Conditions: Anaplastic Astrocytoma Brain Stem Glioma Childhood Mixed Glioma Fibrillary Astrocytoma Giant Cell Glioblastoma Glioblastoma Gliosarcoma Untreated Childhood Anaplastic Astrocytoma Untreated Childhood Brain Stem Glioma Untreated Childhood Fibrillary Astrocytoma Untreated Childhood Giant Cell Glioblastoma Untreated Childhood Glioblastoma Untreated Childhood Gliosarcoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 66
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and the best dose of veliparib when given together with radiation therapy and temozolomide and to see how well they work in treating younger patients newly diagnosed with diffuse pontine gliomas. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells either by killing the cells or by stopping them from dividing. Giving veliparib with radiation therapy and temozolomide may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To identify the maximum-tolerated dose or recommended Phase II dose of ABT-888 (veliparib) which can be safely administered concurrently with radiation therapy, followed by maintenance therapy with ABT-888 and temozolomide (TMZ), in patients with newly diagnosed diffuse pontine gliomas (DIPG). (Phase I) II. To study the plasma pharmacokinetics (PK) of ABT-888 during ABT-888 and radiation therapy. (Phase I) III. To study the feasibility of intra-patient dose escalation of TMZ during maintenance therapy with ABT-888 and TMZ. (Phase I) IV. To describe the toxicities associated with administering ABT-888 and radiation therapy, followed by ABT-888 and TMZ, in patients with newly diagnosed DIPG. (Phase I) V. To estimate the proportion of newly diagnosed DIPG patients treated on protocol that are determined to have experienced pseudo progression. (Phase I) VI. To estimate the overall survival distribution for newly diagnosed patients with DIPG treated with the combination of ABT-888 and radiation therapy, followed by ABT-888 and TMZ, and compare to Pediatric Brain Tumor Consortium (PBTC) historical controls. (Phase II) VII. To study the feasibility of intra-patient dose escalation of TMZ during maintenance therapy with ABT-888 and TMZ. (Phase II) VIII. To estimate the proportion of newly diagnosed DIPG patients treated on protocol that are determined to have experienced pseudo progression. (Phase II)

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) distribution and to summarize the best tumor responses observed prior to progression or recurrence.

II. To explore the plasma PK of ABT-888 during ABT-888 and radiation therapy. III. To explore peripheral blood mononuclear cell (PBMC) poly (ADP-ribose) polymerase 1(PARP) activity before and after treatment with ABT-888.

IV. To explore quantifying non-homologous end-joining (NHEJ) activity or gamma-H2A histone family, member X (H2AX) levels (as surrogate markers of unrepaired double-strand breaks (DSBs)) in PBMC before and after treatment with ABT-888.

V. To explore quantifying PARP activity and deoxyribonucleic acid (DNA)-repair protein levels in biopsied atypical pontine gliomas, if available.

VI. To explore associations of molecular parameters from secondary aims III, IV, and V with PFS and overall survival (OS) after conclusion of clinical trial.

VII. To explore the quantitative magnetic resonance (MR) measures of relative cerebral blood volume (rCBV), vascular permeability (Ktrans, fractional plasma volume \[vp\], and extravascular extracellular space volume fraction \[ve\] values), and apparent diffusion coefficient (ADC) within the first six months of initiating protocol treatment to correlate with disease outcome and determine whether such metrics differentiate patients with pseudo progression from those with true early progressive disease.

VIII. To explore the potential utility of urine biomarkers as a novel, non-invasive method of detecting and tracking changes in the status of pediatric brain stem gliomas.

OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a phase II study.

DOSE-ESCALATION: Patients receive veliparib orally (PO) twice daily (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) once daily (QD) 5 days a week for 6-7 weeks.

MAINTENANCE THERAPY: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 3 years.

Arms:
arm 1: DOSE-ESCALATION: Patients receive veliparib PO BID 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D-CRT or IMRT QD 5 days a week for 6-7 weeks.

MAINTENANCE THERAPY: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: 3-Dimensional Conformal Radiation Therapy intervention 2: Intensity-Modulated Radiation Therapy intervention 3: Laboratory Biomarker Analysis intervention 4: Pharmacological Study intervention 5: Temozolomide intervention 6: Veliparib
Intervention descriptions: intervention 1: Undergo 3D-CRT intervention 2: Undergo IMRT intervention 3: Optional correlative studies intervention 4: Correlative studies intervention 5: Given PO intervention 6: Given PO

Protocol document:
Prot_SAP_000.pdf: 
NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
i 
 
SUMMARY OF CHANGES 
 
For Protocol Amendment #7 (v.6.0 ) to: A Phase I/ II Study of ABT-888, an Oral Poly( ADP-
ribose) Polymerase Inhibitor, and Concurrent Radiation Therapy, Followed by ABT-888 and 
Temozolomide, in Children with Newly Diagnosed Diffuse Pontine Gliomas (DIPG) 
 
NCI Protocol #: PBTC-033 
Local Protocol #: PBTC-033 
 
NCI Version Date: February 4, 2014 
Protocol Date: February 4, 2014 
Updated Date: February 4, 2014 
 
Version 5.1: Administrative Changes by Principal Investigator in response to recommendations 
following review of v5.0 dated 12/15/13: 
 
# 
Section 
Page 
Change 
1.
7.3.1 
47 
Please correct the paragraph below : 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification 
is to be made to CTEP by telephone at 301-897-7497. Once Internet 
connectivity is restored, the 24-hour notification phoned in or entered 
electronically into AdEERS by the original submitter at the site. Also, if 
internet connectivity is not re-established within 24 hours, notify the following 
by telephone and or email. 
 
Response – revised as requested: 
Expedited AE reporting for this study must use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP Web site 
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented 
in the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which 
can be downloaded from the CTEP Web site (http://ctep.cancer.gov).  These 
requirements are briefly outlined in the tables below (section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification 
is to be made to CTEP by telephone at 301-897-7497.  Once Internet 
connectivity is restored, the 24-hour notification phoned in must be entered 
electronically into CTEP-AERS by the original submitter at the site. Also, if 
internet connectivity is not re-established within 24 hours, notify the following 
by telephone and or email.  
2.
8.1 
50 
Please note that the protocol includes the following patient care 
instructions: 
 
 
 
 
 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
ii 
 
 
 
 
 
 
 
 
 
  
 
 
Version 6.0 Changes by Principal Investigator  
 
# 
Section 
Page 
Change 
1.
 
 
Adverse Event Expedited Reporting System (CTEP-AERS)” has been 
changed to “CTEP Adverse Event Reporting System (CTEP-AERS)” 
throughout the protocol. 
2.
3.1.6, 
6 
& 10 
26 
42 
& 
63 
Request in CTEP RRA from Dr. Nita Seibel dated 1/16/14: 
Specific Protocol Revisions to Address Risk Mitigation Plan:  
 
Response: 
Our eligibility requirements, frequency of liver function testing and dose 
modifications meet the recommendations in the RRA dated 1/16/14 
3.
7.1.2 
46 
Table 14 revised to include ‘Hepatic failure’ in response to CTEP RRA 
from Dr. Nita Seibel dated 1/16/14.  
 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
3 
 
NCI Protocol #: 
PBTC-033 
 
Local Protocol #: 
PBTC-033 
 
TITLE:  PBTC-033 A Phase I/ II Study of ABT-888, an Oral Poly( ADP-ribose) Polymerase Inhibitor, and 
Concurrent Radiation Therapy, Followed by ABT-888 and Temozolomide, in Children with Newly Diagnosed 
Diffuse Pontine Gliomas (DIPG) 
 
Coordinating Center: 
 
 
Operations and Biostatistics Center (OBC) for the Pediatric Brain Tumor 
Consortium (PBTC), St. Jude Children’s Research Hospital 
 
Principal Investigator: 
 
Patricia A. Baxter, M.D. 
Pediatric Hematology-Oncology 
Texas Children’s Cancer Center 
Baylor College of Medicine 
1102 Bates Street Suite 1030.17 
Houston Texas 77030 
Tel: 832-824-4681 
Fax: 832-825-4038 
 
 
Email: pabaxter@txch.org 
 
 
Co-Chair 
 
 
Jack Su, M.D., M.S. 
Pediatric Hematology-Oncology 
Texas Children's Cancer Center 
Baylor College of Medicine 
6701 Fannin Street, CC1410 
Houston, Texas 77030 
Tel: 832-822-4306 
Fax: 832-825-1503 
 
 
E-mail: jmsu@txch.org 
 
Co-Investigators 
 
Susan Blaney, MD, TXCCC 
 
smblaney@txch.org 
 
 
Patrick Thompson, MD  
pathomps@txch.org 
Adekunle Adesina MD, PhD TXCCC* 
amadesin@txch.org 
 
Radiation Oncology Coordinator 
Arnold Paulino, MD* 
Methodist Hospital 
Houston, TX 
 
 
apaulino@tmhs.org 
 
 
Biostatistician 
Arzu Onar, PhD  
Department of Biostatistics 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Tel:  901-595-5499 
Fax  901-595-8843 
Email:arzu.onar@stjude.org 
Biostatistician 
Catherine Billups 
Department of Biostatistics 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Tel:  901-595-3709 
Fax  901-595-4585 
Email: catherine.billups@stjude.org 
PBTC Protocol Coordinator 
Stacye Richardson, MSHS, BSMT, 
CCRP 
Department of Biostatistics 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Telephone:  901-595-3783 
Fax: 901-595-4585 
Email: stacye.richardson@stjude.org  


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
4 
Pharmacokinetics Laboratory  
 
 
  
 
 
 
 
 
 
 
Biology Correlative Study Laboratory 
 
 
 
 
 
 
 
 
 
Biology Correlative Study 
Laboratory 
Xiao-Nan Li, MD, PhD* 
Texas Children’s Cancer Center 
1102 Bates, Rm 1030 
Houston, TX  77030 
Tel: 832-824-4580 
Fax : 832-825-1503 
Email: xxli@txch.org 
 
CRA/Nursing Committee Reps 
Susan Burlingame, TXCCC 
Email: sxburlin@txch.org 
Correlative Study Laboratory – Urine 
Biomarkers 
Edward R. Smith, MD* 
Director, Pediatric Cerebrovascular 
Surgery 
Department of Neurosurgery 
Children's Hospital Boston / Harvard 
Medical School 
300 Longwood Avenue 
Boston, MA 02115 
Tel: 617-355-8414 
Fax: 617-730-0906 
E-mail:  
edward.smith@childrens.harvard.edu 
PBTC Neuroimaging Center 
Tina Young Poussaint, M.D.* 
Director, PBTC Neuroimaging Center 
Children’s Hospital of Boston 
Department of Radiology 
300 Longwood Avenue 
Boston, MA 02115 
Tel:  617- 355-6450 
Fax:  617-730-0573 
Email: 
tina.poussaint@childrens.harvard.edu 
Neuroradiology Co-Investigators 
Meng Law, MD and Mark Shiroishi, 
M.D.* 
Division of Neuroradiology 
Department of Radiology 
Keck School of Medicine 
University of Southern California 
1500 San Pablo St 
 
Los Angeles, CA 90033 
Tel:323-442-7483 
Fax:323-226-4059 
Email:meng.law@usc.edu 
Email: mshiroishi@gmail.com 
This protocol is for research purposes only, and should not be copied, redistributed or used for any other purpose.  The 
procedures in this protocol are intended only for use by clinical oncologists in carefully structured settings, and may not prove 
to be more effective than standard treatment.  A responsible investigator associated with this clinical trial should be consulted 
before using or attempting any procedure in this protocol. Contents of this document may not be extracted without permission 
from the Study Chair. 
 
 
NCI Supplied Agent: ABT-888 (Veliparib) 
 
IND Sponsor:  CTEP/NCI/NIH 
 
Commercial Agent: Temozolomide (Temodar™)/NSC# 362856 
Temozolomide is available from commercial sources by the treating hospital pharmacy. 
 
Protocol Type / Version # / Version Date: Amendment/Version 6.0/ February 4, 2014 
 
 
 
 
 
 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
5 
Pediatric Brain Tumor Consortium Institutions and Principal Investigators 
James M. Boyett, Ph.D.* 
Executive Director of OBC for the PBTC 
St. Jude Children’s Research Hospital 
Department of Biostatistics  
262 Danny Thomas Place 
Memphis, TN  38105 
TEL: (901) 595-3370 
FAX:   (901) 595-8843 
EMAIL:  james.boyett@stjude.org 
Larry Kun, M.D. 
St. Jude Children's Research Hospital 
Dept. of Radiation Oncology 
262 Danny Thomas Place 
Memphis, Tennessee  38105-2794 
TEL:  (901) 595-3565 
FAX:  (901) 595-3113 
EMAIL:larry.kun@stjude.org 
 
Murali Chintagumpala, M.D. 
Baylor College of Medicine  
Texas Children’s Cancer Center 
Dept. of Pediatrics 
6621 Fanin St. C1510 
Houston, Texas  77030 
TEL:  (832) 822-4266 
FAX:  (832) 824-4202 
EMAIL: mxchinta@txch.org 
Sridharan Gururangan, M.D. 
Duke University Medical Center 
The Preston Robert Tisch Brain Tumor Center 
Duke University Medical Center 
047 Baker House, Trent Drive 
Durham, North Carolina  27710 
TEL:  (919) 684-3506 
FAX:  (919) 668-2485 
EMAIL: gurur002@mc.duke.edu 
Ian Pollack, M.D. 
Children's Hospital of Pittsburgh of UPMC 
FP, 4th Floor – Neurosurgery Department 
Children’s Hospital Drive 
45th and Penn Avenue 
Pittsburgh, Pennsylvania  15201 
TEL:  (412) 692-5881 
FAX:  (412) 692-5921 
EMAIL: Pollaci@chp.edu 
Kathy Warren, M.D. 
NIH/NCI/NOB 
National Cancer Institute 
Pediatric Oncology Branch 
Bldg.10 CRC, Room 1-5750 
9000 Rockville Pike 
Bethesda, MD 20892 
TEL:  (301) 435- 4683 
FAX: (301) 480-2308 
EMAIL: warrenk@mail.nih.gov 
Roger Packer, M.D. 
Children's National Medical Center 
Dept. of Neurology 
111 Michigan Avenue, NW 
Washington, DC  20010 
TEL:  (202) 884-2120 
FAX:  (202) 884-5226 
EMAIL:  rpacker@cnmc.org 
Stewart Goldman, M.D. 
Children's Memorial Hospital 
2300 Children's Plaza 
Chicago, IL  60614-3394 
TEL:  (773)  880-4562 
FAX:  (773) 880-3223 
EMAIL: sgoldman@northwestern.edu 
Paul Graham Fisher, M.D. 
Stanford University and Lucile Packard Children's 
Hospital 
Neurology and Pediatrics, Chief, Division of Child 
Neurology 
750 Welch Road, Suite 317, Palo Alto, CA 94304-1510 
TEL:  (650) 721-5889 
FAX:  (650) 723-7299 
EMAIL: pfisher@stanford.edu 
Maryam Fouladi, M.D. 
Cincinnati Children’s Hospital Medical Center 
Dept. Of Hematology/Oncology 
MLC 7015 
3333 Burnet Ave, 
Cincinnati, OH 45229 
TEL: (513) 803 0721  
FAX: (513) 636-3549 
EMAIL: maryam.fouladi@cchmc.org 
Ira Dunkel, M.D. 
Memorial Sloan Kettering Cancer Center 
Department of Pediatrics 
1275 York Avenue , New York, NY 10065 
TEL: 212-639-2153  
FAX: 212-717-3239 
EMAIL:  dunkeli@mskcc.org 
Girish Dhall, MD 
Children's Hospital Los Angeles 
Children's Center for Cancer and Blood Diseases  
Neuro-Oncology Program, 
Mail Stop #54 
4650 Sunset Blvd; Los Angeles, CA 90026 
TEL:  323-361-4629 
FAX:  323-361-8165 
EMAIL:  gdhall@chla.usc.edu 
* NOT RESPONSIBLE FOR PATIENT CARE 
 
 
 
 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
6 
PROTOCOL ABSTRACT AND SCHEMA  
 
This is a phase I/II study to determine: 1) the maximum tolerated dose (MTD) or recommended 
phase II dose of ABT-888 in combination with radiation therapy, and 2) the efficacy of 
administering ABT-888 concurrently with radiation therapy, followed by maintenance therapy 
with ABT-888 and temozolomide (TMZ), in children with newly diagnosed diffuse intrinsic 
pontine glioma (DIPG).  
 
This study consists of two parts: the phase 1, dose-finding component of the trial to estimate the 
MTD or recommended phase II dose of ABT-888 in combination with radiation therapy, and the 
phase 2 component of the study to evaluate the efficacy of ABT-888 and radiation therapy, 
followed by maintenance therapy with ABT-888 and TMZ, in children with newly diagnosed 
DIPG. Upon completion of ABT-888 and radiation therapy, patients enrolled in the Phase I study 
will continue with maintenance therapy with ABT-888 at 25 mg/m2 bid and TMZ at 135 
mg/m2/day for 5 days every 28 days, the recommended phase II doses determined from PBTC-
027. After Phase I is completed, all patients will receive radiation and ABT-888, at the 
MTD/recommended phase II dose determined from the Phase I study, followed by maintenance 
therapy with ABT-888 at 25 mg/m2 bid and TMZ at 135 mg/m2/day for 5 days every 28 days, the 
recommended phase II doses determined from PBTC27.  
 
Since PBTC-027 enrolled patients who commonly received multiple prior chemotherapy 
treatments, and patients for PBTC-033 will be newly diagnosed, chemotherapy-naïve, and 
presumably have intact bone marrow reserve, we hypothesize that children for this clinical trial 
may tolerate higher combination doses of ABT-888 and TMZ compared to the children studied 
on PBTC-027. Therefore, during the maintenance therapy phase of both the Phase I and Phase II 
studies, intra-patient dose escalation of TMZ will be studied. Each patient will start maintenance 
therapy with ABT-888 at 25 mg/m2 bid and TMZ at 135 mg/m2/day for 5 days every 28 days. 
The TMZ dose will be escalated to 175 mg/m2/day and then to 200 mg/m2/day for 5 days every 
28 days if no minimal toxicity is observed after each course. 
 
The primary endpoints for the Phase I study will be toxicity and safety monitoring of ABT-888 
in combination with radiation therapy and will include DLTs and toxic death.  Dose-modifying 
toxicities for maintenance therapy will also be monitored to guide intra-patient dose escalation of 
TMZ and to terminate intra-patient dose escalation if excessive toxicity is observed (section 
5.1.3). The primary endpoint for the Phase II study will be the evaluation of the treatment 
efficacy as measured by 1-year overall survival (OS), with 1-year progression-free survival 
(PFS) and best tumor responses observed prior to tumor progression as the secondary measures 
of treatment efficacy.  
 
PARP activity, non-homologous end-joining (NHEJ) activity, and γ–H2AX level in peripheral 
blood monocytes (PBMCs) will be quantified pre-treatment, 2 weeks after starting ABT-888 and 
irradiation, during the last week of ABT-888 and irradiation, and during the first course of 
maintenance therapy, as surrogate measures of intra-tumoral PARP inhibition and unrepaired 
double-stranded DNA breaks (DSB).  In atypical pontine gliomas that are biopsied, PARP 
activity and DNA repair protein status will be studied either in frozen tumor material or FFPE 
samples as described in section 9.1.3. These molecular data will be correlated retrospectively 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
7 
with efficacy measures outlined above. Pharmacokinetic studies of ABT-888 on day 1 and day 4 
of ABT-888 and radiation treatment will also be performed. These PK studies will be required 
for Phase I and optional for Phase II of the study. 
 
To differentiate pseudoprogression from true early progressive disease, quantitative MR 
measures of relative cerebral blood volume (rCBV), permeability (Ktrans, vp, and ve values), 
and apparent diffusion coefficient (ADC) will be obtained at diagnosis and during the first six 
months after starting protocol therapy and correlated with disease outcome, including whether 
such metrics differentiate patients with pseudoprogression from those with true early progressive 
disease.   
 
Urine biomarkers will be employed to study the feasibility of a novel, non-invasive method to 
detect the presence, progression and response to therapy of pediatric brain tumors.   
 
Schema:  
Phase I Study 
ABT-888 will be given twice daily on Monday through Friday, for 6-7 weeks, during daily 
radiation therapy (see table below). The first dose of ABT-888 should ideally be given 60-120 
minutes prior to timing of radiation treatment. For patients who require sedation for radiation 
treatment and must remain NPO in the morning, ABT-888 should be given nightly prior to sleep, 
with the day time dose given shortly after the child awakens from sedation, adhering as closely 
to an every 12 hour schedule as possible.  
 
Schema – Radiation Phase of Therapy 
Week 
1 
2 
3 
4 
5 
6 
Week 7-10 
ABT-888, BID 
Twice daily, M-F, for 6-7 weeks 
Rest/ Evaluation 
Radiation Therapy 
Daily, M-F for 6-7 weeks 
 
Dose Level 1 of ABT-888 during radiation treatment will be approximately 80% of the dose that 
has been safely tolerated in adults (100 mg BID). It is also expected that the 150 mg bid dose 
level in adults will be declared tolerable shortly.  Dose escalation/de-escalation will be done 
using a standard phase I, 3 + 3 design in increments of approximately 30% (see the table below).  
If the adult dose of 150 mg bid with radiation has been declared tolerable by the time this trial 
begins patient accrual, and the starting dose level of 50 mg/m2 bid is also tolerated in children, 
we propose to proceed from dose level 1 directly to dose level 3 (85 mg/m2 bid, equivalent to the 
adult dose of 150 mg bid). If dose level 3 is not tolerated, then we will de-escalate to dose level 
2. If dose level 3 is tolerated, we will study dose level 4 only if supported by adult clinical data 
and PBMC PARP inhibition data from our ongoing trial.*   
 
ABT-888 Dose Level During Radiation, for Phase I 
Dose Level 
ABT-888 dose (mg/m2/dose BID), M-F 
0 
35 mg/m2/dose BID 
1 (starting dose level) 
50 mg/m2/dose BID 
2 
65 mg/m2/dose BID 
3 
85 mg/m2/dose BID 
4 (pending supporting data)* 
110 mg/m2/dose BID 
 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
8 
Upon completing radiation treatment and ABT-888, all patients from Phase I of the study will 
continue with maintenance therapy starting week 11, as outlined below. 
 
Schema- Maintenance Phase of Therapy 
Each Course 
May receive a maximum of 10 courses 
Day 
1 
2 
3 
4 
5 
6-28 
ABT-888, BID 
x,x 
x,x 
x,x 
x,x 
x,x 
Rest/Evaluation 
Temozolomide, once daily 
x 
x 
x 
x 
x 
Rest/Evaluation 
 
Phase II Study 
Phase II of the study will begin when the MTD/recommended phase II dose of ABT-888 in 
combination with radiation therapy has been determined from the Phase I study.   Maintenance 
therapy will consist of ABT-888 and TMZ beginning at week 11 (3-4 weeks after the completion 
of radiation and ABT-888).   Starting doses of maintenance therapy will be 25 mg/m2 bid of 
ABT-888 and 135 mg/m2/day of TMZ, for 5 days every 28 days, which are the recommended 
phase II doses from PBTC-027. Since this dose determination was based on children with 
refractory brain tumors, many of whom were heavily pre-treated, it is possible that children with 
newly diagnosed DIPG, who are chemotherapy naïve at entry, will tolerate higher doses of ABT-
888 and TMZ during maintenance. In an effort to maximize the TMZ dose (and potentially the 
efficacy of the combination treatment) that can be administered with ABT-888 for each patient, 
intra-patient dose escalation of TMZ will be studied only for patients with minimal 
hematologic toxicities in each course, defined as ≤ Grade 1 thrombocytopenia and ≤ Grade 
2 neutropenia, and minimal non-hematologic toxicities not meeting the definition of dose-
modifying toxicities in section 5.1.3.1, after their first course of maintenance therapy at Dose 
Level 1. These patients’ TMZ dose will be escalated for Course 2 to 175 mg/m2/day (Dose Level 
2), and subsequently (Course 3) to 200 mg/m2/day of TMZ (Dose Level 3) if the toxicities 
observed after 1 course of protocol therapy at each dose level meet the above criteria. 
 
