A Phase 1/2 Trial of ABT-888, an Inhibitor of Poly(ADP-ribose) Polymerase (PARP), and Topotecan (TPT) in Patients With Solid Tumors (Phase 1) and Relapsed Ovarian Cancer or Primary Peritoneal Cancer (Phase 2) After Prior Platinum Containing First-Line Chemotherapy
Phase: PHASE1
Conditions: Metastatic Malignant Solid Neoplasm, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Unresectable Solid Neoplasm
Sponsor: National Cancer Institute (NCI)

NCI Protocol #:  8329 
Local Protocol #: MC0861  
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8329 / MC0861: A Phase I/II Trial of ABT-888, an Inhibitor of Poly(ADP-ribose) 
Polymerase (PARP), and Topotecan (TPT) in Patients with Solid Tumors (Phase I) and 
Relapsed Ovarian Cancer or Primary Peritoneal Cancer (Phase II) After Prior Platinum 
Containing First-Line Chemotherapy 
 
Summary of Changes 
 
From Review of Amendment 19 dated September 29, 2016: 
 
I. Comments Requiring a Response – Major Issues: 
# 
Section 
Comments 
1. 
ICD 
In response to CTEPs previous disapproval of the proposed amendment for this 
trial it was written: 
PI Response: Please note that the Mayo Clinic IRB is the IRB of record for this 
study. As Mayo Clinic IRB has disapproved the replacement of the existing risk list 
with the condensed risk list format in previous CTEP-held IND studies, we 
respectfully decline to incorporate this at this time. We have ensured that all risks 
listed in the condensed risk list format are already included in this consent form. 
Please provide a letter from the Mayo IRB detailing their justification for not 
accepting the Condensed Risk List for CTEP-held IND studies. Additionally, 
please provide the list of previous studies in which the Mayo clinic IRB has 
disapproved the use of the CTEP ICD Condensed Risk List. 
 
PI Response: Mayo IRB previously reviewed and disapproved the replacement of 
the very lengthy list of medication risks with the CTEP ICD Condensed Risk List 
in the Mayo consent form for protocol 8821 / MC093C;  Mayo IRB did not wish 
to remove any risks from the consent form.  We note that this disapproval came 
from the same Mayo IRB committee that reviews this protocol 8329 / MC0861.  
 
As responsibility for IRB oversight must now be transferred from Mayo IRB to the 
NCI CIRB, this is no longer a concern.  The Condensed Risk Lists for both ABT-
888 and topotecan are included in the CIRB consent form. 
 
 
 
 
 

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II. Company Comments - Requiring a Response: 
# 
Section 
Comments 
1. 
8 
In Section 8.0 Dose Modification Based on Adverse Events- phase 2 reductions, 3 
levels of reductions are outlined for ‘Neutrophil count decreased < 500 and/or 
Platelet count decreased < 25, 000,’ but only one reduction is specified for 
‘Neutrophil count decreased 500 – 1000 and/or Platelet count decreased 25,000 – 
50,000.’ Footnotes suggest that 3 modifications are allowed. The investigators may 
want to clarify the other modifications for this second group. 
PI Response: Additional dose modifications have been added to the second group 
specified above. 
 
 
III. CTSU Revisions: 
# 
Section 
Comments 
1. 
Title 
page 
 
Changed Lead Org and Participating Organizations as this will be conducted 
under ETCTN 
2.  
6 
ETCTN language inserted in this section. 
3. 
18 
ETCTN language inserted in this section. 
 
 
IV. PI initiated Revisions: 
# 
Section 
Comments 
1. 
Throughout 
Protocol 
A notation added that the phase 1 portion of the study is complete and the 
phase 2 portion of the study is open. 
2.  
Throughout 
Protocol 
Information applicable only to Mayo Clinic removed. 
3. 
Title 
Page 
Daniel Satele added as a statistician. 
4. 
1.54 
Updated to current study results. 
5. 
3.15 
PTT value corrected to 48 from 42 seconds (1.5 x ULN) 
6. 
3.2.2 
Prior therapy with topotecan is added as an exclusion 
7. 
3.2.14 
Prior immunotherapy clarified to not be an exclusion. 
8. 
14.1 
Clarified that pharmacogenetics tests are mandatory and BRCA tests are 
optional.  
9. 
14.2 
Clarified that pharmacogenetics and BRCA tests can be performed from the 
same blood sample.  
 
 

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Table of Contents 
 
MC0861: A Phase I/II Trial of ABT-888, an Inhibitor of Poly(ADP-ribose) Polymerase (PARP), 
and Topotecan (TPT) in Patients with Solid Tumors (Phase I) and Relapsed Ovarian Cancer or 
Primary Peritoneal Cancer (Phase II) After Prior Platinum Containing First-Line Chemotherapy 1 
Protocol Resources......................................................................... Error! Bookmark not defined. 
Table of Contents ............................................................................................................................ 4 
Schema: Phase 1 Dose Escalation ................................................................................................... 7 
Schema: Phase 2 MTD.................................................................................................................... 8 
1.0 
Background ......................................................................................................................... 9 
1.1 Poly (ADP-ribose) Polymerase (PARP) Activity ............................................................... 9 
1.2 Veliparib (ABT-888) ........................................................................................................ 10 
1.3  Topotecan in Ovarian Cancer ........................................................................................... 13 
1.4 Rationale for the Combination of ABT-888 and Topotecan ............................................ 14 
1.5 Results from the Phase 1 Dose Escalation Portion of MC0861........................................ 14 
1.6 Correlative Studies Overview and Rationale .................................................................... 15 
2.0 
Goals ................................................................................................................................. 18 
2.1 Phase 1 .............................................................................................................................. 18 
2.3 Phase 2 .............................................................................................................................. 19 
3.0 
Patient Eligibility .............................................................................................................. 19 
3.1 Inclusion Criteria .............................................................................................................. 19 
3.2 Exclusion Criteria ............................................................................................................. 21 
4.0 
Test Schedule .................................................................................................................... 23 
5.0 
Grouping Factor ................................................................................................................ 24 
6.0 
Registration/Randomization Procedures ........................................................................... 24 
6.1 Prior to Registration ........................................................... Error! Bookmark not defined. 
6.2 Registration Phase 1 ........................................................... Error! Bookmark not defined. 
6.3 Registration Phase 2 ........................................................... Error! Bookmark not defined. 
6.4 Correlative Studies ............................................................. Error! Bookmark not defined. 
6.5 Document Verification....................................................... Error! Bookmark not defined. 
6.6 Treatment Locations .......................................................... Error! Bookmark not defined. 
6.7 Treatment Start................................................................... Error! Bookmark not defined. 
6.8 Pretreatment Tests/Procedures ........................................... Error! Bookmark not defined. 
6.9a Following Patient Registration .......................................... Error! Bookmark not defined. 
6.9b Study Drug  ........................................................................ Error! Bookmark not defined. 
7.0 
Protocol Treatment............................................................................................................ 28 
7.1 Treatment Schedule .......................................................................................................... 28 
7.2 Dose Escalation (Phase 1) ................................................................................................. 30 
8.0 
Dosage Modification Based on Adverse Events ............................................................... 33 
9.0 
Ancillary Treatment/Supportive Care ............................................................................... 37 
9.1 Colony Stimulating Factors .............................................................................................. 37 
9.2 Full Supportive Care ......................................................................................................... 37 
9.3 Concurrent Enrollment on Any Other Therapeutic Study ................................................ 37 
10.0 
Adverse Event (AE) Reporting and Monitoring ............................................................... 37 
10.1 Common Terminology Criteria......................................................................................... 37 
10.2 Assessment of Attribution................................................................................................. 38 

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10.3 Expedited Adverse Event Reporting Requirements ......................................................... 39 
10.4 Adverse Events to be Graded ............................................................................................ 42 
11.0 
Treatment Evaluation ........................................................................................................ 43 
11.1 Definitions......................................................................................................................... 43 
11.2 Response Criteria .............................................................................................................. 43 
11.3 Guidelines for Evaluation of Measurable Disease ............................................................ 45 
11.4 Duration of Response ........................................................................................................ 46 
12.0 
Descriptive Factors ........................................................................................................... 47 
12.1 Number of Prior Chemotherapy Regimens....................................................................... 47 
12.2 Dose Level ........................................................................................................................ 47 
12.3 BRCA Status ..................................................................................................................... 47 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient .................................................. 47 
13.1 No Progressive Disease (PD) ............................................................................................ 47 
13.2 No PD, Unacceptable Toxicity ......................................................................................... 47 
13.3 Progressive Disease / Refuse Further Treatment .............................................................. 47 
13.4 Off Protocol Treatment ..................................................................................................... 47 
13.5 Cohort 1 Dose Escalation.................................................................................................. 47 
13.6 Major Violation ................................................................................................................. 47 
13.7 Ineligible ........................................................................................................................... 48 
13.8 Cancel ............................................................................................................................... 48 
14.0 
Body Fluid Biospecimens ................................................................................................. 49 
14.1 Summary Table of Mandatory Biospecimens for This Protocol ...................................... 49 
14.2 Specimen Collection and Processing ................................................................................ 50 
14.3 Background/Methodology Information ............................................................................ 52 
14.4 Results of Genetic Testing ................................................................................................ 54 
15.0 
Drug Information .............................................................................................................. 54 
15.1 Veliparib (NSC 737664, ABT-888, IND #
)............................................................ 54 
15.2 Topotecan (Hycamtin®) .................................................................................................... 60 
16.0 
Statistical Considerations and Methodology .................................................................... 61 
16.1 Overview ........................................................................................................................... 61 
16.2 Phase 1 portion (Cohort 1) ................................................................................................ 63 
16.3 Phase 2 portion (Cohort 2) ................................................................................................ 64 
16.4 Phase 2 Portion Analysis Plan .......................................................................................... 66 
16.5 Inclusion of Women and Minorities ................................................................................. 69 
17.0 
Pathology Considerations/Tissue Biospecimens .............................................................. 71 
17.1 Summary Table of Optional Biospecimens for This Protocol .......................................... 71 
17.2 Background/Methodology ................................................................................................ 72 
18.0 
Records and Data Collection Procedures .......................................................................... 73 
18.1 Phase 1 (Dose Escalation and MTD) ................................. Error! Bookmark not defined. 
18.2 Phase 2 Submission Timelines (Mayo generic Case Report Forms) Error! Bookmark not 
defined. 
19.0 
Budget ............................................................................................................................... 76 
19.1 Costs Charged to Patient ................................................................................................... 77 
19.2 Tests to be Research Funded ............................................................................................. 77 
19.3 Other Budget Concerns ..................................................................................................... 77 
20.0 
References ......................................................................................................................... 78 

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Appendix I: ECOG Performance Status ....................................................................................... 84 
Appendix II: New York Heart Association Classifications .......................................................... 85 
Appendix III: Study Medication Diary ......................................................................................... 86 
Appendix IV: Cooperative Research and Development Agreement (CRADA) .......................... 88 
Appendix V: Patient Drug Information Handout and Wallet Card .............................................. 90 
 

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1.0 
Background 
 
1.1 
Poly (ADP-ribose) Polymerase (PARP) Activity 
 
1.1.1 Rationale for PARP as a Target of Anti-Cancer Therapeutics 
 
Poly (ADP-ribose) polymerases (PARPs) are a highly conserved family of 
enzymes whose predominant function is to preserve genomic integrity following 
DNA damage (Burkle et al., 2001; Jagtap et al., 2005; Gagne et al., 2006; Hassa 
et al., 2008).  Although 18 members of this enzyme family have been identified in 
mammalian cells, only 6 have been shown to actually synthesize ADP-ribose 
polymers (Hassa et al., 2008).  Of these, PARP1 (referred to as PARP throughout 
the remainder of this protocol), the founding member and most abundant of these 
enzymes, has been shown to play critical roles in DNA repair, regulation of 
genomic stability, modulation of cellular energy pools, and the regulation of 
transcription (Burkle et al., 2001; Jagtap et al., 2005; Gagne et al., 2006; Hassa et 
al, 2008).   
 
Adequate levels of PARP and normal activity are essential for normal function of 
the base excision repair (BER) pathway (op cit.).  In addition, PARP appears to 
play a critical role in homologous recombination (Helleday et al., 2005).  Further, 
emerging evidence suggests that PARP is activated by and plays a role in repair of 
DNA double strand breaks that occur when replication forks stall and then 
collapse (Yang et al., 2004; Haince et al., 2005).  Consistent with this possibility, 
data from several sources indicate that poly (ADP-ribose) (PAR) synthesis is 
stimulated by camptothecin-induced stalled replication forks when proliferating 
cells are exposed to camptothecin for prolonged periods of time (Sugimura et al., 
2008; 
 and 
, unpublished observations).  Moreover, this 
polymer synthesis can be inhibited by simultaneous treatment with a variety of 
PARP inhibitors, including NO125 (Sugimura et al., 2008), PJ-34 (
, 
unpublished observations) or ABT-888 (S. Kaufmann, unpublished observations). 
As described below, this combined treatment with a topoisomerase I (topo I) 
poison and PARP inhibitor is accompanied by increased activation of the intra-S 
checkpoint and increased killing by the topo I poison.  
 
Based on the roles of PARP in DNA repair, there has been substantial interest in 
assessing whether PARP inhibitors increase the cytotoxicity of DNA damaging 
agents (Jagtap et al., 2005; Haince et al., 2005; Curtin et al., 2005; Tentori et al., 
2005; Plummer et al., 2006; Ratnam et al., 2007; Drew and Calvert, 2008). A 
variety of preclinical studies have demonstrated that PARP inhibitors enhance the 
cytotoxicity of monofunctional alkylating agents such as temozolomide, which 
induce lesions that are reversed, in part, by BER (Delaney et al., 2000; Calabrese 
et al., 2004; Thomas et al., 2007; Liu et al., 2008b). 
 

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1.1.2 The Emerging Role of PARP Inhibitors in Ovarian Cancer 
 
The tumor suppressors BRCA1 and BRCA2 are important components of a 
network of DNA repair pathways that contribute to the maintenance of genomic 
stability in the face of various lesions (Venkitaraman et al., 2004).  Current 
evidence suggests that BRCA1 and BRCA2 are particularly important in DNA 
double-strand break repair. 
 
These observations led to the hypothesis that BRCA1- and BRCA2-deficient cells 
would, because of their defective double-strand break repair, be more dependent 
on other DNA repair mechanisms for their survival.  In support of this hypothesis, 
two groups reported that BRCA1/2-deficient cell lines are selectively killed by 
PARP inhibitors (Bryant et al., 2005; Farmer et al., 2005).  Subsequent studies 
have demonstrated that defects on other components of the DNA response 
network, including ATM, ATR, Chk1, Chk2, Rad51 and components of the 
Fanconi anemia pathway, also sensitize to PARP inhibitors (McCabe et al., 2006). 
In contrast, PARP inhibitors by themselves have little or no toxicity in normal 
tissues (Ratnam et al., 2007). 
 
BRCA1 and BRCA2 are mutated in 10-15% of all ovarian cancers (Risch et al., 
2001).  Acting on the assumption that BRCA1/2 mutant tumors, like the cell lines, 
would be hypersensitive to PARP inhibitors, Yap et al. completed a phase 1 trial 
of the PARP inhibitor AZD2281 in ovarian cancer patients with BRCA1/2 
mutations and demonstrated an ~40% response rate (Ashworth et al., 2008; Drew 
and Calvert, 2008). 
 
While the preceding study was limited to patients with documented BRCA1/2 
mutations, it is important to emphasize that the same pathway(s) can be 
inactivated by methylation or other chromatin alterations involving either the 
BRCA loci or some of the other loci listed above. Accordingly, it has been 
suggested that a substantial fraction of sporadic ovarian cancers might have 
dysfunction of this pathway (Turner et al., 2004), providing the impetus for 
studying these inhibitors in patients with sporadic ovarian cancer as well 
(Ashworth et al., 2008). 
 
