatin to maximize chemotherapeutic 
exposure in absence of veliparib.  
 
2.4 
Rationale 
Building on recent demonstrations that veliparib enhances the antineoplastic effects of 
topotecan and carboplatin, we conducted a study evaluating veliparib incorporation into 
leukemia induction therapy using a backbone associated with significant DNA damage.42  Using 
a standard 3+3 trial design, we dose-escalated veliparib in combination with topotecan + 
carboplatin in relapsed and refractory acute leukemias, aggressive myeloproliferative neoplasms 
(MPNs) and CMML. A total of 99 patients were treated with veliparib 10-100 mg orally twice 
daily on Days 1-8, 1-14 or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m2/d + 

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carboplatin 120-150 mg/m2/d on Days 3-7. The maximum tolerated dose was veliparib 80 mg 
twice daily with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting 
and correlated with higher veliparib exposure. The duration of veliparib administration was 8 
days during the dose escalation. Veliparib dosing was extended in two MPN/CMML cohorts to 
14 and 21 day durations after completion of the topotecan/carboplatin infusion to take advantage 
of the PARP inhibitor sensitivity and defective DNA repair inherent in some CMML and MPN 
cells. Veliparib systemic exposure in plasma positively correlated with bone marrow supernatant 
but not blasts.43 Overall response rate was 33% (33/99), with 14 CR, 11 CRi, and 8 PR. Patients 
with antecedent or associated MPNs or CMML had an overall response rate of 64% (14/22). The 
median survival for patients with antecedent or associated MPN or CMML was 13.3 months vs 
5.1 months for those without antecedent myeloid neoplasms. The one-year relapse free survival 
for MPN and CMML patients was 41% vs 12 % for those without prior MPNs or CMML. 
Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced 
FANCD2 monoubiquitination, had modestly better survival. A single 80 mg dose of veliparib, as 
well as veliparib in combination with topotecan + carboplatin, induced DNA damage as 
manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater damage 
being detected in cells from responders. Utilizing the data from the Phase I trial, an exposure-
response analysis was performed. 43  Despite shallow exposure-efficacy relationship, doses lower 
than 80 mg do not exceed veliparib single agent preclinical IC50. Shallow exposure-mucositis 
relationship also supports the 80 mg dose. Based on benefit/risk assessment, veliparib at a dose 
of 80 mg BID for at least 14 days in combination with topotecan plus carboplatin is 
recommended to be studied in patients with advanced MPNs or CMML. 
 
We now propose a phase II study evaluating the efficacy of the addition of veliparib to 
topotecan and carboplatin in accelerated phase CMML and MPNs44 as well as both newly 
diagnosed and relapsed/refractory CMML- or MPN-related AML. Eligible patients would be 
randomized between ARM A (Topotecan 1.2 mg/m2/d + Carboplatin 150 mg/m2/d IV on days 3-
7 plus veliparib 80 mg PO BID Day 1-21) vs ARM B (Topotecan 1.6 mg/m2/d + Carboplatin 150 
mg/m2/d IV on days 1-5). In conjunction with the clinical trial, we aim to evaluate and validate 
potential biomarkers of response defined in our initial Phase I trial or subsequently identified that 
may predict for response to the T/C/V combination. The dosing of topotecan in ARM B (1.6 
mg/m2/day) chosen for study is the recommended phase II dose of topotecan when given in 
combination with carboplatin for acute leukemia.   
 
2.5 
Correlative Studies Background 
 
2.5.1.  Leukemia Mutation Panel 
Molecular analysis of AMLs, MPNs and CMML has revealed a broad array of mutations contained 
in the malignant clone.  Characterization of specific mutations associated with MPN- and CMML-
associated acute leukemia in the context of response to therapy has the potential to allow for patient 
specific therapies with improved efficacy.  We intend to use a standard leukemia mutation panel 
(MDL JHH) to examine the molecular features of the leukemias treated on this study and examine 
for response predictors in the post-trial analysis.  
 
 

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10 
2.5.2.   RAD51 Focus forming assay 
An impaired DNA damage response, as evidenced by lack of development of RAD51 foci 
in response to ionizing radiation, was observed in ~40% of MPN samples assayed (Figure 1).39  
This observation suggests that the HR pathway is impaired in those samples.  These results are 
consistent with prior observations of 
extensive 
chromosomal 
and 
subchromosomal copy number changes 
in MPN,33,45 which are another hallmark 
of HR deficiency.46  Because formation 
of RAD51 foci only provides an 
assessment of HR pathway integrity 
upstream of RAD51 and is unaffected by 
changes downstream, e.g., loss of 
RAD51C,47 it is important to emphasize 
that the results in Figure 1 might 
underestimate the true frequency of HR 
repair defects in MPNs. 
The causes of this HR pathway 
dysfunction in MPNs are incompletely 
understood at present. Some of the samples with impaired RAD51 foci formation also exhibited 
diminished formation of H2AX foci (Fig. 1). Because H2AX phosphorylation after double strand 
breaks typically reflects activation of ATM and phosphorylation of its substrate MDC1,48 
diminished formation of both phospho-H2AX and RAD51 foci might reflect a defect in ATM or 
its activation as described in other neoplasms. Other samples formed phospho-H2AX foci but 
nonetheless failed to form RAD51 foci, suggesting one or more defects between these two events 
in the DNA damage response. Consistent with this heterogeneity, we have previously examined 
144 cases of MPN via SNP arrays and found that 26% have heterozygous deletions in genes 
encoding one or more DNA repair pathway proteins such as BRCA2, ATM, FANCC or FANCL.49 
Because the other copy remains intact, however, it is unclear whether these heterozyogous 
deletions cause sufficient changes in protein expression to impact the HR pathway.  Accordingly, 
we have examined a subset of MPN samples for methylation changes in FANC proteins, ATM, 
and BRCA2 but did not observe frequent changes in methylation that would confer increased 
genomic instability.39 BRCA1 promoter methylation was found in a 6 of 27 samples analyzed but 
also was not associated with increased sensitivity to PARP inhibition ex vivo.39  Given the apparent 
relationship between impaired formation of radiation-induced RAD51 foci and PARP inhibitor 
sensitivity in MPNs and CMML ex vivo, we propose to examine this assay as a potential predictor 
of sensitivity to the T/C/V and T/C arms. 
 
2.5.3. Stabilization of topoisomerase (topo) I-DNA covalent complexes 
 
The first step in the action of topo I poisons is stabilization of topo I-DNA covalent complexes. 
We have recently raised a monoclonal antibody that specifically detects these covalent topo I-
DNA complexes.50 This reagent has confirmed that topo I-DNA covalent complexes are 
stabilized by platinum agents as well as topotecan. Subsequent studies have demonstrated that 
staining with this antibody, which can detect covalent topo I-DNA complexes in tumor cells50 
Figure 1 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 
and normal tissues51 in situ, discriminates between BRCA wildtype patient-derived xenografts 
that are sensitive vs. resistant to a topo I poison/PARP inhibitor combination (
 
 ms. in preparation). These observations provide the 
impetus for assessing Topotecan-stabilized topo I-DNA covalent complexes in the context of the 
present trial. 
  
2.5.4 Whole Exome sequencing 
Examination of genomic aberrations outside known leukemia mutations may identify somatic 
genetic mutations conferring sensitivity to PARP targeted therapy.  In order to examine both 
somatic and germline samples, pre-treatment tumor samples along with peripheral blood for t-
cell specific germline DNA will be collected and analyzed as part of the ETCTN-DNA-RNA 
tissue procurement protocol.   
 
 
 
 

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12 
3. PATIENT SELECTION 
 
3.1 
Pre-Registration Eligibility Criteria  
 
3.1.1 Patient has or suspected to have one of the following:  
-Newly diagnosed Acute Myeloid Leukemia (AML) associated with antecedent 
myeloproliferative disorder (Polycythermia Vera, Essential Thrombocythemia, 
Myelofibrosis, atypical Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia 
and related undifferentiated myeloproliferative/myelodysplastic disorders) 
 
-Relapsed/refractory AML associated with antecedent myeloproliferative disorder 
(Polycythermia Vera, Essential Thrombocythemia, Myelofibrosis, atypical Chronic 
Myeloid Leukemia , Chronic Myelomonocytic Leukemia and related undifferentiated 
myeloproliferative/myelodysplastic disorders) who have received two or fewer prior 
induction chemotherapy courses 
 
-Accelerated phase myeloproliferative disorders per Zeider et al44 with two or fewer prior 
therapies. 
 
- 
For aggressive phase MPD (P. Vera, essential thrombocythemia, Ph-negative 
chronic myelogenous leukemia), one or more of the following criteria must be 
met: marrow blasts >5%, peripheral blood blasts plus progranulocytes > 10%, 
new onset or increasing myelofibrosis, new onset or > 25% increase in 
hepatomegaly or splenomegaly, new onset constitutional symptoms (fever, 
weight loss, spleni pain, bone pain). Zeider et al44  
- 
For Chronic Myelomonocytic Leukemia (CMML), the following criteria must be 
met: 5-19% bone marrow blasts (aggressive) or > 20% marrow blasts 
(transformation).  
 
3.1.2 Bone marrow and/or peripheral blood specimens will be submitted for correlative studies 
as outlined in Section 9. Patients with a dry tap will still be eligible. 
 

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13 
3.2 
Randomization Eligibility Criteria 
 
3.2.1 Bone marrow aspirate and/or peripheral blood specimens were submitted to the central 
lab and site has confirmation by the local institution that the patient meets one of the 
criteria specified in 3.1.1 above. 
 
3.2.2 Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of veliparib in combination with topotecan and carboplatin in patients <18 years of 
age, children are excluded from this study, but will be eligible for future pediatric trials. 
 
3.2.3 ECOG performance status ≤2 or Karnofsky ≥60% (see Appendix A). 
 
3.2.4 Patients must have normal organ function as defined below: 
 
 
Total bilirubin 
less than 2.0 mg/dL unless due to Gilbert’s Syndrome,              
then less than 5.0 mg/dL 
 
AST(SGOT)/ALT(SGPT) less than 5 × institutional upper limit of normal 
 
Creatinine Clearance  
GFR greater than 30 ml/min per modified Cockcroft-
Gault formula 
 
3.2.5 Interval of greater than 4 weeks since allogeneic blood or marrow transplantation (BMT) 
if performed; and absence of active GVHD  
 
3.2.6 The effects of veliparib on the developing human fetus are unknown.  For this reason and 
because PARP inhibiting agents as well as topoisomerase inhibitors and platinating 
agents are known to be teratogenic, women of child-bearing potential must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and for 6 months following the last 
dose of study drug.  Should a woman become pregnant or suspect she is pregnant while 
she or her partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 4 months 
after completion of veliparib administration. 
 
3.2.7 Ability to understand and the willingness to sign a written informed consent document. 
 
3.3 
Exclusion Criteria 
 
3.3.1 Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the 
study with the exception of hydroxyurea for cytoreduction.  Therapy with tyrosine kinase 
inhibitors (TKIs) directed against JAK2, BCR-ABL or FLT3 will be allowed to be 
continued until 24 hours prior to start of therapy on trial. 
 
3.3.2 Patients with active uncontrolled infection.  Antibiotic therapy for fevers, and 
continuation of treatment of prior infection are allowed.   
 