 
 
 
 
 
 
 
 
 
 
Intra-Patient Dose Escalation during Maintenance Therapy 
(Days 1-5 per 28 day cycle) 
Dose Level 
ABT-888 
TMZ Dose 
0 
20 mg/m2 BID 
135 mg/m2/day 
1 (Starting Dose) 
25 mg/m2 BID 
135 mg/m2/day 
2 
25 mg/m2 BID 
175 mg/m2/day 
3 
25 mg/m2 BID 
200 mg/m2/day 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
9 
TABLE OF CONTENTS 
SUMMARY OF CHANGES ...................................................................................................................... I 
PROTOCOL ABSTRACT AND SCHEMA ............................................................................................. 6 
1. 
OBJECTIVES .................................................................................................................................. 11 
1.1 PHASE I PRIMARY OBJECTIVES ...................................................................................................... 11 
1.2 PHASE II PRIMARY OBJECTIVES ..................................................................................................... 11 
1.3 SECONDARY OBJECTIVES............................................................................................................... 11 
2. 
BACKGROUND............................................................................................................................... 12 
2.1 STUDY DISEASE(S) ......................................................................................................................... 12 
2.2 CTEP IND AGENT ......................................................................................................................... 12 
2.3 RATIONALE .................................................................................................................................... 18 
2.4 CORRELATIVE STUDIES BACKGROUND ......................................................................................... 19 
2.5 SUMMARY ...................................................................................................................................... 25 
3. 
PATIENT SELECTION .................................................................................................................. 25 
3.1 ELIGIBILITY CRITERIA ................................................................................................................... 25 
3.2 EXCLUSION CRITERIA .................................................................................................................... 27 
3.3 INCLUSION OF WOMEN AND MINORITIES ...................................................................................... 27 
3.4 TREATMENT AT PRIMARY INSTITUTION ........................................................................................ 27 
3.5 CRITERIA TO START THERAPY ....................................................................................................... 27 
4. 
REGISTRATION PROCEDURES ................................................................................................ 28 
4.1 GENERAL GUIDELINES ................................................................................................................... 28 
4.2 PATIENT REGISTRATION ................................................................................................................ 28 
5. 
TREATMENT PLAN ...................................................................................................................... 28 
5.1 AGENT ADMINISTRATION .............................................................................................................. 28 
5.2 DEFINITION OF DOSE-LIMITING TOXICITY (DLT) ......................................................................... 39 
5.3 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................. 39 
5.4 DURATION OF THERAPY ................................................................................................................. 40 
5.5 DURATION OF FOLLOW UP ............................................................................................................. 40 
5.6 CRITERIA FOR REMOVAL FROM STUDY ......................................................................................... 41 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................................ 42 
6.1 DOSE MODIFICATION FOR DLT DURING ABT-888 AND RADIATION ............................................ 42 
6.2 DOSE MODIFICATION FOR ABT-888 AND TMZ DURING MAINTENANCE ...................................... 43 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ....................................... 44 
7.1 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST (CAEPR) ............................... 44 
7.2 ADVERSE EVENT CHARACTERISTICS ............................................................................................. 47 
7.3 EXPEDITED ADVERSE EVENT REPORTING ..................................................................................... 47 
7.4 ROUTINE ADVERSE EVENT REPORTING ......................................................................................... 49 
7.5 SECONDARY MALIGNANCY ........................................................................................................... 49 
7.6 SECOND MALIGNANCY .................................................................................................................. 50 
8. 
PHARMACEUTICAL INFORMATION ...................................................................................... 50 
8.1 ABT-888 (NSC # 737664) ............................................................................................................. 50 
8.2 TEMOZOLOMIDE (TEMODAR™; NSC#:  362856) .......................................................................... 53 


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9. 
CORRELATIVE AND SPECIAL STUDIES ................................................................................ 53 
9.1 LABORATORY CORRELATIVE STUDIES .......................................................................................... 53 
9.2 SPECIAL STUDIES ........................................................................................................................... 59 
10. 
STUDY CALENDAR .................................................................................................................. 63 
11. 
MEASUREMENT OF EFFECT ................................................................................................ 65 
11.1 TUMOR RESPONSE CRITERIA ......................................................................................................... 65 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .................................................. 65 
12.1 DATA REPORTING .......................................................................................................................... 66 
12.2 CTEP MULTICENTER GUIDELINES ................................................................................................ 66 
12.3 COLLABORATIVE AGREEMENTS LANGUAGE ................................................................................. 66 
13. 
STATISTICAL CONSIDERATIONS ....................................................................................... 68 
13.1 PHASE I STUDY DESIGN/ENDPOINTS ............................................................................................. 68 
13.2 PHASE II STUDY DESIGN/ENDPOINTS: ........................................................................................... 69 
13.3 PROJECTED ACCRUAL RATE AND STUDY DURATION .................................................................... 73 
13.4 ANALYSIS OF SECONDARY ENDPOINTS ......................................................................................... 74 
14. 
REFERENCES ............................................................................................................................. 76 
APPENDIX A ............................................................................................................................................ 80 
APPENDIX B ............................................................................................................................................ 81 
APPENDIX C ............................................................................................................................................ 82 
APPENDIX D ............................................................................................................................................ 83 
APPENDIX E ............................................................................................................................................ 87 
APPENDIX F ............................................................................................................................................ 88 
APPENDIX G ............................................................................................................................................ 91 


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1. OBJECTIVES 
 
1.1 
Phase I Primary Objectives 
1. To identify the maximum tolerated dose or recommended Phase II dose of ABT-888 which 
can be safely administered concurrently with radiation therapy, followed by maintenance 
therapy with ABT-888 and TMZ, in patients with newly diagnosed DIPG. 
2. To study the plasma pharmacokinetics (PK) of ABT-888 during ABT-888 and radiation 
therapy.  
3. To study the feasibility of intra-patient dose escalation of TMZ during maintenance therapy 
with ABT-888 and TMZ. 
4. To describe the toxicities associated with administering ABT-888 and radiation therapy, 
followed by ABT-888 and TMZ, in patients with newly diagnosed DIPG.  
5. To estimate the proportion of newly diagnosed DIPG patients treated on protocol that are 
determined to have experienced pseudoprogression. 
 
1.2 
Phase II Primary Objectives 
1. To estimate the overall survival distribution for newly diagnosed patients with DIPG treated 
with the combination of ABT-888 and radiation therapy, followed by ABT-888 and TMZ, 
and compare to PBTC historical controls.  
2. To study the feasibility of intra-patient dose escalation of TMZ during maintenance therapy 
with ABT-888 and TMZ. 
3. To estimate the proportion of newly diagnosed DIPG patients treated on protocol that are 
determined to have experienced pseudoprogression. 
 
1.3 
Secondary Objectives 
 
1. To estimate the progression free survival distribution and to summarize the best tumor 
responses observed prior to progression or recurrence. 
2. To explore the plasma pharmacokinetics (PK) of ABT-888 during ABT-888 and radiation 
therapy.  
3. To explore peripheral blood mononuclear cell (PBMC) PARP activity before and after 
treatment with ABT-888. 
4. To explore quantifying non-homologous end-joining (NHEJ) activity or -H2AX levels (as 
surrogate markers of unrepaired DSBs) in PBMC before and after treatment with ABT-888. 
5. To explore quantifying PARP activity and DNA repair protein levels in biopsied atypical 
pontine gliomas, if available. 
6. To explore associations of molecular parameters from secondary aims 3, 4 and 5 with PFS 
and OS after conclusion of clinical trial. 
7. To explore the quantitative MR measures of relative cerebral blood volume (rCBV), vascular 
permeability (Ktrans, vp, and ve values), and apparent diffusion coefficient (ADC) within the 
first six months of initiating protocol treatment to correlate with disease outcome and 
determine whether such metrics differentiate patients with pseudoprogression from those 
with true early progressive disease. 
8. To explore the potential utility of urine biomarkers as a novel, non-invasive method of 
detecting and tracking changes in the status of pediatric brain stem gliomas. 


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2. BACKGROUND 
 
2.1 
Study Disease(s) 
Pediatric Diffuse Intrinsic Pontine Gliomas 
Prognosis for children with diffuse pontine glioma (DIPG) remains dismal and has not changed 
substantially during the last three decades. The combined 1-year PFS from three recent PBTC 
clinical trials for 140 patients with newly diagnosed DIPG was 15.9 ± 3.1% (section 13.1), 
highlighting the continued need for novel treatment approaches in this population. Assuming that 
these aggressive tumors are generally irradiation resistant, and intensification of traditional 
chemotherapy agents failed to improve outcome, it is reasonable to hypothesize that novel agents 
that target a critical tumor-specific pathway mediating irradiation and/or chemotherapy 
resistance may be worthy of clinical investigation. 
 
2.2 
CTEP IND Agent 
ABT-888 - Poly(ADP-Ribose) Polymerase (PARP) and DNA Repair 
Most chemotherapy drugs induce single-stranded DNA breaks (SSB), and irradiation induces 
double-stranded DNA breaks (DSB). It is hypothesized that refractory pediatric CNS tumors 
have enhanced SSB and DSB repair and are therefore resistant to chemotherapy and irradiation, 
respectively. Repair of SSB is mediated by multiple mechanisms, including the base-excision 
repair (BER), and DSBs are repaired by the homologous recombination repair (HRR) and non-
homologous end-joining (NHEJ) repair pathways. Poly(ADP-ribose) polymerase (PARP) is a 
critical enzyme that binds to SSBs and DSBs and recruits and activates repair proteins from the 
BER,1 NHEJ,2 and HRR3 pathways. Elevated PARP expression and/or activity may therefore 
mediate chemotherapy and irradiation resistance in CNS tumors. 
 
PARP Over-Expression in Pediatric CNS Tumors 
We have previously shown that 56 out of 59 pediatric medulloblastomas (MB) and 16 out of 18 
pediatric glioblastoma multiforme (GBM) have elevated PARP expression by 
immunohistochemistry (IHC), compared to absent expression in age-matched normal brain (JM 
Su and XN Li, unpublished data; data previously summarized in PBTC-027). Other investigators 
have also demonstrated PARP over-expression in pediatric CNS tumors,4 including DIPG.5 
These data suggest that elevated PARP activity in pediatric brain tumors may enhance DNA 
repair after irradiation or chemotherapy, mediate treatment resistance, and serve as a potential 
therapeutic target for enhancing sensitivity to radiation therapy and chemotherapy. 
 
2.2.1 Preclinical Studies  
2.2.1.1 
ABT-888 Enhances Pediatric CNS Tumor Response to Chemotherapy 
ABT-888 is a potent oral PARP inhibitor that potentiates chemotherapy drugs and enhances 
radiation efficacy in xenograft models of human tumors.6,7  We previously showed that ABT-888 
effectively penetrates the blood-brain barrier (CSF to plasma ratio 57 +/- 7% in non-human 
primate models)8 and enhanced in vivo tumor response to temozolomide (TMZ) in a pediatric 
GBM and MB intracranial xenograft models (Figure 1A, 1B; JM Su and XN Li, unpublished 
data). 


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2.2.1.2 
Preferential accumulation of ABT-888 in brain tumor versus plasma 
GBM and MB xenografts and neighboring cerebrum or cerebellum were harvested immediately 
after 5 days of ABT-888 treatment and analyzed for ABT-888 concentrations by liquid 
chromatography-mass spectroscopy. ABT-888 accumulated preferentially in the xenografts 
compared to normal neighboring brain, and the tumor to plasma ratio of ABT-888 was 8.25 +/- 6 
(n = 10 mice; JM Su and XN Li, unpublished data). This preferential accumulation of ABT-888 
in intracranial xenograft tumors was also previously confirmed by Donawho et al.6 This 
preferential accumulation of ABT-888 in brain tumors, achieving concentration exceeding 5-fold 
of the plasma level, is a potential therapeutic advantage in targeting CNS tumors.  
 
2.2.1.3 
ABT-888 Enhances Pediatric MB and GBM Response to Irradiation 
Using primary cultured cells from freshly resected surgical specimens (6 pediatric MB and 5 
GBM), we studied the potential of in vitro radiation enhancement by ABT-888 treatment. 
Potential CD133+ tumor stem cells were isolated by flow cytometry and cultured separately 
from non-stem tumor cells in 96-well plates. We selected an ABT-888 concentration range of 1 
to 5 µM, corresponding to plasma concentration of ~ 50 to 244 ng/ml (assuming a tumor to 
plasma ratio of 5, which we and others have demonstrated in xenograft models), which has been 
safely achieved in adult and pediatric trials (see data below). Tumor cells were pre-treated with 
ABT-888 for 24 hours, followed by a single fraction of irradiation, and then drug treatment was 
continued for 14 days, and cell viability was estimated with cell counting kit 8 (CCK8). ABT-
888 treatment resulted in radiation sensitization of either non-stem or stem-like tumor cells in 5 
out of 6 MB and 4 out of 5 GBM models (Figure 2).  
 


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Using an intracranial pediatric GBM model established from a fresh surgical tumor specimen,9 
we proceeded to study the in vivo radiation potentiation effect of ABT-888. Tumor cells were 
injected intra-cerebrally as previously described, and treatment was initiated two weeks 
afterward. The control group received radiation therapy consisting of 2 Gy daily fractions for 5 
days, and the test group received ABT-888 by intra-peritoneal injections twice daily, with the 
morning dose delivered 30-60 minutes prior to daily irradiation. Animals were then observed 
after 5 days of treatment. We started with ABT-888 at 12.5 mg/kg bid (25 mg/kg/day), the dose 
that has been shown to optimize chemotherapy potentiation without causing excessive toxicities. 
While there was a trend toward increasing survival in the group of animals that received ABT-
888 and radiation, the result did not achieve statistical significance (data not shown). 
 
 
 
 we repeated the in vivo experiments described above but with increased dosing of ABT-
888 (at 50 mg/kg/day and 100 mg/kg/day). Animals that received ABT-888 (50 mg/kg/day) with 
radiation showed statistically significant improved survival compared to control animals that 
received radiation or ABT-888 alone (Figure 3). In the cohort of animals that received ABT-888 
at 100 mg/kg/day, those mice that received ABT-888 and radiation also showed improved 
survival, but the survival curve is not finalized yet (data not shown). 
 


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2.2.2 Adult Clinical Trials 
2.2.2.1 
Phase I Trial of ABT-888 and Chemotherapy in Adults 
AbbVie Laboratories has completed a phase I clinical trial of ABT-888 and TMZ in adults with 
recurrent/progressive solid tumors. 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
2.2.2.2 
Phase I Trial of ABT-888 and XRT in Adults 
AbbVie Laboratories began a phase I clinical trial of ABT-888, TMZ, and XRT, followed by 
ABT-888 and TMZ for 4 additional courses in adults with newly diagnosed GBM in early 2010 
(NCT00770471). 
 
 
 
 
 
 
AbbVie Laboratories is also completing another phase I study of ABT-888 and whole-brain 
irradiation in adults with solid tumors metastatic to the brain (NCT00649207). Irradiation is 
administered in either 15 fractions (2.5 Gy daily) for 3 weeks, for a total of 37.5 Gy, with ABT-
888 given bid daily throughout the duration of XRT. No DLT has been observed with ABT-888 
at 50 mg or 100 mg bid (6 and 7 patients, respectively), and the trial is continuing with patients 
receiving ABT-888 at 150 mg BID, with the expectation that this dose level will be declared 
tolerable by the end of October 2011 (
 Alice Chen, 
CTEP, personal communication). 
 


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2.2.3 Pediatric Studies 
2.2.3.1 
Phase l Trial of ABT-888 and TMZ in Children with Recurrent CNS Tumors 
We have completed a phase I clinical trial of ABT-888 and TMZ in children with 
recurrent/refractory CNS tumors through the Pediatric Brain Tumor Consortium (PBTC-027; 
NCT00946335). The initial treatment schema was as follows: 
Table 1 
Dose Levels 
Dose Level 
ABT-888 Dose, mg/m2/dose BID 
x 5 days 
TMZ Dose,  
mg/m2/day x 5 days 
-1 
15 mg/m2 /dose BID 
150 mg/m2/day 
0 
15 mg/m2 /dose BID 
180 mg/m2/day 
1 (Starting dose level) 
20 mg/m2 /dose BID 
180 mg/m2/day 
2 
25 mg/m2 /dose BID 
180 mg/m2/day 
3 
30 mg/m2 /dose BID 
180 mg/m2/day 
4 
30 mg/m2 /dose BID 
200 mg/m2/day 
 
Three patients on Dose Level 1 and two patients on Dose Level 0 experienced hematologic 
DLTs (grade 4 neutropenia and grade 4 thrombocytopenia). Six additional children were enrolled 
onto Dose Level -1, and only 1 patient had a hematologic DLT (a delay in ANC recovery). One 
patient developed grade-5 encephalopathy and white matter changes, but these toxicities were 
ultimately attributed to severe pre-existing hypertension and not related to study drugs. No other 
DLTs have been observed. 
 
2.2.3.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
Pharmacokinetic data from children enrolled onto PBTC-027 (Table 2) showed that, based on 
AUC0->12hr and steady state Cmax, pediatric ABT-888 drug exposure at 15 mg/m2 is similar to 
adult dosing at 20 mg bid, and pediatric ABT-888 drug exposure at 20 mg/m2 bid is slightly 
lower than adult dosing at 40 mg bid (AUC0->12hr 1.55 µg•hr/mL in 1 child vs 1.87 +/- 0.49 
µg•hr/mL in 3 adults). Based on maximally effective AUC0->24hr of 3 µg•hr/mL predicted from 
animal models and observed AUC0->24hr of 3.74 µg•hr/mL in adults receiving ABT-888 at 40 mg 
bid, it appears that pediatric dosing of 20 mg/m2 bid or higher would be required to match the 
drug exposure seen in adults receiving 40 mg bid. Furthermore, PARP inhibition in PBMCs from 
children on PBTC-027 was highly variable, averaging only 31.5 +/- 33.6% inhibition in seven 
patients. 
Table 2 
Pharmacokinetic Data, PBTC-027 versus Adult 
Mean ± Standard Deviation 
 
PBTC-027 
20 mg/m2 
PBTC-027 
15 mg/m2 
Adult 
40 mg bid 
(22 mg/m2) 
Adult 
20 mg bid 
(11 mg/m2) 
Number of patients 
1 
6 
3 
3 
AUC0->12hr (µg•hr/mL) 
1.55 
1.05 ± 0.42 
1.87 ± 0.49 
0.99 ± 0.37 
Steady State Cmax (ng/ml) 
379 
222 ± 64 
348 ± 55 
171 ± 39 
 
Based on the preliminary PK and pharmacodynamic data from PBTC-027, the trial was amended 
in an effort to optimize ABT-888 drug exposure and PARP inhibition. The revised treatment 
schema is as follows: 


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Table 3 
 
Three children treated on revised Dose Level 1 did not have any DLT. One out of 3 children 
treated on revised Dose Level 2 had grade 4 thrombocytopenia. Another patient on Dose Level 2 
had ~40% tumor reduction after 1 course of protocol therapy but also had a symptomatic 
ischemic infarction within the tumor/brainstem. This complication has not been observed in 
more than 472 adult patients receiving ABT-888 on various phase I trials to date (CTEP, Alice 
Chen, personal communication).  However, since a possible attribution to ABT-888 could not be 
completely excluded, three additional patients were enrolled onto Dose Level 1, and no DLTs 
were observed in the six patients treated on Dose Level 1. 
 
Pharmacokinetic data from children on the revised treatment schema are as follows: 
 
Table 4 
Preliminary Pharmacokinetic Data, PBTC-027 versus Adult 
Mean ± Standard Deviation 
 
PBTC-027 
20 mg/m2 
PBTC-027 
25 mg/m2 
Adult  
40 mg bid 
(~22 mg/m2) 
Adult  
20 mg bid 
(~11 mg/m2) 
Number of patients 
3 
3 
3 
3 
AUC0->12hr (µg•hr/mL) 
1.35 ± 0.16 
2.0 ± 0.64 
1.87 ± 0.49 
0.99 ± 0.37 
Steady State Cmax (ng/ml) 
293 ± 58 
372 ± 148 
348 ± 55 
171 ± 39 
 
It appears that children who received ABT-888 at 25 mg/m2 bid showed PK profile that is 
essentially identical to adults who received the drug at 40 mg bid, the recommended phase II 
dose in current adult trials. 
 
PARP inhibition from PBMC from the revised study is as follows: 
 
Table 5 
PBTC-027 PARP Inhibition 
Patient 
Dose Level 
ABT-888 Dose 
PARP Inhibition 
3541* 
1* 
20 mg/m2 bid 
10.1% 
13182 
1 
20 mg/m2 bid 
9.1% 
14968 
1 
20 mg/m2 bid 
42.5% 
15804 
1 
20 mg/m2 bid 
38.8% 
16816 
2 
25 mg/m2 bid 
68.9% 
17354 
2 
25 mg/m2 bid 
96.0% 
18147 
2 
25 mg/m2 bid 
47.2% 
* Patient 3541 was treated prior to the first amendment and received ABT-888 at 20 
mg/m2 bid with TMZ at 180 mg/m2 
 
Revised Treatment Schema 
Dose Level 
ABT-888 Dose, mg/m2/dose BID 
x 5 days 
TMZ Dose, mg/m2/dose daily x 5 
days 
0 
15 mg/m2 /dose BID 
135 mg/m2/day 
1 (starting dose level) 
20 mg/m2 /dose BID 
135 mg/m2/day 
2 
25 mg/m2 /dose BID 
135 mg/m2/day 


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Although the sample sizes at each dose level are small, it appears that PARP inhibition is greater 
at 25 mg/m2 bid versus 20 mg/m2 bid. 
 
Based on available PK and PARP inhibition data, and with the aim of optimizing drug exposure 
and biological effect, we amended the PBTC-027 trial to enroll additional patients at Dose Level 
2 (ABT-888 at 25 mg/m2 bid, TMZ at 135 mg/m2/day, for 5 days every 28 days) with close 
monitoring for CNS toxicity. Three additional patients were enrolled on Dose Level 2, and no 
DLTs were observed. Thus, Dose Level 2 (ABT-888 at 25 mg/m2 bid, TMZ at 135 mg/m2/day, 
for 5 days every 28 days) is the recommended phase II dose (RP2D) for children with recurrent 
or refractory CNS tumors.  
 
To date, a total of twelve patients on PBTC27 have been treated on RP2D, and except for one 
grade-4 thrombocytopenia and the grade-5 ischemic infarction seen in the first two patients, no 
other dose-limiting toxicities were reported. 
 
2.3 
Rationale 
This will be a Phase I/II study of ABT-888 and concurrent radiation treatment, followed by 
maintenance with ABT-888 and TMZ, in children with newly diagnosed DIPG. Phase I of the 
study will be the dose-finding portion of the trial to determine the MTD/recommended phase II 
dose of ABT-888 that can be safely administered with radiation treatment. Dosing of ABT-888 
during irradiation will start at 80% of the adult dose (100 mg bid) that has been safely tolerated 
(section 2.2.2 and 5.1.1.2). After completion of ABT-888 and radiation treatment, patients in 
Phase I of the study will continue with maintenance therapy, receiving ABT-888 and TMZ at the 
recommended phase II doses determined from PBTC-027 (section 5.1.3). Intra-patient dose 
escalation of TMZ will also be studied to optimize TMZ exposure for individual patients (section 
5.1.3.1). 
 
The Phase II study will commence once the MTD/recommended phase II dose of ABT-888 that 
can be safely administered with radiation has been determined from the Phase I study. All 
patients in the Phase II study will also continue with maintenance therapy, starting with ABT-
888 and TMZ at the recommended phase II doses determined from PBTC-027. Intra-patient dose 
escalation of TMZ will continue to be studied unless excessive toxicities are observed (section 
5.1.3.1).  In the absence of excessive toxicities or disease progression, all patients can receive up 
to 10 courses of maintenance therapy.  ABT-888 may be available for patients beyond the 10th 
course of maintenance if the patient is benefiting from the treatment, has at least clinical and 
radiographic stable disease at the end of course 10 and the investigator and subject agree to 
continue treatment for up to an additional 13 courses.  
 
2.3.1 Rationale for ABT-888 and Radiation Therapy  
Pre-clinical studies have confirmed ABT-888’s radiation potentiation in several adult cancers, 
and we have shown similarly that ABT-888 treatment inhibited DSB repair and enhanced 
efficacy of radiation in pediatric CNS tumors, including GBM. It is therefore reasonable to study 
ABT-888 concurrently with irradiation in children with newly diagnosed DIPG tumors. 
 
2.3.2  Rationale for ABT-888 and TMZ 
TMZ treatment concurrently with radiation therapy and continuing as maintenance therapy for 


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six months is now the standard of care for adults with GBM. Although in children with high-
grade glioma and DIPG, a COG clinical trial (ACNS0126) of TMZ and irradiation followed by 
maintenance TMZ has not demonstrated superior survival compared to historical series, we 
hypothesize that TMZ resistance may account for the lack of therapeutic benefit in the majority 
of patients. Several pre-clinical studies have demonstrated that PARP inhibition enhanced in 
vitro and in vivo TMZ cytotoxicity in multiple malignant glioma cell lines and xenograft models, 
and such enhanced TMZ cytotoxicity was observed despite enhanced MGMT expression and/or 
MMR deficiency,10-12 two of the known tumor mechanisms for TMZ resistance. We have 
similarly demonstrated that ABT-888 enhanced TMZ efficacy in xenograft models of pediatric 
GBM. Collectively, available pre-clinical data suggest that PARP inhibition by ABT-888 may 
reverse TMZ resistance in pediatric gliomas. 
 
2.3.3 Rationale for Targeting Children with Brainstem Gliomas 
We and others have shown that PARP is highly expressed in pediatric GBMs and brainstem 
gliomas. As radiation treatment only leads to a transient response in these aggressive tumors, it is 
highly likely PARP over-expression, either at the time of diagnosis or in response to irradiation, 
contributes to apparent radiation resistance. We therefore propose to study the benefit of ABT-
888, a PARP inhibitor, in overcoming the radiation resistance in pediatric DIPG. 
 