1.2 
Veliparib (ABT-888) 
 
1.2.1 Preclinical Anti-Cancer Activity 
 
Veliparib (ABT-888) is an orally administered, potent and specific, small 
molecule inhibitor of PARP1 and PARP2 (Donawho et al., 2007; Penning et al., 
2009).  ABT-888 potentiates the cytotoxic actions of a number of DNA damaging 
agents, including temozolomide, cisplatin, cyclophosphamide and ionizing 
radiation in multiple in vitro and xenograft models (Donawho et al., 2007; ABT-
888 IB, 2008; Albert et al.,  2007; Liu et al., 2008b; Penning et al., 2009).  

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was determined to unlikely be emetic or to elicit adverse GI effects at efficacious 
plasma concentrations.  
 
A detailed discussion of the pre-clinical toxicology, metabolism, and 
pharmacology can be found in the Information for Investigator's Brochure. 
 
1.2.4 Clinical Trials 
 
ABT-888 has been administered as a single dose, ranging from 10 to 50 mg, to 9 
subjects enrolled in an exploratory investigational new drug (IND) study 
conducted by the Cancer Therapy Evaluation Program (CTEP).  Preliminary 
pharmacokinetic data indicate ABT-888 peak plasma levels generally occurred 
between 0.5 and 1.5 hours post dosing.  At a dose of 25 mg, plasma 
concentrations of ABT-888, averaging 0.151 µg/mL, were above the efficacious 
threshold of 0.070 μg/mL for an average of 4.1 hours.  These results are consistent 
with the projected human pharmacokinetic profile based on preclinical data.  
 
Preliminary data from this same Phase 0 trial have demonstrated inhibition of 
poly(ADP-ribose) polymer synthesis in human samples using an enzyme-linked 
immunosorbent assay for polymer (Liu et al., 2008a; Kinders et al., 2008).  A 25 
mg dose administered to 3 subjects resulted in greater than 85% decrease in 
polymer levels in peripheral blood mononuclear cells (PBMCs) in 2 of the 3 
subjects; and significant inhibition of polymer levels (92% to 100%) was also 
observed in tumor tissue from all 3 subjects.  A 50 mg dose resulted in complete 
inhibition of PBMCs in 3 subjects.  For this dose group, PARP activity inhibition 
in tumor biopsies averaged 75% 3 to 6 hours after dosing (n = 3) and averaged 
74% 24 hours after dosing (n = 3).  No significant adverse events have occurred in 
subjects receiving a single dose of ABT-888. 
 
Preliminary pharmacokinetic results are also available from a Phase 1 study of 
ABT-888 in combination with temozolomide (M06-862).  Doses of 20 and 40 mg 
BID produce areas under the concentration-versus-time curve over 24 hours 
(AUC00–24) mean values of 2.0 μg•hr/mL and 3.7 μg•hr/mL, respectively, and 
maximum concentrations (Cmax) in plasma mean values of 0.17 μg/mL and 0.35 
μg/mL, respectively.  These values span the optimal human exposure of an AUC 
of 3.0 μg•hr/mL and the optimal human Cmax of 0.21 μg/mL predicted from 
preclinical studies.  Preliminary safety results are available from 2 Phase 1 studies 
of ABT-888 in combination with a DNA-damaging agent.  In Study M06-862, 
doses ranged from 10 mg ABT-888/150 mg temozolomide to 40 mg ABT-
888/200 mg temozolomide. The most common adverse events were nausea, 
vomiting, fatigue, anorexia, and thrombocytopenia.   
 
In CTEP Study 7981, doses ranged from 10 mg ABT-888 with 1.2 mg/m2/day 
topotecan (x 5 days) to 50 mg ABT-888 with 1.5 mg/m2/day topotecan (x 5 days). 
In this study, more than half of the subjects experienced decreases in neutrophils 
or leukocytes.  Other potential hematologic toxicities were decreased platelets and 

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decreased hemoglobin.  The causality assessment of these events to ABT-888 is 
complicated by the high rate of grade 4 platelet and neutrophil counts occurring 
with topotecan monotherapy on this 5-day schedule.  Importantly, no new dose-
limiting toxicity has been reported with doses of ABT-888 as high as 40 mg BID.   
 
1.3  
Topotecan in Ovarian Cancer 
 
1.3.1 FDA-Approved Daily x 5 Schedule 
 
Topotecan (9-[(dimethyl amino) methyl]-10-hydroxycamptothecin) is water 
soluble camptothecin with excellent antitumor activity in vitro.  Tumour 
xenograft models showed activity in many tumor types, including 
adenocarcinomas of the ovary and colon, tumors of the central nervous system, 
and sarcomas.  Initial phase I clinical trials showed that the dose-limiting toxic 
effect was myelosuppression.  Although phase 1 studies seemed to suggest a 
higher response rate with extended infusions or frequent dosing, phase 2 studies 
in unresectable and metastatic non-small-cell lung cancer and in advanced breast 
cancer did not confirm this apparent advantage. Indications of activity in ovarian 
and small-cell lung cancer in phase 1 trials led to further investigation of 
topotecan in these diseases. 
 
The pivotal study in the 1996 FDA approval of topotecan for relapsed ovarian 
cancer was a randomized phase 3 trial by ten Bokkel Huinink and colleagues (ten 
Bokkel Huinink et al., 1997).  In this study, patients with ovarian cancer that 
failed to respond to or recurred after a platinum-containing regimen were 
randomized to topotecan versus paclitaxel.  Topotecan was administered at 1.5 
mg/m2 daily for 5 days, repeated every 21 days. Topotecan demonstrated 
significant benefit over paclitaxel in time to progression (23 vs 14 weeks, p = 
0.002). 
 
1.3.2 Weekly Topotecan Schedule More Widely Used for Ovarian Cancer 
 
Due to concerns about the high rate of myelosuppression seen with the daily x 5 
topotecan schedule in previously treated ovarian cancer patients, which might 
reflect decreased clearance as a consequence of cisplatin-induced renal 
dysfunction (Armstrong, 2004; Markman, 2005), alternative regimens have been 
investigated to improve or maintain efficacy while decreasing toxicity (Morris, 
2002; Rowinsky, 2002).  With this in mind, at least 10 phase 1 and phase 2 
studies have examined the safety and efficacy of weekly topotecan in patients 
with pretreated ovarian cancer (Hoskins et al., 1998; Homesley et al., 2001; 
O'Malley et al., 2005; Spannuth et al., 2007; Vandenput et al., 2007; Safra et al., 
2007; Morris et al., 2008; Abushahin et al., 2008; Le et al., 2008; Muntz et al., 
2008).  A phase 1 study in previously treated ovarian cancer patients 
demonstrated an MTD of 4 mg/m2/dose when topotecan was administered 
intravenously as a bolus infusion on days 1, 8 and 15 every 21 days (Homesley et 
al., 2001).  Grade 2 anemia, fatigue and gastrointestinal toxicity limited further 

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dose escalation. A phase 2 study investigating weekly topotecan (median starting 
dose approximately 2.5 mg/m2) on days 1, 8, and 15 of a 28-day cycle had a 
response rate of 18% in platinum refractory/resistant patients (O'Malley et al., 
2005).  With this alternative schedule, the myelosuppression was again mild, with 
no grade 4 toxicities observed.  The experience in subsequent trials has been 
similar, with grade 4 neutropenia occurring in 15% or fewer of the patients 
(Spannuth et al., 2007; Vandenput et al., 2007; Safra et al., 2007; Morris et al., 
2008; Abushahin et al., 2008; Le et al., 2008). Response rates (PR + CR) have 
ranged from 9% (Vandenput et al., 2007; Le et al., 2008) to 24% (Safra et al., 
2007; Morris et al., 2008) depending on eligibility criteria; and another 25-40% of 
patients had prolonged disease stabilization. This less myelosuppressive weekly 
regimen of topotecan provides the starting point for the present clinical trial. 
 
1.4 
Rationale for the Combination of ABT-888 and Topotecan 
Studies described above suggest that topotecan and PARP inhibitors are active in ovarian 
cancer.  Beyond the simple rationale of combining two active agents, a number of further 
observations support the development of topotecan/PARP inhibitor combinations.  
Preclinical studies with a number of different PARP inhibitors have demonstrated that 
PARP inhibition sensitizes tumor cells to camptothecin and/or topotecan in vitro and in 
vivo  (White et al., 2000; Delaney et al., 2000; Canon Koch et al., 2004; Calabrese et al., 
2003; Calabrese et al., 2004; Tikhe et al., 2004; Smith et al., 2005; Thomas et al., 2007; 
Smyth et al., 2001; Smith et al., 2005).  While a number of mechanisms have been 
proposed to explain this observation, including i) a requirement for PARP to facilitate the 
resealing of DNA by topoisomerase I (Malanga et al., 2004; Park et al., 2005); ii) a 
requirement for PARP to help resolve stalled replication forks (Haince et al., 2005; Yang 
et al, 2004), which are the types of lesions that are initially produced upon treatment with 
topoisomerase I poisons (Flatten et al., 2005); and iii) the apparent involvement of the 
BER pathway in helping remove some of the topoisomerase I molecules that become 
covalently bound to DNA in the presence of camptothecin or topotecan (Smith et al., 
2005; He et al., 2007), the mechanism of the synergy between topo I poisons and PARP 
inhibitors remains incompletely understood. 
 
In addition to these studies with other PARP inhibitors, preclinical studies in the 
laboratory of Scott Kaufmann at Mayo have demonstrated that ABT-888 enhances the 
antiproliferative effects of topotecan in a variety of human ovarian cancer cell lines, 
including Ovcar3, Ovcar5, Ovcar8, SKOV3 and A2780. These effects are seen at a 
readily achievable concentration of 0.1 µM in vitro (Patel et al., 2012).  In view of the 
activity of PARP inhibitors in ovarian cancer and their ability as a class to synergize with 
topoisomerase poisons (see above), the present trial will assess the effect of combining 
ABT-888 with the less myelosuppressive weekly schedule of topotecan. 
 
1.5 
Results from the Phase 1 Dose Escalation Portion of MC0861 
 
The goal of the phase 1 dose escalation portion of this clinical trial was to determine the 
MTD of the combination of ABT-888 and weekly topotecan in adult patients with 

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advanced solid tumors as well as to identify any pharmacokinetic interactions between 
ABT-888 and topotecan.  58 patients were enrolled between November 3, 2009 and 
February 9, 2015.   
 
1.5.1 MTD   
Dose-limiting toxicity, consisting of grade 4 neutropenia lasting > 5 days, was 
observed in 2 of 3 patients at dose level 13 and 1 of 6 patients at dose level 12.  
Accordingly, the MTD was dose level 12, i.e., ABT-888 at 300 mg twice daily by 
mouth on days 1-3, 8-10 and 15-17 along with topotecan 3 mg/m2 intravenously 
on days 2, 9 and 16.  Six patients were replaced due to adverse events or refusal 
but toxicity information was entered.  One patient enrolled but was replaced 
before receiving any treatment.  Therefore, there were 57 evaluable patients.  
1.5.2 Toxicities 
For cycle 1, the only grade 4 toxicities at least possibly related to treatment in the 
study were cytopenias (neutropenia in 11 patients, thrombocytopenia in 3 patients 
and leukopenia in 2 patients) and one febrile neutropenia.  For all cycles, the most 
common grade 3-4 toxicities at least possibly related to treatment were again 
hematologic and included neutropenia (23), thrombocytopenia (12) and 
leukopenia (19) as well as grade 3 fatigue (1), grade 3 nausea (1) and 1 patient 
with electrolyte derangements.  
1.5.3 Time On Study 
The numbers of cycles ranged from 1 to 26.  One woman with uterine cancer 
remained on study for 26 cycles with PR as her best response. There were 10 
women with ovarian cancer who remained on study for 6 or more cycles (up to 18 
cycles).  The mean number of cycles for all patients on study was 4.5 cycles. 
 
1.5.4 Responses 
22 patients had stable disease as best response with 9 patients having stable 
disease for 6 or more cycles and 3 with 9 or more cycles.  One patient had a 
complete response and remained on study for 14 cycles before disease 
progression.  Four patients had partial response as their best response.  The 
objective response rate for the trial was 10%; and the clinical benefit rate is 
42%with the inclusion of stable disease for at least 4 cycles (and up to 26 cycles). 
 
 
1.6 
Correlative Studies Overview and Rationale 
 
1.6.1 Assessment of TPT and ABT-888 Pharmacokinetics 
 

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In order for ABT-888 to modulate the activity of topotecan, sufficient levels need 
to be achieved.  Because topotecan and ABT-888 are both cleared in the kidney, 
there is the potential for pharmacological interaction between these agents.  To 
provide essential information for determining whether ABT-888 levels are 
sufficient to modulate PARP activity (Palma et al., 2008) and rule out a 
pharmacological interaction, plasma pharmacokinetics of topotecan and ABT-888 
will be measured. 
 
1.6.2 Poly(ADP-ribose) polymer measurements 
 
Analysis of poly (ADP-ribose) polymer in peripheral blood mononuclear cells 
(PBMCs) in the dose escalation portion of the phase 1 will be performed to permit 
confirmation that PARP1 has been inhibited by ABT-888 at the levels achieved. 
The hypotheses being tested are i) that plasma drug levels are lower in patients 
where polymer synthesis is not inhibited  and ii) failure to inhibit polymer 
synthesis correlates with a  poor response to the topotecan/ABT-888 therapy. 
 
1.6.3 Assessment of BRCA1/2 Mutational Status in the Phase 2 Portion of this Trial. 
 
Cells lacking BRCA1, BRCA2 and other homologous recombination (HR) repair 
proteins are hypersensitive to ABT-888 (Ashworth, 2008).  Additional data 
indicate that cells lacking BRCA2 are also hypersensitive to topo I poisons 
(Marple et al, 2006; A. Patel et al, 2012) and are sensitized even further by ABT-
888 (A. Patel et al, 2012).  On the one hand, these results suggest that the 
combination might be particularly efficacious against HR-deficient tumors.  On 
the other hand, these observations also raise the possibility that BRCA1 or 
BRCA2 haploinsufficiency might enhance the toxicities of TPT and ABT-888 in 
normal tissues of carriers.  In view of reports that i) a fraction of BRCA1 
mutations in ovarian cancer (as opposed to breast cancer) are somatic (Merajver, 
et al., 1995), ii) many other HR genes are also disrupted at low frequency in 
familial or sporadic ovarian cancers (e.g., Walsh et al., 2011) and iii) 
chemotherapy can induce BRCA2 secondary mutations that could affect 
subsequent therapeutic response (Edwards et al., 2008; Sakai et al., 2008), we 
propose to determine mutation status using tumor DNA from pretreatment 
biopsies, when available, and then sequence germline DNA of patients whose 
tumors are HR repair gene-mutant, if available.  The hypotheses being tested are 
that i) patients bearing tumors with mutant BRCA1, BRCA2 or other HR repair 
genes have a higher response rate to the topotecan/ABT-888 therapy and/or ii) 
patients with germline BRCA1/BRCA2/HR gene mutations experience more 
toxicity with this regimen. 
 
1.6.4 Expression of polypeptides Affecting Efficacy of the TPT/ABT-888 Combination 
in the Phase 2 Portion of the trial. 
 

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The polypeptides include topo I, PARP1, XRCC1, TDP1, BRCA1, BRCA2, 
BCRP and P-glycoprotein. 
 
Because variations in levels of each of these polypeptides have been implicated in 
sensitivity to TPT or ABT-888, relative levels of these polypeptides in cancer 
cells will be evaluated by IHC using formalin-fixed pretreatment tumor biopsies, 
if available. In particular, if all other factors were equal, we know that response 
might be affected by levels of: 
 
• Topo I—cells expressing more topo I are more sensitive to topo I poisons 
(Madden and Champoux 1992; Hann et al., 1998); and higher topo I levels 
predicted a more favorable outcome in our recent 
TPT/carboplatin/cyclophosphamide phase I trial  (Litzow et al., 2008). 
 