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14 
3.3.3 Patients who have active CNS disease are excluded. Patients with known active CNS 
leukemia should be excluded from this clinical trial because of their poor prognosis and 
because they often develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events. 
 
3.3.4 Patients who are receiving any other investigational agents.  Patients who have completed 
therapy with an investigational agent should be off this therapy for at least 5 half-lives or 
two weeks, whichever is shorter. 
 
3.3.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to veliparib, topotecan or carboplatin. 
 
3.3.6 Uncontrolled intercurrent illness including, but not limited to, active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.3.7 Pregnant women are excluded from this study because veliparib is PARP inhibiting agent 
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 veliparib, breastfeeding should be discontinued if the mother is treated with 
veliparib.  These potential risks may also apply to topotecan and carboplatin used in this 
study. 
 
3.3.8 HIV-Patients positive patients are not excluded if they have CD4+ cells > 250/mm3 and 
negligible viral load and are on a stable combination antiretroviral therapy.  
 
3.2.9    History of uncontrolled seizure disorder, including focal or generalized seizure within the 
past year 
 
3.4 
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. 
 
 

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16 
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, and 
 Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment, or as the CI on the DTL must be rostered at the enrolling site with a 
participating organization (i.e., Alliance).  
 
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). 
 
For trials that will include sites using their local IRB or REB as well as for a trial with non-
U.S.-based NCTN and NCORP sites, include the following paragraph and the three associated 
bullet points:  
 
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. 

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17 
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: 
 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.  
 
 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-MD017, 
and protocol number 10147, 
 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 as described above.)  
 
4.2.2 Requirements For NCI protocol #10147 Site Registration: 
 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments. The enrolling site will select their credentialed provider treating the subject in 
the OPEN credentialing screen, and may need to answer additional questions related to 
treatment in the eligibility checklist.   
 
 A Site initiation visit (SIV) is required for each participating site prior to activation. The 
local site PI must participate on the call as well as their research nurse, study coordinator, 

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19 
4.3 
Patient Registration 
 
4.3.1 Pre-Registration Procedures 
In order to submit the baseline bone marrow aspirate and biopsy and peripheral blood 
samples, the patient must be pre-registered and assigned a subject ID. The following 
should be confirmed by the site prior to pre-registering the patient:  
 Informed consent: the patient must be aware of the neoplastic nature of his/her 
disease and willingly consent after being informed of the procedure to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, 
side-effects, risks, and discomforts. Current human protection committee 
approval of this protocol and a consent form is required prior to patient consent 
and registration.  
 Correlative Studies: bone marrow and/or peripheral blood will be submitted for 
correlative studies for all patients pre-registered to this study. Note: If the 
procedure is a dry tap, the patient is still eligible. The peripheral blood must be 
submitted. 
 
4.3.2 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. 
 If a DTL is required for the study, 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. 
 
4.3.3 OPEN/IWRS User Requirements 
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.  If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
 
 
 

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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. Please print this confirmation for your records.  
 
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. 
 
4.3.4 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 609-619-7802 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.3.5 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. 
 
 
 
 

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4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 3 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. 
[*Note:  For leukemia protocols, treatment should be started as rapidly as possible.] 
 
 

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5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an inpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. Patient’s adherence to oral therapy 
will be documented through hospital charting.  
 
Arm A : Veliparib 80 mg by mouth twice daily days 1-21.  Topotecan 1.2 mg/m2/d and 
Carboplatin 150 mg/m2/day continuous intravenous infusion (CIV) over 5 days for a total 
of 120 continuous hours on days 3-7.  
Arm B : Topotecan 1.6 mg/m2/d and Carboplatin 150 mg/m2/day continuous intravenous 
infusion (CIV) over 5 days for a total of 120 continuous hours on days 1-5. 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Topotecan 
Premedicate with 
minimum of 
ondansetron 8 mg 
IV twice daily 
ARM A: 1.2 
mg/m2/day in 
250 mL D5W 
ARM B: 1.6 
mg/m2/day in 
250 mL D5W 
IV as continuous 
infusion over 24 
hours for 5 days 
Days 3-
7***(ARM 
A) or Days 
1-
5***(ARM 
B)   
28 days: if 
responding, 
second cycle 
can be 
administered 
as early as 
day 28 but 
no later than 
day 63. 
Responding 
patients may 
receive up to 
3 more 
cycles (4 
total) (see 
Section  6.1) 
 
 
 
Carboplatin  
150 mg/m2/day 
in 250 cc D5W 
IV as continuous 
infusion over 24 
hours for 5 days 
Days 3-7*** 
(ARM A) or 
Days 1-
5***(ARM 
B)   
Veliparib**  
80 mg  
PO twice daily  
Days 1-21 
(ARM A) 
**Randomized administration. 
***Begins at the start of Day 3 or 1 and runs for 5 days continuously, i.e., through the end of Day 7 
or 5  
 
 

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23 
5.1.1 Veliparib 
 
Because there is a potential for interaction of Veliparib with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  
 
Veliparib is not known to be a potent inhibitor of the major human CYPs in vitro, indicating a 
low risk for drug-drug interactions at the proposed dosing concentrations.  
 
5.1.2 Topotecan and Carboplatin 
 
Carboplatin and Topotecan each have 24 hour stability information described in 
literature(carboplatin)52 or package insert (Topotecan). Additionally, Topotecan and Carboplatin 
were tested in a Simulated Y-site administration using glass vials for a study period of 4 hours. 
The volume past the Y site is about 5 mL and at the current rate (500 mL over 24 hrs = 21 
mL/hr), the drugs will only be in the line together for ~ 15 minutes. This is much less than the 4 
hour study period and the agents should be stable through this period.53 No special 
premedications are required for these agents except for anti-emetics described in section 5.1 & 
5.1.2. Topotecan is a mild irritant, and subjects will be monitored closely for extravasation 
during administration. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
5.2.1 Antiemetics 
 
Antiemetics will be used according to standard practices with a minimum of ondansetron 8 mg 
IV (or equivalent) twice daily starting prior to topotecan/carboplatin through completion of 
topotecan and carboplatin.     
 
5.2.2 Hyperuricemia prophylaxis 
 
To prevent the occurrence and complications of tumor lysis-induced hyperuricemia, all patients 
without known allergy will receive Allopurinol 300 mg daily orally 24 hours prior to beginning 
veliparib and continuing through the period of maximal tumor lysis (at least through Day 8). 
 
5.2.3 Hyperphosphatemia prophylaxis 
 
For individuals at risk for tumor lysis-induced hyperphosphatemia, sevelamer carbonate 800 mg 
with each meal (or institutional standard) orally day 1-8 can be instituted on admission and 
continued as tolerated until maximum tumor lysis has abated.   
 
5.2.4 Menstrual suppression 
 
To achieve menstrual suppression please follow institutional standard practices.  
 
As noted in Section 3.2, women who are pregnant or lactating will not be eligible for this trial, as 

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24 
the antiproliferative activities of the experimental combination therapy may be harmful to the 
developing fetus or the nursing infant. 
 
5.2.5 Antibiotic Prophylaxis 
 
 Patients will receive prophylaxis directed against gram-negative gastrointestinal infections (GI), 
candidiasis, and/or herpes simplex virus (HSV), according to individual institutional practices. 
With regard to GI prophylaxis to prevent local and disseminated aerobic gram-negative 
infections, the use of moxifloxacin 400 mg by mouth daily (or other quinolone) will begin Day 1 
of therapy and continue for the entire duration of profound neutropenia (unless parenteral 
quinolones are administered). Due to the high risk of typhlitis, prophylaxis with metronidazole 
500 mg PO TID should begin day 1, and continue through day 14. In the event of patient allergy  
or hypersensitivity, institutional standards for antibacterial prophylaxis should be followed.  
HSV prophylaxis with Acyclovir or Valacyclovir will begin on Day 1 and will continue until 
absolute neutrophil count exceeds 100/mm3. Prophylaxis against candidal infections (e.g. 
posaconazole 300 mg po daily) may be instituted according to institutional practices. 
 
5.2.6 Prevention of perianal mucositis 
 
All patients will receive daily bulk laxatives (e.g., psyllium) and a stool softener (e.g., docusate 
sodium) unless diarrhea is present, in order to prevent straining at stool and the possibility of 
perirectal tears. 
 
5.2.7 Need to capture all concurrent medications on case report forms 
 
Because there is a potential for interaction of Veliparib with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential for drug interactions. The study team 
should check a frequently-updated medical reference for a list of drugs to avoid or minimize use 
of.  Appendix C (Patient Drug Information Handout and Wallet Card) should be provided to 
patients if available. 
 
5.2.8 Seizure risk.  
 
Seizures with veliparib were seen in some animal toxicology studies, although at doses much 
higher than those anticipated for this study. Seizures in animals were successfully treated with 
lorazepam. 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 4 cycles 
(total) or until one of the following criteria applies: 
 
 
 

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25 
 
Failure to meet response criteria of CR, CRi, PR or MR as defined by protocol  
 
Disease progression 
 
Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Patient decides to withdraw from the study 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
Patient non-compliance 
 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
Termination of the study by sponsor 
 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
5.4 
Duration of Follow Up 
 
Patients will be followed for minimum of 30 days, or longer after removal from protocol 
treatment or until death, whichever occurs first.  Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event. 
 
 
 
 

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26 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1  Dosing Delays 
Once a cycle is started, prescribed therapy will not be delayed. Patients unable to take veliparib 
due to toxicity will have those doses skipped.  
For patients achieving CR, CRi, PR, or MR following cycle 1, a repeat cycle of the same 
regimen may be administered beginning no sooner than Day 28 of the preceding cycle and 
no later than Day 63 from the initiation of the previous cycle (see Section 5.1). Delays 
beyond day 63 should be reviewed with the principal investigator and may be approved if 
patient is deemed be achieving clinical benefit.   
 
6.2  Veliparib Dose Reductions 
Veliparib dose will not be adjusted due to end organ dysfunction.   
 
6.3  Topotecan and Carboplatin Dose Reductions 
Topotecan should dose-reduced for decreases in creatinine clearance (CrCl) using modified 
Cockgroft-Gault formula as follows: 
 
CrCl >40 ml/min: no reduction 
 
CrCl 20-39 ml/min: 50% reduction 
 
CrCl <20 ml/min: topotecan will not be given 
Carboplatin should be dose-reduced for decreases in CrCl as follows: 
 
CrCl 40-59 ml/min: 30% reduction (give 70% original dose) 
 
CrCl 16-39 ml/min: 45% reduction (give 55% original dose) 
 
CrCl < 15 ml/min: carboplatin will not be given. 
 
 
 
 

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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
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: 
 
 Study specific documents:  Protocols > Documents > Education and Promotion, and   
 Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU Operations 
Information > User Guides. 
 

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28 
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/aeguidelines.p
df. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf for 
further clarification. 
NOTE:  Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.  
 