2.3.4 Rationale for ABT-888 Dosing During Radiation 
Although it appears that, from the adult clinical trials, ABT-888 administered concurrently with 
TMZ and irradiation is associated with dose-limiting hematologic toxicities, administration of 
ABT-888 concurrently with radiation therapy only has been well tolerated. No DLT was 
observed at 100 mg BID and cumulative radiation doses of 37.5 Gy and it is anticipated that the 
dose of 150 mg BID in adults will be declared tolerable by the end of October 2011 (
 
AbbVie Laboratories and Alice Chen, CTEP, personal communication). We therefore 
propose to start at the 80% of the adult dose (100 mg bid) that has been safely tolerated and 
allow for 2 dose escalations to reach a pediatric dose that is equivalent to 150 mg BID in adults. 
 
2.4 
Correlative Studies Background 
 
2.4.1 Rationale for Biology Studies  
2.4.1.1 
Potential Mechanism of Resistance against PARP Inhibition 
Pre-clinical studies have shown that ABT-888 induces SSB, collapses replication forks, and 
results in unrepaired DSB,13 but tumors capable of enhancing their DSB repair, e.g. by up-
regulating HRR, may acquire resistance to PARP inhibition.14  Conversely, tumors with deficient 
DSB repair, e.g. BRCA1 or BRCA2 deficient breast or ovarian cancers, should be theoretically 
hypersensitive to PARP inhibition, whether as a single drug or in combination treatment, and this 
hypothesis has been confirmed pre-clinically15 and most recently in two clinical trials.16,17  
Therefore, it is imperative to document the baseline and post-treatment DSB repair capability in 
tumors, as these molecular markers may predict sensitivity to PARP inhibitors such as ABT-888. 
 
As outlined above, tumors with deficient DSB repair should be hypersensitive to PARP 
inhibition, whether as a single agent or in combination treatment, and conversely, tumors capable 
of enhancing their DSB repair may become resistant to PARP inhibition. We therefore propose 
to study the baseline and post-treatment DSB capability in patients’ peripheral blood monocytes 


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(PBMC) and plan to correlate results retrospectively with clinical outcomes. We also propose to 
document pre- and post-treatment PARP activity in PBMC as a surrogate measure of ABT-888 
biological activity in tumor. In tumors that are atypical appearing and must be biopsied and 
proven to be high-grade gliomas prior to patients’ enrollment, we also propose to quantify PARP 
activity and DNA repair protein levels (Ku 70, Ku 80, DNA-PK, BRCA 1, BRCA 2, Rad51, and 
ATM) in either frozen tumors or FFPE samples. These molecular data will help in guiding the 
design of a future phase 3 clinical trial. 
 
2.4.2 Rationale for Imaging Studies 
If ABT-888 is effective in enhancing radiation effect in DIPG as we hypothesize, it is possible 
that the rate of pseudoprogression may be higher for this proposed study compared to historical 
series. In parallel with earlier pediatric DIPG trials, for patients showing possible tumor 
progression on MRI during the first 6 months after the initiation of ABT-888 and irradiation (on 
required MRI studies performed at weeks 10, week 18, or 26), the treating physician will have 
the option of allowing the patient to remain on study, continuing protocol therapy, and repeating 
disease reassessment in 4-6 weeks. Provided that the patient does not show clinical deterioration 
consistent with tumor progression, has been on a stable or declining dose of steroids, and the 
subsequent MRI demonstrates tumor regression or stable disease, then the patient will remain on 
study and continue protocol therapy, and the frequency of subsequent MRI will revert to pre-
specified intervals. If the repeat MRI after 4-6 weeks shows disease progression, rather than 
pseudo-progression, then the time of progression will be the date of the initial MRI, not the 
follow up scan. 
 
Key to assessing disease course and potential pseudoprogression is inclusion of detailed clinical 
data documenting each patient’s status at the time of scheduled imaging or upon institutional call 
of “progressive disease.”  The ability to track neurologic status, symptoms or signs potentially 
heralding or reflecting progressive disease, or apparent neurologic stability is important in 
correlating clinical status with imaging findings, and documenting the clinical and/or imaging 
findings that prompt the investigator to call “progressive disease.” We recently documented a 
relationship between tumor volume and diffusion (measured by serial echoplanar diffusion 
imaging) prior to and immediately after irradiation in a cross-protocol analysis of prior PBTC 
newly diagnosed DIPG patients. Tumors with larger diffusion values seemed to respond early to 
radiation therapy and percent reduction in ADC values correlated with both progression-free and 
overall survival rates.18   Tracking MR imaging volumetric, serial findings in the context of a 
phase II study of tipifarnib and irradiation showed pseudoprogression in just one of the 40 
patient’s studied.19  
 
As a secondary objective, we shall study relative cerebral blood volume (rCBV), vascular 
permeability (Ktrans) along with both fractional plasma volume (vp) and the extravascular volume 
fraction (ve), and the apparent diffusion coefficient (ADC) as parameters hypothesized to 
differentiate pseudoprogression from true early disease progression (PD). These parameters will 
be studied with serial imaging over the first 6 months after the initiation of ABT-888 and 
irradiation; quantitative MR metrics will be retrospectively correlated with clinical outcomes to 
study if they reliably distinguish pseudo-progression from early PD.   
 
Recent preliminary work with adult glioblastoma patients has shown the potential of MR 


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perfusion and permeability imaging to differentiate between pseudoprogression and true early 
progression.20-25   True early progression appears to demonstrate increased relative cerebral blood 
volume and permeability compared to pseudoprogression.   
 
While there appears to be some controversy regarding the utility of diffusion weighted MR 
imaging in the context of pseudoprogression, there is evidence to suggest that ADC values can 
be used to differentiate residual/recurrent tumor from necrosis.26   This is predicated upon the 
idea that successful therapy will show increased ADC values secondary to a decrease in 
cellularity and an increase in the extracellular space.   
 
We hypothesize that in the first 6 months following treatment with ABT-888 and concurrent 
radiation therapy, pseudoprogression will be marked by significantly lower relative cerebral 
blood volume (rCBV) compared to that seen in true early progression. T2*-weighted dynamic 
susceptibility-contrast MR imaging will be acquired to determine serial rCBV values. 
 
In addition, we hypothesize that pseudoprogression will demonstrate significantly lower vascular 
permeability (Ktrans) and fractional plasma volume (vp) compared to cases with true early 
progression. The lower vp is postulated to be the result of the absence of angiogenesis that 
typically characterizes progressive tumor.  Extravascular extracellular space volume fraction (ve) 
will likely be significantly higher in pseudoprogression versus true early progression. This is 
postulated to be the result of a decrease in cellularity and an increase in the extracellular space 
seen in necrosis. T1-weighted dynamic contrast enhanced MR imaging will be used to determine 
the Ktrans, vp, and ve values serially during the first 6 months after irradiation and ABT-888.   
 
We also hypothesize that pseudoprogression will be associated with significantly higher ADC 
values compared to those seen in true early progression.  Using diffusion tensor MR imaging, we 
shall determine the ADC values of pseudoprogression and true early progression in the first 6 
months following therapy and shall assess ADC values over time using DTI. 
 
Short and long-term effects of irradiation on the brainstem structures will be assessed using 
diffusion tensor imaging. Previous work has shown that radiation therapy affects the white 
matter anisotropy.27-29   Changes have been noted in the brainstem, following treatment for 
posterior fossa tumors arising outside brainstem itself.30   Diffusion tensor imaging will be used 
to assess the fractional anisotropy and ADC values within the tumor, within the white matter of 
the pons, and within the uninvolved midbrain and medulla. 
 
2.4.3 Rationale for Pharmacokinetic Studies 
Based on pre-clinical data demonstrating ABT-888’s radiation potentiation in pediatric CNS 
tumor models and adult phase I clinical data, we will be administering ABT-888 at doses higher 
than 50 mg/m2/day (the highest dose studied in PBTC-027) concurrently with radiation therapy. 
It would be imperative that we characterize PK profile of ABT-888 when given at higher doses 
in combination with radiation therapy, especially if unanticipated toxicities are encountered. 
Furthermore, these PK data will be critical in optimal planning of a future phase III study. 
Therefore, PK studies for ABT-888 during radiation therapy will be REQUIRED FOR THE 
PHASE I STUDY. PK studies for ABT-888 during radiation for the Phase II study will also be 
performed but will be optional. 


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2.4.4 Rationale for Urine Correlative Study 
Despite recent advances in the imaging and treatment of brain tumors, the ability to 
prospectively screen for new tumors or to detect tumor recurrence remains limited.  Clinicians 
need to know when a tumor is present and – if previously treated – whether recurrence or tumor 
progression is occurring in order to most effectively direct therapy.  For some of the most 
common pediatric brain tumors, such as medulloblastoma, ependymoma and juvenile pilocytic 
astrocytoma, patient outcome is closely linked with extent of resection.31-36 Timely diagnosis of 
the presence of disease – including recurrence - is of particular importance in the brain, where 
radical maneuvers to contain tumor spread are often not possible because of eloquent neural 
tissue.  Clinical detection (through observation of neurologic deterioration) of recurrent brain 
tumors is twice as likely as asymptomatic radiographic recurrence, yet for patients with 
recurrence detected radiographically before symptoms became present – the patients with early 
detection who are less likely to have widespread tumor dispersal - had better survival.37  Thus, 
earlier detection of recurrence could improve patient outcomes by identifying the mass when it is 
small, before tumor cells have migrated, increasing the chances for a curative surgical resection.  
 
Unfortunately, certain subtypes of brain tumors remain challenging to treat at any time due to 
growth within sensitive parts of the brain or intrinsic biologic characteristics conferring 
resistance to therapy.  Yet even with these types of tumors, such as diffuse intrinsic pontine 
gliomas (DIPG) and glioblastoma multiforme (GBM), the ability to identify tumor status and 
response to therapy or progression is important so that clinicians provide patients and families 
with accurate prognostic information.   
 
We therefore propose to study the feasibility of a novel, non-invasive method employing urinary 
biomarkers to detect the presence, progression and response to therapy of pediatric brain tumors.  
Studies from our laboratory, now confirmed by others, support the premise that tumor stage and 
progression may correlate with urinary levels of specific biomarkers,38,39  specifically that 
biomarkers related to regulation of vascular stability in the urine of affected patients might 
represent a novel, non-invasive method of detecting disease status, progression and therapeutic 
efficacy.38-42  Our biomarker selection has been based on targeting specific tumor-related 
molecules and pathways, in contrast to other more general methods of high-throughput 
proteomic analyses. 
 
Current methods of brain tumor diagnosis and follow-up center around the use of infrequent 
clinical examinations and expensive radiographic studies, such as computerized tomography 
(CT) and magnetic resonance imaging (MRI) that often require sedation or anesthesia in 
children.  By contrast, urine collection carries no risks to the patient and is far less expensive 
(100-fold less than MRIs) so it can easily be done at frequent intervals, potentially enabling 
earlier detection of recurrent disease and dynamic evaluation of response to therapy.  Urine 
collection is easy, non-invasive, and can be done locally, saving families travel to tertiary care 
centers. Analysis is rapid, with a turnaround time of 24 hours. Test results are numerical and are 
compared to specific statistical cutpoints, obviating the need for analysis that relies on subjective 
measures, such as film review or tissue staining.  Additionally, biomarkers provide a method of 
assessment that relies on metabolic activity; a different – and complementary – approach to the 
current method of neuroimaging evaluation. 


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2.4.4.1 
Preliminary data 
We reported the first demonstration of the utility of urinary biomarkers in brain tumors, 
including the use of molecules specifically related to the regulation of vascular stability43 and 
recently published a proof-of-principle case series, that specifically evaluated the ability of a 
panel of urinary biomarkers  such as MMP-2, MMP-9, NGAL and VEGF (See Figure 4 and 
Table 6 and Table 7).44  The results of this series support the premise that levels of urinary 
biomarkers can not only predict the presence of brain tumors but also that they change in 
response to effective surgical therapy (see Figure 5).  
 
 
 
 
 
We have subsequently identified additional biomarkers that can be detected in urine in 
association with pediatric brain tumors.  These new markers (HB-EGF, EGF, HGF and TIE-2) 
allow for greater sensitivity in identifying the presence of disease.  Specific to this project, these 
markers have been evaluated in pediatric patients with various subtypes of high grade glioma, 
including both GBM and anaplastic astrocytoma. 
 
 


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Table 6 
Demographics, MMP’s and VEGF for Brain Tumor Patients and Controls 
Variable 
Control Group (n=23) 
Brain Tumor Group (n=28) 
P 
 
Median 
IQR 
Range 
Median 
IQR 
Range 
 
Age, yr 
22 
4-55 
0-71 
32 
8-58 
1-73 
0.37 
MMP-9 
0 
0-0 
0-6 
0.6 
0-5.7 
0-294 
<0.001* 
MMP-9/NGAL 
0 
0-0 
0-12.8 
0.8 
0.2-1.0 
0-1.1 
<0.001* 
MMP-2 
0 
0-0 
0-3 
4.3 
0.8-8.8 
0-27 
<0.001* 
VEGF 
25 
0-250 
0-391 
753 
451-957 
25-4462 
<0.001* 
Female sex, no. (%) 
11(48) 
 
13 (46) 
 
0.92 
 
Table 7 
Results of Receiver Operating Characteristic (ROC) Curve Analysis and Diagnostic Performance Indices 
of MMP-2 and VEGF 
Biomarker 
AUC 
95% CI 
P value 
MMP-2 (ng/ml) 
0.894 
0.800-0.987 
<0.0001 
VEGF (pg/L) 
0.965 
0.913-0.999 
<0.0001 
 
 
 
 
Cutoff Points 
Sensitivity (95% CI) 
Specificity (95% CI) 
Accuracy (95% CI) 
MMP-2 >0.4 ng/ml 
82.1 (65.2-94.0) 
95.7 (78.1-99.9) 
88.2 (76.1-95.6) 
VEGF >350 pg/L 
95.2 (76.2-99.9) 
89.5 (66.9-98.8) 
92.5 (80.0-98.5) 
 
2.4.4.2 
Selection of Brainstem Glioma 
The proof-of-principle data described above suggests that urinary biomarkers may have potential 
to identify the presence of brain tumors.  Further validation of this hypothesis would be bolstered 
by increasing the number of patients studied and following individual patients longitudinally to 
evaluate whether changes in disease status (response to therapy or progression) are reflected in 
corresponding changes in biomarker levels.   
 
This project will focus on urinary biomarker levels in children with brainstem glioma.  These 
patients represent a relatively homogenous population, minimizing variability in age (children), 
tumor pathology (high grade glioma), location (pontine, without concern for dissemination 
within the neuraxis) and treatment regimens.  As these lesions are not treated with surgical 
excision, the imprecision inherent to measuring the degree of resection will not be present.  The 
near-uniform progression of these tumors within a short window of time (>80% of patients 
manifest disease progression within 1 year) allows for data to be collected within a manageable 
time frame.  In combination, these characteristics support the use of this group as an ideal study 
population.   
 
2.4.4.3 
Justification for Data Collection 
One of the objectives of this study is to identify whether biomarker levels correlate with changes 
in tumor status.   In order to accurately reflect current practice, we will collect clinical data (as 
measured by Karnofsky and Lansky scores) and several different types of radiographic measures, 
including changes in size, altered enhancement pattern and the radiologist’s overall assessment 
of tumor status. 
 
Control urines will be obtained from a pre-existing, institutional review board approved urine 
bank in the Vascular Biology Program at Children’s Hospital Boston.  These samples come from 
children with radiographic evaluation of their central nervous system by MRI.  Children may 


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have no evident pathology or evidence of congenital fatty fila (thickening of the terminal end of 
the spinal cord) or Chiari I malformation (herniation of the cerebellar tonsils below the foramen 
magnum).  No patients have radiographic or clinical histories of tumor, recent trauma, 
hydrocephalus or arteriovenous malformation (AVM). We currently have control samples from 
approximately 50 children and collect 1-2 additional samples per week. Thus we anticipate that 
at the time of analysis we will have a large number of control samples with adequate diversity to 
enable us to match each clinical sample with an age- and sex-matched control.   
 
2.5 
Summary 
In conclusion, ABT-888, combined with chemotherapy or radiation, has demonstrated anti-tumor 
activity in orthotopic xenograft models of pediatric GBM and has shown an acceptable toxicity 
profile in adult and pediatric phase I trials.  Available data suggests that PARP is over-expressed 
in multiple malignancies, including pediatric high-grade gliomas, and therefore inhibition of this 
target may overcome chemotherapy and/or radiation resistance. Given the dismal prognosis for 
children with DIPG, it is appropriate to evaluate the combination of ABT-888 and radiation, 
followed by maintenance therapy with ABT-888 and TMZ, in this patient population.  
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
The eligibility criteria listed below are to be interpreted literally and cannot be waived.  No 
exceptions will be given.  All clinical and laboratory data required to determine eligibility of a 
patient enrolled on this trial must be available in the patient’s medical or research record. 
 
3.1.1 Age  
Patients must be ≤ 21 years of age at registration 
 
3.1.2 Tumor 
Patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined as 
tumors with a pontine epicenter and diffuse intrinsic involvement of the pons, are eligible 
without histologic confirmation. Patients with brainstem tumors that do not meet these 
criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if 
the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma 
multiforme, gliosarcoma, anaplastic mixed glioma or fibrillary astrocytoma.  
 
Note: Patients with juvenile pilocytic astrocytoma, pilomyxoid astrocytoma, 
gangliogliomas, or other mixed gliomas without anaplasia are not eligible. Patients with 
disseminated disease are not eligible, and MRI of spine must be performed if 
disseminated disease is suspected by the treating physician 
 
3.1.3 Neurological Status 
Patients must be able to swallow oral medications to be eligible for study enrollment.  
 


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3.1.4 Performance Status 
Karnofsky >50% for patients >16 years of age or Lansky 50 for patients  16 years of 
age.  Patients who are unable to walk because of paralysis, but who are up in a 
wheelchair, will be considered ambulatory for the purpose of assessing the performance 
score. See Appendix A. 
 
3.1.5 Prior Therapy 
Patients must have not received any prior therapy other than surgery and/or steroids. 
 
3.1.6 Organ Function  
Patients must have normal organ and marrow function documented within 14 days of 
registration and within 7 days of the start of treatment as defined below: 
 
 
Absolute neutrophil count 
>1,000/mm3 
 
Platelets    
 
 
 
>100,000/ mm3 (unsupported) 
 
Hemoglobin  
 
 
 
≥10g/dl (unsupported 
 
Total bilirubin  
 
 
 
≤1.5 times upper limit of normal (ULN) for age  
 
ALT(SGPT)  
 
 
 
<5 x institutional upper limit of normal for age 
 
Albumin  
 
 
 
 
 
≥2g/dl 
 
Creatinine clearance or radioisotope GFR >70 mL/min/1.73 m2 or 
Serum creatinine based on age/gender as follows: 
 
Table 8 
Serum Creatinine for age/gender  
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the 
Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 
106:522, 1985) utilizing child length and stature data published by the 
CDC. 
 
 
3.1.7 Pregnancy Status 
Female patients of childbearing potential must not be pregnant or breast-feeding.  Female 
patients of childbearing potential must have a negative serum or urine pregnancy test.   
 
3.1.8  Pregnancy Prevention 
Patients of childbearing or child fathering potential must be willing to use a medically acceptable 
form of birth control, which includes abstinence, while being treated on this study. 
 


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3.1.9  Informed Consent 
Signed informed consent according to institutional guidelines must be obtained. Assent, when 
appropriate, will be obtained according to institutional guidelines. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Concurrent Illness 
Patients with any clinically significant unrelated systemic illness (serious infections or 
significant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromise the 
patient’s ability to tolerate protocol therapy or would likely interfere with the study procedures or 
results. 
 
3.2.2 Inability to Participate 
Patients with inability to return for follow-up visits or obtain follow-up studies required to assess 
toxicity to therapy.  
 
3.2.3   Seizures 
Patients with active seizures or a history of seizure are not eligible for study entry, with the 
exception of patients with documented febrile seizure. 
 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
3.4 
Treatment at Primary Institution 
All experimental protocol therapy should be dispensed and all imaging studies obtained at the 
primary institution. Laboratory studies, excluding pharmacokinetic and biologic assays, may be 
performed at a CLIA certified laboratory of the investigator’s choice.  
 
3.5 
Criteria to Start Therapy 
Protocol therapy must begin no later than 30 days after the date of radiographic diagnosis or 
surgery, whichever is the later date. 
 
All clinical and laboratory studies/assessments required to determine eligibility (excluding 
diagnosis of the tumor) must be performed within 14 calendar days prior to registration unless 
otherwise indicated.  Imaging evaluations necessary to establish eligibility for study entry must 
be done within two (2) weeks prior to registration. 
 
Patients must begin therapy no later than 7 calendar days after study registration. If more than 7 
calendar days elapse between the date eligibility studies outlined in section 10 were obtained and 
the start date of treatment, then the following studies must be repeated prior to treatment:  
• CBC with differential 
• Bilirubin 
• ALT (SGPT) 
• Serum creatinine 
 
If any of these repeat laboratory studies are outside the parameters required for eligibility or the 
patient’s clinical condition worsens so they no longer meet eligibility requirements (labs may 


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again be repeated within 48-72 hours), then the patient will not be eligible for protocol therapy. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
4.1.1 Prior to Consent 
Prior to consent the protocol’s status should be verified via the PBTC Protocol Status web page, 
to ensure the study is open to accrual. 
 
4.1.2 Informed Consent 
Informed consent must be obtained prior to patient registration.  
 
Furthermore, consent should be obtained prior to the initiation of any clinical procedures or 
assessments performed for the purpose of determining protocol eligibility, which would not 
otherwise be consistent with the institution’s standards of clinical practice.  
 
4.2 
Patient Registration 
Patients must be registered prior to any protocol treatment.  Patient registration is only available 
to authorized personnel using the PBTC automated registration system.  The registration 
procedures are available in the CRA manual, which is posted on the PBTC members’ website. 
The PBTC Protocol Coordinator may also be contacted at (901) 595-3783 for assistance in the 
registration process. 
 
Reservations may also be made through the registration system providing time to assess the 
patient’s eligibility.  Reservations will be held for a maximum of 7 calendar days by which time 
the patient must have been registered on study. The patient’s reservation should be canceled as 
soon as it is determined that the patient is not eligible or that the family/patient has decided not to 
consent to the trial.  
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in section 7.  Appropriate dose modifications are described in section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
All patients will receive ABT-888 plus radiation followed by maintenance therapy with ABT-
888 plus TMZ during the Phase I study.  The Phase I portion of this trial is a dose finding phase 
for ABT-888 during the radiation phase of therapy.  The Phase II portion of this trial is an 
efficacy study. Patients will be given a diary (located on the PBTC-033 Protocol webpage) to 
record the date and time the study drug was taken as well as any comments (e.g. side effects, 
vomiting, missed doses). If emesis occurs within 10 minutes of administration of ABT-888 or 
TMZ, the dose should be repeated. A missed dose will not be made up, but the missed dose and 
reason for missing the dose should be recorded in the diary. The completed Patient dairy will be 
reviewed weekly during radiation and at each clinic visit during maintenance.  


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5.1.1 ABT-888 plus Radiation (Phase I) 
Patients will receive ABT-888 throughout radiation therapy as outlined in Table 9.  Radiation 
therapy will be administered by 3D-conformal or IMRT to a dose of 54 Gy in 30 daily fractions, 
treating 5 days per week (typically M-F each week) as outlined in section 5.1.4. Irradiation will 
not be interrupted for ABT-888 related DLTs unless clinically indicated.  
 
Table 9 
 
 
Schema – Radiation Phase of Therapy 
Week 
1 
2 
3 
4 
5 
6 
Week 7-10 
ABT-888, BID 
Twice daily, M-F, for 6-7 weeks 
Rest/ 
Evaluation 
Radiation Therapy 
Daily, M-F, for 6-7 weeks 
 
ABT-888 will be given twice daily, Monday through Friday during radiation therapy (6-7 
weeks total). The first dose of ABT-888 should begin on the first day of radiation therapy, except 
for those children who require sedation for irradiation (see below). Dosing will be based on the 
BSA determined at the beginning of radiation therapy.  The morning dose of ABT-888 
should ideally be given 60-120 minutes prior to daily radiation treatment. For patients who 
require sedation for radiation treatment and are not able to take the oral medication due to local 
requirements for NPO prior to sedation, ABT-888 may be given nightly, and the daytime dose 
given shortly after the child awakens from sedation, adhering as closely to an every 12-hour 
schedule as possible. However, if local sedation guidelines permit, then the morning ABT-888 
dose should be taken 60-120 minutes prior to radiation. Periodic adjustments in the timing of 
twice daily ABT-888 administration are allowed if needed to accommodate patient/family 
convenience provided that the daytime dose is given as close to 60-120 minutes prior to daily 
irradiation whenever possible and adherence to an every 12-hour dosing schedule is attempted 
whenever possible. 
 