• PARP1-on the one hand, it has been reported that high PARP1 levels are 
associated with a poor outcome in serous ovarian cancers (Brustmann, 
2007).  On the other hand, preliminary data from the Kaufmann lab (Patel 
et al, 2012) suggest that cells expressing more PARP1 are more likely to 
be sensitized to TPT by ABT-888. 
 
• BRCA1 and BRCA2— previous results not only indicate that cells lacking 
functional BRCA1 or BRCA2 are inhibited by PARP inhibitors (Bryant, et 
al, 2005; Farmer et al., 2005), but also suggest that lack of functional 
BRCA1 or BRCA2 confers hypersensitivity to topo I poisons such as 
topotecan (Marple et al., 2006; S. Kaufmann, unpublished observations). 
In addition, it has been suggested that a substantial fraction of ovarian 
cancers have functional inactivation of the BRCA1/BRCA2 pathway 
despite the lack of mutations (Turner et al., 2004). To complement the 
sequence analysis described above, we will also stain biopsies for BRCA1 
and BRCA2 to assess expression at the protein level. This assay will 
detect tumors with diminished BRCA1 or BRCA2 as a consequence of 
gene methylation or other epigenetic changes.  
 
• XRCC1 and TDP1—Previous reports (Smith et al., 2005; A Patel, 
unpublished observations) indicate that XRCC1-deficient cells are 
hypersensitive to TPT; and the same hypersensitivity to topo I poisons is 
expected in TDP1 deficient cells (Pouliot et al., 1999). 
 
• BCRP and P-glycoprotein—previous data from the Kaufmann laboratory 
(Hendricks et al., 1992; Erlichman et al., 2001) and others (Chen et al., 
1991; Rasheed and Rubin, 2003) have demonstrated that P-glycoprotein 
and BCRP modestly affect TPT accumulation and cytotoxicity. 
 
Thus, the hypotheses being tested with the immunohistochemical assays are that 
response to therapy during the phase II portion of this trial will correlate with high 

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topo I content, high PARP content, low BRCA1 or BRCA2 expression, low 
XRCC1, low TDP1, low BCRP or low P-glycoprotein.   
 
1.6.5 Transcriptional Profiling of Pretreatment Biopsies from Phase 2 Portion of this 
Trial 
 
To complement the examination of candidate proteins that might correlate with 
response, we will also extract RNA from snap frozen aliquots of pretreatment 
biopsies, if available, and determine whether there is a transcriptional signature 
that correlates with outcome on this trial.  The hypothesis to be tested (if the 
regimen appears promising) is that response to therapy correlates with a particular 
mRNA profile.  
 
Collectively these assays are designed to not only confirm that ABT-888 is able to 
decrease TPT-induced poly (ADP-ribose) polymer synthesis in PBMCs (phase 1 
portion) but also examine features of the tumor cells that might predict response 
to this combination.  
 
2.0 
Goals 
 
2.1 
Phase 1 
 
2.1.1 To determine the maximum tolerated dose of the combination of ABT-888 and 
weekly topotecan in adult patients with advanced solid tumors. 
 
2.1.2 To identify any anti-tumor activity of this treatment combination, as assessed by 
objective response in patients with advanced solid tumors. 
 
2.2 
Phase 1 Correlative Goals 
 
2.2.1 To identify any pharmacokinetic interactions between ABT-888 and topotecan. 
 
2.2.2  To determine whether topotecan stimulates ADP-ribose polymer formation in 
circulating peripheral blood mononuclear cells.  
 
2.2.3 To determine whether ABT-888 inhibits basal or topotecan-stimulated ADP-
ribose polymer formation. 
 
 
 
 
 
 
 
 
 

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2.3 
Phase 2 
 
2.3.1 Primary endpoint: To assess the confirmed response rate for patients with 
epithelial ovarian cancer, fallopian tube cancer or primary peritoneal carcinoma 
treated with the combination of ABT-888 and weekly topotecan. 
 
2.3.2  Secondary endpoint: To assess the progression free response (PFS) for patients 
with epithelial ovarian cancer, fallopian tube cancer or primary peritoneal 
carcinoma treated with the combination of ABT-888 and weekly topotecan.  
 
2.4 
Phase 2 Correlative Goals 
 
2.4.1 To assess differences in the toxicity and/or efficacy of this regimen based on 
BRCA1/2 mutational status  
 
2.4.2 To determine whether pretreatment tumor cell levels of topoisomerase I, PARP, 
BRCA1, BRCA2, XRCC1, TDP1, P-glycoprotein or BCRP predict response to 
this regimen. 
 
2.4.3  To identify, in an exploratory manner, any transcriptional profiles that may 
predict response to this regimen. 
 
 
3.0 
Patient Eligibility  
 
Phase 1 Only: Prior to checking eligibility, contact the Mayo Clinic Registration 
Office at (507) 284-2753 for study status and dose level. 
 
3.1 
Inclusion Criteria  
 
3.1.1 Age ≥ 18 years. 
 
3.1.2 Phase 1: Adult patients with histologically confirmed solid tumor malignancy that 
is metastatic or unresectable and for which standard curative measures or other 
therapy definitely capable of extending life expectancy does not exist. 
 
Phase 2:  All patients enrolled in the Phase 2 portion of this trial must have a 
history of biopsy-proven ovarian, fallopian tube or primary peritoneal cancer.  
 
3.1.3 Patients must have received < 3 lines of prior therapy and have relapsed less than 
a year from their last platinum regimen.  Regimens that are used twice (for 
example carboplatin and paclitaxel) can be counted as one.  If a regimen is 
changed during the course of treatment due to side effect profile or allergy, the 
course of therapy is counted as one regimen. (For example, if docetaxel is 
substituted for paclitaxel due to a reaction during the initial course of adjuvant 
therapy, this is considered one regimen).  

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3.1.4 Patients must have measurable disease as defined in Section 11.0 with at least one 
lesion whose longest diameter can be accurately measured as ≥ 2.0 cm with 
conventional techniques or as ≥ 1.0 cm with spiral CT.  If spiral CT is used, it 
must be used for both pre- and post- treatment tumor assessments. 
 
3.1.5 
The following laboratory values obtained ≤ 7 days prior to registration: 
• 
Absolute neutrophil count ≥ 1500/mcL 
• 
Hemoglobin ≥ 9.0 g/dL 
• 
Platelets ≥ 100,000/mcL 
• 
Total bilirubin ≤ 1.5 x the upper limit of normal (ULN) 
• 
SGPT (ALT) or SGOT (AST) ≤ 2.5 x ULN in the absence of hepatic 
metastasis.  SGPT (ALT) ≤ 3 x ULN or SGOT (AST) ≤ 5 x ULN in the 
presences of hepatic metastasis 
• 
Creatinine ≤ 1.5 x ULN 
• 
INR ≤ 1.4 unless receiving therapeutic doses of coumadin  
• 
PTT ≤ 48 seconds (1.25 x ULN) 
 
 
 
 
3.1.6 ECOG Performance Status (PS) 0, 1, or 2. (See Appendix I). 
 
3.1.7 Ability to provide informed consent. 
 
3.1.8 Willingness to return to enrolling institution for follow-up. 
 
3.1.9 Life expectancy ≥ 12 weeks. 
 
3.1.10 Correlative Research 
 
Willingness to provide the biologic specimens is required by the protocol. This is 
part of the mandatory correlative research component.  (See Sections 6.9a and 
14.0).  These specimens include: 
 
• 
Phase 1: Peripheral blood for plasma pharmacokinetic analysis and 
PBMC polymer assessment from 0-24 h after drug administration on 
days 1 and 2 of cycle 1 as well as day 2 of cycle 2; urine for assessment 
of ABT-888 renal clearance for 24 h after administration of drugs on 
days 1 and 2 of cycle 1 as well as day 2 of cycle 2; and a pretreatment 
peripheral blood sample for possible sequencing of the BRCA1, BRCA2 
loci as well as possible pharmacogenomic analysis (see Section 14 for 
further information). 
 

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3.1.11 Negative urine or serum pregnancy test done ≤ 7 days prior to registration for 
females of child bearing potential only. 
 
3.1.12 Able to swallow and absorb the medication 
 
 
3.2 
Exclusion Criteria  
 
3.2.1 Known standard therapy for the patient’s disease that is potentially curative or 
definitely capable of extending life expectancy. 
 
3.2.2 Prior treatment with a PARP inhibitor or topotecan 
 
3.2.3 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.2.4 Any of the following prior therapies: 
• Chemotherapy ≤ 4 weeks prior to registration 
• Mitomycin C/nitrosoureas ≤ 6 weeks prior to registration 
• Immunotherapy ≤ 4 weeks prior to registration 
• Biologic therapy ≤ 4 weeks prior to registration 
• Radiation therapy ≤ 4 weeks prior to registration 
• Radiation to > 25% of bone marrow  
• Investigational therapy or any ancillary therapy considered investigational 
(utilized for a non-FDA-approved indication and in the context of a 
research investigation) ≤ 4 weeks prior to registration. Subjects with 
prostate cancer will be permitted to continue hormone therapy 
 
3.2.5 Failure to fully recover from acute, reversible effects of prior chemotherapy 
regardless of interval since last treatment. 
 
3.2.6 New York Heart Association classification III or IV (See Appendix II). 
 
3.2.7 Known CNS metastases or seizure disorder. Patients with known brain metastases 
that have been successfully treated and stable for ≥ 6 months without requirement 
for corticosteroids and without seizure activity will be eligible. 
 
3.2.8 Any of the following, because this study involves both ABT-888, an 
investigational agent whose genotoxic, mutagenic and teratogenic effects on the 
developing fetus and newborn are unknown, and topotecan, an agent that has 
known genotoxic, mutagenic and teratogenic effects: 
• Pregnant women 

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• Nursing women 
• Men or women of childbearing potential who are unwilling to employ 
adequate contraception  
 
3.2.9 Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.2.10 Immunocompromised patients (other than that related to the use of 
corticosteroids) including patients known to be HIV positive. 
 
3.2.11 Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.2.12 Other active malignancy, except non-melanotic skin cancer or carcinoma-in-situ 
of the cervix.  Note: If there is a history of prior malignancy, they must not be 
receiving other specific treatment (other than hormonal therapy) for their cancer. 
 
3.2.13 History of myocardial infarction ≤ 6 months, or congestive heart failure requiring 
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias. 
 
3.2.14 More than 2 prior chemotherapy regimens for the current malignancy.  Full dose 
chemotherapy used in conjunction with concurrent radiation therapy will be 
included as prior therapy. Note: Prior hormonal therapy (e.g. leuprolide, 
aromatase inhibitors, and tamoxifen) and immunotherapy will be allowed and not 
included as a prior chemotherapy.  If the chemotherapy regimen is altered during 
the course due to issues with tolerability or safety, the regimen will be counted as 
one. Using the same regimen at recurrence is counted as one regimen. The 
addition of bevacizumab to a prior regimen is considered one regimen. 
 
 
 

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4.0 
Test Schedule 
 
 
Active Monitoring Phase 
Tests and procedures 
≤ 21 days 
prior to 
registration 
≤ 7 days 
prior to 
registration 
During 
treatment 
During 
interval 
between 
treatment 
Prior to 
subsequent 
cycles 
History and Physical Exam 
including weight and 
Performance Status (PS)  
 
X 
 
 
X 
Height 
 
X 
 
 
 
Adverse Event Assessment 
 
X 
 
 
X 
Hematology1 
 
X 
 
Weekly 
X 
Chemistry2 
 
X 
 
 
X 
Urine or serum 
pregnancy test3 
 
X 
 
 
 
INR and PTT 
 
X 
 
 
 
Chest X-ray4 
X 
 
 
 
 
Phase 2 only: CA-125  
X 
 
 
 
X5 
Tumor Measurement 
(CT, MRI imaging) 
X 
 
 
 
X5 
Phase 1 only:  
Mandatory research  
blood specimensR 
(see Section 14.0) 
 
 
X 
 
 
Phase 2 only:  
Optional research  
blood specimensR 
(see Section 14.0) 
X 
 
 
 
 
PharmacogeneticsR 
X 
 
 
 
 
Phase 1 only:  
PharmacokineticsR 
 
 
X 
 
 
Phase 2 only:  
Optional tissue specimenR 
(see Section 17.0) 
X 
 
 
 
 
 
Footnotes for Section 4.0 Test Schedule appear on the following page 
 

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Footnotes for Section 4.0: 
1.  Hematology group includes total WBC (leukocytes), absolute neutrophil count (ANC), 
hemoglobin and platelets.   
 
 2. Chemistry group includes electrolytes, total bilirubin, creatinine, alkaline phosphatase, 
SGOT (AST) and SGPT (ALT). 
 
3. For females who are of child bearing potential only.   
 
4. A chest X-ray is not required if a chest CT was performed. 
 
5. CT or MRI imaging and CA-125 to be performed after the completion of even cycles of 
therapy.  Please use the same imaging modality throughout the study. 
 
R. Research funded. 
 
 
 
5.0 
Grouping Factor 
 
Grouping Factor:  Phase 1 (Dose Escalation) vs. Phase 2.   
 
 
6. Registration Procedures 
 
6.1 
Investigator and Research Associate Registration with CTEP 
 
6.1.1 CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator registration.htm. 
 
For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk by email at pmbregpend@ctep.nci.nih.gov. 

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6.1.2 CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only.  (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
 
An active CTEP-IAM user account is required to access all CTEP applications and, if 
applicable (e.g., all Network trials), all Cancer Trials Support Unit (CTSU) applications 
and websites. 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm. 
 
For questions about Associate Registration or CTEP-IAM Account Creation, please 
contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov. 
 
6.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to: an active Federal Wide Assurance (FWA) number, an active roster 
affiliation with the Lead Network or a participating organization, a valid IRB approval, 
and compliance with all protocol specific requirements. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this 
study are not required to submit IRB approval documentation to the CTSU Regulatory 
Office. For sites using the CIRB, IRB approval information is received from the CIRB 
and applied to the RSS in an automated process. Signatory Institutions must submit a 
Study Specific Worksheet for Local Context (SSW) to the CIRB via IRBManager to 
indicate their intent to open the study locally.  The CIRB’s approval of the SSW is then 

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communicated to the CTSU Regulatory Office.  In order for the SSW approval to be 
processed, the Signatory Institution must inform the CTSU which CIRB-approved 
institutions aligned with the Signatory Institution are participating in the study. 
 
6.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 8329 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-MN026, and 
protocol #8329. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
6.2.2 Requirements For 8329 Site Registration 
 
• CTSU Transmittal Sheet (optional)  
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
 
6.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.  
 
ONLINE:  www.ctsu.org (members’ section)  Regulatory Submission Portal 
(Note: The use of the Regulatory Submission Portal will become 
mandatory in early 2017.) 
EMAIL:    CTSURegulatory@ctsu.coccg.org (for regulatory document submission    
only) 
FAX:    
215-569-0206 
MAIL:  
CTSU Regulatory Office 
       
1818 Market Street, Suite 1100 
       
Philadelphia, PA 19103 
 

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6.2.4 
Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
6.3 
Patient Registration 
 
6.3.1 
OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
6.3.2 
OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 

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6.3.3 
OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
 
6.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 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. 
 
 
 
 
 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule 
Use actual weight or estimated dry weight if fluid retention for Topotecan.  Treatment 
will be administered on an outpatient basis.   
 
Note: The Phase 1 Dose Escalation part of the study is completed; the phase 2 MTD part of 
the study is open. 
 