7.1.1 CAEPRs for CTEP IND Agent 
 
7.1.1.1 
CAEPR for Veliparib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR)  
for 
ABT-888 (Veliparib, NSC 737664) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 2310 patients. Below is the CAEPR for ABT-888 (Veliparib). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 2.4, May 13, 20181 

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30 
that there was a reasonable possibility that ABT-888 (Veliparib) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Blood and lymphatic system 
disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Cardiac disorders - Other (Takotsubo cardiomyopathy); Heart failure; Left ventricular 
systolic dysfunction; Palpitations; Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Colonic obstruction; Dental 
caries; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; 
Gastroesophageal reflux disease; Lower gastrointestinal hemorrhage; Mucositis oral; Obstruction gastric; Rectal 
hemorrhage; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Fever; Flu 
like symptoms; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (cirrhosis) 
INFECTIONS AND INFESTATIONS - Appendicitis; Catheter related infection; Infections and infestations - 
Other (peritonsillar abscess); Lung infection; Lymph gland infection; Mucosal infection; Sepsis; Shingles; Skin 
infection; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; Radiation 
recall reaction (dermatologic) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; Cardiac troponin I increased; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypernatremia; Hypoalbuminemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Back pain; Bone 
pain; Generalized muscle weakness; Muscle cramp; Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) -Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of consciousness; 
Dysarthria; Extrapyramidal disorder; Intracranial hemorrhage; Lethargy; Memory impairment; Movements 
involuntary; Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; Presyncope; Reversible 
posterior leukoencephalopathy syndrome; Stroke; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Psychiatric disorders - 
Other (emotional instability); Psychosis; Restlessness 
RENAL AND URINARY DISORDERS - Dysuria; Hematuria; Proteinuria  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Hypoxia; 
Nasal congestion; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail changes; 
Palmar-plantar erythrodysesthesia syndrome; Pruritus; Purpura; Rash acneiform 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; Vascular disorders - Other 
(brainstem infarction)  
 
Note: ABT-888 (Veliparib) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
7.1.2 Adverse Event List(s) for Topotecan and Carboplatin 
Please refer to appropriate package inserts for the comprehensive list of adverse events for each 
agent. 
 
Topotecan: Myelosuppression, fatigue, nausea, vomiting, oral/colonic/perianal mucositis, 
abdominal pain, anorexia, constipation or diarrhea, alopecia, fever. 

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31 
Carboplatin: Myelosuppression, nausea, vomiting, rash, transaminitis, nephrotoxicity (mainly 
when given with other potential nephrotoxins), electrolyte wasting, peripheral neuropathy (rare).
 
 
7.2 
Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
 For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when 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 phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 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 

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32 
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.  
 
7.3.3 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. 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.  
 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any pregnancy loss should be 
reported expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium 
and perinatal conditions SOC. A pregnancy loss should NOT be reported as a Grade 5 
event under the Pregnancy, puerperium and perinatal conditions SOC, as currently 
CTEP-AERS recognizes this event as a patient death.  
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under 
the General disorders and administration SOC. 
 
 
 
 

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34 
 
CTCAE SOC 
Adverse Event 
Grade 
≥24h 
Hospitalizationa 
Anemia 
Anemia 
Any 
No 
Leukopenia 
White blood cell decreased 
Any 
No 
Neutropenia 
Neutrophil count decreased 
Any 
No 
Neutropenic fever 
Febrile neutropenia with or 
without hospitalization 
Any 
No 
Infection 
Infection with Grade 3 or 4 
neutrophils  with or without 
hospitalization 
Any 
No 
Thrombocytopenia 
Platelet count decreased 
Any 
No 
Mucositis 
Mucositis oral/esophagitis 
Any 
No 
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient. 
 
7.4 
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. 
 
7.5 
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.  
 
7.6 
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).  

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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 CTEP-AERS. Options are available to describe the 
event: 
 Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (excluding AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
Reports of secondary malignancy will be reported within 30 days in RAVE and will include a 
pathology report and staging information if available.  
 
7.7 
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. 
 
 
 
 

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8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s)  
 
8.1.1 Veliparib NSC 737664, ABT-888, IND #TBD) 
 
Chemical Name: 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide  
 
Other Names: 
A-861695.0, ABT-888 
 
Classification: Poly (ADP-ribosome) polymerase (PARP) Inhibitor 
 
Molecular Formula: 
C13H16N4O  
M.W.:  244.29 
 
Approximate Solubility: ABT-888 (veliparib) is freely soluble at pH < 6.9, soluble at pH 6.9 to 7.1, and 
slightly soluble at pH > 7.1. 
 
Description: light orange opaque capsule with two black bands  
 
Mode of Action: Veliparib inhibits the formation of poly (ADP-ribose) (PAR) polymers in vitro and in vivo. 
It inhibits the repair of DNA when the DNA is damaged by cytotoxic agents. Veliparib increases antitumor 
efficacy when added to DNA-damaging therapies such as temozolomide, cisplatin, carboplatin, 
cyclophosphamide, irinotecan, topotecan or radiation therapy. 
 
Storage:  Store intact bottles between 150 and 250 C (590 to 770 F). 
 
 
Stability:  Shelf-life stability studies for veliparib capsules are on-going.  
 
Route(s) of Administration:  Oral. Veliparib capsules may be administered without regard to meals. 
 
Drug Interactions: Nonclinical studies suggest ABT-888 (veliparib)  is a substrate of P-gp, OCT2, and 
MATE1/MATE2K transporters.  Co-administration of ABT-888 (veliparib)  with strong inhibitors of P-gp, 
OCT2, and MATE1/MATE2K drugs may result in a decrease of ABT-888 (veliparib)  renal clearance and an 
increase in ABT-888 (veliparib)  plasma concentration. Therefore, use caution when administering ABT-888 
(veliparib) with strong inhibitors of P-gp, OCT2, and MATE1/MATE2K drugs.  At high dose (e.g., 400 mg 
BID), ABT-888 (veliparib)  may inhibit OCT1 in the liver and MATE1/MATE2K in the kidney.  
 
ABT-888 (veliparib)  is not a potent inhibitor of the major human CYPs and does not significantly induce 
activities of major human CYP isoforms, suggesting a negligible potential for CYP-mediated drug-drug 
interactions as a perpetrator at the anticipated therapeutic concentrations. 
 
In human, ABT-888 (veliparib)  clears primarily in the urine as intact parent drug along with metabolites 
suggesting that renal function plays an important role in the drug clearance and its metabolites. Drug-associated 
with kidney toxicities or kidney diseases could change ABT-888 (veliparib)  pharmacokinetics. Use cautions 
when concomitantly administer oxalipaltin, carboplatin, cisplatin, and topotecan in patients with pre-existing 
renal impairment.  

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Pharmacokinetics  
Absorption: The absorption of veliparib after oral dosing was relatively rapid, with average time to maximum 
observed plasma concentration (Tmax) ranging from 1 to 2 hours across dose levels. The maximum observed 
plasma concentration (Cmax) and the area under the plasma concentration curve from time zero to infinity 
(AUC∞) of veliparib were approximately dose-proportional across the dose range studied, with minimal 
accumulation following BID dosing. Available data, while not definitive, shows an absence of significant food 
effect.  
 
Distribution: The apparent volume of distribution (V/D) of veliparib was large, and oral clearance was rapid.  
 
Metabolism: Results from in vitro analysis reveal that this agent is metabolized by multiple isoenzymes – 
CYP1A1, 2D6, 2C19 and 3A4. Veliparib has one major metabolite in plasma, M8, a lactam derivative of the 
parent drug. The cellular PARP-inhibitory activity of M8 is 18-fold lower than veliparib.  
 
Excretion: The average terminal half-life (t½) of veliparib ranged from 4 to 5 hours across dose levels. 
Recovery of the dose as parent drug in the urine over 24 hours after dosing averaged 78% (N = 6). Following 
multiple oral doses given twice daily, total recovery of the dose in the urine (as both parent drug and M8 
metabolite) over 12 hours averaged 86% (N = 34). Veliparib is primarily cleared in the urine as intact parent 
drug along with metabolites, suggesting that renal function plays an important role in the clearance of veliparib 
and its metabolites. 
 
Patient Care Implications: Patients may feel fatigue or tiredness. Loss of appetite and losing weight are 
common. Provide appropriate supportive care for diarrhea.   
 
How Supplied: Veliparib (NSC 737664) will be provided free of charge by AbbVie Inc. and distributed 
by the Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation Program (CTEP), 
Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI).  
 
Veliparib 40 mg will be supplied as immediate release capsules in bottles containing 16 capsules or 64 
capsules. The veliparib capsule contains veliparib, microcrystalline cellulose, colloidal silicon dioxide, 
magnesium stearate, gelatin, sodium lauryl sulfate, and titanium dioxide. May contain FD&C blue #1, 
FD&C yellow #6, or FD&C yellow #5.   
 
ABT-888 capsules may be repackaged from the supplied HDPE bottles into amber (or other low-actinic) 
child resistant pharmacy dispensing bottles.  Expiration will be 30 days from the repackaging date (or the 
original retest date, whichever is earlier) when stored at 15°C to 25°C (59°F to 77°F). 
 
Questions about drug orders, transfers, returns, or accountability should be addressed to the PMB by 
calling (240) 276-6575 Monday through Friday between 8:30am and 4:30pm Eastern Time. You may also 
contact the PMB via e-mail at PMBAfterHours@mail.nih.gov.  
 
 
8.1.2 Agent Orders 
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 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).  

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
38 
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. 
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.   
Agent 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. 
 
 
8.1.3 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 
and a “current” password.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
 
8.1.4 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/index.jsp 
 CTEP Associate Registration and 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) 
 
 
 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
39 
8.2 
Commercial agent: Topotecan hydrochloride (Hycamptin) 
 
Product Description:  Topotecan hydrochloride is commercially available in vials containing 4 
mg sterile lyophilized powder (pH adjusted to 3), 60 mg mannitol and 25 mg tartaric acid for 
reconstitution in sterile water, and is stable at room temperature. 
 
Solution Preparation:  Lyophilized Topotecan powder is reconstituted in 5% Dextrose Injection 
USP. Since the powder does not contain any preservatives, reconstituted drug should be used 
immediately and should be discarded 24 hours after reconstitution. Please refer to the 
commercial package insert for complete prescribing and safety information. 
  
Administration:  Carboplatin and Topotecan have 24 hour stability information described in 
literature(carboplatin)52 or package insert (Topotecan) after dilution into PVC bags. Additionally, 
Topotecan and Carboplatin were tested in a Simulated Y-site administration using glass vials for 
a study period of 4 hours. The volume past the Y site is about 5 mL and at the current rate (500 
mL over 24 hrs = 21 mL/hr), the drugs will only be in the line together for ~ 15 minutes. This is 
much less than the 4 hour study period and the agents should be stable together. 53 Topotecan and 
carboplatin will not be mixed together, but the IV solutions can be administered via a Y-site IV 
line.  
 
Agent Ordering:  Topotecan hydrochloride is commercially available and will not be provided 
by the study. 
 
8.3 
Commercial agent: Carboplatin 
 
Product Description:  Carboplatin (CBDCZ, Paraplatin) is a second generation tetravalent 
organic platinum compound that is commercially available in vials of 50, 150 and 450 mg. Intact 
vials are stored at room temperature protected from light. 
 
Solution Preparation:  Carboplatin is reconstituted in sterile water or 5% dextrose to yield a 
concentration of 10 mg/ml. Reconstituted solution is stable for at least 24 hrs. Please refer to the 
commercial package insert for complete prescribing and safety information. 
 