For patients taking the oral solution, the dose of ABT-888 should be rounded to the nearest 1 mg 
(e.g. 1.4mg to be rounded to 1.0 mg and 1.5mg to be rounded to 2mg).   Specific instructions for 
handling ABT-888 are provided Appendix B.  For patients unwilling to take the oral solution of 
ABT-888, dosing tables for patients with BSA ≥ 1.0 m2 who choose to take only capsules is 
located in Appendix D. Patients are not allowed to take a combination of capsules and the oral 
solution of ABT-888.   
 
All patients from the Phase I portion of the study, after completing radiation treatment and ABT-
888, will continue with maintenance therapy starting week 11, as outlined in section 5.1.3. 
 
5.1.1.1 
Dose-finding Period for the Phase I study 
The observation period for DLTs (Course 1) during Phase I of the study includes the entire 
duration of radiation therapy (approximately 6 to 7 weeks, allowing for delays in XRT for 
holidays, mask adjustments, etc.) and the rest period between the end of radiation therapy and the 
start of maintenance treatment on week 11.  Dose limiting toxicities are defined in section 5.2.  
Guidelines for dose modifications (if required) are provided in section 6.1. 
 


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5.1.1.2 
Dose Escalations during ABT-888 and Irradiation 
Dose Level 1 of ABT-888 during radiation treatment will be approximately 80% of the adult 
dose of 100 mg bid, which has been well tolerated. It is also expected that the 150 mg bid dose 
level in adults will be declared tolerable shortly.  Dose escalation/de-escalation will be done 
using a standard phase I, 3 + 3 design in increments of approximately 30% (see Table 10 below). 
If the adult dose of 150 mg bid with radiation has been declared tolerable by the time this trial 
begins patient accrual, and the starting dose level of 50 mg/m2 bid is also tolerated in children, 
we propose to proceed from dose level 1 directly to dose level 3 (85 mg/m2 bid, equivalent to the 
adult dose of 150 mg bid). If dose level 3 is not tolerated, then we will de-escalate to dose level 
2. If dose level 3 is tolerated, we will study dose level 4 only if supported by adult clinical data 
and PBMC PARP inhibition data from our ongoing trial.*   
 
Table 10 
ABT-888 Dose Levels During Radiation, Phase I of the Study 
Dose Level 
ABT-888 dose (mg/m2/dose BID), M-F 
0 
35 mg/m2/dose BID 
1 (starting dose level) 
50 mg/m2/dose BID 
2 
65 mg/m2/dose BID 
3 
85 mg/m2/dose BID 
4 (pending supporting data)* 
110 mg/m2/dose BID 
 
There will be no intra-patient dose escalation during the irradiation phase of the study (ABT-888 
and radiation treatment). Phase I of the study will be completed when MTD/recommended phase 
II dose of ABT-888 that can be safely administered with radiation has been determined. 
 
5.1.2 Drug Administration during Radiation - Phase II 
The Phase II portion of the trial is to evaluate the efficacy of ABT-888 and radiation therapy (at 
the maximum tolerated or recommended ABT-888 dose level from the Phase I study), followed 
by maintenance therapy with 10 cycles of ABT-888 and temozolomide in patients with newly 
diagnosed DIPG.  Follow instructions for administering ABT-888 during radiation for the Phase 
II portion of the study as previously outlined in section 5.1.1. 
 
5.1.3 Drug Administration - Maintenance Therapy (Phase I and Phase II) 
Maintenance therapy of ABT-888 and TMZ will begin approximately at week 11 (3-4 weeks 
after the completion of irradiation and ABT-888) provided that the patient’s bone marrow, renal, 
and hepatic organ functions continue to meet on study criteria.  ABT-888 will be given twice 
daily, with the morning dose given 60-120 minutes prior to the daily dose of TMZ.  ABT-888 
and TMZ will be given on day 1-5, and each course of treatment will be a minimum of 28 days 
in length (Table 11).  
Table 11 
Schema- Maintenance Phase of Therapy 
Each Course 
May receive a maximum of 10 courses 
Day 
1 
2 
3 
4 
5 
6-28 
ABT-888, BID 
x,x 
x,x 
x,x 
x,x 
x,x 
Rest/Evaluation 
Temozolomide, once daily 
x 
x 
x 
x 
x 
Rest/Evaluation 
 
All patients (Phase I and Phase II), will start maintenance therapy on week 11 with 25 mg/m2 bid 


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of ABT-888 and 135 mg/m2/day of TMZ (the starting dose for maintenance therapy, Table 12), 
for 5 days every 28 days, which represent the recommended phase II doses from PBTC-027. 
Dosing of ABT-888 and TMZ will be based on the BSA determined prior to each course. 
Since this dose determination was based on children with refractory brain tumors, many of 
whom were heavily pre-treated, it is possible that children with newly diagnosed DIPG, who are 
chemotherapy naïve at entry, will tolerate higher doses of ABT-888 and TMZ during 
maintenance.   
 
5.1.3.1 
Intra-patient Dose Escalation of TMZ during Maintenance 
In an effort to maximize the TMZ dose (and potentially the efficacy of the combination 
treatment) that can be administered with ABT-888 for each patient, intra-patient dose 
escalation of TMZ will be studied only for patients with minimal toxicities, considered at 
least possible related, in each course. These patients’ TMZ dose will be escalated (per Table 
12) to 175 mg/m2/day (Dose Level 2), and subsequently to 200 mg/m2/day of TMZ (Dose Level 
3) if the toxicities observed after 1 course of protocol therapy at each dose level meet the defined 
criteria. In patients who are not eligible to dose escalate after course 1due to greater than 
minimal toxicities, there will be no further attempts to escalate the dose of temozolomide.  
Patients eligible to dose escalate after course 1 but are not dose escalated due to site related 
issues may start dose escalation in a subsequent course provided they meet all criteria for dose 
escalation.  
 
Dose escalation of TMZ is not allowed if any of the following conditions exist: 
Hematological Toxicity 
 > Grade 1 thrombocytopenia 
 > Grade 2 neutropenia 
Non-hematologic Toxicity 
 Any grade 4 non-hematologic toxicity 
 Any grade 3 non-hematologic toxicity with the exception of: 
o Grade 3 nausea and vomiting of < 5 days 
o Grade 3 elevation of transaminases that returns to levels meeting 
eligibility criteria within 7 days of study drug interruption and does not 
recur upon restarting drug.  
o Grade 3 fever or infection of fewer than 5 days in duration 
o Grade 3  hypophosphatemia,   hypokalemia,   hypocalcemia  or   
o hypomagnesemia   responsive   to   oral   supplementation 
 Any grade 2 non-hematologic toxicity that persists for > 7 days and is 
considered medically significant or sufficiently intolerable by patients that 
requires treatment interruption. 
 
Table 12 
Intra-Patient Dose Escalation of TMZ during Maintenance Therapy (Days 1-5 per 28 day cycle) 
Dose Level 
ABT-888 Dose 
TMZ Dose 
0 
20 mg/m2 BID 
135 mg/m2/day 
1 (Starting Dose) 
25 mg/m2 BID 
135 mg/m2/day 
2 
25 mg/m2 BID 
175 mg/m2/day 
3 
25 mg/m2 BID 
200 mg/m2/day 
 


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A patient who experience any dose-modifying toxicity (defined in section 6.2) during intra-
patient TMZ dose escalation will not be dose-escalated again, and he/she will receive the 
remaining maintenance therapy at the highest dose level on which no dose-modifying toxicity 
was observed in that patient (for example, a patient who experiences any dose-modifying toxicity 
on Dose Level 2 will complete the remainder of maintenance therapy on Dose Level 1). Intra-
patient dose escalation to a given dose level will be halted based on similar rules employed in 
traditional 3+3 designs, i.e. if 2 out of first 2-6  patients 4 out of first 12 patients, etc. experience 
dose modifying toxicities. 
 
Patient specific dose de-escalations will occur as needed when dose-modifying toxicities arise 
(section 6.2). Dose level 0, namely ABT-888 at 20 mg/m2 bid and TMZ at 135 mg/m2, is 
provided to allow for one dose de-escalation for patients experiencing dose-modifying toxicities 
at Dose Level 1.  Any patient who experiences dose-modifying toxicities at dose level 0 will be 
taken off protocol therapy.  
 
5.1.3.2 
Criteria for starting subsequent courses - Maintenance 
Patients will start each subsequent course of maintenance therapy with recovery of ANC 
≥1,000/µl and Platelet count ≥100,000/µl.  
 
5.1.4 Radiation Therapy Guidelines 
General Guidelines 
All patients will receive radiation therapy on this protocol with the targeted volume based on the 
extent of disease defined by neuroimaging prior to radiation therapy. This study specifies a 1 cm 
clinical target volume margin and mandates the use of CT-MR registration to define the target 
volume. The allowed treatment methods are restricted to conformal or intensity-modulated 
radiation therapy using photons and electronic data submission is required. Proton therapy is not 
allowed. 
 
Treatment Planning Specifics 
The goal of the treatment planning process is to develop a plan to deliver a uniform dose to the 
planning target volume which includes all known tumor plus the specified clinical target volume 
margin. The protocol specified total dose is 54 Gy using conventional fractionation. Because the 
total dose does not exceed the recommended dose limits for the spinal cord and optic chiasm, 
volume reductions are not required nor recommended. 
 
Required Benchmark and Questionnaires 
Radiation therapy will be administered using photons. Required photon methods include 3D 
conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT).Centers 
participating in this protocol using 3D-CRT are required to complete the 3D benchmark; those 
using IMRT must complete the IMRT benchmark and questionnaire or phantom. All centers 
participating in this protocol must complete the QARC CT/MR image fusion benchmark. 
Benchmark materials and questionnaires may be obtained from the Quality Assurance Review 
Center (www.qarc.org) and must be submitted before patients on this protocol can be evaluated. 
For information regarding the IMRT phantoms, please contact the RPC 
(http://rpc.mdanderson.org/rpc). If IMRT is used, the monitor units generated by the IMRT 
planning system must be independently checked prior to the patient’s first treatment.  


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Measurements in a QA phantom can suffice for a check as long as the plan’s fluence 
distributions can be recomputed for a phantom geometry. 
 
Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed for the use of 
IMRT in National Cancer Institute sponsored cooperative group trials. These guidelines are 
available through www.qarc.org. These guidelines require that the protocol explicitly state their 
requirements and methods for localization and immobilization; the use of volumetric imaging; 
target and organ motion management; nomenclature, definitions, and rationale for targets and 
organs at risk; target volume coverage and normal tissue dose constraints; effects of 
heterogeneity in tissues; and quality assurance. 
 
5.1.4.1 
Indications for Radiation Therapy 
All patients enrolled on this protocol will receive concurrent ABT-888 and radiation therapy. 
 
5.1.4.2 
Timing 
All patients should be seen in consultation by a radiation oncologist at the time of study 
enrollment. The purpose of the consultation is to participate in the initial evaluation and to 
review the adequacy of the initial diagnostic imaging studies that will be used for subsequent RT 
planning. If additional imaging studies are pursued, thin section MR (T2-weighted and FLAIR) 
sequences should be obtained for registration to the CT data set to assist in treatment planning. 
 
Patients are not allowed to have received radiation therapy prior to enrollment on this protocol 
and urgent irradiation is not envisioned under any circumstance. 
 
The first dose of ABT-888 should ideally be given 60-120 minutes prior to timing of radiation 
treatment. 
 
5.1.4.3 
Equipment and Methods of Delivery and Verification 
 Beam Energy 
For 3D-CRT, photon energy of > 4 MV shall be used. For IMRT, photon energy from 4 to 10 
MV shall be used. 
 Treatment Planning 
CT (volumetric) based planning is required to optimize dose to the PTV while protecting normal 
tissues. Organs at risk within the irradiated volume should be contoured including those required. 
A DVH is necessary to determine target coverage and evaluate dose to normal tissues. CT 
section thickness should be < 5 mm although 2-3 mm is preferred. 
 In-room verification of spatial positioning 
Portal imaging is the most common system used to verify patient position, in particular when the 
target volume is believed to possess a fixed spatial relationship with visualized bony anatomy. 
Orthogonal paired (AP and lateral) portal images (MV or kV) are required for IMRT and 3D-
CRT to verify that the isocenter is in correct alignment relative to the patient position. 
 
Volumetric imaging is allowed in this study. This includes in room kV or MV cone beam or 
conventional CT imaging. Please submit representative axial images showing the isocenter and 
the correct alignment in relationship to the patients’ position. For CT tomography where 


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isocenters are not used, a printout of the isodoses overlaid on the fused CT images can be printed 
to demonstrate in room verification. 
 
5.1.4.4 
Target Volumes 
 General Comments 
International Commission on Radiation Units and Measurements (ICRU) Reports 50, 62 and 78 
(www.icru.org) define prescription methods and nomenclature that will be utilized in this study. 
MRI obtained immediately prior to RT will be utilized for treatment planning. MR pre- and post-
gadolinium T1 and T2 sequences shall be reviewed. Usually the T2 weighted images are used to 
determine target volumes but a combination of T2 and FLAIR can be used. The GTV, CTV, 
PTV and normal tissues must be outlined on all axial imaging slices on which the structures 
exist. 
 Definition of GTV, CTV and PTV 
Gross tumor volume (GTV) is based on the most recent MRI. The GTV is defined as the 
abnormal signal on MRI (usually T2 weighted, but a combination of T2 or FLAIR abnormality 
on the appropriate MR sequence). Investigators should register the immediate pre-irradiation MR 
imaging sequences that demonstrated tumor and contour the GTV. 
 
The clinical target volume (CTV) includes the GTV with an added margin that is meant to treat 
subclinical microscopic disease and is anatomically confined (i.e. the CTV is limited to the 
confines of the bony calvarium, falx and tentorium where applicable or extends up to but not 
beyond neuroanatomic structures through which tumor extension or invasion is certain not to 
have occurred). The CTV may be manually moved inward to the inner table of the bony 
calvarium. For diffuse pontine gliomas, spread usually occurs to the confines of the brainstem 
circumferentially, rostral to the midbrain and distal to the medulla. The CTV margin will be 1.0 
cm for all patients, with most of the CTV growth superiorly and inferiorly as the CTV will not be 
beyond the brainstem circumferentially. The CTV margin chosen for this study requires 
treatment planning MR and/or diagnostic MR imaging data with image section thickness ≤ 5mm. 
 
The planning target volume (PTV) includes a margin which is added to the CTV in 3-dimensions 
to create the PTV. It is geometric and not anatomically defined. The PTV has 2 components, the 
internal margin (IM) and the set-up margin (SM). The IM is meant to compensate for all 
movements and variations in size and shape of the tissues contained within the CTV. The SM is 
meant to account for set-up, mechanical and dosimetric uncertainties related to daily patient 
positioning, treatment equipment and software. For this study, the PTV margin should be 3 or 5 
mm. The use of PTV margin of 3 mm requires written documentation that image guided 
radiation therapy (IGRT) methods are used on a daily basis or alternatively a head fixation 
system or verification system was used with weekly imaging. For this study, IGRT is defined as 
2- or 3-dimensional digital imaging positioning. For all other cases, a PTV margin of 5 mm shall 
be used. Given that the CTV is generally confined to the intracranial space, the PTV may extend 
into or beyond bone but is unlikely to extend beyond the surface of the patient. The PTV margin 
chosen by the treating investigator requires treatment planning MR and/or diagnostic MR 
imaging data with imaging section thickness ≤ the chosen PTV margin. 
 
5.1.4.5 
Target Dose 
 Dose Definition 


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Photon dose is specified in centigray (cGy)-to-muscle. 
 Prescribed Dose and fractionation 
Planning Target Volume: The total dose to the PTV will be 5400 cGy administered in 30 
fractions of 180 cGy.  
 Dose Uniformity 
At least 95% of the protocol-specified dose should encompass 100% of the PTV. No more than 
10% of the PTV should receive greater than 110% of the protocol dose as evaluated by DVH. 
The 100% isodose line should be equal to the protocol specified dose. Wedges, compensators 
and other methods of generating more uniform dose distributions are encouraged. 
 Tissue heterogeneity 
Calculations must take into account tissue heterogeneity and should be performed with CT-based 
treatment planning to generate dose distributions and treatment calculations from CT densities. 
For questions about heterogeneity corrections or approved algorithms, please contact QARC 
(www.qarc.org). 
 Treatment Interruptions, Delays and Dose Modifications 
The patient should be treated with one fraction per day, 5 days per week. All fields shall be 
treated each day. There will be no planned rests or breaks from treatment, and once radiation 
therapy have been initiated, treatment will not be interrupted except for life threatening infection 
or severe hematological toxicity during the course of treatment. The reason for any interruptions 
greater than 3 treatment days should be recorded in the patient treatment chart and submitted 
with the QA documentation. There should be no modifications in dose fractionation due to age or 
field size. 
 
5.1.4.6 
Treatment Technique 
 Beam configuration 
Every attempt should be made to minimize dose to organs at risk without compromising 
coverage of the target volume. 3DCRT (coplanar or non-coplanar) or IMRT are required to 
minimize dose to normal tissues. 
 Field Shaping 
Field shaping for photons will be done with either customized cerrobend blocking or multileaf 
collimation. 
 Simulation 
Patient positioning and immobilization device- Reproducible set-up is critical and the use of an 
immobilization device is to be used. The imaging studies should provide a clear assessment of 
the target volume with the patient in the treatment position. Anesthesia or sedation may be 
required in some patients to prevent movement during simulation and daily treatments. 
 Special Considerations 
Anesthesia or sedation may be required in certain patients, such as very young patients, to 
prevent movement during simulation and daily treatments. 
 
5.1.4.7 
Organs at Risk 
The organs at risk (OAR) guidelines in this section are recommendations. If the recommended 
doses to the OAR are exceeded because of target volume coverage requirements or other 
conditions, an explanation should be included in the quality assurance documentation. In some 
cases, IMRT may be the preferred treatment method to meet these requirements and the required 
target volume coverage guidelines. 


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Dose Constraints: 
 Right and Left Optic Nerves and Chiasm 
D90% < 1000cGy, D50% < 5400cGy and D10% < 5600cGy – Goal 
D90% < 5400cGy, D50% < 5600cGy and D10% < 5800cGy – Maximum 
Comment – Effort should be made to avoid direct treatment of the optic nerves and chiasm 
without compromising target volume coverage. In the event that the recommended maximum 
dose constraints provided in this section would be exceeded, the treating radiation oncologist 
may use their discretion to reduce target volume coverage. 
 
Structure definition – The optic nerve may be contoured on CT or MR. The contour should 
appear on at least two successive CT or MR images. 
 
 Optic Globes 
D90% < 500cGy, D50% < 1000cGy and D10% < 3500cGy – Goal 
D90% < 1000cGy, D50% < 2000cGy and D10% < 5400cGy – Maximum 
Comment – Effort should be made to avoid direct treatment of the anterior chamber of the eye 
and minimize dose to the entire eye without compromising target volume coverage. In the event 
that the recommended maximum dose constraints provided in this section would be exceeded, 
the treating radiation oncologist may use their discretion to reduce target volume coverage. 
 
Structure definition - Each eye should be separately contoured on the treatment planning CT or 
MR as a circular structure from the most superior to inferior aspect. 
 
 Spinal Cord 
D90% < 300cGy, D50% < 2600cGy and D10% < 5700cGy – Goal 
D90% < 900cGy, D50% < 5000cGy and D10% < 5900cGy – Maximum 
Comment – Effort should be made to minimize dose to the spinal cord without compromising 
target volume coverage. 
 
Structure Definition - For the purposes of this study, the upper aspect of the spinal cord begins at 
the inferior border of the foramen magnum and should be contoured on the treatment planning 
CT. For purposes of comparison and consistency with dose volume data, the spinal cord should 
be contoured on a number of images to be determined by the image section thickness (CT section 
thickness, n=number of images; 2mm, n=30; 2.5 mm, n=24; 3 mm, n=20). Using these 
guidelines, only the superior-most 6cm of anatomic spinal cord is contoured. 
 
 Cochleae 
D50% < 3500cGy – Goal (each cochlea) 
D50% < 2000cGy – Preferred (each cochlea) 
Comment – There is no dose limit for the cochleae. 
 
Structure definition - Each cochlea will be contoured on the treatment planning CT as a circular 
structure within the petrous portion of the temporal bone. The contour should appear on at least 
two successive CT images. 
 


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5.1.4.8 
Dose Calculation and Reporting 
 Prescribed Dose 
The dose prescription and fractionation shall be reported on the RT-1/IMRT Dosimetry 
Summary Form. The total dose delivered shall be reported on the RT-2 Radiotherapy Total Dose 
Record. If IMRT is used, the monitor units generated by the IMRT planning system must be 
independently checked prior to the patient’s first treatment. Measurements in a QA phantom can 
suffice for a check as long as the patient’s plan can be directly applied to a phantom geometry. 
 Normal Tissue Dosimetry 
The dose to the critical organs indicated should be calculated whenever they are directly included 
in a radiation field. The total dose shall be calculated and reported on the RT-2 Radiotherapy 
Total Dose Record form. The appropriate dose-volume histograms should be submitted. If IMRT 
is used for the primary tumor, a DVH must be submitted for a category of tissue called 
“unspecified tissue,” which is defined as tissue contained within the skin, but which is not 
otherwise identified by containment within any other structure. DVH data for the following 
organs is required: Total Brain, Optic Nerves (Left and Right), Optic Chiasm, Brainstem, Spinal 
Cord, Cochleae (Left and Right), Unspecified Tissue 
 
5.1.5  Radiation Quality Assurance 
Within a week after completion of RT, detailed treatment data shall be submitted for review.   
 
5.1.5.1 
External beam Treatment Planning System 
 Digitally reconstructed radiographs (DRR) or simulator films for each treatment field and 
orthogonal (anterior/posterior and lateral) images for isocenter localization for each group 
of concurrently treated beams. When using IMRT, orthogonal isocenter images are 
sufficient.  
 
 Isodose distributions for the treatment plan in the axial, sagittal and coronal planes at the 
center of the treatment or planning target volume. The planning target volume, isocenter 
and the normalization method must be clearly indicated. 
 
 Dose volume histograms (DVH) for all target volumes and required organs at risk. A 
DVH shall be submitted for the organs at risk specified in section 5.1.4.8. When using 
IMRT, a DVH shall be submitted for a category of tissue called “unspecified tissue.” This 
is defined as tissue contained within the skin, but which is not otherwise identified by 
containment within any other structure. 
 
 Treatment planning system summary report that includes the monitor unit calculations, 
beam parameters, calculation algorithm, and volume of interest dose statistics. Beams-
eye-view (BEV) of portals showing collimator, beam aperture, target volume and critical 
structures are required when not using IMRT. 
 
5.1.5.2 
Digital Data 
Submission of the treatment plan in digital format is required. Please refer to www.QARC.org 
and click on "Digital Data" for guidelines regarding digital submission. All submissions, 
including those that are digital, require hard copy submission of the other items included in this 
list. If there are any problems with digital data submission, please contact QARC. 


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5.1.5.3 
Supportive Data 
All diagnostic imaging used to plan the target volume. This includes CT or MRI PRIOR to 
attempted surgical resection of the primary tumor. Digital format is preferred. 
  
Radiotherapy record (treatment chart) including prescription and daily and cumulative doses to 
all required areas and organs at risk. Documentation of an independent check of the calculated 
dose when IMRT is used should be included. If the recommended doses to the organs at risk are 
exceeded, an explanation should be included for review by the QARC and the radiation oncology 
reviewers. 
 
If a PTV margin of 3 mm is used, written documentation that image-guided radiation therapy 
(IGRT) methods are used on a daily basis or alternatively that a head fixation system or 
verification system was used with weekly or more frequent imaging. See section 5.1.4.4. 
 
Forms 
RT-1/IMRT Dosimetry Summary Form. 
RT-2 Radiotherapy Total Dose Record Form. 
 
These data should be forwarded to: 
Quality Assurance Review Center 
640 George Washington Highway Suite 201 
Lincoln, Rhode Island 02865-4207 
Phone: (401) 753-7600 
Fax: (401) 753-7601 
 
Questions regarding the dose calculations or documentation should be directed to: 
COG Protocol Dosimetrist 
Quality Assurance Review Center 
640 George Washington Highway Suite 201 
Lincoln, Rhode Island 02865-4207 
 
5.1.5.4 
Definitions of Deviations in Protocol Performance 
Table 13 
 
 
 DEVIATION 
 
Minor 
Major 
Prescription Dose 
 
Difference in prescribed or computed dose 
is 6-10% of protocol specified dose 
Difference in prescribed or computed 
dose is > 10% of protocol specified 
dose 
Dose Uniformity 
 
>10% PTV received > 110% of the 
prescription dose or 95% isodose covers < 
100% of CTV 
90% isodose covers < 100% of 
CTV 
 
Volume 
 
PTV and CTV margins are less than the 
protocol specified margins in the absence of 
anatomic barriers to tumor invasion or 
without written justification 
GTV does not encompass MR visible 
tumor 
 
Organs at Risk 
 
Dose to any OAR exceeds the goal 
dose stated in section 5.1.4.7 
Dose to any OAR exceeds the 
maximum dose stated in section 5.1.4.7 


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5.2 
Definition of Dose-Limiting Toxicity (DLT) 
Toxicities will be graded according to the NCI Common Terminology Criteria for Adverse 
Events v4.0 (CTCAE) http://ctep.cancer.gov/reprting/ctc.html.  Dose limiting toxicities (DLT) 
will be defined as any of the following events that are at least (possibly, probably, or definitely) 
attributable to ABT-888 observed during the dose finding phase (the first 10 weeks of therapy).  
 