Phase 1:  
Agent 
Dose 
Route 
Day 
Retreatment 
ABT-888* 
As assigned 
by the 
registration 
office 
Oral 
Days 1, 2, 3, 
8, 9, 10, 15, 
16, 17 
Every 28 
days 
Topotecan** 
Intravenous 
Days 2, 9, 16 
** Topotecan administered over 30 minutes 
 
 
Phase 1 Cycle 2 only* 
Agent 
Dose 
Route 
Day 
ABT-888 
MTD 
Determined 
by Phase 1 
Dose 
Escalation 
Oral 
Days  8, 9, 
10, 15, 16, 17 
Topotecan** 
Intravenous 
Days 
2, 9, 16 

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** Topotecan administered over 30 minutes 
 
 

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Phase 2 (Phase 2 studies at MTD):  MTD has been established at Dose Level 12. 
Agent 
Dose 
Route 
Day 
Retreatment 
ABT-888 
300 mg PO 
twice daily 
 
Oral 
Days, 
1, 2, 3, 8, 9, 
10, 15, 16, 17 
Every 28 
days 
Topotecan** 
3 mg/m2 
 
Intravenous 
Days 
2, 9, 16 
** Topotecan administered over 30 minutes 
 
 
7.2 
Pretreatment Medication   
 
Premedications will not be used routinely for this protocol.  Anti-emetics will be 
provided on an as needed basis.   For patients who do experience nausea and/or emesis, 
prophylactic use of a 5-HT3 antagonist (e.g., ondansetron) and/or other agents with anti-
emetic properties (phenothiazines, steroids, benzodiazepines) will be permitted. 
 
7.1.2 Treatment Administration 
ABT-888 is to be taken by mouth twice a day with or without meals.  The patient 
will be given a patient diary and to return the diary at each clinic visit.  (Appendix 
III).  Patients will also be given a patient drug information handout and wallet 
card for the potential drug interactions (Appendix V).  Topotecan will be given 
via intravenously over 30 minutes on days 2, 9 and 16 of every 28-day cycle. 
 
Note: The Phase 1 Dose Escalation part of the study is completed; the phase 2 MTD part of 
the study is open 
 
7.3 
Dose Escalation (Phase 1) 
 
Dose Level 
ABT-888**   
(mg twice daily) 
Topotecan  
 (mg/m2) 
-2 
10 
1.0 
-1 
10 
1.5 
-1a 
20 
1.5 
1* 
10 
2 
2 
20 
2 
2a 
10 
2.5 
3 
10 
3 
4 
20 
3 
5 
20 
4 
6 
30 
4 
7 
30 
3 
8 
50 
3 
9 
100 
3 
10 
150 
3 
11 
200 
3 

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*Starting Dose  
 **See Section 7.26 for Dose de-escalation instructions. 
 
 
7.3.1 Evaluation at Enrolling Institution 
For this protocol, the patient must return to the enrolling institution for evaluation 
at least every 4 weeks.  
 
7.3.2 Dose Levels 
Three patients will be treated at each dose level and observed for a minimum of 4 
weeks (i.e. one full cycle) before new patients are treated.  Doses will not be 
escalated in any individual patient. 
 
7.3.3 Definition of DLT 
For this protocol, dose-limiting toxicity (DLT) will be defined as a cycle 1 
adverse event attributed (definitely, probably, or possibly) to the study treatment 
and meeting the following criteria: 
 
 
Toxicity 
DLT Definition 
Blood and lymphatic 
system disorders 
Grade 4 anemia: 
Life-threatening consequences; urgent intervention 
indicated 
Investigations 
Grade 4 neutrophil count decrease: 
ANC < 500 (> 5 days) 
 
Grade 4 platelet count decrease: 
< 25,000 
 
Creatinine increased:  
Serum creatinine ≥ 2 times baseline or ≥ 2 times the 
upper limit of normal if baseline is < the upper limit of 
normal 
Other non-hematologic 
≥ Grade 3 as per NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0** 
 
* ≥ Grade 3 nausea, vomiting, or diarrhea with maximal supportive treatment(s) will be 
considered dose-limiting. Grade 3 fatigue or anorexia will not be considered dose 
limiting.    
 
7.3.4 MTD Determination 
 
7.3.4.1 MTD is defined as the dose level below the lowest dose that induces 
dose-limiting toxicity in at least one-third of patients (at least 2 of a 
12  (MTD) 
300 
3 
13 
400 
3 

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maximum of 6 new patients).  A total of 6 patients treated at the MTD 
will be sufficient to identify common toxicities at the MTD.  For 
instance, those toxicities with an incidence of at least 25% will be 
observed with a probability of at least 82 % (1-(1-0.25). 
 
7.3.4.2 Three patients will be treated at a given dose level combination and 
observed for at least 4 weeks to assess toxicity. 
 
7.3.4.3 If dose-limiting toxicity (DLT) is not seen in any of the 3 patients, 3 new 
patients will be accrued and treated at the next higher dose level.  If DLT 
is seen in 2 or 3 of 3 patients treated at a given dose level, then the next 
3 patients will be treated at the next lower dose level, if only 3 patients 
were enrolled and treated at this lower dose level.  
 
7.3.4.4 If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level.  If 
DLT is seen in at least one of these additional three patients (≥ 2 of 6), 
the MTD will have been exceeded, and further accrual will cease to 
this cohort (see 7.55 for further details).  If potentially dose-limiting 
toxicity (DLT) is not seen in any of the three additional patients, 3 new 
patients will be accrued and treated at the next higher dose level. 
 
7.3.4.5 After enrolling 6 patients on a specific dose level, if DLT is observed in 
at least 2 of 6 patients, then the MTD will have been exceeded and 
defined as the previous dose unless only 3 patients were treated at the 
lower dose level.  In that case, 3 additional patients will be treated at this 
lower dose level.  
 
 
7.3.5 
Dose De-Escalation 
 
If dose-limiting toxicity is seen at dose level 1, patients will be entered at a dose 
level of -1.  If no dose-limiting toxicity is seen at this dose, further patients will be 
accrued at the dose level of 1. 
 
If dose de-escalation is required at dose level 2, the dose will be reduced to level  
-1a instead of dose level -1 (see section 7.2).   
 
 
7.3.6 Unable to Complete Initial therapy 
 
If a patient fails to complete the initial course of therapy (defined as drug administration 
and 4 weeks observation) for reasons other than toxicity, the patient will be regarded as 
uninformative with respect to the goals of the study treatment and an additional patient 

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will be treated at the current dose level; however, all toxicity information will be utilized 
in the analysis.   
7.3.7 Missed Does of Topotecan 
If a patient misses 2 doses of topotecan for grade 3 neutropenia or 
thrombocytopenia, the patient will be regarded as treatment intolerant and an 
additional patient will be treated at the current dose level.  However, all toxicity 
information will be utilized in the analysis.  
 
In the dose expansion cohort and phase 2 portion of this trial, ABT-888 and 
topotecan will be administered at the same dose and schedule as the MTD 
determined during the phase I portion of the study.  This dose has been 
established at Dose Level 12 (300 mg twice a day of ABT-888 and 3 mg/m2 
topotecan per schedule as described in Section 7.1)  
 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table until individual treatment tolerance can be 
ascertained.  If multiple adverse events are seen, administer dose based on greatest 
reduction required for any single adverse event observed.  Dose modifications apply to 
the treatment given in the preceding cycle and are based on adverse events observed since 
the prior dose.  Omitted doses will not be made up.  
 
ALERT:  ADR reporting may be required for some adverse events.  See Section 10. 
 
Note: The Phase 1 Dose Escalation part of the study is completed; the phase 2 MTD part of 
the study is open 
 
Phase 1 
BASED ON INTERVAL ADVERSE EVENTS 
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENTS 
DOSE  
MODIFICATIONS* 
 
Investigations 
Neutrophil count decreased < 500 
and/or 
Platelet count decreased < 25, 000 
 
 
ABT-888 
and 
Topotecan 
Omit therapy until neutrophil 
≥ 1500 and/or platelets  
≥ 100,000, and decrease 
topotecan dose only by 2 dose 
levels (if dose level 1, 
decrease by 1 dose level); 
treatment will be discontinued 
if toxicity persists beyond 14 
days.  

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Neutrophil count decreased 500 - 1000 
and/or   
Platelet count decreased 25,000 – 
50,000 
         
Omit therapy until neutrophils 
≥ 1500 and/or platelets  
≥ 100,000, and decrease 
topotecan dose only by 1 dose 
level; treatment will be 
discontinued if toxicity 
persists beyond 14 days.  
Other 
 
 
Non-hematologic 
Grade 3 or 4 
           
ABT-888 
and 
Topotecan 
Omit therapy until severity 
decreases to grade 0-1 and 
decrease topotecan dose only 
by one level; treatment will be 
discontinued if toxicity 
persists beyond 14 days.  
 
AT SCHEDULED RETREATMENT (Day 1) 
Investigations 
Neutrophil count decreased < 500 
and/or 
Platelet count decreased < 25, 000 
 
 
ABT-888 
and 
Topotecan 
Hold therapy (up to 14 days) 
until neutrophils ≥ 1500 and/or 
platelets ≥ 100,000, and 
decrease topotecan dose only 
by 2 dose levels (if dose level 
1, decrease, by one dose level; 
treatment will be discontinued 
if toxicity persists beyond 14 
days. 
Neutrophil count decreased 500 - 1000 
and/or   
Platelet count decreased 25,000 – 
50,000 
 
Hold therapy (up to 14 days) 
until neutrophils ≥1500 and/or 
platelets ≥ 100,000, and 
decrease topotecan dose by 1 
dose level; treatment will be 
discontinued if toxicity 
persists beyond 14 days. 
Other 
 
Non-hematologic 
Grade 3 or 4 
ABT-888 
and 
Topotecan 
Hold therapy (up to 14 days) 
until severity decreases to 
grade 0-1 and decrease 
topotecan dose only by one 
level; treatment will be 
discontinued if toxicity 
persists beyond 14 days 
* Topotecan should be reduced to the next lower dosage.    
 
 

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Phase 2  
BASED ON INTERVAL ADVERSE EVENTS 
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENTS 
DOSE  
MODIFICATIONS* 
Investigations 
Neutrophil count decreased < 500 
and/or 
Platelet count decreased < 25, 000 
 
ABT-888 
and 
Topotecan 
Omit therapy until neutrophils 
≥ 1500 and/or platelets ≥ 
100,000, and decrease 
topotecan dose to 2 mg/m2 
. Decrease the ABT-888 to 
200 mg twice daily at second 
occurrence and to 150 mg 
twice daily at third 
occurrence.  Treatment will be 
discontinued if toxicity 
persists beyond 14 days. 
Neutrophil count decreased 500 - 1000 
and/or   
Platelet count decreased 25,000 – 
50,000 
 
Omit therapy until neutrophils 
≥ 1500 and/or platelets ≥ 
100,000, and decrease 
topotecan dose only to 2.5 
mg/m2  Decrease the 
topotecan to 2 mg/m2 at 
second occurrence and 
decrease ABT-888 to 200 mg 
twice daily at third 
occurrence. Treatment will be 
discontinued if toxicity 
persists beyond 14 days.  
Other 
 
 
Non-hematologic 
Grade 3 or 4 
           
ABT-888 
and 
Topotecan 
 
Omit therapy until severity 
decreases to grade 0-1 and 
decrease topotecan dose only 
to 2.5 mg/m2 ; treatment will 
be discontinued if toxicity 
persists beyond 14 days. Dose 
modification of ABT-888 is 
left to physician discretion 
(consider the dose reductions 
as per hematologic toxicities). 
 
 
If dose limiting toxicities persist beyond three dose reductions, consider discontinuation of 
the study unless evidence of stable disease or disease response. 
 
 

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Phase 2 
AT SCHEDULED RETREATMENT (day 1) 
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENTS 
DOSE  
MODIFICATIONS* 
Investigations 
Neutrophil count decreased < 500 
and/or 
Platelet count decreased < 25, 000 
 
ABT-888 
and 
Topotecan 
 
Hold therapy (up to 14 days) 
until neutrophils ≥ 1500 
and/or platelets ≥ 100,000, 
and decrease topotecan dose 
only to 2 mg/m2; treatment 
will be discontinued if 
toxicity persists beyond 14 
days. Decrease the ABT-888 
to 200 mg twice daily at 
second occurrence and to 150 
mg twice daily at third 
occurrence.   
Neutrophil count decreased 500 – 1000  
and/or 
Platelet count decreased 25, 000 -  
50,000 
Hold therapy (up to 14 days) 
until neutrophils ≥ 1500 
and/or platelets ≥ 100,000, 
and decrease topotecan dose 
only to 2.5 mg/m2  Decrease 
the topotecan to 2 mg/m2 at 
second occurrence and 
decrease ABT-888 to 200 mg 
twice daily at third 
occurrence. Treatment will be 
discontinued if toxicity 
persists beyond 14 days.  
Other 
 
Non-hematologic 
Grade 3 or 4 
Hold therapy (up to 14 days) 
until severity decreases to 
grade 0-1 and decrease 
topotecan dose only to 2.5 
mg/m2 ; treatment will be 
discontinued if toxicity 
persists beyond 14 days. Dose 
modification of ABT-888 is 
left to physician discretion 
(consider the dose reductions 
as per hematologic toxicities). 
 
 
If dose limiting hematologic toxicities persist beyond three dose reductions, consider 
discontinuation of the study unless evidence of stable disease or disease response. 
 

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9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Colony Stimulating Factors 
Routine use of colony-stimulating factors (G-CSF or GM-CSF) is not recommended.  
Prophylactic use of colony-stimulating factors during the study is not allowed during 
cycle one of therapy; prophylactic use may be employed, at physician discretion, if a 
patient has developed grade 3 or 4 neutropenia during a previous cycle.  Therapeutic use 
in patients with serious neutropenic complications such as tissue infection, sepsis 
syndrome, fungal infection, etc., may be considered at physician discretion.  
Recombinant erythropoietin to maintain adequate hemoglobin levels and packed red 
blood cell transfusions are allowed. 
 
9.2 
Full Supportive Care 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such as 
antidiarrheals, analgesics, and anti-emetics received from the first administration of study 
drugs until 30 days after the final dose are to be recorded in the medical record. 
 
9.3 
Concurrent Enrollment on Any Other Therapeutic Study 
Patients participating in this clinical trial are not to be considered for concurrent 
enrollment in any other study involving a pharmacologic agent (drugs, biologics, 
immunotherapy approaches, gene therapy) whether for symptom control or therapeutic 
intent. 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Common Terminology Criteria 
This study will utilize the Common Terminology Criteria for Adverse Events (v4.0) for 
adverse event (AE) monitoring and reporting.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0. The CTCAE version 4.0 can be 
accessed from the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.).   
 
10.1.1 Adverse Event Monitoring 
 
Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE.  Next, 
determine whether the event is expected or unexpected (as reflected with the 
CTEP Agent Specific Adverse Event List [ASAEL], see Sections 10.12 and 15.0) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.13).  With this information, determine whether an adverse event 
should be reported as an expedited report (see Section 10.2) in addition to the 
routinely reported clinical data (see Sections 10.3 and 18.0). 
 

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Expedited adverse event reporting under a CTEP Investigational New Drug 
Application (IND) requires submission of a CTEP Adverse Event Reporting 
System (CTEP-AERS) report(s).  Other expedited reporting requirements and 
systems may also apply.  Expedited reports are to be completed within the 
timeframes and via the mechanisms specified in Sections 10.2 and 10.3. 
 
 
10.1.2 Expected vs. Unexpected Events  
 
Agents provided under a CTEP IND: 
• Expected AEs for expedited reporting purposes are listed on the 
ASAEL. The ASAEL is a component of the Comprehensive 
Adverse Events and Potential Risks List (CAEPR).  Refer to 
Section 15.0 of this protocol to locate the CAEPR for the CTEP 
IND agent(s). 
 
• Unexpected AEs are those not listed in the ASAEL.  
 
Non-CTEP IND agents: 
• The determination of whether an AE is expected for commercial 
agents is based on agent-specific adverse event information 
provided in Section 15.0 of the protocol. 
 
• Unexpected AEs for commercial agents are those not listed in the 
agent-specific adverse event information provided in Section 15.0 
of the protocol. 
 