Administration:  Carboplatin and Topotecan each have 24 hour stability information described 
in literature(carboplatin)52 or package insert (Topotecan) after dilution into PVC bags. 
Additionally, Topotecan and Carboplatin were tested in a Simulated Y-site administration using 
glass vials for a study period of 4 hours. The volume past the Y site is about 5 mL and at the 
current rate (500 mL over 24 hrs = 21 mL/hr), the drugs will only be in the line together for ~ 15 
minutes. This is much less than the 4 hour study period and the agents should be stable 
together.53 Topotecan and carboplatin will not be mixed together, but the IV solutions can be 
administered via a Y-site IV line. 
 
Agent Ordering: Carboplatin is commercially available and will not be provided by the study. 
 
 
 
 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
40 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies –  
 
The present study contains the following laboratory correlative studies: 
 
 Limited pharmacokinetic sampling for veliparib exposure (Section 9.2) – integrated 
biomarker 
 Leukemia mutation panel to provide molecular diagnostic information (Section 9.3.1) – 
exploratory biomarker 
 Rad51 focus formation assay in pretreatment marrow samples to assess homologous 
recombination pathway integrity (Section 9.3.2) – exploratory biomarker 
 Assay for topotecan-induced topoisomerase I-DNA covalent complexes (Section 9.3.3) – 
exploratory biomarker 
 Whole exome sequencing (Section 9.3.4) – exploratory biomarker 
 
# 
Correlative Assay 
Timepoint 
Sample 
information 
Integrated 
1 
Pharmacokinetic 
assessments 
(Blood) 
Pre-treatment: Day 1, Day 8, 
Day 15, Day 22 (~24 hrs post 
last dose) (ARM A only) 
6 mL peripheral blood 
in a 6 mL green top 
heparin tube 
Integrated 
2 
Pharmacokinetic 
assessments 
(Bone marrow) 
Pre-Registration (All Pts) and 
Pre-treatment Day 14 (Arm A 
only) 
7 mL bone marrow 
aspirate in a 10 mL 
green top heparin tube 
Exploratory 
1 
Leukemia Mutation 
Panel 
Pre-treatment bone marrow 
aspirate 
3 mL bone marrow 
aspirate in lavender 
EDTA vial 
Exploratory 
2 
Rad 51 Focus 
Formation Assay 
Pre-treatment bone marrow 
aspirate 
6-8 mL total bone 
marrow aspirate in 
two 4 ml green top 
heparin tube 
Exploratory 
3 
 
Assay for Topotecan-
induced Topo I-DNA 
complexes 
i) Pre-treatment peripheral 
blood, 
ii)  peripheral blood 
immediate-ly before start 
of topotecan/ carboplatin 
infusion; and 
iii) peripheral blood 72 ± 24 
into topotecan/carboplatin 
infusion 
5 mL peripheral blood 
in a 6 mL lavender top 
EDTA tube 
Exploratory 
4 
Whole exome 
sequencing 
Pre-treatment peripheral blood  
3 mL peripheral blood 
in a 3 mL lavender 
EDTA vial 
Exploratory 
5 
Analysis of 5-mC and 
5-h-mC 
Pre-treatment peripheral blood 
5 mL peripheral blood 
in a 6 mL lavender 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
41 
EDTA tube 
Exploratory 
6 
Sample of ChIPseq 
Pre-treatment peripheral blood 
7 mL peripheral blood 
in a 10 mL lavender 
EDTA tube 
 
9.2 
Integrated Correlative Studies 
 
9.2.1.1 
Veliparib exposure–  – Integrated Laboratory Correlative Study #1 (ARM A 
only) 
Collection of Specimen(s): ARM A patients will have ~6 ml samples of blood 
collected in tubes containing heparin as an anticoagulant (green top; i.e., Becton 
Dickinson Catalog # 367878 or 367866, Franklin Lakes, NJ) at the time points 
specified below: 
Plasma 
C1D1: Pre-treatment 
C1D8: Pre-treatment 
C1D15: Pre-treatment 
C1D22: ~24 hours after the last dose  
 
- 
Obtain venous blood by standard phlebotomy technique from a peripheral access point.  
NOTE:  Suggest using a minimum 18G needle to avoid sample hemolysis.  
- 
Fill-up the tubes as much as possible until blood flow stops. 
- 
GENTLY invert each tube several times (8-10 times) immediately after collection to 
avoid sample hemolysis. 
- 
Place samples immediately on ice after collection; samples must be processed within 30 
minutes. 
 
9.2.1.2 
Handling of Specimens(s)  
  
Processing instructions 
 
1. Invert sample 8-10 times and immediately place on ice.   
2. Within 30 minutes of collection, invert sample 8 times and centrifuge at 3000 rpm for 
10 minutes at 4ºC in a refrigerated centrifuge.  Make sure that the centrifuge reaches 
speed and is maintained throughout the entire spin. 
3. Carefully remove tube from centrifuge.  
4. Using a pipette, transfer equal aliquots of plasma into 2-3 labeled 2 mL cryovials, not 
exceeding 1.5 mL per cryovial.   
5. Label samples as Veliparib Plasma PK, including protocol number (NCI-10147), 
unique patient ID assigned at registration, initials, date of collection, draw time, time 
point, and protocol time point.  
6. Store plasma samples at -70ºC or below until shipment or transfer to Johns Hopkins. 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
42 
9.2.1.3 
Shipping of Specimen(s)  
 
Specimens should be stored through the end of Cycle 1 of T/C/V and shipped as a batch 
by participant (more than one participant/shipment is acceptable if the site has >1 
participant on-study). A participant's samples should be shipped to the APC lab within 
6 months of the last sample's collection date. (i.e., if C1D18 sample is collected on 
1/1/2018, all of that participant's samples should be at the APC lab by 7/1/2018). The 
APC lab may contact the study team to request shipment off-schedule.   
Please ship 1-2 aliquots to the APC laboratory. Once receipt is confirmed, the 
back-up aliquot may be shipped.  The back-up can be shipped later.  For Johns 
Hopkins samples, the normal SOPs should be followed for specimen transfer. 
 
Preparing the shipment  
*Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH).  
*Please organize the samples by Patient and Time point in the box.  
*Do not store in plastic bags (they break on dry-ice and labels will detach).  
*A copy of each of the pharmacokinetic sample collection forms, available on the 
CTSU website, for the respective patients is to be included with each shipment. To 
prevent problems with illegible writing on tubes, consider numbering them (in 
addition to sample label) and numbering samples on the sample sheet.  
*Note the study number, PI, and the drugs used/to be measured.  
*A name, phone number and email address should be included with samples so that 
receipt can be acknowledged.  
*Please notify the lab by telephone (410-502-7192 or 410-955-1129) or fax (410-502-
0895) at least 24 hours prior to shipment.  
 
Shipping  
*Samples collected at Johns Hopkins University can be transferred utilizing the 
current SOPs. 
*All samples should be shipped via overnight express courier in insulated containers 
with enough dry ice to maintain the samples in a frozen state.  
*Overnight shipments should occur on Monday through Wednesday (Tuesday is the 
preferred day) except when the following day is a holiday. 
 
Analytical Pharmacology Core Laboratory* 
Attn: NCI10147 Veliparib/T/C Study Samples 
1650 Orleans St. CRB1 Rm 184 
Baltimore, MD 21231-1000** 
Phone: 410-502-7192 or 410-955-1129 
Fax: 410-502-0895 
 
**This zip code is for FedEx shipments.  If UPS will be utilized, please ship to the 
following zip code: 21287 
 
 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
43 
Site(s) Performing Correlative Study Sidney Kimmel Cancer Center at Johns 
Hopkins, Analytical Pharmacology Core  
 
9.2.2.1 
Veliparib exposure–  – Integrated Laboratory Correlative Study #2 (ARM A only) 
Collection of Specimen(s): ARM A patients will have 7 ml samples of bone marrow 
(or peripheral blood in an inaspirable bone marrow patient) collected in tubes 
containing heparin as an anticoagulant (green top) at the time points specified below: 
 
Bone marrow  
 
C1 Pretreatment: Pre-treatment (SOC) 
C1D14: Pre-treatment 
 
- 
Obtain Bone marrow samples at time of day 14 bone marrow assessment.  
- 
Place samples immediately on ice after collection; samples must be processed within 30 
minutes. 
 
9.2.2.2 
Handling of Specimens(s)  
  
Processing instructions 
 
1. Invert sample 8-10 times and immediately place on ice. 
2. Within 30 minutes of collection, centrifuge at 1000xg for 10 minutes at 4ºC in a 
refrigerated centrifuge. 
3. Without disturbing the buffy cell layer, make three 1mL aliquots of plasma using 
2mL cryovials labeled as VELIPARIB PK BMA - PLASMA.   **IF PERIPHERAL 
BLOOD WAS PROCESSED - label cryovials as VELIPARIB PK DRY TAP (PB)-
PLASMA** 
4. Transfer the entire remaining content (cell layers) from the NaHep tube into a new 
50mL conical tube and dilute with 10mL RPMI 1640. 
5. Prepare a 50mL conical tube with 15mL Ficoll.  Overlay Ficoll with the diluted cells 
from step 3. 
6. Centrifuge at 600xg for 5 minutes at 4 degrees C, NO BREAK  (if proper separation 
has not occured, centrifuge again for 15 minutes at 600xg at 4 degrees C, NO 
BREAK). 
7. Transfer the buffy coat to a new 15mL conical tube and bring volume up to 14mL 
with PBS. 
8. (WASH 1) Centrifuge at 400xg for 10 minutes at 4 degrees C. 
9. Without disturbing the cell pellet, aspirate and discard the supernatent. 
10. Resuspend cell pellet with 10mL PBS and perform cell count per BR/SAC standard 
protocol. 
11. Record the TOTAL VIABLE cell count. 
12. (WASH 2) Centrifuge at 400xg for 10 minutes at 4 degrees C. 
13. Resuspend cell pellet with 1mL PBS and transfer to one 2mL cryovial. 
14. Centrifuge at 400xg for 10 minutes at 4 degrees C. 
15. Without disturbing the cell pellet, aspirate and discard the supernatent. 
16. Label cryovial as VELIPARIB PK BMA - CELL PELLET and record TOTAL 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
44 
VIABLE cell count on label.  (The cell pellet will NOT be suspended in any freezing 
media).  **IF PERIPHERAL BLOOD WAS PROCESSED - label cryovial as 
VELIPARIB PK DRY TAP (PB)-CELL PELLET and record TOTAL VIABLE cell 
count on label.** 
17. Store three plasma aliquots and one cell pellet at -70 degrees C. 
 
9.2.2.3      Shipping of Specimen(s)  
 
Please see Section 9.2.1.3 for shipping instructions.  The plasma and bone marrow 
samples can be shipped in the same box at the same time. 
 
9.3 
Exploratory/Ancillary Correlative Studies 
 
9.3.1 Leukemia Mutation Panel – Exploratory/Ancillary Laboratory Correlative Study #1 
 
9.3.1.1 
Collection of Specimen(s): 3 mL of bone marrow aspirate (or peripheral blood in the 
event of an inaspirable marrow) collected in a lavender top EDTA tube at the time of 
screening prior to therapy.  
 
9.3.1.2 
Handling of Specimens(s):  No processing needed. Refrigerate specimens at 4 degrees 
C until shipped. Do not freeze. 
 