5.2.1 Dose-Limiting Toxicities during Phase I 
During the Phase I portion of the study, the observation period for DLTs includes the entire 
duration of radiation therapy (approximately 6 to 7 weeks, allowing for delays in XRT for 
holidays, mask adjustments, etc.) and the rest period between the end of radiation therapy and the 
start of maintenance treatment (week 1 through week 10). All dose modifications are to follow 
the guidelines provided in section 6.1. 
 
5.2.1.1 
Interruption of Radiation Treatment 
Any interruption of irradiation, related to protocol therapy and lasting 5 consecutive days or 10 
cumulative days during irradiation is defined as a DLT. 
 
5.2.1.2 
Non-Hematologic Dose Limiting Toxicity 
 Any grade 4 non-hematologic toxicity 
 Any grade 3 non-hematologic toxicity with the exception of: 
o Grade 3 nausea and vomiting of < 5 days 
o Grade 3 elevation of transaminases that returns to levels meeting 
eligibility criteria within 7 days of study drug interruption and does not 
recur upon restarting drug 
o Grade 3 fever or infection of fewer than 5 days in duration 
o Grade 3 hypophosphatemia,  hypokalemia,  hypocalcemia or  
hypomagnesemia  responsive  to  oral  supplementation 
 Any grade 2 non-hematologic toxicity that persists for > 7 days and is 
considered medically significant or sufficiently intolerable by patients that 
requires treatment interruption. 
 
5.2.1.3 
Hematological Dose Limiting Toxicity 
 ≥ Grade 3 thrombocytopenia 
 Grade 4 neutropenia  
 
5.2.1.4 
Any ABT-888 related adverse event during the observation period for DLTs that 
leads to a dose reduction or results in the permanent cessation of therapy will be 
considered dose limiting.  
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
Record the use of all concomitant medications listed in this section.  
 
5.3.1 Steroids 
Corticosteroids should be used at the lowest dose to control symptoms of edema and mass effect, 
and discontinued, if possible.  
 


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5.3.2 Anticonvulsants 
Anticonvulsants should be used, if indicated.  
 
5.3.3 Growth Factors 
Growth factors that support white cell count or function can only be administered as outlined in 
sections 6.1 and 6.2 or for documented infection and/or sepsis.  
 
5.3.4 Anti-emetics 
Patients may receive daily prophylactic ondansetron or granisetron during the radiation phase 
(receiving ABT-888 and radiation) per local practice. During maintenance therapy, patients 
should receive prophylactic ondansetron or granisetron during the 5-day course of ABT-888 and 
TMZ, and such treatment may be continued beyond the 5-day period, if clinically indicated. 
Corticosteroids should not be used as anti-emetics. The use of additional anti-emetics will be at 
the treating physician’s discretion.   
 
5.3.5 Febrile neutropenia 
Febrile neutropenia should be managed according to the local institutional guidelines.   
 
5.3.6 Concomitant Therapy  
Other anti-cancer or experimental agents or therapies are not permitted.  
 
5.4 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for 10 cycles. 
See section 2.4.2 or 13.2.1 for guidelines on possible pseudo-progression on MRIs performed at 
weeks 10, 18, and 26. All patients will conclude protocol based therapy at the completion of 10 
cycles of maintenance treatment. At the end of protocol defined therapy, the patient should 
complete all end of treatment assessments. 
 
5.4.1 Extended Therapy  
ABT-888 may be available for patients beyond the 10th course of maintenance if the patient is 
benefiting from the treatment, has at least clinical and radiographic stable disease at the end of 
course 10 and the investigator and subject agree to continue treatment for up to an additional 13 
courses (total maximum duration of maintenance therapy is  23 courses). During this therapy, all 
study specific assessments will cease and procedures consistent with good clinical care will 
continue.  Patients will be followed during this additional period for dates of drug administration, 
adverse events, laboratory results, date of disease progression, date of last follow up and date of 
death. 
 
5.5 
Duration of Follow Up 
The “Off Treatment Date” is to be recorded in the eCRF and is to be consistent with the reason 
given for going off treatment. Date of “off treatment” must be the greatest of the date of last 
treatment and date of procedure, date of patient assessment or notification of patient/family 
decision, or decision made by the physician that resulted in the patient being taken off protocol 
treatment. The reason for discontinuation of treatment must be documented by the attending 
investigator in the medical record and recorded in the eCRF. 
 


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The “Last Treatment Date” is also to be recorded via the “Off Treatment and Off Study” eCRF 
and is defined as the last date that the patient received protocol based therapy.  The “Off 
Treatment Date” and the “Last Treatment Date” should be the same for patients that complete all 
protocol defined treatment (see sections 7, 5.5.2 and the Required Data and Timetable 
Submission from located on the 033 protocol webpage). 
 
5.5.1 Patients will be considered Off Treatment for the following reasons: 
 Development of unacceptable toxicity as outlined in 5.2 or 6.2. See section 5.5.2 
for specific reporting requirements. 
 Progressive disease (PD), as outlined in section 11.1.4  
 Development of a medical or psychiatric illness, that in the investigator's 
judgment renders the patient incapable of further therapy on this protocol. 
 The patient, parent or legal guardian refuses further treatment on this protocol. 
 Completion of all protocol defined treatment. 
 Pregnancy 
 Non-compliance 
 
Patients who are off protocol therapy must be followed until an “Off Study Criterion” is 
met. 
5.5.2 Off-Treatment Data Submission Schedule 
Patients will be followed for the resolution of all toxicities considered at least possibly related to 
ABT-888 occurring while on treatment and for 30 days after the last administration of study 
drug. Patients will be followed for 3 years from the initiation of protocol treatment for the 
monitoring of unexpected later developing toxicities or other morbidity and to document disease 
progression and survival. Data should be updated quarterly in the PBTC RDC database. 
 
For patients who are eligible for extended therapy (5.4.1) they will be followed during this 
additional period for dates of drug administration, adverse events that are possibly, probably or 
definitely related to study drug, laboratory results,  date of disease progression, and date of last 
follow up and date of death. At the completion of the additional 13 courses  of therapy the 
patient is considered to have completed protocol therapy and should be taken off treatment (per 
protocol section 5.5). At the completion of the appropriate follow up period (per protocol section 
5.6), the patient should be considered off study. 
 
5.6 
Criteria for Removal from Study 
The date and reason for the patient coming off study must be documented in the eCRF and the 
Operations and Biostatistics Center must be notified according to standard reporting guidelines 
(see sections 7, 5.6.2 and the Required Data and Timetable Submission from located on the 033 
protocol webpage). 
 
5.6.1 Patients will be considered Off Study for the following reasons: 
 Patient determined to be ineligible. 
 Parent, patient, or guardian withdraws consent for continued participation. 
 Patient death while on study. The IRB, Investigational Drug Branch (IDB), Study 
Chair and OBC must be notified as per section 7. 
 Patient has been followed for 3 years from the initiation of protocol treatment. 


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5.6.2 Off-Study Data Submission 
No data will be collected documenting treatment or reporting events or disease status that occurs 
subsequent to the official “off study” date with the exception of adverse events with an 
attribution of possible, probable, or definite that occur after the “off study” date for agents being 
studied under a CTEP IND (see section 7).   
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The study chair must be notified of any proposed dose modifications.  After consultation with the 
Study Chair, the site should follow the dose modification guidelines in this section.  
 
6.1 
Dose Modification for DLT during ABT-888 and Radiation 
6.1.1 Non-Hematologic 
For ABT-888-related non-hematologic DLTs during radiation therapy, ABT-888 will be 
withheld until the toxicity resolves to meet on study parameters (section 3.1.6), and the patient 
will restart ABT-888 at one dose level lower (see Table 10), if not already at Dose Level 0.  
Patients who experience a non-hematologic DLT on Dose Level 0 will complete radiation 
without ABT-888.  
 
6.1.2 Hematologic 
For ABT-888-related hematologic DLTs, ABT-888 will be withheld until criteria described 
below are met, and ABT-888 will be restarted at one dose level lower, if not already at Dose 
Level 0. If the same DLT is experienced at the lower dose level, then ABT-888 should be 
discontinued.  If a different DLT is encountered, then the patient may restart ABT-888 at the 
next lower dose level, if not already at Dose Level 0. 
 
In the event of hematological DLT, CBC should be checked twice weekly until recovery of ANC 
≥ 1,000/mm3 and platelet ≥ 100,000/mm3. A patient who experiences any DLT despite being 
treated at Dose Level 0 will complete radiation therapy without ABT-888. Irradiation should 
be continued despite ABT-888-related DLT, unless there is a clinical contraindication.  
 
a. ≥ Grade 3 thrombocytopenia: Platelet transfusion is permissible and strongly encouraged 
for patients with dose-limiting thrombocytopenia to minimize the risk of intra-tumoral 
hemorrhage. ABT-888 should not be restarted until platelet count has recovered to 
≥100,000/mm3 (transfusion independent). Radiation therapy should not be interrupted 
unless clinically indicated. 
 
b. Patients with grade 4 neutropenia may receive filgrastim (G-CSF) support only for 
documented infection and/or sepsis, and they should re-start ABT-888 at the next lower 
dose level without GCSF support.  ABT-888 should not be restarted until the ANC is 
≥1,000/mm3 for at least 48 hours without G-CSF support. Radiation therapy should not 
be interrupted unless clinically indicated. 
 
Patients who experience ABT-888-related DLTs during irradiation will still receive ABT-888 
during maintenance therapy, provided that they meet the criteria to start subsequent course of 


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therapy and all prior ABT-888-related toxicities have resolved to baseline.  
 
6.2 
Dose Modification for ABT-888 and TMZ during Maintenance  
Dose modifying toxicities will be defined as any of the following events that are at least 
(possibly, probably, or definitely) attributable to ABT-888 and TMZ. Dose de-escalation during 
maintenance should occur if any of the following dose modifying toxicities are present: 
6.2.1 Non-Hematologic Toxicity 
 Any grade 4 non-hematologic toxicity 
 Any grade 3 non-hematologic toxicity with the exception of: 
o Grade 3 nausea and vomiting of < 5 days 
o Grade 3 elevation of transaminases that returns to levels meeting 
eligibility criteria within 7 days of study drug interruption and does not 
recur upon restarting drug.  
o Grade 3 fever or infection of fewer than 5 days in duration 
o Grade 3  hypophosphatemia,   hypokalemia,   hypocalcemia  or  
hypomagnesemia   responsive   to   oral   supplementation 
 Any grade 2 non-hematologic toxicity that persists for > 7 days and is 
considered medically significant or sufficiently intolerable by patients that 
requires treatment interruption 
 
For any of the above non-hematologic toxicities during maintenance therapy, ABT-888 and 
TMZ will be withheld until the toxicity resolves to meet on study parameters (section 3.1.6), and 
the patient will restart ABT-888 and TMZ at the next lower dose level (see Table 12). Protocol 
therapy will be discontinued if a non-hematologic dose modifying toxicity occurs at dose level 0.  
 
6.2.2  Hematological Toxicity 
 ≥ Grade 3 thrombocytopenia 
 Grade 4 neutropenia  
 A delay of > 14 days in starting subsequent cycles of maintenance due to ANC 
< 1,000/mm3 and/or platelet < 100,000/mm3 (for example, a patient never 
experienced grade 3 thrombocytopenia, but his/her platelet count lingered 
between 50,000 to 100,000/ mm3 beyond 42 days after the start of the previous 
course of maintenance therapy) 
 
For the hematologic toxicities outlined above that occur during maintenance therapy, ABT-888 
and TMZ will be withheld until criteria described below are met, and ABT-888 and TMZ will be 
restarted at the next lower dose level (see Table 12). Protocol therapy will be discontinued if a 
hematologic dose-modifying toxicity occurs at dose level 0. 
 
a. ≥Grade 3 thrombocytopenia: Platelet transfusion is permissible and strongly encouraged 
for patients with dose-limiting thrombocytopenia to minimize risk of intra-tumoral 
hemorrhage. ABT-888 and TMZ should not be restarted until platelet count has 
recovered to ≥ 100,000/mm3 (transfusion independent).  
 
b. Patients with grade 4 neutropenia may receive filgrastim (G-CSF) support only for 
documented infection and/or sepsis. ABT-888 and TMZ should not be restarted until the 


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ANC is ≥ 1,000/mm3 and for at least 48 hours without G-CSF support. Patients should 
start the subsequent cycle at the next lower dose level, without G-CSF support. 
 
Complete blood counts should be repeated twice weekly for any hematological toxicity described 
above until counts recover to meet criteria for starting subsequent course of maintenance therapy.  
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (section 7.1) and the characteristics of an observed AE (section 7.2) will 
determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting.   
 Baseline Abnormalities 
Any baseline (pretreatment) abnormalities observed during the initial physical 
examination should be recorded in the PedBraTum database. 
 
 Routine AE Recording 
Only record adverse events grades 1 and 2 if the attribution is at least possibly related to 
ABT-888.  Record all adverse events grades 3 through 4 and deaths (while on treatment 
or within 30 days of treatment), regardless of attribution on the electronic case report 
forms (PedBraTum RDC database).   
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
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 of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements’ 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm for 
further clarification.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously via CTEP-AERS.  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. 
 
 


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. 
 
7.1.2 Adverse Event List for Temozolomide 
 
Table 14 
Known Toxicities of Temozolomide 
 
Likely (≥20%) 
Less Likely (≤20%) 
Rare but Serious (<5%) 
Immediate: 
within 1-2 days of 
receiving drug 
Anorexia 
Constipation 
Nausea  
Diarrhea 
,Abdominal pain, 
Headache, Itching, Rash, 
Urinary frequency and/or 
infection, Vomiting, 
Dizziness, Anxiety, 
Confusion 
Ataxia, Convulsions, Dysphagia, 
Hemiparesis, Thromboembolism 


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Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression 
Lethargy, Mucositis, 
Peripheral edema; Fever 
(associated with low 
neutrophil count), Weight 
gain, Back pain, Breast 
pain, peripheral neuropathy, 
Upper respiratory infection, 
cough, sore throat, Myalgia,  
Amnesia, Depression, 
Visual changes, Insomnia 
Myelosuppression for prolonged 
period with increased risk of 
infection or death; Hepatic failure 
Delayed: 
Anytime later during 
therapy, excluding the 
above conditions 
 
Alopecia  
Hepatotoxicity 
Late: 
Any time after 
completion of therapy 
 
 
Secondary tumors or cancers 
 
 
7.2 
Adverse Event Characteristics  
 CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
 
For expedited reporting purposes only:   
AEs for the investigational agent that are bold and italicized in the CAEPR (i.e., 
those listed in the SPEER column, section 7.1.1) should be reported through CTEP-
AERS only if the grade is above the grade provided in the SPEER. 
 
 
Attribution of the AE: 
 
Definite – The AE is clearly related to the study treatment. 
 
Probable – The AE is likely related to the study treatment. 
 
Possible – The AE may be related to the study treatment. 
 
Unlikely – The AE is doubtfully related to the study treatment. 
 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (Adverse Event 
Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and 
DCP INDs and IDEs” which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov).  These requirements are briefly outlined in the tables below 
(section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 


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made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. Also, if internet connectivity is not re-established within 24 
hours, notify the following by telephone and or email.  
 
 
 
 
 
 
 
 
 
 
 
 
7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature 
for other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
PBTC-033 Study Chair: 
Patricia Baxter, M.D. 
Pediatric Hematology-Oncology 
Texas Children’s Cancer Center 
Baylor College of Medicine 
1102 Bates Street Suite 1030 17 
Houston Texas 77030 
Tel: 832-824-4681 
Fax: 832-825-4038 
Email: pabaxter@txch.org 
PBTC OBC: 
Stacye Richardson, MSHS, BSMT 
St. Jude Children’s Research Hospital 
Department of Biostatistics 
Tel:  (901) 595-3783  
Fax: (901) 595-4173 or 595-4184 
Email: stacye.richardson@stjude.org 


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subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.4 
Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
 
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 45)  
 Myelodysplastic syndrome (MDS)  
 Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 


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7.6 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agent administered in this study can be found in section 7.1. 
 
8.1 
ABT-888 (NSC # 737664) 
 
Chemical Name: 1H-Benzimidazole-7-carboxamide, 2-[(2R)-2-methyl-2-pyrrolidinyl]- 
Other Names: Veliparib, A-861695.0 
Classification: Poly (ADP-ribosome) polymerase (PARP) Inhibitor 
CAS Registry Number: 912444-00-9 
Molecular Formula: 
C13H16N4O 
 
M.W.:  244.29 
 
Mode of Action: ABT-888 is a potent oral PARP1/2 inhibitor whose pharmacological properties 
include high solubility (crosses the blood brain barrier), linear PK, and low potential drug-drug 
interactions.  In vivo and in vitro, ABT-888 inhibits the formation of poly (ADP-ribose) (PAR) 
polymer and prevents the repair of DNA that is damaged by cytotoxic agents. Furthermore, 
ABT-888 can increase antitumor efficacy of temozolomide, cisplatin, carboplatin, 
cyclophosphamide, irinotecan, or radiation therapy. 
 
Route of Administration: The oral solution can be administered with water or juice if needed. 
ABT-888 will be administered twice daily (~12 hours apart), Monday through Friday, during 
radiation therapy. The morning dose of ABT-888 should ideally be given 60-120 minutes prior 
to daily irradiation. For children who require sedation for irradiation and must remain NPO in the 
morning, ABT-888 may be given each night prior to bedtime, and the morning dose should be 
given shortly after the child recovers from sedation, adhering as closely to an every-12-hour 
schedule as possible. However, if permitted by the local sedation/anesthesia guidelines, ABT-
888 may be given each morning prior to sedation, ideally 60-120 minutes prior to irradiation. See 
additional administration instructions in section 5.1. See Appendix D for calculated dose of 
ABT-888 capsules for patients taking capsules only. 
 
During the maintenance therapy (starting on week 11 of protocol therapy), ABT-888 will be 
given twice daily (~12 hours apart), on days 1-5 of each 28-day course, with the morning dose of 
ABT-888 to be given 60-120 minutes prior to the morning temozolomide dose. The capsules 
should be swallowed whole without breakage. See Appendix E for the calculated dose for the 
ABT-888 capsules during maintenance for patients taking capsules only.  ABT-888 capsules or 
the oral solution may be administered without regard to meals. If emesis occurs within 10 
minutes of administration, the dose should be repeated. 
 
Potential Drug Interactions: Clinical studies evaluating the metabolism of ABT-888 have not 
been conducted.  However, results from the in vitro analysis reveal that this agent is metabolized 
by multiple isoenzymes – CYP1A1, 2D6, 2C19 and 3A4.  ABT-888 is neither a potent inhibitor 


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nor a potent inducer of the CYP-450 isoenzymes.  Use caution when concomitantly administer 
with drugs that are substrate, inhibitor, inducer of CYP1A1, 2D6, 2C19 and 3A4. 
 
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. Use caution 
when concomitantly administer with oxalipaltin, carboplatin, cisplatin, and topotecan in patients 
with pre-existing renal impairment.  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
   
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 


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Availability:  ABT-888 in both capsule and oral solution formulations are provided to the NCI 
under a Collaborative Agreement between the Pharmaceutical Collaborator and the DCTD, NCI 
(see section 12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
NCI supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained.)  The CTEP assigned protocol number must be used for ordering all CTEP supplied 
investigational agents.  The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial 
Disclosure Form (FDF).  If there are several participating investigators at one institution, CTEP 
supplied investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx.  Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account 
https://eapps-ctep.nci.nih.gov/iam/ and the maintenance of an “active” account status and a 
“current” password.  For questions about drug orders, transfers, returns, or accountability, call 
(240) 276 - 6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email PMB 
after hours@mail.nih.gov anytime. 


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For the radiation phase of the protocol treatment, for patients taking capsules only, please order 
sufficient number of capsules for 30 days of treatment. For patients receiving the oral solution 
drug must be ordered and dispensed monthly during radiation.  
 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents received from DCTD using the NCI Drug 
Accountability Record Form (DARF).  (See the NCI Investigator’s Handbook for Procedures for 
Drug Accountability and Storage.) 
 
8.2 
Temozolomide (Temodar™; NSC#:  362856) 
Sites should refer to the FDA approved package insert for additional information on the 
commercial drug. 
 
Formulation:  
Temozolomide is available in 5 mg, 20 mg, 100 mg, 140 mg, 180mg and 250 mg capsules.  
 
Stability & Storage:  Capsules should be stored at 25ºC (77ºF); excursions permitted to 15-30ºC 
(59-86ºF). The commercial product has an expiration date on the bottle.   
 
Procedure for Proper Handling and Disposal 
Chemotherapy precautions should be utilized in preparation.   
 
Route/Frequency of Administration: Dose should be rounded to the nearest 5 mg. See Appendix 
E for dosing determination. Temozolomide should be administered 60-120 minutes after the 
morning ABT-888 dose. If a patient has emesis within 10 minutes of receiving a dose, the dose 
should be repeated.  
 
For patients unable to swallow intact capsules, capsules may be opened and mixed with apple 
juice or applesauce immediately prior to administration.  If opening of capsules is necessary, it 
should be performed by hospital staff trained in handling chemotherapeutics whenever possible.   
However, if necessary, adult family members are allowed to open the temozolomide capsules at 
home, provided that they follow the instructions in Appendix C strictly, as well any additional 
instructions given by hospital pharmacists trained in handling chemotherapeutics. 
 
Agent Ordering 
Temozolomide is available from commercial sources by the treating hospital pharmacy. 
 
9. CORRELATIVE AND SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
9.1.1 Plasma Pharmacokinetics Studies 
Participation in the pharmacokinetic studies is required during the Phase I portion of the study 
and strongly encouraged but optional during Phase II.  Plasma pharmacokinetics samples will be 
obtained on days 1 (first dose) and 4 (steady state) during the first week of ABT-888 and 


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radiation treatment.  If day 4 falls on a Saturday, please collect steady state PK samples on day 3. 
If day 4 falls on a Sunday, please collect steady state PK samples on day 5. 
 
9.1.1.1 
Sampling Strategy for Pharmacokinetic Study 
First dose pharmacokinetic study of ABT-888, Day 1 of ABT-888 and Radiation treatment 
Blood samples will be collected prior to the first dose of ABT-888 on day 1 of radiation 
treatment, and then at 0.5, 1, 2 and 6-8 hours after the first dose of ABT-888. Blood samples may 
be obtained either by repeated phlebotomies or through temporary or permanent intravenous 
catheters/devices. The pre-ABT-888 sample may be obtained at study entry, provided that the 
specimen is processed and stored appropriately per section 9.1.1.2. 
 
For children who require sedation for radiation and are not able to take the p.o. medication due to 
local requirements for NPO prior to sedation, the pre-ABT-888 sample may be obtained at study 
entry or at any time prior to the first dose of ABT-888 (to be administered the night prior to first 
day of radiation treatment). Subsequent PK samples outlined above (at 0.5, 1, 2 and 6-8 hours 
after a dose of ABT-888) should be collected after the child awakens from sedation and after the 
second dose of ABT-888 is given on day 1 of radiation treatment. 
 
Steady state pharmacokinetic study of ABT-888, Day 4 of ABT-888 and Radiation treatment 
Blood samples should be obtained prior to the A.M. ABT-888 dose on day 4 of radiation 
treatment, and then at 2 hours after the A.M. dose.  Blood samples may be obtained either by 
repeated phlebotomies or through temporary or permanent intravenous catheters/devices.  
 
For children who require sedation for radiation and must remain NPO in the morning, the day 4 
samples should be obtained after the child awakens from sedation on day 4 and then at 2 hours 
after the day-4 ABT-888 dose has been given. 
 
9.1.1.2 
Sampling Collection and Processing Instructions  
Blood samples (a minimum of 2.5 ml for children < 12 kg, and 3-5 ml for children > 12 kg) 
should only be collected in potassium EDTA tubes, provided by AbbVie.  All information about 
the PK kits and ordering instructions are available on the PBTC-033 members’ website in the 
Protocol Specific Instructions/Forms section. Sites are to record the exact time that the sample is 
drawn along with the exact time that the study drug is administered on the PK Sample 
Transmittal form located in the PBTC-033 Protocol Specific Instructions/Forms section of the 
PBTC members’ webpage.  
 
9.1.1.3 
Sampling Handling and Shipping Instructions 
Samples should be immediately inverted 8 to 10 times to reduce the likelihood of clot formation 
and centrifuged within 30 minutes at sufficient speed and time to separate plasma (e.g. 1300 x g 
for 10 minutes).  Plasma should be transferred to labeled cryovials (labels and cryovials provided 
by AbbVie) within one hour of collection and stored immediately at -20°C or colder. 
 