10.2 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the investigational agent(s). 
Probable - The adverse event is likely related to the investigational agent(s). 
Possible - The adverse event may be related to the investigational agent(s). 
Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
Unrelated - The adverse event is clearly NOT related to the investigational agent(s). 
 
 
Additional instructions for trials that include both investigational agent(s) (those under 
an IND) and a commercial agent(s): 
 
When an investigational agent (an agent under an IND) is used in combination with a 
commercial agent(s) on the same treatment arm, the combination is considered 
investigational.  Expedited reporting will follow the requirements for investigational 
agents.  However, if the event occurs prior to the participant having received any 

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investigational agent, expedited reporting may follow the requirements for commercial 
agents. 
 
10.3 
Expedited Adverse Event Reporting Requirements 
 
10.3.1 CTEP Expedited AE Investigational Agent Reporting Requirements 
 
Phase 1 Trials Utilizing an Agent under a CTEP IND:  CTEP-AERS Reporting 
Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of 
the Investigational Agent 
 
Note:  All deaths on study must be reported using expedited reporting regardless of  
causality.  Attribution to treatment or other cause should be provided. 
 
• 
Expedited AE reporting timelines defined: 
 “24 hours; 3 calendar days” – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 3 calendar days of the initial 24-hour report. 
 “7 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
Unexpect
ed 
 
 
Expected 
Unexpected 
Expected 
Unexpected 
and 
Expected 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
7 
Calendar 
Days 
Not 
Required 
7 
Calendar 
Days 
Not 
Required 
24-Hour; 
3 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
24-Hour; 
3 
Calendar 
Days 
24-Hour; 
3 
Calendar 
Days 
7 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days 
after the last dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS  24-hour notification followed by complete report within 5 calendar days for: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 4 unexpected events  
• Grade 5 expected events and unexpected events 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive 
disease, a full report is required as outlined in the table. 
 
December 15, 2004 

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hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
 
• Use the NCI protocol number and the protocol-specific patient ID provided during    
trial registration on all reports. 
 
• SECONDARY MALIGNANCIES (defined as “cancer caused by treatment for a 
previous malignancy”, e.g., treatment with radiation or chemotherapy) are to be 
reported through CTEP-AERS, as noted in Section 10.22.  Secondary malignancies 
are not considered metastasis of the initial neoplasm.  Secondary malignancy is 
unrelated to the first cancer that was treated, and may occur months or even years 
after initial treatment.   
 
Note:  Second Primary malignancy (malignancy not due to prior treatment) should 
not be reported through CTEP-AERS.  
 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements  
 
In the rare event when Internet connectivity is disrupted, a 24 hour notification 
must be made to NCI by telephone.  An electronic report must be submitted 
immediately upon establishment of internet re-connection.  Refer to section 10.24 
for NCI Contact Information or Technical Help regarding CTEP-AERS reporting. 
 
Mayo Clinic Cancer Center (MCCC) Institutions:  Fax copies of the UPIRTSO and 
cover sheet to the MCCC Regulatory Affairs Unit (RAU) Risk Information Specialist 
at (507) 538-7164.  The RAU will determine and complete IRB reporting and send to 
the MCCC SAE Coordinator. 
 
10.3.2 Other Required Reporting 
 
Event 
REPORTING PROCEDURE 
Other Grade 4 or 5 
Events and/or Any 
Hospitalizations During 
Treatment Not Otherwise 
Reportable 
Complete a Notification Form: Grade 4 or 5 Non-AER Reportable 
Events/Hospitalization Form electronically via the MCCC Remote 
Data Entry System within 5 working days of the date the clinical 
research associate (CRA) is aware of the event(s) necessitating the 
form. 
If CTEP-AERS or other expedited report has been submitted, this 
form does not need to be submitted. 

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10.3.3 Contact Information for NCI Safety Reports 
 
Website for submitting expedited  reports 
https://webapps.ctep.nci.nih.gov/openapps/plsql/gctep-
aersmain$.startup 
CTEP-AERS MD Help Phone (for CTEP)* 
301-897-7497 Monday through Friday, 7:00 AM to 
7:00 PM (US Eastern Time) 
CIP Help Phone for SAE reporting* 
301-897-1704 Monday through Friday, 7:00 AM to 
7:00 PM (US Eastern Time) 
Fax for expedited report supporting Medical 
Documentation for CTEP trials 
301-230-0159 (back-up FAX:  301-897-7404) 
Fax for expedited report supporting Medical 
Documentation for CIP trials 
301-897-7402 
CTEP-AERS MD Help Email: 
 CTEP-AERSmd@tech-res.com 
CIP SAE Reporting Email 
CIPSAEReporting@tech-res.com 
Technical (e.g., IT or computer issues 
ONLY) Help Phone* 
1-888-283-7457 or 301-840-8202 
CTEP-AERS Technical Help Email 
ncictephelp@ctep.nci.nih.gov.  
CTCAE v4 Help/Questions Email 
ncictcaehelp@mail.nih.gov 
CTEP-AERS FAQs link 
https://webapps.ctep.nci.nih.gov/ctep-html/adr_faq.htm 
CTEP-AERS Computer Based Training  link 
http://ctep.cancer.gov/reporting/ CTEP-AERS 
_CBT_v3/start.html 
*Office phone and fax are accessible 24 hrs per day 7 days a week (The CTEP-AERS MD phone 
line is staffed from Monday through Friday, 7:00 AM to 7:00 PM ET.  Any phone call after these 
hours will go to voicemail.  Please leave contact information and the phone call will be returned 
the following business day. 
 
 
 

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10.4 
Adverse Events to be Graded 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per Common Terminology Criteria for Adverse Events (CTCAE) 
v 4.0 grading unless otherwise stated: 
 
System Organ Class 
(SOC) 
Adverse Event 
Baseline 
Each 
evaluation 
 
 
Alopecia 
X 
X 
Skin and subcutaneous 
tissue disorders 
Pruritus 
X 
X 
 
Rash maculo-papular 
X 
X 
Blood and lymphatic system 
disorders 
Anemia 
X 
X 
 
 
Neutrophil count decreased 
X 
X 
Investigations 
Platelet count decreased 
X 
X 
 
White blood cell decreased 
X 
X 
 
Weight loss 
X 
X 
 
Creatinine increased 
X 
X 
 
Nausea 
X 
X 
 
Vomiting 
X 
X 
Gastrointestinal disorders 
Number of Stools per day 
X 
 
 
Diarrhea 
 
X 
 
Constipation 
X 
X 
Metabolism and nutrition  
Anorexia 
X 
X 
disorders 
Dehydration 
X 
X 
General disorders and 
administration site 
conditions 
Gait disturbance 
X 
X 
 
Fatigue  
X 
X 
Nervous system disorders 
Tremor 
X 
X 
 
Seizure 
X 
X 
 
10.4.1 Phase II only: Submit the following AEs experienced by a patient and not 
specified in Section 10.3: 
 
10.4.1.1 Grade 1 and 2 AEs deemed possibly, probably, or definitely related to 
the study treatment or procedure. 
 
10.4.1.2 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure 
 
 

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10.4.1.3 Grade 5 AEs (Deaths) 
 
10.4.1.3.1 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure 
 
10.4.1.3.2 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
11.0 
Treatment Evaluation 
 
For the purposes of this study, patients should be re-evaluated every 8 weeks.  In addition 
to a baseline scan, confirmatory scans should also be obtained 8 weeks following initial 
documentation of objective response.  Modified Response Evaluation Criteria in Solid 
Tumors (RECIST) criteria will be used. 
 
11.1 
Definitions 
 
11.1.1 
Measurable disease: the presence of at least one measurable lesion.  If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should 
be confirmed by cytology/histology. 
 
11.1.2 
Measurable lesions: lesions that can be accurately measured in at least one 
dimension with longest diameter > 20 mm.  With spiral CT scan, lesion must be 
> 10 mm in at least one dimension. 
 
11.1.3 
Non-measurable lesions: all other lesions, including small lesions (longest 
diameter < 20 mm with conventional techniques or < 10 mm with spiral CT) 
and other non-measurable lesions.  These include: bone lesions; leptomeningeal 
disease; ascites; pleural /pericardial effusion; inflammatory breast disease; 
lymphangitis cutis/pulmonis; abdominal masses that are not confirmed and 
followed by imaging techniques; and cystic lesions. 
 
11.2 
Response Criteria 
 
11.2.1 
Evaluation of Target Lesions 
 
A maximum of 3 measurable lesions should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically).  
A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD.  The baseline sum LD will be used as 
reference to further characterize the objective tumor response of the measurable 

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dimension of the disease. 
 
Complete Response (CR): Disappearance of all target lesions 
 
Partial Response (PR): At least 30% decrease in the sum of the longest diameter 
(LD) of target lesion taking as reference the baseline sum LD. 
 
Progression (PD): As least a 20% increase in the sum of LD of target lesions 
taking as reference the smallest sum LD recorded since the treatment started or 
the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as references the smallest sum LD. 
 
11.2.2 
Evaluation of Non-Target Lesions 
 
All other lesions (or sites of disease) should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements are not required, and 
these lesions should be followed as “present” or “absent.” 
 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor maker level. 
 
Non-Complete Response: (Non-CR): Persistence of one or more non-target 
lesions or/and maintenance of tumor marker level above the normal limits. 
 
Progression (PD): Appearance of one or more new lesions.  Unequivocal 
progression of existing non-target lesions.  Although a clear progression of 
“non-target” lesions only is exceptional, in such circumstances, the opinion of 
the treating physician should prevail, and the progression status should be 
confirmed at a later time by the review panel (or study chair). 
 
Note: 
• 
If tumor markers are measured and are initially above the upper 
normal limit, they must normalize for a patient to be considered in 
complete clinical response.   
 
• Cytology and histology. 
If the measurable disease is restricted to a solitary lesion, its  
neoplastic nature should be confirmed by cytology/histology. 
 
These techniques can be used to differentiate between PR and CR in 
rare cases (for example, residual lesions in tumor types such as germ 
cell tumors, where known residual benign tumors can remain).  
 
The cytological confirmation of the neoplastic origin or any effusion 

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that appears or worsens during treatment when the measurable tumor 
has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a 
side effect of the treatment) and progressive disease. 
 
11.2.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Target  
Lesions 
Non-Target 
Lesions 
New  
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ 
Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression 
at that time should be reported as “symptomatic deterioration.”  Every effort 
should be made to document the objective progression even after 
discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue.  When the evaluation of complete response depends upon this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
All measurements should be recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
 
Note: Tumor lesions in a previously irradiated area are not optimally considered 
measurable disease. 
 

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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment. 
 
• Clinical lesions will only be considered measurable when they are superficial 
(e.g. skin nodules, palpable lymph nodes).  In the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of 
the lesion is recommended. 
 
• Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable. 
 
• Conventional CT and MRI should be performed with cuts of 10mm or less in 
slice thickness contiguously.  Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm.  This applies to the chest, abdomen, and 
pelvis.  Head and neck and extremities usually require specific protocols. 
 
11.4 
Duration of Response 
 
11.4.1 
Confirmation 
 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat studies that should be performed 4 weeks after the criteria 
for response are first met.  In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 
8 weeks. 
 
11.4.2 
Duration of Overall Response 
 
The duration of overall response is measured from the time measurement 
criteria are met for CR/PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease that smallest measurements recorded since the treatment 
started). 
 
The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that recurrent 
disease is objectively documented. 
 
11.4.3 
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.  
 

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12.0 
Descriptive Factors 
 
12.1 
Number of Prior Chemotherapy Regimens 
 
12.2 
Dose Level  
(Phase 1 only): To be assigned by Registration Office): -2 vs. -1 vs. 1 vs. 2 vs. 3 vs.   4 
vs. 5 vs. 6 vs. 7 vs. 8 vs. 9 vs. 10 vs. 11 vs. 12 vs. 13 
 
12.3 
BRCA Status  
Mutated vs. normal 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
 
13.1 
No Progressive Disease (PD) 
Patients who have not had PD at time of their reassessment and have not experienced 
intolerable toxicity will be allowed to continue protocol treatment at the same dose level 
until PD. 
 
13.2 
No PD, Unacceptable Toxicity 
Those patients who have not had PD but have experienced unacceptable toxicity may be 
eligible for retreatment at a lower dose (see Section 8.0). 
 
13.3 
Progressive Disease / Refuse Further Treatment 
Those patients with PD or who refuse further treatment will go off treatment and will be 
followed for the purpose of this study as described in Section 18.0. 
 
13.4 
Off Protocol Treatment 
Patients who go off protocol treatment for reasons other than PD will be followed for the 
purpose of this study as described in section 18.0.  
 
13.5 
Cohort 1 Dose Escalation 
If a patient enrolled to Cohort 1 dose escalation part of the study fails to complete the 
initial course of therapy (defined as drug administration and 4 weeks observation) for 
reasons other than dose-limiting toxicity defined adverse events, the patient will be 
regarded as uninformative in regard to the primary study goal and an additional patient 
will be treated at the current dose level; however, all toxicity information will be utilized 
in the analysis. 
 
13.6 
Major Violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study (Phase 

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2) or 3 months of follow-up (Phase 1).  The patient may continue treatment off-protocol 
at the discretion of the physician as long as there are no safety concerns, and the patient 
was properly registered.   
 
13.7 
Ineligible  
A patient is deemed ineligible if after registration, it is determined that the patient did not 
satisfy each and every eligibility criteria for study entry.   
 
• If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Follow-up will be required per Section 18.0 
of the protocol (Phase 1 dose escalation and MTD, and Phase 2 patients). 
• If the patient never received treatment,  
o Phase 1 MTD and Phase 2 patients only: on-study material must be 
submitted. No further data submission is necessary.  
o Phase 1 dose escalation patients: refer to section 13.5 for patient 
replacement if possible. On-study material must be submitted. No 
further data submission is necessary 
 
13.8 
Cancel  
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  Phase 1 patients will be replaced at that dose level and no 
further data submission is necessary.  On-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted for all patients. No further data 
submission is necessary. 
 
 

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14.0 
Body Fluid Biospecimens 
 
NOTE: Patients must have consented to submission of the biospecimen(s) listed in the 
following table.  Label all specimens with protocol number, patient initials, patient study 
number, date of birth, collection date, visit and timepoint. 
 
14.1 
Summary Table of Mandatory Biospecimens for This Protocol  
 
 
Note: The Phase 1 Dose Escalation part of the study is completed; the phase 2 MTD part of 
the study is open. 
 
Phase 1 Dose Escalation only 
Correlative Study 
Optional 
or 
Mandatory 
Type of 
Sample 
Collected 
Volume of 
Sample 
Collected 
Timepoints  
to collect 
Shipping 
and Storage 
Conditions 
Pharmacogenetics  
(Section 14.21) 
 
Mandatory 
Whole 
Blood, 
EDTA 
purple top 
tube 
One 10 mL 
tube 
Baseline 
 Refrigerate/ 
Cold Pack 
(Section 
14.31)  
Possible BRCA1 and 
BRCA2 sequencing 
(Section 14.21) 
Mandatory 
Whole 
Blood, 
EDTA 
purple top 
tube 
One 10 mL 
tube 
Baseline 
Refrigerate/ 
Cold Pack 
(Section 
14.31) 
PBMCs 
(Section 14.22) 
Mandatory 
Whole 
Blood,  
CPT 
tube 
One 10 mL 
tube 
Multiple 
timepoints 
(See Section 
14.42)1 
Ambient; 
(Section 
14.32) 
1  Timepoints to collect are at 0, 2, 4 and 8 h after ABT-888 administration on C1D1 and 
C1D2; and at 0, 2, 4 and 8 h after start of topotecan infusion on C2D2. 
 