9.3.1.3 
Shipping of Specimens(s):  Ship one lavender top tube (3 ml bone marrow) harvested 
prior to therapy and Shipping Manifest form, available on the CTUS website, by 
Federal Express priority overnight with cold pack to (no receipt on Saturday, Sunday 
or holidays): 
 
Molecular Diagnostics Lab 
Johns Hopkins Genomics 
1812 Ashland Avenue, Room 245 
Baltimore, MD 21205 
 
Notify the Molecular Diagnostics Lab of the upcoming shipment, preferably 24 
hours prior to sending the specimens: molecularpathresults@jhmi.edu. 
 
Specimens collected on a Friday or day before a Holiday will be refrigerated at 4 
degrees C until and shipped the next business day to arrive Monday through Friday. 
 
9.3.1.4 
Site(s) Performing Correlative Study: Johns Hopkins MDL.  
 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
47 
9.3.4.2   
Shipping of Specimen(s): Ship one lavender top tube (3ml peripheral blood) 
harvested prior to therapy and the Shipping Manifest form, available on the CTSU 
website, by Federal Express overnight with cold pack to (no receipt on Saturday, 
Sunday or holidays): 
 
Molecular Diagnostics Lab 
Johns Hopkins Genomics 
1812 Ashland Avenue, Room 245 
Baltimore, MD 21205 
 
Notify the Molecular Diagnostics Lab of the upcoming shipment, preferably 24 
hours prior to sending the specimens: molecularpathresults@jhmi.edu. 
 
Specimens with an expected delivery day of Saturday, Sunday or holiday may be held 
refrigerated at 4 degrees C until shipped. 
 
 
Harvested DNA specimens will be shipped from SKCCC MDL to the MoCha lab.  
 
9.3.4.3   
Site(s) Performing Correlative Study: DNA libraries for WES will be generated at the 
central sequencing laboratories by standard procedures.  Sequencing will be carried 
out on an Illumina HiSeq 2500 sequencer and these results will have variant calling 
through the procedures associated with the Genomic Data Commons. Analysis of 
sequencing results will be performed at Johns Hopkins. Mutation status will be 
correlated with clinical outcomes for the patients on study. 
 
9.3.5 Analysis of 5-mC and 5-h-mC – Exploratory/Ancillary Laboratory Correlative Study #5. 
 
9.3.5.1   
Collection and Handling of Specimen(s): Analysis of 5-methylcytosine (5-mC) and 5-
hydroxymethylcytosine (5-h-mC) will be performed in the laboratory of 
 
 at Mayo Clinic. 5-mc will be analyzed RRBS and a 850 kb array; and 5-h-mc  
will be analyzed by DIP-seq, TAB-RRBS, and 5-H-MC pull down. These analyses 
will be performed on pre-treatment samples containing 500 ng of DNA previously 
collected and stored as allowed by protocol. Patients will have 5 ml of peripheral 
blood collected in a lavender EDTA tube.  
Patients will have at least 5 ml of peripheral blood collected in a 6 ml lavender 
EDTA tube. 
 
9.3.5.2   
Shipping of Specimen(s): Peripheral blood specimens will be shipped on the day they 
are drawn to Dr. 
, Mayo Clinic, overnight by Federal Express. Ship 
purple top tube (5 cc peripheral blood) harvested prior to therapy to: 
 
 
, M.D., Ph.D. 
 
Division of Oncology Research 
 
Gonda 19-205B 
 
Mayo Clinic 
 
200 First St., S.W. 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
49 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy. 
Baseline labs must be repeated if done greater than 7 days prior to C1D1. 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. 
 
 
Pre- 
Reg 
Pre- 
Rand 
Day1-7 
Day 
8-
13 
Day 14 (± 
2d) 
Day 15-
22 (+/- 
2d) 
Recovery assessment  
(day 28-42) 
Veliparib ARM A 
 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
Topotecan/Carboplatin ARM A 
 
 
 
 
A 
A 
A 
A 
A 
 
 
 
 
Topotecan/Carboplatin ARM B 
 
 
B 
B 
B 
B 
B 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
 
X--------------------------------------------------------------------X 
 
Physical exam 
 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Vital signs 
 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Performance status 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
CBC w/diff, plts 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistrya 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG (as indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor Lysis Labsd 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X (day 
22) 
 
Adverse event evaluation 
 
 
 
 
X-------------------------------------------------------------------------X 
X 
B-HCG 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow Aspirate/Biopsyc 
X 
 
 
 
 
 
 
 
 
 
Xe 
 
X 
Peripheral blood sampleg 
 
Xg 
 
 
Xg 
 
Xg 
 
 
 
 
 
 
Leukemia mutation panel 
/Whole exome sequencing 
sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
RAD51 Assay 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic bloodf 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
WES peripheral blood for T 
cells 
 
X 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
50 
 
 
 
A: 
Veliparib 80mg PO BID day1-21 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium. 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
Cytogenetics, immunophenotype, histochemistries; bone marrow aspirate and/or biopsy as medically indicated and to document 
remission. Bone marrow PK(screening)  
d:      Phosphorous, Uric Acid, LDH, PT, APPT, Fibrinogen,  
e:      Day 14 bone marrow assays: Aspirate differential, Bone marrow core, bone marrow PK.   
f:       ARM A only See Section 9. Day 15 PK +/- 2d, Day 22 PK, only day 20 or 21 pre-treatment is allowed alternative 
g:      For patients with greater than 5000 circulating blasts/mcm3, one peripheral blood sample harvested at the time of on-study marrow, one 
right before initiation of topotecan/carboplatin infusion, and third after 48-72 hours of topotecan/carboplatin administration will be 
assayed for detectable topo I-DNA covalent complexes. 
 
 
 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
51 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Hematologic Tumors 
 
11.1.1 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.  
 
11.1.2 Progression-Free Survival 
PFS is defined as the duration of time of randomization to time of progression or death, 
whichever occurs first. 
 
11.1.3 Response Review 
 
Response will be graded by the principle investigator, and will be according to the 
response criteria below.  
 
Aggressive Myeloproliferative Disorders 
 
Complete remission (CR): The patient must be free of all symptoms or signs related to MPD and 
have a white blood cell count (WBC) between 1 and 10 x 109/L with no peripheral blood blasts, 
promyelocytes or myelocytes and normalization of bone marrow (<5% blasts in normocellular or 
hypercellular marrow) for at least 4 weeks; resolution of pretreatment cytopenias including Hgb 
> 12.0 gm/dl (> 11.0 gm/dl for females) without erythropoietin or transfusion support; ANC > 
1.0 x 109/L and platelet count >100x109/L without support; and resolution of pretreatment 
hyperleukocytosis and/or thrombocytosis (>450 x 109/L). 
 
Partial remission (PR): improvement in two or more of the following: 1) ANC increase of 100% 
up to >109/L for neutropenia and WBC count between 1 and 10 x 109/L with persistence of 
immature cells (blasts, progranulocytes, myelocytes); 2) increase in Hgb of 2 gm/dl if baseline 
value was <10 gm/dl and a decrease in transfusion requirements by at least 50% (frequency 
and/or volume); 3) persistent thrombocytosis >450 x 109/L but <50% of pretreatment values; 4) 
reduction in bone marrow blasts to < 5% if blasts were >10% in normocellular or hypercellular 
marrow; and 5) reduction in splenomegaly and/or hepatomegaly by 50% of pretreatment 
dimensions. 
 

NCI Protocol #: 10147 
Version Date: 10/24/2019 
 
52 
These definitions are consistent with those published by Giles et al. (48). 
 
MPDs Transformed to Acute Leukemias  
 
Complete remission (CR): The patient must be free of all symptoms related to leukemia and have 
a neutrophil count >1x109/L and platelet count >100x109/L, and normal marrow differential 
(<5% blasts). Must have clearance of extramedullary disease (including splenomegaly). 
 
Partial remission (PR): meets the above criteria with the exception that leukemic blasts in the 
bone marrow may range from 6-25%, or  50% decrease in bone marrow blasts. May have 
persistent splenomegaly.  
 
Hematologic Improvement: As per PR but ANC < 1x109/L and platelet count <100x109/L. May 
have persistent splenomegaly and/or hepatomegaly.  
 
These definitions are consistent with Giles et al (48) and Cheson, et al (49). 
 
Chronic Myelomonocytic Leukemia (CMML) 
 
The definitions below are consistent with those detailed by Cheson, et al (50). 
 
Complete response is defined by bone marrow showing <5% myeloblasts with normal trilineage 
maturation without dysplasia. When erythroid precursors constitute <50% of marrow cells, the 
blast percentage is based on total nucleated cells; otherwise, the blast percentage is based on non-
erythroid compartment. Peripheral blood criteria consist of Hemoglobin >11 gm/dl, ANC > 1 x 
109/L, Platelets > 100 x 109/L, absence of peripheral blood blasts, all in the absence of 
transfusions and growth factors.  
 
Partial response is defined by all of the above criteria with the exception of bone marrow blasts 
decreasing by >50% from pretreatment levels and/or achievement of a less advanced MDS FAB 
classification. 
 
Stable Disease is defined by failure to achieve PR but without progression for at least 2 months. 
 
Progression is defined according to initial blast percentages: 
For patients with <5% blasts: >50% increase in blasts to >5% 
For patients with 5-10% blasts: >50% increase in blasts to >10% 
For patients with >10-20% blasts: >50% increase in blasts to >20% 
For patients with >20-30% blasts: >50% increase in blasts to >30% 
 
In addition, there must be >1 of the following criteria: >50% decrease from maximum response 
levels in granulocytes or platelets, a decrease in hemoglobin concentration by at least 2 gm/dl, or 
becoming transfusion dependent. 
 
 
 

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Acute myeloid leukemia 
 
The following definitions are consistent with those published by Cheson/Dohner et al for acute 
leukemia (47). 
 
Complete Remission (CR): Bone marrow showing less than 5% leukemic blasts with normal  
maturation of all cell lines, an ANC of at least 1000/L and a platelet count of 100,000/L, 
absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, 
clearance of disease-associated cytogenetic abnormalities, and clearance of any previously 
existing extramedullary disease. Repeat marrow confirmation 4-6 weeks following the marrow 
documenting CR is not required due to the need for continued treatment in CR. 
 
Complete Remission with Incomplete Recovery (CRi): All CR criteria except for residual 
neutropenia (ANC < 1000/μL) or thrombocytopenia (platelets < 100,000/μL). 
 
Partial remission (PR): The presence of trilineage hematopoiesis in the bone marrow with 
recovery of ANC and platelets to the above stated levels, but with 5 to 25% bone marrow blasts, 
AND at least 50% decrease in bone marrow blast percentage from baseline.  
 
Clinical improvement/Minor Response (MR): Non-progressive disease with at least a 20% 
decrease in marrow blasts and/or a decrease in leukemia-related symptoms (e.g., fever, bone 
pain, splenic pain, transfusion requirements) and signs (decrease in extramedullary site of 
leukemia).  
 
Treatment Failure (TF):  
 Resistant Disease (RD). Failure to achieve CR or CRi; only includes patients who 
survive > 7 days following completion of initial treatment, with evidence of persistent 
leukemia by blood and/or bone marrow examination. 
 Death in Aplasia (DA). Deaths occurring > 7 days following completion of initial 
treatment while cytopenic without evidence of persistent leukemia. 
 Death from Indeterminate Cause (DIC). Death occurring before completion of therapy 
or < 7 days following its completion, or deaths occurring > 7 days following completion 
of initial therapy with no blasts in the blood but without bone marrow available. 
 
Relapse: Bone marrow blasts > 5%; or reappearance of blasts in the blood; or development of 
extramedullary disease. 
 