Each tube must be labeled with the labels provided in the collection kits. These will include the 
patient’s accession number, the study number, and the planned time of sampling relative to 
dosing.  Data should be recorded on the Pharmacokinetic Sample Transmittal Form located on 
the PBTC-033 ‘Protocol Specific Instructions/Forms’ section of the PBTC Members’ webpage.  


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The transmittal form must accompany the sample(s). 
 
Samples from day 1 and day 4 PK studies for each patient should be batched together and 
shipped via express carrier (Monday through Wednesday only).  Samples are to be shipped at  
-20°C or colder (on dry ice) to: 
 
 
 
  
 
 
 
 
 
 
 
Please ship each patient’s PK samples as soon as the complete set has been collected rather than 
waiting to batch multiple patients’ samples together.  Please FAX the completed form to AbbVie 
Sample Receiving on the day of shipment.  Also, be sure to include the completed PK Specimen 
transmittal form in the shipment as it will provide an inventory of the samples included in the 
shipment.  PK samples must be shipped within 30 days of Day 4 sample collection in order to 
receive cost reimbursement. 
 
9.1.1.4 
Description of Pharmacokinetic Analysis  
Plasma concentration of ABT-888 will be analyzed using a previously validated LC/MS/MS 
technique.  These samples will be analyzed at AbbVie Laboratories, located in AbbVie Park, IL.   
 
9.1.2 Correlative Biology Studies in PBMC 
Participation in the correlative biology studies is strongly encouraged but optional. 
 
9.1.2.1 
Collection of Specimen(s) 
Whole blood samples (a minimum of 5 ml for children < 12 kg, and 10 ml for children > 12 kg) 
should be collected in either ACDA (Acid citrate dextrose solution A; yellow top) or heparinized 
(sodium or lithium heparin; green top) tubes. Blood samples should be collected at the following 
time points: 
 
1. Prior to start of first dose of ABT-888 and radiation treatment (sample may be collected at 
the time of study entry or any time prior to start of 1st dose of ABT-888) 
2. On day 3-4 during the third week of ABT-888 and radiation treatment, 2 hours after the 
day-time dose of ABT-888; if day 4 falls on a Friday, collect this sample on day 3 
3. On day 3-4 during the sixth week of ABT-888 and radiation treatment, 2  hours after the 
day-time dose of ABT-888; if day 4 falls on a Friday, collect this sample on day 3 
4. On day 4 during the first course of maintenance ABT-888 and TMZ, 2 hours after the day-
time dose of ABT-888; if day 4 falls on a Friday, collect this sample on day 3; if day 4 falls 
on a Sunday, collect this sample on day 5; if day 4 falls on a Saturday, collect this sample 
on day 2. 


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Record the exact date and time that the sample is drawn along with the exact time ABT-888 was 
administered on the Biologic Specimen Transmittal Form located on the PBTC-033 Protocol 
Specific Instructions/Forms section of the PBTC members’ webpage. 
 
 
If possible, avoid collecting samples on a Friday to avoid weekend sample shipment. If 
unavoidable, please contact Drs. Patricia Baxter at (832) 824-4681 (pabaxter@txch.org) or Jack 
Su at (832) 822-4306 (jmsu@txch.org) to arrange for Saturday delivery. 
 
9.1.2.2 
Sample Processing 
No processing is required. Keep the whole blood at room temperature until the time of shipping. 
 
9.1.2.3 
Sample Labeling 
Each tube must be labeled with the patient’s accession number, the study number, the exact date 
and time the sample was drawn and the exact time that the drug was administered.  Data should 
be recorded on the Biologic Specimen Transmittal Form located on the PBTC-033 Protocol 
Specific Instructions/Forms section of the PBTC members’ webpage.  The transmittal form must 
accompany the sample(s). 
 
9.1.2.4 
Shipping Instructions 
Each sample should be shipped immediately on the day of collection.  Samples should be stored 
at room temperature until shipment. Sample handling and shipping instructions are available on 
the PBTC-033 Protocol Specific Instructions/Forms section of the PBTC members’ webpage. 
Samples should be shipped by priority overnight via express carrier (Monday through Thursday 
only).  
 
Patricia Baxter, MD; Attention: Elizabeth Hinojosa 
Feigin Center 
1102 Bates St., Room 1030 
Baylor College of Medicine 
Houston, TX  77030 
(832) 824-4688 
 
Prior to shipping, please contact Drs. Patricia Baxter at (832) 824-4681(pabaxter@txch.org) or 
Jack Su at (832) 822-4306 (jmsu@txch.org) for notification of sample shipment.  
 
9.1.2.5 
Sample Analysis  
PBMCs will be isolated using a CPT™ Cell Preparation Tube with Sodium Citrate.   PARP 
activity will be measured using an established ELISA assay for PAR formation by AbbVie 
Laboratories.46 NHEJ activity will be analyzed via a published assay.47 PBMC γ-H2AX levels 
will be determined using flow cytometry and a monoclonal antibody against γ-H2AX conjugated 
with GFP. PBMC NHEJ activity and γ-H2AX levels will be analyzed in the laboratory of Dr. 
Xiao-Nan Li, located at Baylor College of Medicine, Houston, TX. 
 
9.1.3 Correlative Biology Studies in Tumors 
Participation in correlative studies for tumor specimens is optional but strongly encouraged. 
 


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57 
Frozen Tumor 
9.1.3.1 
Collection and Processing 
If biopsied tumor is available, the sample should be frozen in liquid nitrogen as soon as possible 
and shipped on dry ice. Data should be recorded on the Biologic Specimen Transmittal Form 
located on the PBTC 033 Protocol Specific Instructions/Forms section of the PBTC members’ 
webpage.   
 
9.1.3.2 
Labeling and Shipping 
Samples should be labeled with the patient’s PBTC accession number and the date of surgery. 
Frozen tumor specimens should be shipped Monday through Thursday only. The specimen 
should be accompanied by the Correlative Biology Study Form and shipped by overnight carrier 
to: 
Patricia Baxter, MD; Attention: Elizabeth Hinojosa 
Feigin Center 
1102 Bates St., Room 1030 
Baylor College of Medicine 
Houston, TX  77030 
(832) 824-4688 
 
Prior to shipping, please contact Drs. Patricia Baxter at (832) 824-4681(pabaxter@txch.org) or 
Jack Su at (832) 822-4306 (jmsu@txch.org) for notification of sample shipment.  
 
9.1.3.3 
Sample Analysis 
PARP activity will be measured using an established ELISA assay for PAR formation by 
AbbVie Laboratories.46 NHEJ activity will be evaluated by an enzymatic assay,47 and protein 
levels of Ku 70, Ku 80, DNA-PK, BRCA 1, BRCA 2, Rad51, and ATM will be measured by 
Western analysis in Dr. Xiao-Nan Li’s laboratory. 
 
FFPE Slides 
9.1.3.4 
Collection and Processing 
Fifteen to twenty unstained PLUS glass slides, containing 5-micron thick tumor sections from 
FFPE tumor blocks will ALSO be requested in the event that frozen tumor specimens submitted 
are of insufficient amount or inadequate quality.   
 
9.1.3.5 
Labeling and Shipping 
Slides should be labeled with the patient’s PBTC accession number and the date of surgery. The 
Correlative Biology Study Form located on the PBTC-033 Protocol Specific Instructions/Forms 
section of the PBTC members’ webpage should be completed and shipped with the specimens. 
Slides should be shipped Monday through Thursday only. The slides should be shipped at room 
temperature to the address listed in 8.3.2.  Prior to shipping, please contact Drs. Patricia Baxter at 
(832) 824-4681(pabaxter@txch.org) or Jack Su at (832) 822-4306 (jmsu@txch.org) for 
notification of shipment.  
 


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9.1.3.6 
Sample Analysis 
Immunohistochemical staining of PARP, Ku 70, Ku 80, DNA-PK, BRCA 1, BRCA 2, Rad51, 
and ATM will be performed by standard techniques in Dr. Adekunle Adesina’s laboratory at 
Baylor College of Medicine, Houston, Texas. 
 
9.1.4 Urine Biomarkers 
Participation in the urine biomarker study is strongly encouraged but optional.  
 
9.1.4.1 
Sampling Strategy  
Urine will be collected at time of enrollment (pre-treatment), post ABT-888 plus radiation then 
at the time of each scheduled MRI.   Urine will be collected throughout the time that each patient 
is receiving protocol treatment until disease progression.    
 
9.1.4.2 
Sample Collection  
10-30 milliliters of urine will be collected in a specimen cup and immediately placed in ice.  The 
specimen can remain on ice in the original container for 1-2 hours until transfer to a freezer for 
storage (-20 Celsius).  Samples should be maintained at -20 C until shipped. Urine can be 
collected as a mid-stream catch while voiding or can be collected from a urimeter if the child is 
catheterized.  It is necessary to keep the urine refrigerated to prevent the degradation of peptides.  
The MMPs are particularly sensitive to warmer temperatures and other enzymes within the urine 
will break down biomarkers if not inactivated by refrigeration. 
 
9.1.4.3 
Sample Labeling 
Each urine specimen must be labeled with the patient’s accession number, the study number 
(PBTC-033) and the date collected.  Data should be recorded on the Urine Specimen Transmittal 
Form located on the PBTC-033 Protocol Specific Instructions/Forms section of the PBTC 
members’ webpage.  The transmittal form must accompany the sample(s). 
 
9.1.4.4 
Shipping Instructions 
Samples must be shipped monthly from the site to the laboratory to receive cost reimbursement.  
The sample collection and shipping dates must be documented in the eCRF. All samples should 
be forwarded via FedEx, Monday through Thursday, by completing the internet form at 
http://www.fedex.com/us/ and requesting FedEx to email the laboratory. Fed Ex account 
information for the shipment of samples can be obtained on the PBTC website.  Weekend 
deliveries are not permitted. All urine specimens along with a completed Urine Specimen 
Transmittal Form should be placed within a Styrofoam shipping package with dry ice and mailed 
to the attention of Micah Duggins-Warf. 
Micah Duggins-Warf 
Children's Hospital Boston  
Karp Research Building, 12th Floor 
1 Blackfan Circle 
Boston MA 02115 
(617) 919-2211 
Email: micah.duggins-warf@childrens.harvard.edu 
 


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9.1.4.5 
Description of Urine Biomarker Assay 
All samples will be analyzed for the presence or absence of each of the 8 biomarkers.  
Zymography will be performed to analyze for MMP-2, MMP-9 and MMP-9/NGAL in a blinded 
fashion by the laboratory examiner and recorded as a positive or negative result, following a 
protocol well-established in our laboratory which has been validated in the literature.39   
 
Zymography 
Samples will be frozen immediately after collection and stored frozen (-20C) until assay. 
Aliquots of each sample will be centrifuged at 4,000 rpm for 5 min at 4C and the supernatants 
collected. Urine samples (30 uL) will be mixed with buffer consisting of 4% SDS, 0.15 mol/L 
Tris (pH 6.8), 20% (v/v) glycerol, and 0.5% (w/v) brom-phenol blue. Samples will be applied, 
without boiling, into wells of a 4% acrylamide Laemmli stacking gel/10% SDS-acrylamide 
separating gel containing 0.1% (w/v) gelatin (Life Technologies, Inc.) on a mini gel apparatus. 
Gels will be run at 15 mA/gel during stacking and at 20 mA/gel during the resolving phase at 
room temperature. After electrophoresis, the gels will be soaked in 2.5% Triton X-100 with 
gentle shaking for 30 min at ambient temperature with one change of detergent solution. The gels 
will then be rinsed and incubated overnight at 37ºC in substrate buffer [50 mmol/L Tris-HCI 
buffer (pH 8), 5 mmol/L CaCl2, and 0.02% NaN3,]. After incubation, gels will be stained for 15 
to 30 min in 0.5% Coomassie Blue R-250 in acetic acid, isopropyl alcohol, and water (1:3:6); 
destained in acetic acid, ethanol, and water (1:3:6), and photographed.  The presence or absence 
of each species (MMP-2, MMP-9, MMP-9/NGAL) will be recorded and relative intensities (if 
present) noted. 
 
ELISA 
ELISA will be used to establish quantitative levels of each of the 8 biomarkers.  Kits will be 
obtained from the manufacturers (R&D systems and Bioplex/Bio-Rad).  Specimens, standards 
and reagents will be prepared according to manufacturer’s instructions.  Protein concentration 
will be determined via the Bradford method using bovine serum albumin as the standard.  
Results will be recorded as ng/ml or pg/L. 
 
9.2 
Special Studies 
 
9.2.1 Neuroimaging Studies  
Standard MRI will be obtained within 2 weeks prior to registration, at the end of radiation 
therapy (week 10), within 1 week prior to courses 3, 5, and 8 of maintenance and at the end of 
treatment.  MR perfusion and permeability studies and DTI will also be obtained at the same 
time points as standard MRI through week 26 (6 months from initiation of treatment).  
 
For patients showing possible tumor progression on MRI during the first 6 months after the 
initiation of ABT-888 and irradiation (on scheduled MRI studies), the treating physician will 
have the option of allowing the patient to remain on study, continuing protocol therapy, and 
repeating disease reassessment in 4-6 weeks. The investigational sequences should be obtained 
on this additional scan which is completed due to possible pseudoprogression.  3T imaging is the 
preferred modality of choice. 
 
Standard MR imaging will include Sagittal T1 MPRAGE, axial FLAIR, axial T2, 


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postgadolinium sagittal T1 MPRAGE (with reconstructions) and axial T2 images. Protocol 
standard parameters will be distributed to the sites and posted on the PBTC NIC website. 
 
Volumetric analyses will be done at the Neuroimaging Center (NIC, Children’s Hospital Boston) 
via the Vitrea (Vitrea™) workstation, from the axial FLAIR and T1-weighted post-contrast brain 
images.   
 
9.2.2 MRI Permeability and Perfusion Imaging 
The perfusion protocol will be performed using T1-weighted dynamic contrast-enhanced (DCE) 
permeability MRI to assess immediate biological activity followed by T2*-weighted dynamic 
susceptibility contrast (DSC) perfusion MRI technique.  DSC perfusion MRI dynamics will 
allow assessment of the hemodynamic parameter relative cerebral blood volume (rCBV). DCE 
permeability MRI metrics will include the volume transfer constant between plasma and 
extravascular extracellular space (Ktrans), fractional blood-plasma volume (Vp), and the volume of 
the extravascular extracellular space per unit volume tissue (Ve).  Both DCE and DSC MRI-
derived data will be complementary to conventional contrast-enhanced MR imaging.  
 
9.2.2.1 
DCE permeability MRI 
Please note that there will be a total of 5 sequences: 4 for T1 mapping and the DCE with 
injection).  Also, it is important that the same patient MUST be scanned on the same exact 
scanner (not just the brand/tesla, but actual scanner) if more than one exam is to be done.   
A 3D (not 2D) fast gradient echo type of sequences (fast SPGR, FLASH, THRIVE) must be 
used.  This will be performed as 3D slab in the axial plane.  Normalization or intensity correction 
or flow correction filters such as CLEAR, SCIC or PURE must not be used for any of the series.  
The slice locations and positioning for the T1 mapping and the dynamic series MUST be identical 
(same matrix, slices, FOV, TR, TE, except NEX and FA). Hence copying of the slices is needed. 
The TR and TE for all 4 series (4 T1 maps plus a dynamic series) should be identical. For GE 
systems, reduce Turbo Factor to 1 or 0 if TR and TE do not match across series. T1 Maps should 
be acquired with 2 signal averages and the Dynamic Series with 1.  Temporal Resolution of “T1 
DCE” series (scan time per phase/measurement) should be less than or equal to 6 Seconds, with 
NO gaps between phases.  ASSET/IPAT/Parallel Imaging Parallel imaging is set to be OFF, 
however, if it is not possible to achieve a temporal resolution of less than 6 seconds, this should 
be set to a factor of 2.  The dynamic series should last 5 minutes in total scan time (excluding T1 
mapping series). 
 
The table below describes the image acquisition parameters for the T1 map sequences as well as 
the dynamic scan, in the order of acquisition (first T1 maps then T1 DCE). Make sure this 
happens before DSC perfusion MRI.   
 
The first half dose of contrast agent to be administered 20 sec into “T1 DCE” sequence. Do NOT 
inject prior to T1 DCE or during T1 maps (see Table 16 and Table 17 below). 
 
 
 
 
 
 


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Table 16 
 “T1 DCE” 
Series Name 
Sequence 
Flip Angle 
Notes 
T1 map15 
3D fast GRE 
15 degrees 
Axial, 2 NEX 
T1 map10 
3D fast GRE 
10 degrees 
Axial, 2 NEX 
T1 map05 
3D fast GRE 
5 degrees 
Axial, 2 NEX 
T1 map02 
3D fast GRE 
2 degrees 
Axial, 2 NEX 
T1 DCE 
Dynamic Series, 3D fast GRE 
15 degrees 
Axial, 1 NEX,  inject 20 sec into this 
 
Table 17 
3D T1W specs for T1 Maps and Dynamic Series 
Sequence type 
Spoiled gradient echo 
Imaging mode 
3D 
Slice orientation 
Axial 
Frequency direction 
A/P 
Phase direction 
R/L 
FOV - frequency 
220 mm 
FOV - phase 
220 mm 
Matrix - frequency 
256 
Matrix - phase 
160-192 
In-plane resolution 
 1 mm 
Fat-suppression 
No Fat Sat 
TR 
~4 msec  
TE 
Less than 2 ms or min full 
TI (STIR sequence) 
N/A 
Flip Angle 
DCE -15 degrees; T1 maps - 2, 5, 10 and 15 
Slice thickness (acquired, not interpolated) 
5mm,  maximum 6mm  
Number of slices 
Minimum 10  prior to zero fill 
Slice Gap 
No gap 
Parallel imaging factor 
 2 
Number of averages  
1 for DCE, 2 for T1 maps 
k-space ordering 
standard, non-centric  
Temporal Resolution of “T1 DCE”: (seconds per 
phase/measurement) 
 6 seconds 
“T1 DCE” imaging duration 
 5 minutes  
 
Run the Dynamic multi-phase “T1 DCE” at flip angle of 15 degrees – enable multi-phase (on GE 
systems) and increase the number of phases (or measurements) until the scan time is six minutes.  
Contrast injection should be delivered at 20 sec into T1 DCE, not earlier. Injection rate is 2 
ml/second at 0.05 mmol/kg body weight followed by a 10 cc saline flush at the same rate (all 
should use the same type of contrast agent). 
 
9.2.2.2 
Diffusion tensor imaging  
Diffusion tensor imaging (DTI) or axial T2 weighted imaging can be performed between the 
DCE and DSC MRI acquisitions.  In addition to providing permeability metrics, the gadolinium 
contrast agent from the DCE acquisition will also serve as a “preload” to help correct for leakage 
effects for the DSC perfusion acquisition. 20  
 


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9.2.2.3 
DSC perfusion MRI 
 An axial 2D T2* GRE-EPI sequence will be used.  TR = 2000 ms, TE = 23 ms, matrix = 128 x 
128, FOV = 240 mm, frequency direction R-L, slice thickness = 5.0 mm with 2 mm gap, flip 
angle = 60 degrees, NEX = 1.  Repeat 50-60 times.  Total acquisition time ~ 2 minutes.  Begin 
bolus injection (2 ml/sec) of 0.05mmol/kg BW GdDTPA at 20secs after scanning starts followed 
by a 10 cc saline flush at the same rate.  Regional rates of transverse relaxation enhancement 
(ΔR2*) during contrast agent passage will be calculated from: ΔR2*(t) = (-1/TE) In [S(t)/S(0)] 
from which estimates of rCBV will be derived.   
 
Perfusion MR images will be transferred to the GE Advantage Workstation (4.3.05); Functool 
(4.4.05) (GE Healthcare, Milwaukee, WI) to calculate rCBV maps on a voxel-wise basis.  User 
defined regions of interest (ROIs) measuring 3-5 mm will be placed within areas that 
demonstrate maximal CBV based on color-overlay maps.  Effort will be made to exclude large 
vessels and necrotic-appearing regions from the ROIs.  An ROI will also be placed in the frontal  
normal appearing white matter (NAWM) to provide relative CBV (rCBV) values to normalize 
perfusion data and enable comparison between patient and between serial studies.18  
 
Permeability MR Images will be transferred to the iCAD Workstation (iCAD, Inc., Nashua, NH).  
This utilizes a 2 compartmental pharmacokinetic model allowing voxel-wise calculation of Ktrans, 
Vp, and Ve.  User defined ROIs encompassing the entire contrast-enhancing lesion as well as 
multiple smaller 3-5 mm ROIs will be placed within areas that demonstrate maximal Ktrans, Vp, 
and Ve based on color-overlay maps.  Effort will be made to exclude large vessels and necrotic-
appearing regions from the ROIs. 
 
9.2.3 MR Diffusion Imaging 
MR Diffusion Imaging will consist of 35 direction DTI sequences: slice thickness 2.2 mm, TR= 
8800 ms, TE= 88ms, FOV 220 mm, b value= 1000 s/mm2, 35 directions. Full protocol will be 
provided on the PBTC NIC website.  
 
9.2.4 Image Transfer 
Standard MRI, perfusion/ permeability and DTI images will be electronically transferred to the 
PBTC Neuroimaging Center (NIC).  All patient specific data are stripped from the images and 
replaced with PBTC case-ids prior to sending images to the NIC. All image data transfer is 
accomplished using PGP (pretty-good-privacy) 128-bit encryption which meets industry 
standard for secure communication. 
9.2.5 Central Review 
Central review of imaging studies will be conducted through the PBTC Neuroimaging Center 
(NIC).  The director and one neuroradiologist at NIC will review the imaging studies for 
response and pseudo-progression at study completion.  Post processing of perfusion/permeability 
studies will be done at USC. 
 