 
 

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Phase 2 
Correlative Study 
Optional 
or 
Mandatory 
Type of 
Sample 
Collected 
Volume of 
Sample 
Collected 
Timepoints  
to collect 
Shipping 
and Storage 
Conditions 
Pharmacogenetics  
(Section 14.21) 
 
Mandatory 
Whole 
Blood, 
EDTA 
purple top 
tube 
One 10 mL 
tube 
Baseline 
Refrigerate/ 
Cold Pack 
(Section 
14.31) 
Possible BRCA1 and 
BRCA2 sequencing1 
(Section 14.21) 
Optional 
Whole 
Blood, 
EDTA 
purple top 
tube 
One 10 mL 
tube 
Baseline 
Refrigerate/ 
Cold Pack 
(Section 
14.31) 
 
 
1 If patient has had germline BRCA testing done by Myriad Laboratories, and the results are 
available for review, repeat germline BRCA testing will not be repeated.  If germline BRCA 
testing was done by other organizations, a genetic consultation report from a qualified 
medical profession confirming that the laboratory results should be recognized germ line 
deleterious BRCA1 or BRCA2 mutation or BRCA rearrangement is required to confirm the 
result. 
 
 
14.2 
Specimen Collection and Processing  
 
Collect blood specimens as indicated in the following sections of 14.2.   
 
 Ship specimens Monday – Thursday ONLY.  Do not send samples on weekends or 
holidays. 
 
The listed laboratories will process samples per Section 14.3. 
 
 
14.21 Pharmacogenetic and BRCA Sequencing Specimens  
 
One 10 mL EDTA whole blood specimen will be collected prior to treatment.  
Only one 10 ml tube in total is needed per patient. 
 
Whole bloodc specimens should be kept refrigerated and shipped with cold pack 
(do not freeze) the same day to: 
 
 
Mayo Clinic 
 
BAP Freezer 
 
Attn: BAP Supervisor 
150 Third Street SW 
 
Stabile SL-39 

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Rochester, MN 55902 
 
14.22 Peripheral Blood Mononuclear Cells (PBMCs) Phase 1 only 
 
One 10 mL CPT whole blood specimen will be collected at the following time 
points: 
 
• Cycle 1 Day 1: Draw blood at 0, 2, 4 and 8 hours after ABT-888. 
 
• Cycle 1 Day 2: Draw blood at 0, 2, 4 and 8 hours after ABT-888. 
 
• Cycle 2 Day 2: Draw blood at 0, 2, 4 and 8 hours after start of 
topotecan infusion. 
 
Thus, 12 samples will be collected for a total of 120 ml.   
 
Blood should be cooled to room temperature and delivered to the Kaufmann 
laboratory (Gonda 19-205B, Mayo Clinic Rochester), where peripheral blood 
mononuclear cells will be handled as specified by CTEP. 
 
Peripheral Blood Mononuclear Cell Specimens should shipped ambient on the 
same day as collected to: 
 
Mayo Clinic 
 
Attn: 
   
 
221  4th Ave SW 
 
Gonda 19-205B 
Rochester, MN 55905 
 
 
14.23 Pharmacokinetic Specimens (Blood; Phase 1 Only) 
 
10 mL aliquots of heparinized whole blood will be collected at the following time 
points:  
 
For ABT-888: On C1D1 and C1D2, prior to ABT-888 administration and at 15 
minutes, 30 minutes and 1, 2, 4, 6, 9 hours following administration.   
 
For Topotecan: On C1D1 and C1D2, prior to topotecan infusion; 15 and 30 
minutes after start of infusion and 15 minutes, 30 minutes, 1, 1.5, 3.5, 5.5 and 8.5 
hours after the end of the infusion.   
 
Blood samples will be collected in heparinized tubes and immediately cooled in 
an ice water bath.  Within 20 min of collection, blood will be delivered to the 
central laboratory to isolate plasma. 
 

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Blood will be subjected to centrifugation (2,000 rpm for 10 minutes) in a 
refrigerated centrifuge kept at 4°C.  Following centrifugation, the plasma will be 
aliquoted into at least two samples (one for topotecan and one for ABT-888), 
transferred to polypropylene tubes, capped and immediately frozen at -70°C. Tube 
labels must contain the following data:  patient identification code, date, and time 
elapsed after the oral dose (ABT-888) or after beginning of the 30–minute 
infusion (topotecan).  These same data should be recorded in nurses’ notes, on the 
flow sheet, and on the pharmacology reporting form that is to be sent with the 
samples.  
 
Pharmacokinetic Specimens for each patient should be stored at -20°C.  When all 
samples have been collected for each patient (ship each patient’s samples 
together), frozen plasma samples should be shipped on dry ice to: 
 
Mayo Clinic 
 
Pharmacology Shared Resource 
 
Attn: 
 
 
221 4th Avenue SW 
 
Gonda 19-151 
 
Rochester, MN 55905 
 
 
14.3 
Background/Methodology Information 
 
Patient Considerations 
 
All patients participating in the phase 1 study will be asked to provide blood samples 
during Cycle 1 and Cycle 2 of treatment.  Patients participating in the phase 2 portion of 
the trial will be asked to provide blood samples during Cycle 1 of treatment.  A heparin 
lock will be placed in the arm opposite the infusion device to facilitate this 
pharmacokinetic sampling.   
 
14.3.1 
Pharmacogenetics and Repair Gene Sequencing of Peripheral Blood 
Mononuclear Cell (PBMC) DNA  
 
DNA extraction and storage of DNA for future assays, including possible 
sequencing of the BRCA1, BRCA2 and other repair gene loci (Section 1.6) as 
well as pharmacogenetic assays (e.g., for genetic polymorphisms such as breast 
cancer resistance protein ABCG2 that may correlate with efficacy and 
tolerability) will be performed at the conclusion of the trial.  Dr. Elizabeth 
Swisher’s laboratory at the University of Washington will initially apply Next 
Generation sequencing to sequence the loci encoding BRCA1, BRCA2 and 
other repair genes known or suspected to be mutated in ovarian cancer (Walsh 
et al., 2011) from biopsy samples (see below) and, if abnormal, will sequence 
the germline DNA as well. Genomic DNA, if analyzed, will be screened for 
mutations of the repair gene(s) found to mutated in the cancer. Remaining DNA 

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will be stored frozen by BAP, according to patient consent information (see 
Section 6.9) until specific analyses are identified.  As protocols are developed, 
they will be presented for IRB review and approval.   
 
14.3.2 
Peripheral Blood Mononuclear Cells (Phase 1 Only) 
 
 laboratory will be evaluating the feasibility of monitoring 
poly(ADP-ribose) polymer in circulating peripheral blood mononuclear cells 
(phase I dose escalation portion of this study) to determine/follow the ability of 
ABT-888 to inhibit basal and topotecan-induced polymer formation. 
 
In brief, PBMCs will be isolated using CPT tubes, washed with Plasma-LyteA 
7.4, and quantitated on a hemocytometer.  During the course of the phase I trial, 
replicate aliquots of cells will be  
• snap frozen on liquid nitrogen for shipment to NCI for polymer 
measurement using a validated enzyme-linked immunoassay 
(Kinders et al., 2008);  
• ii) snap frozen on liquid nitrogen for shipment to the 
 lab, 
where polymer measurement will be performed using the Standard 
Operating Procedure provided to phase 2 investigators by CTEP; 
and 
•  iii) immediately lysed in SDS sample buffer under reducing 
conditions  
 
for shipment to the 
 lab, where polymer measurements will be performed 
using their standard protocol (Haince et al, 2004).  Results obtained in the 
 lab and CTEP reference lab will be compared. Because CTEP has 
tentatively decided not to assay polymer in conjunction with phase 2 trials of 
ABT-888, only samples ii) and iii) will be prepared in conjunction with the 
phase 2 portion of the trial. If the two assays yield comparable conclusions 
about the extent of ABT-888-induced polymer decrease in the phase 1 portion 
of this study, the less labor-intensive assay will be performed in conjunction 
with the phase 2 portion. If the two assays yield divergent results, the two 
assays will be compared to physical chemical assays for polymer as described 
previously by the 
 lab (Shah et al, 1996); and the more reliable assay 
performed. 
 
 
Samples should be shipped to: 
 
 
, PhD 
 
Université Laval Research Center 
 
Health and Environment Unit and Department of Medical Biology 
 
2705 Blvd Laurier, Rm 9700 
 
Québec, QC, G1V 4G2, Canada 
 
 

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14.3.3 
Pharmacokinetics (Blood) (Phase 1 Only) 
 
The Mayo Clinic Cancer Center Pharmacology Shared Resource will assess the 
plasma pharmacokinetics of topotecan and ABT-888 as indicated in Table 14.1.  
 
These samples will be analyzed for ABT-888 or topotecan as indicated using a 
validated high performance liquid chromatography assays for topotecan 
(Kaufmann et al., 2005) and ABT-888 (Kinders et al., 2008). 
 
 
14.4 
Results of Genetic Testing 
Because the results generated by the peripheral blood genetic testing for the BRCA1 and 
BRCA2 mutation have clinical relevance, all patients enrolled in the phase 2 portion who 
have not yet been tested for the BRCA1/BRCA2 mutations will be offered a Medical 
Genetics appointment to discuss testing within a CLIA-certified laboratory as well as 
discussion of results if results are requested. 
 
 
 
15.0 
Drug Information 
 
15.1 
ABT-888 (NSC 737664, IND #
 
 
15.1.1 
Background 
Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that recognizes 
DNA damage and facilitates DNA repair. Activation of PARP-1 and PARP-2 
enzymes is an essential step in the recognition of DNA damage that results in 
the poly(ADP-ribosyl)ation of many nuclear target proteins. PARP activity is 
essential for the repair of single-stranded DNA breaks through the base-excision 
repair (BER) pathways and is an important modulator of the nonhomologous 
end-joining and homologous recombination double-stranded break repair 
pathways. Consequently, inhibition of PARP should enhance the effects of 
DNA-damaging agents, including alkylators, platinums, topoisomerase poisons, 
and radiation therapies. 
 
15.1.2 
Formulation   
ABT-888 capsules are available from the National Cancer Institute (NCI) as 10 
mg, 20 mg, 40 mg, 50 and 100 mg immediate release capsules.  The inactive 
ingredients are microcrystalline cellulose, colloidal silicon dioxide, magnesium 
stearate, gelatin, sodium lauryl sulfate, and titanium dioxide.  It may contain 
FD&C blue#1, FD&C yellow #6, or FD&C yellow #5.  The capsules are packaged 
in HDPE bottles, and each HDPE bottle contains 16 capsules or 64 capsules. 
 
 

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15.1.3 
Preparation and Storage  
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).  
Storage: Store the original bottle at 150 to 250 C (590 to 770 F). 
Stability: Shelf-life stability studies for ABT-888 capsules are on-going. 
 
15.1.4 
Administration   
Administer ABT-888 orally without regards to meals.   
 
15.1.5 
Pharmacokinetic Information  
Pharmacokinetic results are available in a limited number of human subjects, 
who received either the oral solution or immediate release capsules given once 
or twice daily. 
 
a)  Absorption –  The absorption of ABT-888 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 ABT-888 were approximately dose-
proportional across the dose range studied, with minimal accumulation 
following BID dosing.  Food does not have a significant effect on ABT-888 
bioavailability. The administration of a high-fat meal had no significant effect 
on AUC and only caused a slight decrease in veliparib Cmax (17%) and a delay 
of approximately 1 hour in Tmax.   
 
b)  Distribution – The apparent volume of distribution (V/F) of ABT-888 was 
large, and oral clearance was rapid. 
 
c)  Metabolism – Results from in vitro analysis reveal that this agent is 
metabolized by multiple isoenzymes – CYP1A1, 2D6, 2C19 and 3A4. ABT-888 
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 ABT-888.  
 
 
d)  Excretion – The terminal half-life (t½) of ABT-888 is about 6 hours with 
minimal accumulation following multiple BID dosing.  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). ABT-888 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 ABT-888 and its metabolites.  Renal excretion is a major pathway 
in ABT-888 elimination.  Coadministration of ABT-888 with oxaliplatin, 
carboplatin, cisplatin, and topotecan should be used with caution in patients 

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with pre-existing renal impairment since the primary elimination route of all of 
these drugs is renal.  
 
15.1.6 
Potential Drug Interactions  
Nonclinical studies suggest ABT-888 is a substrate of P-gp, OCT2, and 
MATE1/MATE2K transporters.  Co-administration of ABT-888 with strong 
inhibitors of P-gp, OCT2, and MATE1/MATE2K drugs may result in a decrease 
of ABT-888 renal clearance and an increase in ABT-888 plasma concentration.  
Therefore, use caution when administering ABT-888 with strong inhibitors of P-
gp, OCT2, and MATE1/MATE2K drugs.  At high dose (e.g., 400 mg BID), ABT-
888 may inhibit OCT1 in the liver and MATE1/MATE2K in the kidney.  
 
Additional clinical studies also demonstrate that ABT-888 is a weak 
inhibitor/inducer of the major CYP450 enzymes such as CYP1A2, 2C8/9, 2C19, 
2D6, or 3A4/5; thus, potential drug-interactions with these CYP enzymes are not 
significant. 
 
In humans, ABT-888 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 pharmacokinetics.  Use caution when 
concomitantly administering oxaliplatin, carboplatin, cisplatin, and topotecan in 
patients with pre-existing renal impairment. 
 
 
15.1.7 
Known Potential Toxicities   
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Veliparib (ABT-888, NSC 737664) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (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 2.3, March 4, 20161 

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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); Infections and infestations - Other (shingles); Lung infection; Lymph gland 
infection; Mucosal infection; Sepsis; Skin infection; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; Injury, 
poisoning and procedural complications - Other (radiation proctitis) 
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; Musculoskeletal and connective tissue disorder - Other (muscle 
spasms); Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Myelodysplastic syndrome; Treatment related secondary malignancy; 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 - Hematuria; Proteinuria; Renal and urinary disorders - Other 
(dysuria) 
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; Palmar-plantar 
erythrodysesthesia syndrome; Pruritus; Purpura; Rash acneiform; Skin and subcutaneous tissue 
disorders - Other (nail bed changes) 
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. 
 
 
15.1.8 
Drug Procurement   
ABT-888 is supplied by Abbott Laboratories and distributed by the Division of 
Cancer Treatment and Diagnosis (DCTD).  Please specify the container size 
(i.e., 16 capsules/bottle and/or 64 capsules/bottle) in your Clinical Drug 
Request Form (CDR) when submitting it to PMB. 
 

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Drug Ordering: 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical 
Management Branch (PMB) policy requires that agent be shipped directly to the 
institution where the patient is to be treated.  PMB does not permit the transfer 
of agents between institutions (unless prior approval from PMB is obtained).  
The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an 
annual submission of FDA Form 1572 (Statement of Investigator), Curriculum 
Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure 
Form (FDF).  If there are several participating investigators at one institution, 
CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead investigator at that institution. 
In general, sites may order initial agent supplies when a subject is being 
screened for enrollment onto the study. 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the PMB 
Online Agent Order Processing (OAOP) application  Access to OAOP requires 
the establishment of a CTEP Identity and Access Management (IAM) account 
and the maintenance of an “active” account status and a “current” 
password.   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.   
 
The following are useful Links and Contacts: 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help:  

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ctepreghelp@ctep.nci.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) 
 
 
15.2 
Topotecan (Hycamtin®) 
 
15.2.1 
Background 
 Topotecan binds to topoisomerase I and stabilizes the cleavable complex so 
that relegation of the cleaved DNA strand cannot occur. This results in the 
accumulation of cleavable complexes and single-strand DNA breaks. Topotecan 
acts in S phase of the cell cycle. 
 
15.2.2 
Formulation  
Commercially available Injection, powder for reconstitution, as hydrochloride: 
4 mg [base] 
 
15.2.3 
Preparation, Storage and Stability 
Store intact vials at room temperature and protect from light. Reconstitute 
with 4 mL Sterile Water for Injection. This solution is stable for up to 28 
days at room temperature. Topotecan should be further diluted in 50-100 
mL of D5W or 0.9% Sodium Chloride. Refer to the treatment section for 
final dilution volume. This solution is stable for 24 hours at room 
temperature or up to 7 days under refrigeration.  
 