 
11.2 
Other Response Parameters 
 
Response criteria typically applied to MPN patients with acute leukemic transformation fails to 
capture meaningful clinical responses per the Cheson criteria(see below). A recent publication by 
the post-Myeloproliferative Neoplasm Acute Myeloid Leukemia Consortium describes revised 
response criteria per Table 1 below.56 As these response criteria have yet to be validated in a 
clinical trial, we intend to report responses both as criteria used in our phase I study(above) and 
as assessed by the proposed criteria by the MPN-AML consortium. These criteria are not to be 

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applied for CMML patients. A separate working group has developed revised response criteria 
for MDS/MPN including CMML which we will use as a secondary assessment for CMML 
patients per Table 2 below. 57   
 
Table 1. 
Myeloproliferative neoplasm in blast phase (MPN-BP) response categories. 
Complete molecular response (CMR) 
Description 
Complete remission of both leukemia and MPN without detectable 
molecular markers associated with either leukemia or MPN 
Hematologic 
profile 
ANC > 1000 
 
Hemoglobin > 10 g/dL 
 
Platelets > 100 × 109/L 
 
Absence of leukoerythroblastosisa 
Spleen 
Non-palpable 
Bone marrow 
Cellularity appropriate for age 
 
Resolution of abnormal morphology 
 
Blasts ≤ 5%b 
 
≤Grade 1 marrow fibrosis 
Cytogenetics 
Normal karyotypec 
Molecular 
markers 
Loss of any previously documented markers associated with either the 
leukemic or MPN cloned 
Complete cytogenetic response (CCR) 
Description 
Complete remission of both leukemia and MPN with detectable molecular 
markers associated with either leukemia or MPN 
Hematologic 
profile 
ANC > 1000 
 
Hemoglobin > 10 g/dL 
 
Platelets > 100 × 109/L 
 
Absence of leukoerythroblastosisa 
Spleen 
Non-palpable 
Bone marrow 
Cellularity appropriate for age 
 
Resolution of abnormal morphology 
 
Blasts ≤ 5%b 
 
≤Grade 1 marrow fibrosis 
Cytogenetics 
Normal karyotypec 
Molecular 
markers 
Residual expression of MPN/leukemia associated gene mutations (e.g. 
JAK2V617F, MPL515L/K)d 
Acute leukemia response-complete (ALR-C) 
Description 
Complete remission of leukemia with residual MPN features 
Hematologic 
profile 
Absence of blastsa 
Spleen 
<25% increase in spleen size by palpation or imaging if baseline spleen 
<10 cm or <50% if baseline spleen ≥10 cm 

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Bone marrow 
Blasts ≤ 5%b 
Cytogenetics 
Loss of cytogenetic abnormality associated with leukemic clone, may have 
persistent abnormality associated with MPN 
Molecular 
markers 
Loss of any previously identified markers in leukemic clone, may have 
persistent molecular markers associated with MPNd 
Acute leukemia response-partial (ALR-P) 
Description 
Decrease in leukemic burden but without resolution of peripheral blood or 
bone marrow blasts and residual MPN features 
Hematologic 
profile 
>50% reduction in blasts 
Spleen 
<25% increase in spleen size by palpation or imaging if baseline spleen 
<10 cm or <50% if baseline spleen ≥10 cm 
Bone marrow 
>50% reduction in blasts 
Cytogenetics 
No new abnormalities 
Molecular 
markers 
No new abnormalities 
Stable disease (SD) 
Description 
Failure to achieve at least LR-P, but no evidence of progression for at least 
8 weeks. 
Progressive disease (PD) 
Description 
Progression of leukemia and/or background MPN 
Hematologic 
profile 
For patients with 10-20% blasts: ≥50% increase to >20% blasts 
 
For patients with >20% blasts: ≥50% increase to >30% blasts 
Spleen 
>25% increase in spleen size by palpation or imaging if baseline spleen 
<10 cm and >50% if baseline spleen ≥10 cm 
Bone marrow 
For patients with 5–10% blasts: ≥50% increase to >10% blasts 
 
For patients with 10–20% blasts: ≥50% increase to >20% blasts 
 
For patients with >20% blasts: ≥50% increase to >30% blasts 
Cytogenetics 
Does not apply 
Molecular 
markers 
Does not apply 
a 
Absence of peripheral blood blasts by morphologic review of the peripheral smear on two 
occasions separated by at least 2 weeks. 
b 
Blast percentage can be assessed by morphologic review of aspirate and in cases of inaspirate 
marrows, immunohistochemical staining of the marrow for CD34+, CD117+ is acceptable. 
c 
Normal karyotype by conventional cytogenetics in peripheral blood or bone marrow aspirate, if a 
cytogenetic abnormality is detected prior to treatment it must not be identified at time of 
assessment; if an abnormality is detected at baseline by FISH it must be absent by FISH at time 
of assessment. 
 
 

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56 
d 
Absence or loss of evidence of mRNA transcript by quantitative PCR assay performed in a 
validated laboratory, this will also include any exploratory biomarkers determined to be positive 
prior to therapy. 
Table 2 
Proposed criteria for measurement of treatment response in adult MDS/MPN 
CR (presence of all of the following improvements)* 
 Bone marrow: ≤5% myeloblasts (including monocytic blast equivalent in case of CMML) with normal 
maturation of all cell lines and return to normal cellularity* 
 Osteomyelofibrosis absent or equal to “mild reticulin fibrosis” (≤grade 1 fibrosis)† 
 Peripheral blood‡ 
  WBC ≤10 × 109 cells/L 
  Hgb ≥11 g/dL 
  Platelets ≥100 × 109/L; ≤450 × 109/L 
  Neutrophils ≥1.0 × 109/L 
  Blasts 0% 
  Neutrophil precursors reduced to ≤ 2% 
  Monocytes ≤1 × 109/L 
 Extramedullary disease: Complete resolution of extramedullary disease present before therapy (eg, 
cutaneous disease, disease-related serous effusions), including palpable hepatosplenomegaly 
Provisional category of CR with resolution of symptoms:‡ CR as described above, and complete resolution 
of disease-related symptoms as noted by the MPN-SAF TSS 
Persistent low-level dysplasia is permitted given subjectivity of assignment of dysplasia* 
Complete cytogenetic remission 
 Resolution of previously present chromosomal abnormality (known to be associated with 
myelodysplastic, syndrome myeloproliferative neoplasms, or MDS/MPN), as seen on classic karyotyping 
with minimal of 20 metaphases or FISH§ 
Partial remission 
 Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and blast 

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equivalents) reduced by 50%, but remaining >5% of cellularity except in cases of MDS/MPN with ≤5% 
bone marrow blasts at baseline 
Marrow response 
 Optimal marrow response: Presence of all marrow criteria necessary for CR without normalization of 
peripheral blood indices as presented above. 
 Partial marrow response: Bone marrow blasts (and blast equivalents) reduced by 50%, but remaining 
>5% of cellularity, or reduction in grading of reticulin fibrosis from baseline on at least 2 bone marrow 
evaluations spaced at least 2 mo apart 
Clinical benefit 
 Requires 1 of the following in the absence of progression or CR/partial response and independent of 
marrow response (cord blood response must be verified at ≥8 wk) to be considered a clinical benefit 
 Erythroid response 
  Hgb increase by ≥2.0 g/dL 
  TI for ≥ 8 wk for patients requiring at least 4 packed red blood cell transfusions in the previous 8 wk 
  Only red blood cell transfusions given based on physician’s judgment for a pretreatment Hgb of ≤8.5 
g/dL will count in the red blood cell TI response evaluation|| 
 Platelet response 
  Transfusion independence when previously requiring platelet transfusions of at least a rate of 4 platelet 
transfusions in the previous 8 wk 
  Pretreatment ≤20 × 109/L: increase from <20 × 109/L to >20 × 109/L and by at least 100% 
  Pretreatment >20 × 109/L but ≤ 100 × 109/L: absolute increase of ≥30 × 109/L|| 
 Neutrophil response 
  Pretreatment ≤0.5 × 109/L at least 100% increase and an absolute increase ≥0.5 × 109/L 
  Pretreatment, >0.5 × 109/L and ≤1.0 × 109/L At least 50% increase and an absolute increase ≥0.5 × 
109/L|| 
 Spleen response 

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  Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at baseline 
or a spleen that is palpable at more than 5 cm at baseline becomes not palpable 
 Symptom response 
  Improvement in symptoms as noted by decrease of ≥50% as per the MPN-SAF TSS scoring <20 were 
not considered eligible for measuring clinical benefit.¶ 
 
↵* Presence of dysplastic changes, which may be interpreted within the scope of normal range of dysplastic changes, may still 
exist in the presence of CR as allowed in MDS IWG. Marrow should exhibit age-adjusted normocellularity in CR. 
 
↵† If there is no significant fibrosis present on the initial bone marrow biopsy, a second biopsy is not required to prove resolution 
of fibrosis. Grading of fibrosis in measurement of treatment response should be according to the European Consensus System.67 
 
↵‡ Given the current lack of a validated tool to assess complete resolution of symptoms in MDS/MPN, “CR with resolution of 
symptoms” (a complete resolution of disease-related symptoms as noted by the MPN-SAF TSS in presence of CR) will be a 
provisional category of disease response. 
 
↵§ Loss of cytogenetic burden of disease by (via FISH or classic karyotyping) known to adversely affect prognosis is required to 
reach complete cytogenetic remission. Decrease in the cytogenetic burden of disease must be by ≥50% (via FISH or classic 
karyotyping) to be indicative of a partial cytogenetic response. Given variability of fluorescent probes used in FISH, cytogenetic 
normalization via FISH will depend on the performance characteristics of the specific probes used. 
 
↵|| Resolution of abnormal peripheral blood counts must persist for at least 2 separate analyses over at least 8 wk. In the case of 
proliferative MDS/MPN, CR will include resolution of thrombocytosis to a normal platelet count (150-450 × 109/L) and 
resolution of leukocytosis to WBC ≤10 × 109 cells/L but ≥1.5 × 109/L. Hgb should be maintained >11 g/dL and platelets ≥100 × 
109/L without the support of transfusions. Clinical benefit may occur when these changes occur in absence of other changes 
required for CR or marrow response. Platelet and packed red blood cell TI would be considered for clinical benefit, and duration 
of TI should be monitored. Reduction in myeloid precursors (promyelocytes, myelocytes, metamyelocytes, nucleated red blood 
cells) to less than appreciable levels (≤2-3%) and/or 1 × 109/L monocytosis in the absence of infection, cytokine treatment, or 
other reactive causes. 
 
↵¶ MPN-SAF TSS validation among patients with MDS/MPN is currently under way (R.A. Mesa, personal communication, 
2014). 
 
 
 

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12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
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. 
 
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. 
 
12.1 
Study Oversight 
 
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 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. 
 
 

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All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
In addition, the Protocol Principal Investigator will have at least monthly conference calls with 
the site Study Investigators and study teams to review accrual, progress, adverse events, and 
unanticipated problems. 
 
12.2 
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. To access Rave via iMedidata: 
 
 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account, and  
 
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site:  Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type, 
o To hold Rave Investigator role, the individual must be registered as an NPIVR or 
IVR, and 
o To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 
 
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 Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  
 

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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.   
 
12.2.1 Method 
 
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) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
12.2.2 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. 
 