 


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63 
10. STUDY CALENDAR 
Table 18 
Standard Clinical and Laboratory Assessments – Phase I  
 
Pre-
therapy 
ABT888 and Radiation 
(Course 1.1) 
Maintenance 
(Courses 2.1 – 2.23) 
End of 
Treatment 
PHYSICAL ASSESSMENTS 
 
ABT 888 
+ RT 
Rest 
Period 
Week  
10 – 1110 
Weekly 
Courses  
1-10 
Prior to 
Courses  
2-10 
Extended Therapy 
Courses 11-23 
 
Medical history,  physical exam and diary 
review 
X 
Weekly 
X9 
X 
 
X 
X12 
X 
Vital signs 
X 
Weekly 
X9 
X 
 
X 
X12 
X 
Performance status 
X 
Weekly 
X9 
X 
 
X 
X12 
X 
Neurologic exam 
X 
 
X9 
X 
 
X 
X12 
X 
Height, Weight, BSA 
X 
 
X9 
X 
 
X 
X12 
 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
CBC  (WBC, Hgb, Hct, Platelets, ANC, ALC) 
X 
Weekly1 
X9 
X 
X1 
 
X13 
X 
Serum Chemistry  (Electrolytes, BUN, 
Creatinine, Calcium, Magnesium, Phosphorous, 
SGOT(AST), SGPT(ALT), Total Bilirubin, 
Albumin) 
X 
Weekly2 
X9 
X 
 
X2 
X13 
X 
Pregnancy test 3 
X 
 
 
X 
 
X 
X 
 
IMAGING ASSESSMENTS 
 
 
 
 
 
 
 
 
Brain MRI 
X4 
 
 
X4 
 
X4,11 
X14 
X11 
MRI Perfusion/Permeability 
X4 
 
 
X4 
 
X 4,11 
 
X11 
Diffusion Tensor Imaging (DTI) 
X4 
 
 
X4 
 
X 4,11 
 
X11 
Correlative Studies 
 
 
 
 
 
 
 
 
Pharmacokinetic Studies5 
X 
X 
 
 
 
 
 
 
Biology Study (PARP,NHEJ and γH2AX) in 
PBMC’s6 
X 
X 
 
 
X6 
 
 
 
Biology study – pre-trial tumor material 
X7 
 
 
 
 
 
 
 
Urine Biomarker8 
X 
 
 
X 
 
X8 
 
 
1. 
CBC is done weekly for all courses. Patients with dose limiting hematologic toxicity (≥Grade 3 thrombocytopenia or Grade 4 neutropenia) should have 
CBC at least twice weekly (3-4 days apart) until toxicities improve to grade 2 or less 
2. 
Patients with grade 3 or 4 non-hematologic toxicity should have relevant laboratory tests repeated twice weekly (3-4 days apart) until they recover to grade 
2 or less 
3. 
Serum or urine pregnancy test is to be repeated within 72 hours prior to enrollment in females of childbearing potential and prior to each course during 
maintenance  
4. 
Neuroimaging assessments are to be completed within 2 weeks of registration, at the end of radiation + ABT888, (week 10-11), within 1 week prior to 
courses 3, 5, 8 and at the end of maintenance. See footnote #11 for details of investigational imaging procedures. For patients with possible tumor 
progression on week 10, 18, or 26 imaging studies, see guidelines in section 2.4.2 or 11.1.4 for frequency of next imaging study. 
5. 
Participation in the pharmacokinetic study is required for the Phase I portion of the study.  See section 9.1.1 for collection schedule 
6. 
Participation in the correlative biology study in PBMC’s is optional.  See section 9.1.2 for collection schedule 
7. 
Participation the biology study – pre-trial tumor material is optional. See section 9.1.3 for processing and shipping instructions. 
8. 
Participation in the urine correlative study is optional. Urine samples should be collected at the time of each scheduled MRI (section 9.1.4) 
9. 
During the rest period, each patient should have at least one visit between weeks 7 and 10.  
10. Laboratory tests and assessments may be completed ±1 week of week 10, prior to starting Maintenance.  
11. For patients showing possible tumor progression on MRI during the first 6 months after initiation of ABT-888 and radiation (on required MRI studies 
performed at week 10, week 18, or 26), the treating physician will have the option of allowing the patient to remain on study, continuing protocol therapy, 
and repeating disease reassessment in 4-6 weeks. The repeat MRI should include MRI perfusion/permeability and DTI.  MRI Perfusion/Permeability and 
DTI will only be obtained on routine MRI studies through week 26; the investigational sequences should be obtained on a scan 4-6 weeks after the 
week 26 study IF the patient is being handled as a potential pseudoprogression. 
12. If a patient receives more than 10 courses, evaluations in subsequent courses should be obtained at the discretion of the treating physician 
13. It is recommended that labs be obtained at least every two weeks during the extended treatment period (i.e. beyond course 10). 
14. It is recommended that standard MRI scans should be done at least every three months during the extended treatment period (i.e. beyond course 10).   
Additional studies may be done as clinically indicated at the investigator’s discretion. 
Note:  Obtain other studies as clinically indicated 
Pre-therapy laboratory evaluations within 7 days of starting treatment will be considered Day 1, Course 1 evaluations 


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Table 19 
Standard Clinical and Laboratory Assessments – Phase II 
 
Pre-
therapy 
ABT888 and Radiation 
(Course 1.1) 
Maintenance 
(Courses 2.1-2.23) 
End of 
Treatment 
PHYSICAL ASSESSMENTS 
 
ABT 888 
+ RT 
Rest 
Period 
Week  
10 – 1110 
Weekly 
Courses  
1-10 
Prior to 
Courses  
2-10 
Extended 
Therapy 
Courses 11-23 
 
Medical history,  physical exam and diary 
review 
X 
Weekly 
X9 
X 
 
X 
X12 
X 
Vital signs 
X 
Weekly 
X9 
X 
 
X 
X12 
X 
Performance status 
X 
Weekly 
X9 
X 
 
X 
X12 
X 
Neurologic exam 
X 
 
X9 
X 
 
X 
X12 
X 
Height, Weight, BSA 
X 
 
X9 
X 
 
X 
X12 
 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
CBC  (WBC, Hgb, Hct, Platelets, ANC, ALC) 
X 
Weekly1 
X9 
X 
X1 
 
X13 
X 
Serum Chemistry  (Electrolytes, BUN, 
Creatinine, SGOT(AST), SGPT(ALT), Total 
Bilirubin,) 
X 
Weekly2 
X9 
X 
 
X2 
X13 
X 
Pregnancy test 3 
X 
 
 
X 
 
X 
X 
 
IMAGING ASSESSMENTS 
 
 
 
 
 
 
 
 
Brain MRI 
X4 
 
 
X4 
 
X 4,11 
X14 
X11 
MRI Perfusion/Permeability 
X4 
 
 
X4 
 
X 4,11 
 
X11 
Diffusion Tensor Imaging (DTI) 
X4 
 
 
X4 
 
X 4,11 
 
X11 
Correlative Studies 
 
 
 
 
 
 
 
 
Pharmacokinetic Studies5 
X 
X 
 
 
 
 
 
 
Biology Study (PARP,NHEJ and γH2AX) in 
PBMC’s6 
X 
X 
 
 
X6 
 
 
 
Biology study – Pre-trial tumor material7 
X 
 
 
 
 
 
 
 
Urine Biomarker8 
X 
 
 
X 
 
X8 
 
 
1. 
CBC is done weekly for all courses. Patients with dose limiting hematologic toxicity (≥Grade 3 thrombocytopenia or Grade 4 neutropenia) should have 
CBC at least twice weekly (3-4 days apart) until toxicities improve to grade 2 or less 
2. 
Patients with grade 3 or 4 non-hematologic toxicity should have relevant laboratory tests repeated twice weekly (3-4 days apart) until they recover to grade 
2 or less 
3. 
Serum or urine pregnancy test is to be repeated within 72 hours prior to enrollment in females of childbearing potential and prior to each course during 
maintenance  
4. 
Neuroimaging assessments are to be completed within 2 weeks of registration, at the end of radiation + ABT888, (week 10-11), within 1 week prior to 
courses 3, 5, 8 and at the end of maintenance. See footnote #11 for details of investigational imaging procedures. For patients with possible tumor 
progression on week 10, 18, or 26 imaging studies, see guidelines in section 2.4.2 or 11.1.4 for frequency of next imaging study. 
5. 
Participation in the pharmacokinetic study is optional for the Phase II portion of the study.  See section 9.1.1 for collection schedule 
6. 
Participation in the correlative biology study in PBMC’s is optional.  See section 9.1.2 9.1.2for collection schedule 
7. 
Participation in the correlative biology study pre-trial tumor material is optional. See Section 9.1.3 for processing and shipping instructions 
8. 
Participation in the urine correlative study is optional. Urine samples should be collected at the time of each scheduled MR (section 9.1.4) 
9. 
During the rest period, each patient should have at least one visit between weeks 7 and 10.  
10. Laboratory tests and assessments may be completed ±1 week of week 10, prior to starting Maintenance.  
11. For patients showing possible tumor progression on MRI during the first 6 months after initiation of ABT-888 and radiation (on required MRI studies 
performed at week 10, week 18, or 26), the treating physician will have the option of allowing the patient to remain on study, continuing protocol therapy, 
and repeating disease reassessment in 4-6 weeks. The repeat MRI should include MRI perfusion/permeability and DTI.  MRI Perfusion/Permeability and 
DTI will only be obtained on routine MRI studies through week 26; the investigational sequences should be obtained on a scan 4-6 weeks after the 
week 26 study IF the patient is being handled as a potential pseudoprogression. 
12. If a patient receives more than 10 courses, evaluations in subsequent courses should be obtained at the discretion of the treating physician 
13. It is recommended that labs be obtained at least every two weeks during the extended treatment period (i.e. beyond course 10). 
14. It is recommended that standard MRI scans should be done at least every three months during the extended treatment period (i.e. beyond course 10).  
Additional studies may be done as clinically indicated at the investigator’s discretion. 
Note:  Obtain other studies as clinically indicated 
Pre-therapy laboratory evaluations within 7 days of starting treatment will be considered Day 1, Course 1 evaluations 
 


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65 
11. MEASUREMENT OF EFFECT 
 
11.1 
Tumor Response Criteria 
11.1.1 Complete Response (CR) 
 Complete disappearance on MR/CT of all enhancing tumor and mass effect, on a stable or 
decreasing dose of corticosteroids (or receiving only adrenal replacement doses), accompanied 
by a stable or improving neurologic examination, and maintained for at least 8 weeks. 
 
11.1.2 Partial Response (PR) 
Greater than or equal to 50% reduction in tumor size by bi-dimensional measurement, as 
compared with the baseline measurements, on a stable or decreasing dose of corticosteroids, 
accompanied by a stable or improving neurologic examination, and maintained for at least 8 
weeks 
  
11.1.3 Stable Disease (SD) 
Neurologic exam is at least stable and maintenance corticosteroid dose not increased, and 
MR/CT imaging meets neither the criteria for PR nor the criteria for Progressive Disease.  If this 
category is to be reported as of possible clinical benefit, Stable Disease status must be 
maintained for 16 weeks.  
 
11.1.4 Progressive Disease (PD) 
Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status 
not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid 
toxicity, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR a greater than 25% increase in 
the bi-dimensional measurement, taking as a reference the smallest disease measurement 
recorded since the start of protocol therapy, OR the appearance of a new lesion, OR increasing 
doses of corticosteroids required to maintain stable neurological status or imaging. 
 
* Consideration for possible pseudo-progression 
For patients showing possible radiographic evidence of tumor progression on MRI during the 
first 6 months after initiation of  ABT-888 and radiation (on required MRI studies performed at 
week 10, week 18, or 26), the treating physician will have the option of allowing the patient to 
remain on study, continuing protocol therapy, and repeating disease reassessment in 4-6 weeks. 
Provided that the patient does not show clinical deterioration consistent with tumor progression, 
has been on a stable or declining dose of steroids, and the subsequent MRI demonstrates tumor 
regression or stable disease, then the patient will remain on study and continue protocol therapy, 
and the frequency of subsequent MRI will revert to pre-specified intervals. If the repeat MRI 
after 4-6 weeks shows disease progression, rather than pseudo-progression, then the time of 
progression will be the date of the initial MRI, not the follow up scan. The addition of steroids is 
allowed, at the time of suspected pseudo-progression, as long as the patient can be maintained on 
a decreasing dose. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in section 7 
(Adverse Events: List and Reporting Requirements). 
 


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66 
 
12.1 
Data Reporting 
12.1.1 Responsibility for Data Submission  
Pre-treatment, on-study and off-treatment data, as well as patient response data are to be 
recorded in the electronic data collection screens using the PBTC RDC database.  See the 
Required Data and Timetable for Submission form located on the 033 Protocol webpage for the 
schedule.  For assistance, contact the PBTC Protocol Coordinator, Stacye Richardson at (901) 
595-3783, email: stacye.richardson@stjude.org. An optional roadmap is located on the PBTC-
033 Protocol Webpage. 
 
12.1.2 Method 
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, either by FTP burst of data or via the CDS web application.  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).    
12.2 
CTEP Multicenter Guidelines 
N/A 
 
12.3 
Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 


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67 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 


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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Phase I Study Design/Endpoints 
13.1.1 Dose Finding 
This phase of the trial is being implemented in order to determine maximum tolerated dose or 
recommended Phase II of ABT-888 that can safely be delivered with RT in the context of 
carrying it forward to the efficacy (Phase II) component of this study.  The traditional 3+3 dose 
finding algorithm will be used. Initially 3 patients will be enrolled on dose level 1 and will be 
observed for dose limiting toxicities during the first 10 weeks (6-7 weeks of radiation therapy 
followed by a rest period), which is the DLT observation period. If none of these three patients 
experience a DLT, escalation to dose level 2 will occur. If, on the other hand, 1 out of three 
patients experience a DLT, then 3 additional patients will be treated at dose level 1. If at most 1 
DLT is observed in these 6 patients, escalation to dose level 2 will occur. Otherwise, if 2 or more 
DLTs are observed in dose level 1, then de-escalation to dose level 0 will take place and the 
same process will be repeated. The highest dose level with fewer than 2 DLTs in 6 patients will 
be carried forward to the Phase II component of this study. If dose level 0 is determined to be too 
toxic (i.e. more than 1 DLT), then the trial will be closed to accrual and the approach will be re-
evaluated. 
 
13.1.2 Definition of Evaluable Patient 
Patients who receive at least 1 dose of the study regimen and are removed from treatment for 
toxicity during the dose-finding period are evaluable for estimating the MTD/recommended 
Phase II dose as long as no additional anti-cancer therapy or supportive care that would confound 
the interpretation of any observed toxicity or side effect is given. 
 
Patients who receive at least 85% of prescribed therapy during the dose-finding period but who 
progress prior to completing the rest/evaluation period may be considered evaluable for 
estimating the MTD, as long as no additional anti-cancer therapy or supportive care that would 
confound the interpretation of any observed toxicity or side effect is given. Patients should have 
completed all of the clinical and laboratory monitoring requirements specified by the protocol up 
to the time of disease progression for them to be considered evaluable for MTD/recommended 
Phase II dose. 
 
Patients who receive less than 85% of the protocol specified therapy and who go off treatment 
for reasons other than toxicity (e.g. progressive disease, withdrawal of consent etc.) will be 
considered inevaluable for estimating the MTD/recommended Phase II and will be replaced.  
 
Patients who complete all therapy during the dose-finding period but who fail to comply with all 
the specified clinical and laboratory monitoring requirements for the dose finding period may be 
considered inevaluable by the study chair for estimating the MTD/recommended Phase II and 
may be replaced. 
 
13.1.3 Feasibility Assessment of Intra-patient Dose Escalation (for patients treated in both 
Phase I and Phase II of the study): 
During maintenance therapy, in an effort to maximize the TMZ dose for each patient, intra-
patient dose escalation will be studied. All patients will initiate maintenance treatment with  


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25 mg/m2 ABT-888 and 135 mg/m2 of TMZ with a possibility to escalate to 175 mg/m2 and to 
200 mg/m2 of TMZ, if no unacceptable toxicities occur following 1 course of treatment at each 
of these dose levels (Table 12). More specifically, intra-patient dose escalation will only be 
considered if a patient meets the escalation criterion following the first course of TMZ as part of 
maintenance therapy. Intra-patient dose escalation will be assessed only in patients who are 
eligible to escalate and escalation to a given dose will be halted based on similar rules employed 
in traditional 3+3 designs, i.e. if 2 out of first 2-6 patients, 4 out of first 12 patients, etc. 
experience dose modifying toxicities during their first course of therapy at a given dose level.  .  
This stopping rule will be applied for patients enrolled during the Phase I and Phase II 
components of the study. Even though these stopping rules will only be enforced during the first 
course of treatment at a given dose level for TMZ, we will periodically monitor for the 
occurrence of dose modifying toxicities in later courses and may revise this approach in the 
event that excessive toxicities are observed.  
 
13.2 
Phase II Study Design/Endpoints: 
The primary efficacy endpoint of this phase II trial is overall survival defined as the time from 
initiation of therapy to the date of death from any cause or to the date patient was known to be 
alive for surviving patients. Progression-free survival (PFS) is a secondary endpoint and is 
defined as the time from initiation of treatment to the earliest date of failure (disease progression, 
death from any cause, or second malignancy) for patients who fail and to the last assessment date 
for patients who have not failed. Patients who start other anti-cancer therapy prior to disease 
progression will be censored in the Kaplan-Meier estimate of PFS as of the date the alternative 
therapy began. Patients who have not failed (died) at the time of analyses will be censored at 
their last date of contact in the Kaplan-Meier estimate of the PFS (overall survival) distribution.  
 
The primary objective of this part of the study will be assessed based on the intent-to-treat (ITT) 
hypothesis. That is, any eligible patient who receives any ABT-888 will be included in the 
primary analysis. Note that patients who were treated at the recommended Phase II dose of 
ABT-888 concurrently with RT during the Phase I component of the study and who meet the 
eligibility criteria for Phase II will be counted towards the accrual goal of the latter. 
 
13.2.1 Definition of an Evaluable Patient 
All patients who receive at least 1 dose of ABT-888 are evaluable for assessing overall survival, 
the primary endpoint of the Phase II part of this study, as well as for evaluating progression free 
survival and objective response rates. 
 
13.2.2 Design for the Phase II Component: 
As mentioned previously OS is the primary endpoint for the assessment of efficacy of the 
proposed regimen in patients with newly diagnosed DIPG. The following design utilizes the 
information available from the PBTC contemporary historical control cohort of eligible patients 
with newly diagnosed non-metastatic DIPG who were treated on the first five PBTC clinical 
trials (-006 [phase I, imatinib]; -007 [phase I & phase II, gefitinab]; and -014 [phase I & phase 
II, tipifarnib]). All patients treated on these trials were between 3 and 18 years of age. Each trial 
is closed to accrual and all surviving patients have been followed for at least two years to 
estimate the distribution of OS.  
 


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Kaplan-Meier estimate of the distribution of overall survival for the 140 patients treated on the 
first five trials is shown in the following figure and table.  
 
 
 
Table 20 
Months since Start of 
Therapy 
All Patients 
# of Risk 
Events 
Censored 
Prob. 
SE 
0 
140 
0 
0 
100.00 
0.00 
6 
140 
19 
1 
86.35 
2.90 
12 
120 
59 
1 
43.75 
4.17 
18 
60 
39 
0 
15.31 
3.00 
24 
21 
7 
0 
10.21 
2.50 
30 
14 
5 
1 
6.56 
2.11 
36 
8 
3 
0 
4.10 
1.64 
42 
5 
1 
4 
2.05 
2.03 
 
We will utilize a design approach based on time to event data rather than building the design on a 
binomial endpoint. Provided a reasonable model could be identified for the outcome data, 
designs based on time to event endpoints are more informative and make more efficient use of 
the available data compared to their binomial counterparts both for the purposes of maximizing 
the overall power of the study and for using the accumulating information for interim 
monitoring. 
 
The Bayesian approach developed by Thall, Wooten and Tannir48 will be used for the purpose of 
determining the sample size as well as establishing a monitoring rule. This approach was 
developed for monitoring time-to-event outcomes in the context of a single arm Phase II trial. 
Failure times are modeled via an Exponential distribution with an Inverse Gamma prior on the 
mean. The approach utilizes periodic monitoring for early stopping. While the OS distribution of 
the PBTC historical cohort is not exponential, the simulation results presented in the Thall, 
Wooten and Tannir48 paper illustrate that the proposed approach is robust in cases where the true 
distribution is Weibull or Lognormal. As shown in the exploratory plots below, Weibull and the 
Lognormal distributions seem to fit our historical data best. 
Overall Survival Distribution for PBTC BSG Cohort
Months since start of therapy
Probability
0
4
8
12
16
20
24
28
32
36
40
0.0
0.2
0.4
0.6
0.8
1.0


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The TTEDesigner software available from MD Anderson software download page 
(https://biostatistics.mdanderson.org/SoftwareDownload/) was used for the necessary calculations. 
 
The prior parameters for the experimental treatment mean were estimated based on the PBTC 
historical cohort described above. As mentioned previously the Inverse Gamma distribution, 
which is the conjugate prior for to the Exponential distribution, will be used to provide the prior 
information on the exponential mean. Besides conjugacy, another attractive aspect of the Inverse 
Gamma distribution is that its parameters have intuitive interpretations. More specifically in this 
setting the distribution is parameterized by αs=number of failures in the historical cohort and 
βs=total time at risk in the historical cohort. The values of these parameters were calculated from 
the PBTC historical control cohort described above. Following the recommended approach by 
Thall, Wooten and Tannir,48  for the experimental treatment, we chose a prior that would result 
in the same median for the experimental treatment as for the historical cohort but with 10 times 
the variance in the former. This would reflect the a priori belief that the two treatments are the 
same but with much less certainty regarding the experimental treatment. We believe it is 
reasonable to choose a prior which reflects the belief that the new treatment will lead to a similar 
outcome as what has been observed to date. If we believe that the experimental treatment is 
inferior, it would be unethical to conduct this study whereas if we choose a prior that reflects a 
favorable opinion about the experimental treatment compared to the historical control then such 
a prior could bias the results in favor of the experimental treatment which is undesirable. 
The desired effect size is parameterized in terms of the median time to death. The median time to 
death estimate based on the current PBTC historical cohort is 10.85 months. Following the Brain 
Malignancy Steering Committee’s recommendation we have set the “effect size” at 5.5 months, 
reflecting a 50% improvement in the primary outcome parameter, which would certainly be a 
notable “success”, if an experimental treatment were to achieve it. 
 
Our historical experience suggests an average accrual rate of 2 patients per month and we 
propose to monitor the outcome information twice a year (approximately every 6 months) for 
early stopping in the event of an unsuccessful treatment. This monitoring schedule coincides 
1000
100
10
90
50
10
1
0.1
os
Percent
1000
100
10
99
90
50
10
1
0.1
os
Percent
1000
100
10
1
0.1
90
50
10
1
0.1
os
Percent
1200
800
400
0
99
90
50
10
1
0.1
os
Percent
Weibull
0.944
Lognormal
0.898
Exponential
*
Normal
0.936
C orrelation C oefficient
Probability Plot for OS for the entire PBTC historical cohort
LSXY Estimates-Censoring Column in c_os
Weibull 
Lognormal 
Exponential 
Normal 


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with the PBTC DSMB meetings and hence provides a convenient way of providing up to date 
outcome information to the PBTC DSMB. With respect to early stopping, the design we present 
below will only stop for futility. This design has a 6.3% probability of stopping early if the 
median time to death is 16.5 months for the experimental treatment and 63.85% chance of 
stopping early if the median time to death is 11 months for the experimental treatment. In the 
latter case, the mean number of patients expected to be enrolled is 45. So on average we would 
save 15 patients and 7.5 months of accrual in the event that the experimental treatment is 
ineffective. Otherwise the trial will enroll 60 patients in approximately 2.5 years. Tables 
providing the input parameters for design specification and the resulting stopping boundaries 
associated with the design detailed above are given in Appendix G. 
 
Barring early stopping, final analysis will be conducted once all patients have been accrued and 
followed for at least 2 years or to death, whichever is earlier. This duration of follow-up should 
be adequate to fully characterize the OS distribution even if the hypothesized 16.5 months for 
median survival is achieved. As mentioned previously, we will provide KM estimates of the OS 
distribution, in order to describe outcome information based on the proposed regimen. We will 
also compare the OS distribution from this trial to the OS distribution of the PBTC historical 
cohort via the log-rank test to test for a difference. In addition, we will perform a Bayesian 
analysis of the outcome information providing a 95% credibility interval for the median survival 
estimate. While it is unlikely, since the prior information is based on the PBTC historical data, if 
the Bayesian and the frequentist analyses lead to conflicting conclusions, additional analyses will 
be undertaken to explain the discrepancy but ultimately the frequentist inference will be favored 
over the Bayesian one.  
 
Under the assumption that the survival distributions are exponentially distributed with the above 
specified medians and that the analysis time is as detailed above, using the unconditional power 
estimate proposed by Korn and Freidlin49 and as implemented in SiZ software package (ver 1.0) 
the estimated power of this log-rank test based on a 1-sided test and α=0.1 is 87.72%. Since the 
asymptotic relative efficiency of the log-rank test is 100% in cases where there is no censoring or 
when there is random but equal censoring in two groups within the family of Weibull 
distributions50 we expect that the power estimate above is relatively accurate. As we have 
indicated previously, the Weibull distribution fits well to our historical control data and given the 
fact that the final analysis will be done 2 years after the last patient is enrolled we expect that 
there will be very little censoring in the data. Additionally even though this estimate relies on a 
normal approximation, Sun, Peng and Tu51 have shown that when the sample size is larger than 
50 the approximation leads to accurate estimates of power. Additionally Sun, Peng and Tu51 
results indicate that the unconditional power formula based on the exponential assumption 
performs well if the true distribution of the historical control is Weibull. So assuming that the 
hazards are proportional between our historical cohort and the cohort to be treated on this study, 
we expect that the above mentioned power estimate to be reasonably accurate. 
While the final analysis of the primary objective will be conducted two years after the last patient 
begins treatment, we will continue to follow all patients for survival information for at least three 
years or until death, whichever is shorter. Annually this additional information will be available 
for reporting. At the time of the final analysis for the primary outcome, we will also provide the 
KM estimate of the PFS distribution. Tumor response refers to the best response prior to failure 
(disease progression, death from any cause or second malignancy). Exact confidence interval 


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estimates will be provided for the sustained objective response (PR + CR) rate. 
This trial will be monitored by the PBTC DSMB and only the DSMB will have access to 
summary outcome information until the primary objective of the trial has been achieved. The 
DSMB meets semi-annually but also meets via teleconferencing if necessary to review and 
discuss critical events; such as interim analyses. Accrual, demographic and safety data will be 
reported to the PBTC membership at the PBTC semi-annual meetings. 
 
13.2.3 Statistical Analysis of Pharmacokinetics  
Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and 
graphical form. Pharmacokinetic parameters of interest, such as apparent volume of the central 
compartment (Vc/F), elimination rate constant (Ke), half-life (t1/2), apparent oral clearance 
(CL/F), and area under the plasma concentration time curve (AUC) will be estimated using 
compartmental methods. Dose proportionality in pharmacokinetic parameters will be 
investigated by performing one-way analysis of variance (ANOVA) on dose-normalized 
parameters. 
  
In addition to estimating individual pharmacokinetic parameters, we will also estimate the 
population parameters using nonlinear mixed effects modeling methods (NONMEM). This 
method estimates the population parameters and both the inter- and intra-subject variability. 
Once the population parameters and corresponding covariance matrix are estimated, individual 
estimates can be obtained using post hoc analysis.  
 
13.3 
Projected Accrual Rate and Study Duration 
Phase I 
The projected accrual rate is 1.5-2.5 patients per month, based on knowledge of the member 
institutions and their commitment to the Consortium. With 2-3 likely dose levels, the total 
sample size and the study duration are expected to be 12-18 and about 1.5-2.0 years, 
respectively. The estimated duration incorporates the planned accrual suspensions for routine 
toxicity monitoring. 
 