15.2.4 
Administration  
Administer IV piggyback over 30 minutes or by 24-hour continuous infusion. 
See specific administration instructions in the treatment section of the protocol. 
 
15.2.5 
Pharmacokinetic Information 
Distribution: Vdss of the lactone is high (mean: 87.3 L/mm2; range: 25.6-
186 L/mm2), suggesting wide distribution and/or tissue sequestering 
Protein binding: ~35% 
Metabolism: Undergoes a rapid, pH-dependent hydrolysis of the lactone 
ring to yield a relatively inactive hydroxyl acid in plasma; metabolized in 
the liver to N-demethylated metabolite 
Half-life elimination: I.V.: 2-3 hours; renal impairment: 5 hours; 
Excretion: I.V.: Urine (51%; 3% as N-desmethyl topotecan); feces (18%; 
2% as N-desmethyl topotecan) 
 
15.2.6 
Potential Drug Interactions  
 
Increased Effect/Toxicity: Filgrastim may cause prolonged and sever 
neutropenia and thrombocytopenia if administered concurrently with 

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topotecan; initiate filgrastim at least 24 hours after topotecan. Platinum 
derivatives (carboplatin, cisplatin, oxaliplatin) may enhance the 
adverse/toxic effects of topotecan; monitor for hematologic toxicity, 
especially if the platinum derivative is administered prior to topotecan. 
 
15.2.7 
Known Potential Adverse Events 
Consult the package insert for the most current and complete information 
including U.S. Boxed Warnings pertaining to severe diarrhea and severe 
myelosuppression. 
 
Common known potential toxicities, > 10%:   
Central nervous system: Fatigue, fever, pain, headache 
Dermatologic: Alopecia, rash 
Gastrointestinal: Nausea, vomiting, diarrhea, constipation, abdominal 
pain, anorexia, stomatitis 
Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia, 
neutropenic fever/sepsis 
Neuromuscular & skeletal: Weakness 
Respiratory: Dyspnea, cough 
 
Less common known potential toxicities, 1% - 10%:  
Hepatic: Transient increase in liver enzymes 
Neuromuscular & skeletal: Paresthesia 
Miscellaneous: Sepsis 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Abdominal pain, allergic reactions, anaphylactoid reactions, 
angioedema, bleeding (severe, associated with thrombocytopenia), 
dermatitis (severe), injection site reactions (mild erythema, 
bruising), neutropenic colitis, pancytopenia, pruritus (severe) 
 
15.2.8 
Drug Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal 
commercial supply chain or wholesaler. 
 
 
 
 
16.0 
Statistical Considerations and Methodology  
 
16.1 
Overview 
This is a phase 1/phase 2 study of the topotecan/ABT-888 combination.  The phase 1 
portion of this study is designed to determine the maximum tolerated dose (MTD) of this 
combination in patients with solid tumors.  The phase 2 portion  will use a 2-stage Simon 
design with interim analysis to assess the efficacy of ABT-888 and weekly topotecan in 

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ovarian cancer and primary peritoneal cancer patients with platinum resistant disease.  
The MTD determined in the phase 1 portion of the trial will be used as the starting dose 
for the phase 2 portion.  
 
16.1.1 
Primary Endpoint 
The primary endpoint of the phase 1 portion of this trial is to find the MTD of 
topotecan+ABT-888.  For the phase 2 portion of the trial, the primary endpoint 
is confirmed response.  Throughout section 16.0, confirmed response will be 
considered synonymous with “success” for the phase 2 portion of this study, 
unless speficied otherwise. 
 
16.1.2 
Sample Size 
The phase 1 portion of this study is expected to require a minimum of 9 patients 
and a maximum of 102 patients The phase 2 portion of this study is expected to 
require a minumum of 26 and a maximum of 44 platinum resistant patients.  We 
anticipate accruing an additional 4 patients during the phase 2 portion of the 
trial to account for ineligibility, cancellation, major treatment violoation, or 
other reasons.  Therefore, the phase 2 portion is expected to accrue a maximum 
of 44 patients and overall sample size will be a maximum of 48 patients. 
 
16.1.2.1 
At the time of Amendment 11 (i.e. after the MTD was determined), 
there were 58 patients accrued to the study.  Since the phase 2 
portion requires between 26 and 44 evaluable patients, and 48 total 
patients to account for ineligibility, cancellation, major treatment 
violation, or other reasons, the maximum study accrual will be 106 
(58+48). 
 
16.1.3 
Accrual Rate and Study Duration 
The anticipated accrual rate for cohort 1 is 3 patients per month.  At this rate, it 
will likely take about 2 months to enroll, treat, and evaluate each set of 3 
patients in the phase 1 portion of this study.  The phase 1 portion is expected to 
take between 7 and 14 months.  The anticipated accrual rate for cohort 2 is 
approximately 1-2 patients per month for platinum resistant disease. Therefore, 
the accrual period is expected to be between 13 and 32 months, depending upon 
whether patients are accrued beyond the first stage.  The total study duration is 
expected to be approximately 38 months until the last patient accrued has been 
observed for at least 6 months. 
 
16.1.3.1  At the time of amendment 10, this study had accrued 36 patients to 
11 cohorts at 9 different dose levels.  This suggests it requires 
approximately 3.3 months to accrue and assess each phase 1 
cohort.  It is expected that at most 5 more cohorts (DL10, 11, 12, 13 
with a confirmatory cohort at level 12 or 13) will be required to 
determine the MTD.  This means it will take approximately 17 more 
months to complete the phase 1 accrual portion of this trial.  At 2 
patients per month for the MTD cohort and phase 2 portion, the 

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estimated maximum accrual time for these portions is 34 months 
(assuming the conservative rate of 1/month for the 20+44+4=68 
required patients).  The phase 2 portion for the trial also has a 
planned stop to assess the primary endpoint for the stage 1 
patients.  This stop will require at least 7 months (6 months for data 
maturation and 1 month for data entry).  In total, the estimated 
accrual duration, from ammendment 10 on is 58 months (17 for the 
phase 1 portion, 34 for accruing the MTD cohort and phase 2 
patients, and 7 months to assess the stage I patients).  Additionally, 
we will require another 7 months for data maturation and entry at the 
end of the phase 2 portion.  These estimates indicate that a final 
analysis can begin on the phase 2 primary endpoint approximately 
65 months from the date of amendment 10. 
 
16.1.3.2 
At the time of Amendment 11 (i.e. after the MTD was determined) 
update: At 2 patients per month, the phase II portion will require 24 
months to fully accrue.  Allowing for patient follow up (~6 months) 
and data entry (~1 month), the means that the final analysis can 
begin on the phase 2 primary endpoint approximately 31 months 
from the date of amendment 11. 
 
 
16.2 
Phase 1 Portion (Cohort 1) 
The phase I portion of this trial is a single arm phase I study utilizing cohort-of-3 design 
to determine the MTD of the combination of ABT-888 and weekly topotecan in the 
treatment of solid tumors.  
 
16.2.1 
MTD Determination   
MTD is defined as the dose level below the lowest dose that induces dose-
limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 
new patients).  See section 7.25 for the MTD determination and section 7.24 for 
DLT definitions. 
 
16.2.2 
Analysis Plans 
All the relevant results pertaining to toxicity, MTD, laboratory correlates will be 
examined in an exploratory and hypothesis-generating fashion. 
 
16.2.2.1 
Adverse Events Profile 
The number and severity of all adverse events (overall, by dose-
level, and by tumor group) will be tabulated and summarized in this 
patient population. The grade 3+ adverse events will also be 
described and summarized in a similar fashion. This will provide an 
indication of the level of tolerance for this treatment combination in 
this patient group 
 
16.2.2.2 
Toxicity Profile 

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The term toxicity is defined as adverse events that are classified as 
either possibly, probably, or definitely related to study treatment. 
Non-hematologic toxicities will be evaluated via the ordinal CTC 
standard toxicity grading. Hematologic toxicity measures of 
thrombocytopenia, neutropenia, and leukopenia will be assessed 
using continuous variables as the outcome measures (primarily 
nadir) as well as categorization via CTC standard toxicity grading. 
Overall toxicity incidence as well as toxicity profiles by dose level, 
patient and tumor site will be explored and summarized.   
 
Toxicity incidence by BRCA mutation will also be evaluated for the 
12-20 patients enrolled in the expanded phase I MTD cohort. 
Frequency distributions, graphical techniques and other descriptive 
measures will form the basis of these analyses. 
 
16.2.2.3 
Response   
Objective responses, as defined per RECIST, will be summarized by 
simple descriptive summary statistics delineating complete and 
partial responses as well as stable and progressive disease.  
 
We will exam response profile by BRCA mutation status in the 
MTD expansion cohort.  Data will be summarized descriptively. 
 
16.3 
Phase 2 Portion (Cohort 2) 
The phase 2 portion of this trial is a single arm two-stage phase 2 study to assess the 
response rate and toxicity of the combination of ABT-888 and weekly topotecan in the 
treatment of platinum resistant epithelial ovarian or primary peritoneal cancer. 
 
16.3.1 
Primary Endpoint 
The primary endpoint is the proportion of tumor responses.   Tumor response 
will be considered synonymous with success, unless specified otherwise.  A 
confirmed tumor response is defined to be a CR, or PR noted as the objective 
status on two consecutive evaluations at least 4-6 weeks apart.  Tumor response 
will be evaluated using all cycles of treatment.  All patients meeting the 
eligibility criteria who have signed a consent form and have begun treatment 
will be evaluable for response. 
 
16.3.2 
Decision Rule 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 15%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 30%.  The following two-stage 2-outcome design uses 
a minimum of 26 and a maximum of 44 patients to test the null hypothesis that 
the true success proportion in a given patient population is at most 15%: 
 
16.3.2.1 
STAGE 1 

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Enter 26 patients into study.  If 4 or fewer successes are observed, 
we will consider this regimen ineffective in this patient population 
and terminate the study.  Otherwise, if at least 5 successes are 
observed, we will proceed to Stage 2 and continue accrual.  
 
16.3.2.2 
STAGE 2 
The regimen will be considered ineffective in platinum resistant 
patients if either enrollment is discontinued after stage 1 or if 9 or 
fewer successes are observed in the first 44 evaluable patients.  This 
regimen will be considered promising in platinum resistant patients 
if 10 or more successes are observed in the first 44 evaluable 
patients. 
 
16.3.2.3 
Over Accrual 
 If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any 
decision making process.  Analyses involving over accrued patients 
are discussed in Section 16.45. 
 
16.3.2.4 
Suspension of Accrual 
We will not suspend accrual between stages to allow the first 20 
patients to become evaluable, unless undue toxicity is observed.  
Given the limited overall sample size and the inclusion of an adverse 
event stopping rule, we feel it is ethical to not halt accrual after the 
first stage.  However, if accrual is extremely rapid, we may 
temporarily suspend accrual in order to obtain safety data on these 
patients before re-opening accrual to further patients. 
 
16.3.3 
Power and Significance Level 
Assuming that the number of successes is binomially distributed, the 
significance level is 0.09, the probability of declaring that this regimen warrants 
further studies (i.e. statistical power) under various success proportions can be 
tabulated as a function of the true success proportion as shown in the following 
table. 
 
If the true response rate is… 
15% 20% 25% 30% 
…then the probability of 
declaring the regimen warrants 
further studies is… 
0.10 0.35 0.65 0.86 
…and the probability of 
stopping after stage 1 is… 
0.65 0.38 0.18 0.07 
 
16.3.4 
Other considerations: Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 

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changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.4 
Phase 2 Portion Analysis Plan 
 
16.4.1 
Primary Endpoint Analysis 
 
16.4.1.1 
Definition 
The primary endpoint is the proportion of tumor responses. Tumor 
response will be considered synonymous with success, unless 
specified otherwise.  A confirmed tumor response is defined to be a 
CR, or PR noted as the objective status on two consecutive 
evaluations at least 4-6 weeks apart.  Tumor response will be 
evaluated using up to 12 cycles of treatment.  All patients meeting 
the eligibility criteria who have signed a consent form and have 
begun treatment will be evaluable for response. 
 
16.4.1.2 
Estimation 
The proportion of successes will be estimated by the number of 
successes divided by the total number of evaluable patients.  
Confidence intervals for the trues success proportion will be 
calculated according to the approach of Duffy and Santner (1987). 
 
16.4.2 
Secondary Endpoint Analyses 
 
16.4.2.1 
Overall Survival 
Survival time is defined as the time from registration to death due to 
any cause.  The distribution of survival time will be estimated using 
the method of Kaplan-Meier (1958). 
 
16.4.2.2 
Progression-Free Survival   
Progression-free survival is defined as the time from registration to 
the earliest date documentation of disease progression or death due 
to any cause. The distribution of progression-free survival will be 
estimated using the method of Kaplan-Meier (1958) 
 
16.4.2.3 
Duration of Response  
Duration of response is defined for all evaluable patients who have 
achieved an objective response as the date at which the patient’s 
earliest best objective status is first noted to be either a CR or PR to 
the earliest date progression is documented.  
 
16.4.2.4 
Time to Treatment Failure 
Time to treatment failure is defined to be the time from the date of 
registration to the date at which the patient is removed from 
treatment due to progression, adverse events, or refusal. If the patient 

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is considered to be a major treatment violation or is taken off study 
as a non-protocol failure, the patient will be censored on the date he 
or she is removed from treatment. 
 
16.4.2.5 
Adverse Events 
Adverse events: All eligible patients that have initiated treatment 
will be considered evaluable for assessing adverse event rate(s). The 
maximum grade for each type of adverse event will be recorded for 
each patient, and frequency tables will be reviewed to determine 
patterns. Additionally, the relationship of the adverse event(s) to the 
study treatment will be taken into consideration. 
 
 
16.4.3 
Analysis of Correlative  Studies 
 
16.4.3.1 
To determine any differences in the toxicity and/or efficacy of this 
regimen based on BRCA1/2 mutational status: The primary endpoint 
is BRCA1 and BRCA2 mutation status.  The primary null hypothesis 
is that there is no association between mutation status and response 
rate or toxicity, as measured by dose limiting neutropenia.  Fisher’s 
exact test will be used to assess significance of relationships between 
mutation status and both response and toxicity.  In addition, 
associations between mutation status and progression free survival 
will be illustrated graphically using Kaplan-Meier curves and log-
rank tests in an exploratory fashion. 
 
16.4.3.2 
To assess whether pretreatment tumor cell levels of topo I, PARP, 
BRCA1, BRCA2, XRCC1, TDP1, P-glycoprotein or BCRP predict 
response to this regimen:   The primary endpoint is biomarker 
expression measured via IHC staining.  The primary null hypothesis 
is that there is no association between expression of a particular 
biomarker and response rate. The best response to therapy will be 
categorized as CR, PR and SD for > 2 cycles or PD. To assess the 
relationship between each potential marker and response, we will 
graph the values obtained for intensity (0, 1+, 2+ or 3+) and 
estimated percentage of positive cells (extent) vs. best response to 
therapy. In addition, staining intensity will be dichotomized two 
ways, high (2+ and 3+) vs. low (0 and 1+) or negative (0) vs. 
positive (1+, 2+ and 3+); extent will be dichotomized into low (e.g., 
≤ 25%) vs. high (> 25%); response will be dichotomized into (CR, 
PR) vs. (SD, PD) or benefit (CR, PR, SD) vs. no benefit (PD).  
 
Appropriateness of dichotomization cut-points will be examined 
based on the distribution of the outcomes. Prevalence of biomarker 
expression will be estimated along with 95% confidence intervals 
overall and within responders vs. non-responders. Fisher’s exact test 

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will be used to assess significance of relationships between these 
dichotomous variables and treatment response. In addition, 
associations between molecular markers and progression free 
survival will be illustrated graphically using Kaplan-Meier curves 
and log-rank tests in an exploratory fashion. 
 