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. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D) and a description of any dose-limiting toxicities 
(DLTs). 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 

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62 
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
). 
 
12.3 
CTEP Multicenter Guidelines 
 
N/A 
 
12.4 
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 

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63 
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 
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).   
 

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64 
No publication, manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/ proprietary information. 
 
12.5 
Genomic Data Sharing Plan 
 
Genomic data obtained as part of this study will be shared according to the data sharing plan of 
the NCI.   Please refer to the NCI Genomic Data Sharing Policy at 
http://www.cancer.gov/grants-training/grants-management/nci-policies/genomic-data for 
considerations regarding the sharing of data, protection of patient confidential information, and 
the provision of adequate information in the patient informed consent. 
 
 
 

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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
This phase II study will randomize patients 2:1 to Arm A (T/C/V) or to the standard Arm B 
(T/C), respectively.  The primary end point is Overall Response (CR/CRi). We expect that these 
MPN patients will fall into two risk categories based on the percent blasts at baseline: < 20% 
blasts versus 20% or higher.  The expected CR/CRi rate with traditional regimens in this group 
of patients ranges from 14% for patients with worse disease to 29% for patients with blasts 20% 
or higher. 
 
For each group, the level of response that would confer interest in pursuing the therapy is a 
CR/CRi rate of 58%. This CR/CRi response rate was the response rate seen in our phase I trial42 
in the subset of MPN patients with a lower response rate (those with less than 20% blasts), where 
we observed responses in 7 out of 12 cases (58.3%). The proportion of patients in each subgroup 
are assumed to be 33% in the low blast count group and 67% in the higher blast count group, 
respectively.  These proportions are considered in the sample size calculation.  The final analysis 
will be by an exact Cochrane-Mantel-Haenszel test, which tests for an overall treatment 
difference while adjusting for subgroup.  The primary analysis will conclude a significant benefit 
for Arm A over Arm B if the one-sided p value < 0.10. 
 
The study design includes interim monitoring for futility (i.e., stopping early if there is high 
probability that the study will not show a significant benefit for Arm A over Arm B). 58  Futility 
is based on the predictive probability of a statistically significant treatment difference at the end 
of the study if the study enters, treats, and follows the total number of patients planned for the 
study.  If we determine at any interim analysis that there is a < 10% chance of ultimately finding 
a statistically significant difference between Arm A and Arm B, we will pause for a safety 
review by the PI, study team, and CTEP if one of the stopping boundaries is hit. We determined 
the predictive probability of a significant trial result through simulations using a beta-binomial 
model to predict future observations conditional on data available at the time of the test.  In the 
simulations, the predicted test was an exact Cochran-Mantel-Haenszel test, and a predicted test 
was significant if the one-sided p value of the test was < 0.10, as stated in the primary analysis. 
 
 
13.2 
Sample Size/Accrual Rate 
We expect to enroll 1-2 patients per month at JHU alone. With 7-8 other centers participating in 
this study, we expect their accrual to average 3 patients per month, for a study-wide total of 3 
patients per month. We fully expect that we will be able to complete accrual in 12-16 months, 
allowing for some patients who may drop out before randomization, and accrual holds for 
interim analysis.  
 
The futility analysis will begin when 24 patients (16 in Arm A, 8 in Arm B) have entered the 
study and received treatment. If the study does not stop after the first interim analysis, a second 
interim analysis will be done when another 18 (12 in Arm A, 6 in Arm B) patients have entered 
the study and received treatment (42 patients total). Each interim analysis will project the 
remaining patients yet to be enrolled and compute the predicted significance level of the primary 
analysis, conditional on the data available at the time of analysis (i.e., predictive power).58  

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The prior distribution for the interim futility analyses is a non-informative beta(1,1) prior.  
Provided the study does not stop for futility, the final sample size will be 60 patients, with 40 in 
Arm A and 20 in Arm B. 
 
The operating characteristics of the design are shown in the table below. We performed 1,000 
simulations with varying values of the underlying probability of a response for each treatment 
and disease subgroup. The table shows that this study will have approximately 91% power to 
detect an increase (given in the first paragraph of this section) in the subgroup-specific 
probabilities of a complete response for Arm A compared to Arm B. 
 
 
Sample 
Size 
 
 
 
 (A/ B) 
Probability of 
a CR in < 20% 
blasts group 
 
 
(A / B) 
Probability of 
a CR in 20% 
or higher 
blasts group 
 
(A / B) 
Estimated 
Power 
Probability of 
stopping early 
at each interim 
analysis 
 
(1st / 2nd) 
Cumulative 
probability 
of stopping 
early 
Probability 
of failing to 
reject at the 
end of the 
study 
40 / 20 
 0.58/ 0.29  
 0.40/0.29  
0.29/ 0.29  
0.58/ 0.14  
0.40/ 0.14  
0.14/ 0.14  
0.91 
0.475 
0.036 
0.042 / 0.014 
0.182 / 0.125 
0.638 / 0.214 
0.056 
0.307 
0.852 
0.034 
0.218 
0.112 
 
13.3 
Stratification Factors 
At the time of randomization, we will stratify according to 1) marrow blast percentage (<20% vs. 
> 20%).  
 
13.4 
 Early Stopping Guidelines 
 
In addition to monitoring for futility, we will stop the trial if there is evidence of excess toxicity.  
We plan to monitor each treatment arm separately for the occurrence of any of following adverse 
events: 
1) Grade 4 or higher generalized infection or 
2) Grade 4 or higher radiologically diagnosed lower GI mucositis or 
3) Grade 3 or higher hand and foot syndrome or 
4) Grade 3 or higher cardiac arrhythmias or 
5) Treatment-related mortality or 
6) Duration of neutropenia exceeding 60 days 
 
Toxicity will be monitored after every 5 patients. If the risk of any of the above adverse events 
convincingly exceeds 30% in Arm A or 20% in Arm B, the study PI will contact CTEP for a 
safety consultation. The stopping rule for toxicity will hold enrollment if the posterior probability 
of risk being larger than 30% (Arm A) or 20% (Arm B) exceeds 0.75. The prior for this toxicity 
monitoring rule for Arm A is a beta (2,4) distribution and for Arm B is a beta (1,4).  This means 
that our prior guesses at the proportion of severe toxicities is 33% for Arm A and 20% for Arm 
B. There is a 90% probability that these proportions are between 7.6% and 65.7%, and 1.2% and 
52.7%, respectively. The operating characteristics of the stopping rule are shown below and 

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67 
based on 5000 simulations. 
 
Toxicity Stopping Rules 
Arm B 
Arm A 
N toxicities 
N patients 
Probability 
of too much 
toxicity * 
N toxicities 
N patients 
Probability 
of too much 
toxicity * 
3 
4 
5 
6 
5 
10 
15 
20 
0.914 
0.870 
0.837 
0.811 
3 
5 
6 
8 
10 
11 
13 
15 
5 
10 
15 
20 
25 
30 
35 
40 
0.850 
0.869 
0.772 
0.811 
0.841 
0.773 
0.807 
0.836 
* The probability of too much toxicity is the posterior probability of toxicity being larger than 
20% for Arm A and 30% for Arm B 
 
Operating Characteristics of stopping rule, based on 5000 simulations: 
Arm B 
Arm A 
True Toxicity 
Rate 
Probability of 
declaring 
treatment too 
toxic 
Average 
sample size 
True Toxicity 
Rate 
Probability of 
declaring 
treatment too 
toxic 
Average 
sample size 
10% 
15% 
20% 
25% 
30% 
35% 
0.030 
0.101 
0.263 
0.457 
0.643 
0.805 
19.7 
19.2 
18.1 
16.4 
14.7 
12.7 
20% 
25% 
30% 
35% 
40% 
45% 
0.113 
0.253 
0.468 
0.660 
0.842 
0.943 
36.8 
33.2 
28.1 
23.1 
17.6 
13.5 
 
To ensure balanced randomization between the 2 arms with respect to disease classification, we 
will stratify up-front according to the two disease categories described above.  
 

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13.5 
 Analysis of Endpoints 
For descriptive purposes, the CR/CRi rate will be reported at the end of the study separately for 
Arm A and Arm B as intent to treat analysis with exact binomial 95% confidence intervals.  The 
final analysis will be by an exact Cochrane-Mantel-Haenszel test, which tests for an overall 
treatment difference while adjusting for subgroup.  The primary analysis will conclude a 
significant benefit for Arm A over Arm B if the one-sided p value < 0.10.  The odds ratio for the 
probability of CR/CRi for Arm A versus Arm B will also be estimated using a logistic regression 
model that adjusts for baseline blast count group, to account for the randomization stratification 
factor.  The estimate will be provided with a 95% confidence interval.  The secondary analysis of 
results will include reporting preliminary estimates of the odds ratio (comparing Arm A over 
Arm B) for the two blast (risk) groups separately. The differences in the odds ratios (i.e., 
differential treatment effect) will be described using an interaction analysis from a logistic 
regression model.   
 
An overall toxicity rate and a rate for each specific toxicity listed above in the early stopping 
guidelines will be reported for Arm A and Arm B separately and together with exact binomial 
95% confidence intervals. 
 
The distribution of mutations in DNA repair defects via assessment in Leukemia mutation panel 
will be summarized using descriptive statistics.  The frequency of patients with functional 
impairment of DNA damage response via assessment with RAD51 assay will be reported with 
exact binomial 95% confidence intervals.  The association between these biomarkers and 
response will be described with appropriate tests for continuously measured biomarkers (t tests, 
Wilcoxon rank sum tests) and categorical biomarkers (Fisher’s exact test).  These descriptive 
analyses for addressing secondary objectives will be performed for the whole cohort and also 
separately for Arms A and B.  Differential treatment outcomes for patient subgroups defined by 
these biomarkers may be explored using appropriate tests for interactions. 
 
Veliparib Exposure 
Pharmacokinetic (PK) sampling studies are proposed for all participating patients on the study 
V/T/C arm.  Plasma trough levels will be obtained weekly through the first cycle to provide a 
steady-state assessment.  Bone marrow or peripheral blood supernatant and blasts will be 
obtained pre-treatment and at C1D15. Samples will be measured using a validated liquid 
chromatography/tandem mass spectrometric (LC/MS/MS) method in the Analytical 
Pharmacology Core Laboratory at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) 
at Johns Hopkins. 42 Steady-state plasma concentrations will be calculated for each patient.  
Exploratory correlative studies between veliparib exposure (plasma and bone marrow) with 
pharmacodynamic (biological endpoints, toxicity and efficacy) will be analyzed using 
nonparametric statistics. Significance for comparisons will be at the p<0.05 level.   
  
 

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PK sample times will be consistent across all patients. Steady-state plasma concentrations will be 
calculated for each patient. Exploratory correlative studies between veliparib exposure (plasma 
and bone marrow) with pharmacodynamic (biological endpoints, toxicity and efficacy) will be 
analyzed using nonparametric statistics. Significance for comparisons will be at the p<0.05 level.   
 
13.7 
Reporting and Exclusions 
 
13.7.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
Veliparib. 
 
13.7.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 
 
 
 
 
 
 
 
 

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71 
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75 
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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76 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug veliparib.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others 
who care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
Veliparib interacts with certain transporter proteins that help move drugs in and out of cells. 
 