16.4.3.3 
To explore the possibility that a particular transcriptional profile 
predicts response to this regimen:  Gene expression results will be 
used to test the hypothesis of differential expression between 
responders and non-responders.  Biological interpretation will be 
aided by pathway analysis.  In addition, log rank tests will be used to 
assess the association of gene expression with time to progression in 
an exploratory manner. 
 
16.4.4 
Over Accrual 
If more than the target number of patients is accrued, the additional patients will 
not be used to evaluate the stopping rule; however, they will be included in final 
endpoint estimates and confidence intervals. 
 
16.4.5 
Data and Safety Monitoring 
 
16.4.5.1 
This study will be monitored by the Phase 1 DOG.  The accrual 
report is available on the web site at 
http://hsrwww.mayo.edu/ccstumor/teams/phase1/phase1team.html.  
The accrual report is updated daily.  Toxicity, efficacy and 
administrative information for this trial will be reviewed by the study 
team routinely.   
 
16.4.5.2 
Phase 2 Adverse Event Stopping Rules 
 
The stopping rules specified below are based on the knowledge 
available at study development. We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study 
reopening to accrual or (2) at any time during the conduct of the trial 
and in consideration of newly acquired information regarding the 
adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected 
adverse event profiles that have not crossed the specified rule below.  
 
Accrual will be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment 
(i.e. an adverse event with attribute specified as “possible”, 
“probable”, or “definite”) that satisfy either of the following:  
 
Overall, if 3  out of the first 10  or if at any time 4 or more patients 
experience grade 4 non-hematologic toxicity, accrual to the study 

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will be suspended to allow for investigation.  After consideration by 
the study team (study chair, statistician) and consultation at the 
Phase 1 DOG,  a decision will be made as to whether accrual can be 
resumed.  
 
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and 
to monitor the emergence of a previously unrecognized treatment-
related adverse event. 
 
16.5 
Inclusion of Women and Minorities 
 
16.5.1 
This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.5.2 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason 
to expect such differences to exist. Therefore, although the planned analysis 
will, as always, look for differences in treatment effect based on racial and 
gender groupings, the sample size is not increased in order to provide additional 
power for subset analyses. 
 
16.5.3 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 3% of patients will be classified as minorities by 
race  There was 1 male in the phase 1 portion (out of 58) and 100% of patients 
will be women for the Phase 2 portion. Expected sizes of racial by gender 
subsets for patients registered to this study (Phase 1 and 2) are shown in the 
following table 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
3  
0  
0 
3 
Not Hispanic or Latino 
102  
1  
0 
103  
Ethnic Category: Total of all subjects* 
105  
1  
0 
106  
Racial Category 
 
American Indian or Alaskan Native 
1 
0 
0 
0  
Asian 
1 
0 
0 
1 
Black or African American 
1  
0  
0 
1  
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
0 
White 
102  
1  
0 
103  
Racial Category: Total of all subjects* 
105  
1  
0 
106  
 

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Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains 
tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, 
Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have 
been recorded as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black 
racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in 
addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any 
of the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 
 
 

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17.0 
Pathology Considerations/Tissue Biospecimens 
 
 
17.1 
Summary Table of Optional Biospecimens for This Protocol  
 
Phase 2 only 
 
Correlative  
Study 
Optional 
or 
Mandatory 
Type of 
Sample 
Collected 
Volume of 
Sample 
Collected 
Timepoints  
to collect 
Shipping and 
Storage 
Conditions 
Biomarkers 
(Section 17.21) 
Optional 
Tumor 
Biopsy 
21 
Baseline 
Snap Frozen; 
-80º C  
Biomarkers 
(Section 17.22) 
Optional 
Tumor 
Biopsy 
21 
Baseline 
Fixed in 10% 
buffered 
neutral 
formalin; 
Ambient  
 
1   Two tissue samples, half of each specimen from 2 needle passes 
 
 
 
Pretreatment biopsies will be obtained after registration and before day 1 therapy unless a 
biopsy including paraffin-embedded material and, preferably, flash frozen material is 
available since the patient’s most recent chemotherapy.  
 
Biopsies should be obtained by interventional radiology using two passes of an 18 gauge 
biopsy needle under ultrasound or CT guidance 
 
Half of each biopsy is to be fixed in 10% buffered neutral formalin.  The other half is to be 
snap frozen in liquid nitrogen, transferred to a properly marked cryovial that has been pre-
cooled to liquid nitrogen temperature, and stored at or below -80°C. 
 
Frozen Tumor Biopsies should shipped on dry ice when collected, and Formalin Fixed 
Paraffin Embedded Tissue should be shipped ambient when available to  Dr. Kaufmann’s 
Laboratory: 
 
 
 
Mayo Clinic 
 
Attn: 
   
 
221 4th Avenue SW 
 
Gonda 19-205B 
 
 
Rochester, MN 55905 
 
 
 

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17.2 
Background/Methodology 
 
During the phase 2 portion of this trial, optional pretreatment tumor biopsies may be 
obtained to assess BRCA1/2 mutational status as well as expression of polypeptides and 
messages that might correlate with response of ovarian cancer to the topotecan/ABT-888 
combination. 
 
Prior biopsies will also be obtained from archival material whenever available. 
 
17.2.1 
Formalin-Fixed Tissue 
 
Using a portion of the formalin-fixed biopsy material, the Tissue and 
Molecular Analysis Shared Resource of the Mayo Clinical Cancer Center will 
create a tissue microarray (TMA) that contains tumor material for pretreatment 
biopsies and, when available, at the time of diagnosis from all patients enrolled 
in the phase 2 portion of the trial. After review of the pertinent biopsies and 
identification of representative tumor areas by a pathologist specializing in 
gynecological oncology, the TMA will be created from patient blocks using a 
custom fabricated device that utilizes a 0.6 mm tissue corer and a mold for the 
216 capacity recipient block. These arrays will incorporate 3-5 cores from each 
specimen. The design of the array will be laid out on a spreadsheet, indicating 
column and row placement of each core, along with relevant tumor 
information. These TMAs will then be stained with antibodies that recognize 
the antigens of interest (see below) using standard histochemical techniques 
that will include dissolution of paraffin in xylene; rehydration; incubation with 
3% H2O2 in methanol to inactivate any endogenous peroxidases; microwave-
induced antigen retrieval; and sequential incubation with primary antibodies, 
biotinylated secondary antibody and horseradish peroxidase-labeled 
streptavidin (Chien et al, 2006).  Antibodies to be used in these studies will 
include the best commercially available antibody to the following antigens: 
topo I (e.g., clone 1A1, GeneTex), PARP1 (e.g., clone E102, Epitomics), 
BRCA1 (e.g., clone GLK-2, Dako), BRCA2 (e.g., clone 234403, R & D 
Systems), XRCC1 (e.g., clone 33-2-5 mouse monoclonal, Acris), TDP1 (e.g., 
polyclonal from ProteinTech), BCRP/ABCG2 (e.g., clone BXP-21, a gift from 
Jan Schellens to the Kaufmann laboratory), and ABCB1/P-glycoprotein (e.g., 
clones C219 and JSB-1, Novus).  
 
Stained TMAs will be scanned in the Tissue and Cell Molecular Analysis 
Shared Resource of the Mayo Clinic Cancer Center using a Bliss "Virtual 
Microscopy" microscope and computer system from Bacus Laboratories. The 
virtual slide will then be accessed (by a pathologist specializing in 
gynecological oncology) via the Mayo intranet and examined at high 
magnification so that each core can be scored for intensity of staining (0, 1+, 
2+, or 3+)  and estimated percentage of cells that are positive.  
 
 

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17.2.2 
Frozen Tissue 
 
Using a portion of the snap frozen tumor, the Swisher laboratory at the 
University of Washington will apply Next Generation sequencing to sequence 
the splice junctions and exons of roughly 50 repair genes, including BRCA1, 
BRCA2, BARD1, BRIP1, CDL12, CHEK2, MRE11A, MSH6, NBN, PALB2, 
RAD50, RAD51C, and TP53, that have been implicated in pathogenesis of 
familial and sporadic ovarian cancer.   
 
To complement the IHC experiments and provide an alternative approach to 
biomarker identification, correlations between pretreatment tumor transcript 
levels and clinical outcome will also be assessed. RNA will be isolated from 
aliquots of snap-frozen pretreatment biopsies obtained from all patients enrolled 
on the phase II portion of this trial as well as earlier biopsies (e.g., obtained at 
diagnosis) when available. In brief, 2 mm aliquots of snap-frozen tumor will be 
lysed in RNA isolation solution and purified using a Qiagen RNeasy kit. For 
paraffin-embedded samples, 1 mm punches will be taken from areas of interest; 
and RNA will be isolated from these cores using the Qiagen RNeasy FFPE kit. 
All further steps will be performed in the Microarray Core of the Mayo 
Advanced Genomics Technology Center. RNA will be analyzed using the 
Agilent BioAnalyzer 2100 to confirm that quality is sufficient for hybridization 
to arrays. Transcriptional profiling will then be completed by synthesis of 
cDNA and hybridization to Affymetrix U133 Plus 2.0 GeneChips, which assay 
expression on > 54,000 transcripts. Differences in Affymetrix profiles will be 
assessed in collaboration with a biostatistician who has an active interest in the 
analysis of transcriptional profiling experiments and a bioinformatics specialist 
from the Microarray Core using software provided by Affymetrix and 
Genespring, as well as more statistically efficient algorithms developed at 
Mayo.  
 
 
18. Study Oversight and Data Reporting/Regulatory Requirements 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10.0 
(Adverse Events: List and Reporting Requirements). 
 
18.1 
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.   
 

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During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators to review accrual, 
progress, and pharmacovigilance.  Decisions to proceed to the second stage of a Phase 2 
trial will require sign-off by the Protocol Principal Investigator and the Protocol 
Statistician through IWRS and Medidata Rave. 
 
All Study Investigators at participating sites who register/enroll patients on a given 
protocol are responsible for timely submission of data via Medidata Rave and timely 
reporting of adverse events for that particular study.  This includes timely review of data 
collected on the electronic CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety 
monitoring plan. 
 
18.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to 
the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles assigned in the Regulatory Support System (RSS).  To access Rave via 
iMedidata, the site user must have an active CTEP IAM account (https://eapps-
ctep.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, or Site 
Investigator) on either the Corresponding Organization or Participating Organization 
roster at the enrolling site.   
 
Upon initial site registration approval for the study in 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 users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata page.  
Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed.  Trainings will be 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.   
 
Users 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, Rave tab under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance).  Additional information on iMedidata/Rave 
is available on the CTSU members’ website under the Rave tab or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
18.2.1 
Method 
 

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The monitoring method will be determined by CTEP and communicated to you.  Please 
use the appropriate text relating to your assigned monitoring method, and DELETE any 
text relating to the unused monitoring methods. 
 
For studies assigned for CTMS Comprehensive Monitoring: 
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/CTMS.  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 ctms@theradex.com for additional support with Rave and completion of CRFs. 
 
 
For studies assigned for CTMS Routine Monitoring: 
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/CTMS.  On-site audits will be conducted on an 18-36 month 
basis as part of routine cancer center site visits. More frequent audits may be conducted if 
warranted by accrual or due to concerns regarding data quality or timely submission.  For 
CTMS monitored studies, after users have activated their accounts, please contact the 
Theradex Help Desk at (609) 799-7580 or by email at ctms@theradex.com for additional 
support with Rave and completion of CRFs. 
 
 
For studies assigned for CDUS monitoring (2 paragraphs): 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, 
July 31, and October 31.  Instructions for submitting data using the CDUS can be found 
on the CTEP Web site  
(http://ctep.cancer.gov/reporting/cdus.html). 
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.  
If your study has been assigned to CDUS-Abbreviated reporting, no adverse event 
reporting (routine or expedited) is required to be reported via CDUS, but expedited 
adverse events are still required to be submitted via CTEP-AERS. 
 
18.2.2 
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 

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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 e
vents.htm)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include 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 
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_e
vents.htm). 
19.0 
Budget  
 

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19.1 
Costs Charged to Patient 
• Routine clinical care 
• Topotecan 
 
 
19.2 
Tests to be Research Funded 
• Biopsy 
• Research blood tests 
 
19.3 
Other Budget Concerns 
Funding through the Ovarian SPORE will be provided for laboratory correlates during 
the Phase 2 portion of the study.   
 
 

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20.0 
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Patel, A. G., K. S. Flatten et al. (2012) "Enhanced killing of cancer cells by poly(ADP-ribose) 
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Oncogene 23(21): 3872-82. 
 

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Appendix I: ECOG Performance Status 
 
 
 
 
Grade 
 
0  
Fully active, able to carry on all pre-disease activities without restriction (Karnofsky 90-
100). 
 
1  
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work (Karnofsky 70-80). 
 
2  
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up 
and about more than 50 percent of waking hours (Karnofsky 50-60). 
 
3  
Capable of only limited self-care, confined to bed or chair 50 percent or more of waking 
hours (Karnofsky 30-40). 
 
4  
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
(Karnofsky 10-20). 
 
5  
Dead 

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Appendix II: New York Heart Association Classifications 
 
 
 
Clinical Evaluation of Functional Capacity of Patients  
with Heart Disease in Relation to Ordinary Physical Activity  
 
Class  
 
Cardiac Symptoms  
 
Limitations  
Need for 
Additional  
Rest* 
Physical Ability 
to work**
  
 
 
I  
None  
None  
None  
Full time  
 
 
 
 
 
II  
Only moderate  
Slight  
Usually only  
 
Usually full time 
 
 
 
slight or  
occasional 
 
 
 
III  
Defined, with  
Marked  
Usually  
Usually part  
 
less than  
 
moderate  
time  
 
ordinary activity  
 
 
 
 
 
IV  
May be present  
Extreme  
Marked  
Unable to work  
 
even at rest,  
 
and any activity  
 
increases discomfort 
 
 
_____________________________________________________ 
*  To control or relieve symptoms, as determined by the patient, rather than as advised by 
the physician.  
**  At accustomed occupation or usual tasks.  
Reference: Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956. (Modified from New 
York Heart Association, 1953).   
                                                  

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Appendix IV: Cooperative Research and Development Agreement (CRADA) 
 
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/default.htm#guidelines_for_collaborations.) 
contained within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual should 
sign a confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements,  
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”.): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NIH, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order.. 
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 

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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: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 

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Appendix V: 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  
 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to the 
patient at the time of enrollment.  Use or modify the text as appropriate for the study agent, so 
that the patient is aware of the risks and can communicate with their regular prescriber(s) and 
pharmacist.  A convenient wallet-sized information card is also included for the patient to clip 
out and retain at all times.  If you choose to use them, please note that the information sheet and 
wallet card will require IRB approval before distribution to patients.] 
 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug ABT-888 (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: 
 
ABT-888 (veliparib) interacts with certain specific enzymes in the liver. 
 
• The enzymes in question are CYP 1A1, 2D6, 2C19, and 3A4.  ABT-888 (veliparib) is 
metabolized by these enzymes and may be affected by other drugs that inhibit or induce 
these enzymes. 
 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
ABT-888 (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.  
 
 

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These are the things that you and they need to know:  
 
ABT-888 (veliparib) must be used very carefully with other medicines that need certain liver 
enzymes 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 CYP 1A1, 
2D6, 2C19, and 3A4.” 
 
•  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.  
•  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  
 
_____________________________________.                                                                                                         May 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
 
You are enrolled on a clinical trial using the experimental study drug 
ABT-888 (veliparib).  This clinical trial is sponsored by the NCI.      
ABT-888 (veliparib) may interact with drugs that are processed by 
your liver.  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. 
 
 
 
ABT-888 (veliparib) interacts with CYP 1A1, 2D6, 2C19, and 3A4, 
and must be used very carefully with other medicines that interact 
with these enzymes and proteins. 
 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 CYP 1A1, 2D6, 2C19, and 3A4” 
 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 _________________________.