 The proteins in question are OCT2, MATE1, MATE2K, and P-gp.  Veliparib is a substrate 
of P-gp, OCT2, and MATE1/2K and may be affected by other drugs that inhibit these 
protein transporters. Veliparib is an inhibitor of OATP1B1, OATP1B3, MATE1/2K, 
OAT1/3and OCT1 and may affect transport of other drugs in and out of cells.  
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Veliparib may interact with other drugs which can cause side effects.  For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part 
in a clinical trial.  
 
These are the things that you and they need to know:  
 
Use caution when administering veliparib with other medicines that need certain transport 
protein to be effective or to be cleared from your system.  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 of P-gp, 
OCT2, and MATE1/2K. 
 
  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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  Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is _____________________________________ 
and he or she can be contacted at  
            _____________________________________.                                                                                               
 
    
 
 
February 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
 
You are enrolled on a clinical trial using the experimental study drug 
Veliparib.  This clinical trial is sponsored by the NCI.      Veliparib may 
interact with drugs that need certain transport proteins in your body.  
Because of this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over‐the‐counter medicine or herbal supplement. 
Use caution as veliparib may interact with medicines that stop 
transport proteins MATE1/2K, OCT2, and P‐gp to process further in 
the body.  
 
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 of P‐gp, MATE1/2K, and OCT2.” 
 Before prescribing new medicines, your regular prescribers 
should go to a frequently‐updated medical reference for a list of 
drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is ________________________  
and can be contacted at _________________________.  

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APPENDIX C 
BIOASSAY TEMPLATES 
 
Leukemia Mutation Panel (JHH) 
Method 
This assay uses next‐generation sequencing to analyze exons of the following genes: ABL1, 
ASXL1, ATM, ATRX, BCOR, BCORL1, BRAF, CALR, CBL, CBLB, CDKN2A, CEBPA, CSF3R, DNMT3A, 
EP300, ERBB2, ETV6, EZH2, FLT3, GATA1, GATA2, GNAS, IDH1, IDH2, IKZF1, JAK2, KDM2B, 
KDM6A, KIT, KMT2A, KMT2D, KRAS, MPL, NF1, NLRP1, NOTCH1, NOTCH2, NPM1, NRAS, NSD1, 
NUP98, PDGFRA, PHF6, PIGA, PTEN, PTPN11, RAD50, RECQL4, RUNX1, SETBP1, SF3B1, SRSF2, 
STAG2, STAT3, TET2, TP53, U2AF1, WT1, ZRSR2. DNA is extracted from blood or bone marrow 
specimens, captured with Agilent SureSelectXT reagents, and sequenced using Illumina paired 
end technology. 97% of all exons within the 60 genes of the Heme Panel are covered by this 
assay. The Heme Panel does not cover mutations occurring in the first exon of the following 
genes: ASXL1, ATRX, BRAF, CALR, CBL, DNMT3A, (NM_153759), ERBB2, FLT3, IDH2, KMT2A, 
MPL, NF1, NOTCH1, PIGA, PTPN11, RECQLR, and WT1. Designated exons from the following 
genes are also not covered by the Heme Panel: CALR (9), CSF3R (7), DNMT3A (2), ERBB2 
(2,3,4,25), MPL (9), NLRP1 (10(9)), NOTCH1 (3,9,11,17,19,24), NPM1 (7), and RECQL4 (2,3,12). 
The remaining exons cover 99% of the variants reported in Cosmic for these genes. *For 
individual specimens, additional target regions that result in coverage depths of <100x will be 
noted in the "Genes with Low Coverage (<100 reads)" section above. Mutations present in a 
low percentage of cells or present in genes with low coverage may not be detected. Analysis 
was performed using the following human reference sequence genome assembly: hg19 (NCBI 
build GRCh37). In a context of lower neoplastic cell percentage, variants with mutation allele 
frequencies of approximately 50% or near 100% may represent germline variations. 
 
Sensitivity 
Base Substitutions at >5% Mutant Allele Frequency 
98% 
 
Insertions/Deletions (1‐40 base pairs) at >5% Mutant 
Allele Frequency 
>95% 
 
Copy Number Alterations 
Not tested 
 
Translocations 
Not tested 
Specificity 
Positive Predictive Value (PPV) 
>99% 
Reproducibility 
Concordance between replicates inter‐batch 
99% 
 
Concordance between replicates intra‐batch 
99% 
RAD51 assay 
RAD51 focus formation assay methods 
Ten  million  Ficoll/Hypaque‐purified  mononuclear  cells  (MNCs)  from  normal  controls  and 
MPN patients were exposed to 10 Gy ionizing radiation (IR) from a Rad Source RS200 X‐ray 
irradiator (Brentwood, TN), then allowed to recover for 6 h in a humidified 37 °C tissue culture 
incubator equilibrated at 5% (vol/vol) CO₂. Leukocytes were pelleted by centrifugation at 200×g 

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for 10 min and fixed in 2% (wt/vol) paraformaldehyde in Dulbecco’s calcium‐ and magnesium‐
free phosphate‐buffered saline (PBS) for 10 min at 20‐22 C. Leukocytes were re‐pelleted as 
above,  washed  with  PBS,  and  stored  in  PBS  at  4  °C.  For  analysis,  2.5  x  104  leukocytes  were 
deposited onto glass coverslips by cytocentrifugation and processed as previously described 37. 
Briefly, coverslips were washed 3 times with PBS, permeabilized in PBS + 0.25 % (vol/vol) Triton 
X‐100 for 10 min, washed an additional 3 times with PBS, then incubated for 1 h in blocking buffer 
[PBS, 1 % (vol/vol) glycerol, 0.1% (wt/vol) gelatin from cold‐water fish, 0.1% (wt/vol) bovine 
serum  albumin,  5%  (vol/vol)  goat  serum  and  0.4  %  (wt/vol)  sodium  azide]  for  1  h  at  room 
temperature. Coverslips were incubated with RAD51 rabbit polyclonal (Active Motif; Carlsbad, 
CA) and phospho‐Ser139‐H2AX mouse monoclonal (Millipore; Billerica, MA) antibodies diluted 
1:500  in  blocking  buffer  overnight  at  4  °C.  Coverslips  were  then  washed  3  times  with  PBS, 
followed by incubation for 1 h in secondary Alexa Fluor 488‐conjugated goat anti‐mouse IgG and 
Alexa Fluor 568‐tagged goat anti‐rabbit IgG (Invitrogen; Carlsbad, CA) diluted 1:1000 in blocking 
buffer. Coverslips were further washed 3 times with PBS, counterstained with 1 g/ml Hoechst 
33258 in PBS, and mounted using UltraLong antifade reagent (Invitrogen, Carlsbad, CA). PEO1 
and PEO4, cell lines with a truncating BRCA2 mutation and a reversion mutation, respectively, 
were utilized as negative and positive controls for radiation‐induced RAD51 foci. Confocal images 
were  captured  on  a  Zeiss  LSM  710  scanning  confocal  microscope  with  a  100×/1.4  N.A.  oil 
immersion objective. For quantitation, 100 cells per sample from greater than 5 fields were 
manually scored for RAD51 and phoshopho‐H2AX foci by an investigator blinded to clongenic 
assay results. Cells with  >5 foci were graded as positive. Quantitation and image processing were 
performed with the Zeiss Zen software package and Adobe Photoshop CS3. 
 
Bioanalytical method for determining Veliparib in plasma, bone marrow supernatant and 
blasts 
1. Name of marker: Veliparib drug concentration 
2. Role of Integrated Biomarker: This is for an integrated assay aimed at assessing drug 
exposure in patients on the clinical trial.  
3. Laboratory who will be considered for conducting the assay for the trial: The Analytical 
Pharmacology Core Laboratory at the Sidney Kimmel Comprehensive Cancer Center at Johns 
Hopkins (SKCCC) will be considered to conduct the assay.  Michelle A. Rudek, PhD., Pharm D. is 
an Associate Professor of Oncology and the director of the SKCCC Analytical Pharmacology 
Core. She has over extensive experience in clinical pharmacology and the early development of 
anticancer agents.  Dr. Rudek has expertise in bioanalysis, drug metabolism, and 
pharmacokinetic and pharmacodynamic analysis. She has the authority to commit equipment, 
space, and professional and technical effort in the SKCCC Analytical Pharmacology Core to this 
project.  The SKCCC Analytical Pharmacology Core is a shared resource that was established in 
1985 and provides expertise in pharmacological trial design, analytical method development, 
quantitative assay implementation, isolation and identification of drug metabolites, metabolic 
profiling, protein binding studies, pharmacokinetic and pharmacodynamic modeling, and data 
interpretation in a centralized and experienced facility. The SKCCC Analytical Pharmacology 
Core is one of the few academic labs in the United States which operates according to Good 
Laboratory Practices (GLP), a standard necessary to ensure FDA‐quality data.  The GLP 

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guidelines are applied toward the development, validation and implementation of analytical 
assays for quantification of drug concentrations. We do not expect technical issues with the 
conduct of the pharmacokinetic and MIC‐1 studies as Dr. Rudek’s laboratory has much 
experience with these bioanalyses. 
5. Describe the assay: An abbreviated assessment of systemic and site of action veliparib 
exposure will be performed.  Veliparib blood levels will be measured by LC‐MS/MS in the blood: 
on C1D1, C1D8, C1D15, and C1D22 pre‐treatment. Bone marrow or peripheral blood 
supernatant and blasts will be obtained pre‐treatment and at C1D15. The analytical assay for 
determining veliparib in human plasma, bone marrow supernatant and blasts by liquid 
chromatography coupled with tandem mass spectrometry (LC‐MS/MS).has been developed and 
validated by the SKCCC Analytical Pharmacology Core. Briefly, p Sample preparation involved a 
single protein precipitation step by the addition of the sample with acetonitrile. Separation of 
veliparib and the internal standard, A620223.69, was achieved on a Atlantis dC(18) column 
(100mmx2.1mm, 3microm) column using a mobile phase consisting of acetonitrile‐ammonium 
acetate (2mM) containing formic acid (0.1%, v/v) using isocratic flow at 0.2mL/min for 3min. 
The analyte and internal standard were monitored by tandem mass spectrometry with 
electrospray positive ionization. Linear calibration curves were generated over the range of 5‐
1000nM. The analytical assay for determining decitabine has been developed and validated by 
the SKCCC Analytical Pharmacology Core on the ABI3000 triple quadrupole instrument in 2009 
and will need to be partially validated (precision/accuracy) on a newer instrument.  The 
analytical method was validated as recommended by the FDA Guidance for Industry: 
Bioanalytical Method Validation, May 2001 59. The LLOQ of veliparib was 5 nM.  No major 
interferences observed at the same retention time as veliparib and the internal standard, 
A620223.69. The average signal to noise ratio of the veliparib LLOQ was 34.4 ± 14.8 for plasma, 
and 78.2 ± 29.7 for bone marrow supernatant and 93.1 ± 23.1 for bone marrow cells.  The 
values for both within day and between day precision and accuracy were well within the 
generally accepted criteria for analytical methods. 
7. Provide data on the clinical utility of the integrated assay as it will be used in the trial:  This 
assay will be utilized to determine veliparib concentrations and ultimately the drug exposure. 
This data will be utilized to: 1) correlate systemic pharmacokinetics to veliparib at the site of 
action (supernatant and cells); 2)) correlate exposure‐response relationships with the reported 
pharmacodynamics output and veliparib exposure.