Phase II 
The projected accrual rate is 1.5-2.5 patients per month, based on knowledge of the member 
institutions and their commitment to the Consortium. The total sample size and the study 
duration are expected to be approximately 60 patients and about 2-3.5 years. The table below is 
for both phases (Phase I and II combined) 
Table 21 
Expected: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
5 
5 
10 
Not Hispanic or Latino 
33 
23 
56 
Ethnic Category: Total of All Subjects * 
38 
28 
66 
Racial Categories 
American Indian / Alaska Native 
1 
0 
1 


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Asian 
2 
2 
4 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
5 
3 
8 
White 
30 
23 
53 
Racial Categories: Total of All Subjects*  
38 
28 
66 
 
13.4 
Analysis of Secondary Endpoints 
13.4.1 Statistical Analysis of Imaging Studies: 
We will describe and summarize the observed values of the proposed quantitative imaging 
parameters, namely rCBV, permeability (Ktrans, vp, and ve values) and ADC as well as changes in 
these parameters via descriptive statistics and plots. If serial values are available from adequate 
number of patients to make such models meaningful, we will also entertain the use of mixed 
effects models in modeling changes in these parameters. Depending on the number of 
pseudoprogression calls observed, we may also explore associations between these imaging 
parameters and pseudoprogression vs. true progression via appropriate models or simply via 
summary statistics and descriptive plots within and across patients. The assessment of true vs. 
pseudo progression will be based on the tumor measurements from subsequent scans.  For the 
primary objective regarding pseudoprogression, we will provide 95% confidence interval 
estimates of the proportion of patients determined to have experienced pseudoprogression. 
 
13.4.2 Statistical Analysis of Biologic Correlates  
13.4.2.1 
NHEJ and PARP Activity 
PARP inhibition in PBMCs will be measured as a ratio of pre/post-treatment values and will be 
summarized by dose level via exact confidence intervals. The values observed in this trial will be 
contrasted to the values reported in adults. 
 
Provided adequate number of events is observed among patients who participate in biology 
studies to make such analyses feasible, we will utilize Cox models to explore associations 
between the molecular parameters from correlative biology aims 1-2, namely PARP and NHEJ 
activity or γ-H2AX levels and PFS and OS. Associations between these parameters and objective 
response may also be explored provided a large enough number of responses are observed. 
Otherwise correlations between PARP and NHEJ activity or γ-H2AX levels with radiographic 
response and clinical outcome will be summarized descriptively. 
 
13.4.3 Urine Biomarkers 
Comparison of Urine Biomarker Levels in Patients vs. Controls: 
In order to determine whether the levels of these urinary biomarkers are elevated in DIPG 
patients, we will compare median levels for tumor patients to levels in healthy age- and gender-
matched controls using the Mann-Whitney U-test. Despite the presence of matched controls, 
Mann-Whitney U-test allows us to utilize a conservative approach compared to the Wilcoxon 
signed-rank test since matching by age and gender is done to reduce variability rather than to 
facilitate the use of methods for paired data. In addition, the percentage of patients and controls 
above the previously established cut-off values for each urinary biomarker will be compared 
using the chi-square test.  Based on a preliminary power analysis for this chi-square test a sample 


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size of 58 brain tumor patients and 58 controls will provide 80% power with a conservative two-
sided alpha level of 0.01 in capturing a difference of 30% between the groups with respect to 
each urinary biomarker. We will also utilize ROC analysis for each biomarker in exploring 
various cut-points for differentiating between the control subjects and DIPG patients. 
Multivariable logistic regression models coupled with ROC analyses will be used to select a 
combination of these biomarkers in an attempt to improve their collective performance as a 
classifier.  
 
Longitudinal Assessment of Changes in Biomarker Values and Their Association with Outcome: 
Using the data for patients who progress, for each biomarker we will compare the levels at 
baseline with levels at progression as determined by MRI to assess whether the biomarker values 
change and if so by how much. This will be done via Wilcoxon signed rank test and exact 
confidence interval estimates of the percent change. We will also tabulate the percentage of 
patients who have biomarker levels above the previously established cut points for each 
biomarker at baseline and at the time of progression. We will investigate whether the percentage 
of patients who are above/below the cutpoints for each of the biomarkers is different between 
baseline and time of progression via the McNemar’s test. Provided adequate number of 
responses is present to make such analyses meaningful, we will also perform similar analyses 
comparing biomarker levels at baseline and at the time of response. 
 
Time-to-event data will be analyzed using the Kaplan-Meier product-limit method and by the log 
rank test to compare the PFS and OS distributions of patients with biomarker values above and 
below the specified cut-off values at baseline.52 Provided adequate number of events exist to 
make such an exercise informative, will also utilize multivariable Cox proportional-hazards 
regression model with each of the 8 urinary biomarkers as time dependent predictors and 
relevant covariates including age and gender to explore associations with PFS and OS.53  


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Appendix A  
 
Performance Status Criteria 
 
MODIFIED LANSKY SCORE (Score as 0 - 100) 
A.  Normal Range 
100 = Fully active 
90 = Minor restrictions in physically strenuous play 
80 = Restricted in strenuous play, tires more easily, otherwise active 
 
B.  Mild to moderate restriction 
70 = Both greater restrictions of and less time spent in active play 
60 = Ambulatory up to 50% of time, limited active play with assistance/supervision 
50 = Considerable assistance required for any active play; full able to engage in quiet play 
 
C.  Moderate to severe restriction 
40 = Able to initiate quiet activities 
30 = Needs considerable assistance for quiet activity 
20 = Limited to very passive activity initiated by others e.g. TV) 
10 = Completely disabled, not even passive play 
  0 = Unresponsive, coma 
 
KARNOFSKY SCALE 
100 = Normal; no complaints 
90 = Able to carry on normal activities; minor signs or symptoms of disease 
80 = Normal activity with effort 
70 = Cares for self.  Unable to carry on normal activity or to do active work 
60 = Requires occasional assistance but able to care for most of his/her needs 
50 = Requires considerable assistance and frequent medical care 
40 = Disabled; requires special care and assistance 
30 = Severely disabled; hospitalization indicated though death not imminent 
20 = Very sick.  Hospitalization necessary.  Active support treatment necessary. 
10 = Moribund 
  0 = Dead 
 
 
 
 
 
 
 
 
 
 
 


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Appendix B  
ABT-888 Oral Solution Handling Guidelines 
 
NSC# 737664 ABT-888 (Veliparib)  
 
ABT-888 Oral Solution Dosing Administration 
Dosing is based on the BSA at the beginning of radiation and each course of maintenance.  The 
attending physician or designee calculates the required dose in mg based on the patient’s BSA and 
assigned dose.  Once the dose is calculated, the attending physician or designee should convert the 
mg/dose into milliliters; calculate the total milliliters to be dispensed to the family and demonstrate at 
least once to family member(s) the correct volume of ABT-888 to be drawn and administered per dose. 
The dose of ABT-888 should be rounded to the nearest 1mg (0.2 ml for the 5 mg/ml concentration).   
 
Care Provider obtains the following from the clinical site:  
1.  ABT-888 oral solution bottle from the pharmacist at the clinical site.  
The ABT-888 oral solution can be used for up to 30 days when stored at room temperature (15°C – 
25°C) , protected from light.  
2.  Oral syringes (5-20 mL).  One syringe will be used per dose. 
 
Procedure for Dosing ABT-888 Oral Solution 
1. Invert the suspension in the closed bottle before each use.  
2. Open the cap and insert the supplied oral dosing syringe into the opening of the press-in bottle adaptor 
(PIBA), maintaining the bottle in an upright position.  
3. Invert the bottle and withdraw the required volume.  Your research doctor will tell you how much 
solution to draw from the bottle for each dose. 
4. Remove the oral dosing syringe and administer the content of the syringe (containing solution from 
Step 3) to patient.  
5. Close the bottle tightly and store upright.  
6.  Place the used syringes in the biohazard bag provided by the research staff.  Return the used syringes 
as well as the ABT-888 solution bottle to the clinic at each visit. 
 
PLEASE FOLLOW STRICTLY ANY ADDITIONAL INSTRUCTIONS GIVEN BY YOUR HOSPITAL’S 
PHARMACIST 
 
 


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Appendix C  
Instructions for Administration of Temodar 
(Patients who are unable to swallow capsules) 
 
Temodar is an oral cancer medicine that your child will be taking for treatment of his/her brain tumor. 
Your child is unable to swallow capsules so the following instructions must be followed for safe 
administration of this medicine. 
 Temodar must be kept in a dark container 
 Temodar should be taken the same time every morning, about 60-120 minutes after the morning 
dose of ABT-888 
 If your child requires a nausea medicine, it should be taken prior to the Temodar 
 If the dose of Temodar is vomited (which is unusual) within 10 minutes of administration, please 
repeat the dose. If vomiting occurred more than 10 minutes after a dose, do not repeat the dose 
 If the person dispensing this medicine is pregnant or suspects that she is pregnant, she should not 
dispense this medicine.  
 
Temodar is an anti-cancer agent, and so special precautions must be taken when handling this medicine. 
There is potential hazard to anyone who handles this medicine once the protective capsule is opened. 
Since your child is unable to swallow the capsule, you will be required to open the capsules and mix the 
contents of the capsule in apple sauce or apple juice. This process must be done according to the 
following guidelines to ensure safe administration of this medicine. 
 Find a place that is as free of air flow as possible and is not an area where food is stored or 
prepared. 
 The work surface should be covered with aluminum foil to reduce exposure to other members of 
the family. 
 Temodar can be mixed in apple sauce or apple juice. 
 Place the apple sauce or apple juice in a disposable container. 
 Put on disposable gloves, mask and goggles (eye protection). 
 Open each capsule and place the powder in a medicine cup. 
 Add the whole contents of the medicine cup to either apple sauce or apple juice. The medicine 
will not dissolve completely if mixing in apple juice, and so have extra apple juice on hand so 
you can add it to any remaining powder in the bottom of the cup. 
o If you need to prepare additional juice or apple sauce, remove your gloves before 
touching the main container, and then place on new gloves before adding the additional 
juice or apple sauce to the medicine. (You do not want to contaminate the main container 
of apple juice/sauce with any powder that may be on your gloves). 
 Anything that comes into contact with the medicine must be disposable, such as the spoon used 
for mixing or eating the apple sauce. 
 Once all of the medicine is taken, throw away the following in the red bag: medicine cup, the 
container the medicine was mixed in, the cover for the work surface, mask, gloves, and anything 
else that has been in contact with the medicine. 
 Once a course of medicine is completed, bring the red bag with you to the clinic so it can be 
disposed properly. 
 
PLEASE FOLLOW STRICTLY ANY ADDITIONAL INSTRUCTIONS GIVEN BY YOUR HOSPITAL’S 
PHARMACIST.


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Appendix D  
ABT-888 Dose Calculation, Capsules (I) During Radiation 
 
(ONLY for Patients with BSA ≥ 1m2) 
 
Dose Level : 35  mg/m2/dose BID 
Min BSA 
Max BSA 
Total Daily Dose (mg) 
A.M. Dose (mg) 
P.M. Dose (mg) 
1.00 
1.07 
70 
40 
30 
1.08 
1.21 
80 
40 
40 
1.22 
1.35 
90 
50 
40 
1.36 
1.50 
100 
50 
50 
1.51 
1.64 
110 
60 
50 
1.65 
1.78 
120 
60 
60 
1.79 
1.92 
130 
70 
60 
1.93 
2.07 
140 
70 
70 
2.08 
2.21 
150 
80 
70 
2.22 
2.35 
160 
80 
80 
2.36 
2.50 
170 
90 
80 
 
Dose Level : 50  mg/m2/dose BID 
Min BSA 
Max BSA 
Total Daily Dose (mg) 
A.M. Dose (mg) 
P.M. Dose (mg) 
1.00 
1.05 
100 
50 
50 
1.06 
1.15 
110 
60 
50 
1.16 
1.25 
120 
60 
60 
1.26 
1.34 
130 
70 
60 
1.35 
1.45 
140 
70 
70 
1.46 
1.54 
150 
80 
70 
1.55 
1.65 
160 
80 
80 
1.66 
1.74 
170 
90 
80 
1.75 
1.85 
180 
90 
90 
1.86 
1.94 
190 
100 
90 
1.95 
2.05 
200 
100 
100 
2.06 
2.14 
210 
110 
100 
2.15 
2.25 
220 
110 
110 
2.26 
2.34 
230 
120 
110 
2.35 
2.44 
240 
120 
120 
2.45 
2.50 
250 
130 
120 
 
 


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Dose Level : 65  mg/m2/dose BID 
Min BSA 
Max BSA 
Total Daily Dose (mg) 
A.M. Dose (mg) 
P.M. Dose (mg) 
1.00 
1.03 
130 
70 
60 
1.04 
1.11 
140 
70 
70 
1.12 
1.19 
150 
80 
70 
1.20 
1.26 
160 
80 
80 
1.27 
1.34 
170 
90 
80 
1.35 
1.42 
180 
90 
90 
1.43 
1.49 
190 
100 
90 
1.50 
1.57 
200 
100 
100 
1.58 
1.65 
210 
110 
100 
1.66 
1.73 
220 
110 
110 
1.74 
1.80 
230 
120 
110 
1.81 
1.88 
240 
120 
120 
1.89 
1.96 
250 
130 
120 
1.97 
2.03 
260 
130 
130 
2.04 
2.11 
270 
140 
130 
2.12 
2.19 
280 
140 
140 
2.20 
2.26 
290 
150 
140 
2.27 
2.34 
300 
150 
150 
2.35 
2.42 
310 
160 
150 
2.43 
2.50 
320 
160 
160 
 
 


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85 
Dose Level : 85  mg/m2/dose BID 
Min BSA 
Max BSA 
Total Daily Dose (mg) 
A.M. Dose (mg) 
P.M. Dose (mg) 
1.00 
1.02 
170 
90 
80 
1.03 
1.08 
180 
90 
90 
1.09 
1.14 
190 
100 
90 
1.15 
1.20 
200 
100 
100 
1.21 
1.26 
210 
110 
100 
1.27 
1.32 
220 
110 
110 
1.33 
1.38 
230 
120 
110 
1.39 
1.44 
240 
120 
120 
1.45 
1.49 
250 
130 
120 
1.50 
1.55 
260 
130 
130 
1.56 
1.61 
270 
140 
130 
1.62 
1.67 
280 
140 
140 
1.68 
1.73 
290 
150 
140 
1.74 
1.79 
300 
150 
150 
1.80 
1.85 
310 
160 
150 
1.86 
1.91 
320 
160 
160 
1.92 
1.97 
330 
170 
160 
1.98 
2.02 
340 
170 
170 
2.03 
2.08 
350 
180 
170 
2.09 
2.14 
360 
180 
180 
2.15 
2.20 
370 
190 
180 
2.21 
2.26 
380 
190 
190 
2.27 
2.32 
390 
200 
190 
2.33 
2.38 
400 
200 
200 
2.39 
2.44 
410 
210 
200 
2.45 
2.50 
420 
210 
210 
 
 
 


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Dose Level : 110  mg/m2/dose BID 
Min BSA 
Max BSA 
Total Daily Dose (mg) 
A.M. Dose (mg) 
P.M. Dose (mg) 
1.00 
1.02 
220 
110 
110 
1.03 
1.06 
230 
120 
110 
1.07 
1.11 
240 
120 
120 
1.12 
1.15 
250 
130 
120 
1.16 
1.20 
260 
130 
130 
1.21 
1.24 
270 
140 
130 
1.25 
1.29 
280 
140 
140 
1.30 
1.34 
290 
150 
140 
1.35 
1.38 
300 
150 
150 
1.39 
1.43 
310 
160 
150 
1.44 
1.47 
320 
160 
160 
1.48 
1.52 
330 
170 
160 
1.53 
1.56 
340 
170 
170 
1.57 
1.61 
350 
180 
170 
1.62 
1.65 
360 
180 
180 
1.66 
170 
370 
190 
180 
1.71 
1.75 
380 
190 
190 
1.76 
1.79 
390 
200 
190 
1.80 
1.84 
400 
200 
200 
1.85 
1.88 
410 
210 
200 
1.89 
1.93 
420 
210 
210 
1.94 
1.97 
430 
220 
210 
1.98 
2.02 
440 
220 
220 
2.03 
2.06 
450 
230 
220 
2.07 
2.11 
460 
230 
230 
2.12 
2.15 
470 
240 
230 
2.16 
2.20 
480 
240 
240 
2.21 
2.24 
490 
250 
240 
2.25 
2.29 
500 
250 
250 
2.30 
2.34 
510 
260 
250 
2.35 
2.38 
520 
260 
260 
2.39 
2.43 
530 
270 
260 
2.44 
2.47 
540 
270 
270 
2.48 
2.50 
550 
280 
270 
 
 
 


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87 
Appendix E  
ABT-888 Dose Calculation, Capsules (II) During Maintenance 
(ONLY for Patients with BSA ≥ 1m2) 
 
Dose Level : 20 mg/m2/dose BID 
Min BSA 
Max BSA 
Total Daily Dose (mg) 
A.M. Dose (mg) 
P.M. Dose (mg) 
1.00 
1.12 
40 
20 
20 
1.13 
1.37 
50 
30 
20 
1.38 
1.62 
60 
30 
30 
1.63 
1.87 
70 
40 
30 
1.88 
2.12 
80 
40 
40 
2.13 
2.37 
90 
50 
40 
2.38 
2.5 
100 
50 
50 
 
Dose Level : 25 mg/m2/dose BID 
Min BSA 
Max BSA 
Total Daily Dose (mg) 
A.M. Dose (mg) 
P.M. Dose (mg) 
1.0 
1.09 
50 
30 
20 
1.1 
1.29 
60 
30 
30 
1.3 
1.49 
70 
40 
30 
1.5 
1.69 
80 
40 
40 
1.7 
1.89 
90 
50 
40 
1.9 
2.10 
100 
50 
50 
2.11 
2.30 
110 
60 
50 
2.31 
2.50 
120 
60 
60 
 
 


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Appendix F  
Temozolomide Dosing Tables 
135 mg/m2/day 
Min BSA (m2) 
Max BSA (m2) 
Daily TMZ 
Dose (mg) 
Min BSA (m2) 
Max BSA (m2) 
Daily TMZ 
Dose (mg) 
0.2 
0.2 
25 
1.36 
1.38 
185 
0.21 
0.24 
30 
1.39 
1.42 
190 
0.25 
0.27 
35 
1.43 
1.46 
195 
0.28 
0.31 
40 
1.47 
1.49 
200 
0.32 
0.35 
45 
1.5 
1.53 
205 
0.36 
0.38 
50 
1.54 
1.57 
210 
0.39 
0.42 
55 
1.58 
1.61 
215 
0.43 
0.46 
60 
1.62 
1.64 
220 
0.47 
0.49 
65 
1.65 
1.68 
225 
0.5 
0.53 
70 
1.69 
1.72 
230 
0.54 
0.57 
75 
1.73 
1.75 
235 
0.58 
0.61 
80 
1.76 
1.79 
240 
0.62 
0.64 
85 
1.8 
1.83 
245 
0.65 
0.68 
90 
1.84 
1.87 
250 
0.69 
0.72 
95 
1.88 
1.9 
255 
0.73 
0.75 
100 
1.91 
1.94 
260 
0.76 
0.79 
105 
1.95 
1.98 
265 
0.8 
0.83 
110 
1.99 
2.01 
270 
0.84 
0.87 
115 
2.02 
2.05 
275 
0.88 
0.9 
120 
2.06 
2.09 
280 
0.91 
0.94 
125 
2.1 
2.12 
285 
0.95 
0.98 
130 
2.13 
2.16 
290 
0.99 
1.01 
135 
2.17 
2.2 
295 
1.02 
1.05 
140 
2.21 
2.24 
300 
1.06 
1.09 
145 
2.25 
2.27 
305 
1.1 
1.12 
150 
2.28 
2.31 
310 
1.13 
1.16 
155 
2.32 
2.35 
315 
1.17 
1.2 
160 
2.36 
2.38 
320 
1.21 
1.24 
165 
2.39 
2.42 
325 
1.25 
1.27 
170 
2.43 
2.46 
330 
1.28 
1.31 
175 
2.47 
2.49 
335 
1.32 
1.35 
180 
2.50 
2.50 
340 
 
 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
89 
 
175 mg/m2/day 
Min BSA (m2) 
Max BSA (m2) 
Daily TMZ 
Dose (mg) 
Min BSA (m2) 
Max BSA (m2) 
Daily TMZ 
Dose (mg) 
0.20 
0.21 
35 
1.36 
1.38 
240 
0.22 
0.24 
40 
1.39 
1.41 
245 
0.25 
0.27 
45 
1.42 
1.44 
250 
0.28 
0.29 
50 
1.45 
1.47 
255 
0.30 
0.32 
55 
1.48 
1.50 
260 
0.33 
0.35 
60 
1.51 
1.52 
265 
0.36 
0.38 
65 
1.53 
1.55 
270 
0.39 
0.41 
70 
1.56 
1.58 
275 
0.42 
0.44 
75 
1.59 
1.61 
280 
0.45 
0.47 
80 
1.62 
1.64 
285 
0.48 
0.49 
85 
1.65 
1.67 
290 
0.50 
0.52 
90 
1.68 
1.69 
295 
0.53 
0.55 
95 
1.70 
1.72 
300 
0.56 
0.58 
100 
1.73 
1.75 
305 
0.59 
0.61 
105 
1.76 
1.78 
310 
0.62 
0.64 
110 
1.79 
1.81 
315 
0.65 
0.67 
115 
1.82 
1.84 
320 
0.68 
0.70 
120 
1.85 
1.87 
325 
0.71 
0.72 
125 
1.88 
1.90 
330 
0.73 
0.75 
130 
1.91 
1.92 
335 
0.76 
0.78 
135 
1.93 
1.95 
340 
0.79 
0.81 
140 
1.96 
1.98 
345 
0.82 
0.84 
145 
1.99 
2.01 
350 
0.85 
0.87 
150 
2.02 
2.04 
355 
0.88 
0.89 
155 
2.05 
2.07 
360 
0.90 
0.92 
160 
2.08 
2.09 
365 
0.93 
0.95 
165 
2.10 
2.12 
370 
0.96 
0.98 
170 
2.13 
2.15 
375 
0.99 
1.01 
175 
2.16 
2.18 
380 
1.02 
1.04 
180 
2.19 
2.21 
385 
1.05 
1.07 
185 
2.22 
2.24 
390 
1.08 
1.09 
190 
2.25 
2.27 
395 
1.10 
1.12 
195 
2.28 
2.29 
400 
1.13 
1.15 
200 
2.30 
2.32 
405 
1.16 
1.18 
205 
2.33 
2.35 
410 
1.19 
1.21 
210 
2.36 
2.38 
415 
1.22 
1.24 
215 
2.39 
2.41 
420 
1.25 
1.27 
220 
2.42 
2.44 
425 
1.28 
1.29 
225 
2.45 
2.47 
430 
1.30 
1.32 
230 
2.48 
2.49 
435 
1.33 
1.35 
235 
2.50 
2.50 
440 
 
 
 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
90 
200 mg/m2/day 
Min BSA (m2) 
Max BSA (m2) 
Daily TMZ 
Dose (mg) 
Min BSA (m2) 
Max BSA (m2) 
Daily TMZ 
Dose (mg) 
0.20 
0.21 
40 
1.37 
1.38 
275 
0.22 
0.23 
45 
1.39 
1.41 
280 
0.24 
0.26 
50 
1.42 
1.43 
285 
0.27 
0.28 
55 
1.44 
1.46 
290 
0.29 
0.31 
60 
1.47 
1.48 
295 
0.32 
0.33 
65 
1.49 
1.51 
300 
0.34 
0.36 
70 
1.52 
1.53 
305 
0.37 
0.38 
75 
1.54 
1.56 
310 
0.39 
0.41 
80 
1.57 
1.58 
315 
0.42 
0.43 
85 
1.59 
1.61 
320 
0.44 
0.46 
90 
1.62 
1.63 
325 
0.47 
0.48 
95 
1.64 
1.66 
330 
0.49 
0.51 
100 
1.67 
1.68 
335 
0.52 
0.53 
105 
1.69 
1.71 
340 
0.54 
0.56 
110 
1.72 
1.73 
345 
0.57 
0.58 
115 
1.74 
1.76 
350 
0.59 
0.61 
120 
1.77 
1.78 
355 
0.62 
0.63 
125 
1.79 
1.81 
360 
0.64 
0.66 
130 
1.82 
1.83 
365 
0.67 
0.68 
135 
1.84 
1.86 
370 
0.69 
0.71 
140 
1.87 
1.88 
375 
0.72 
0.73 
145 
1.89 
1.91 
380 
0.74 
0.76 
150 
1.92 
1.93 
385 
0.77 
0.78 
155 
1.94 
1.96 
390 
0.79 
0.81 
160 
1.97 
1.98 
395 
0.82 
0.83 
165 
1.99 
2.01 
400 
0.84 
0.86 
170 
2.02 
2.03 
405 
0.87 
0.88 
175 
2.04 
2.06 
410 
0.89 
0.91 
180 
2.07 
2.08 
415 
0.92 
0.93 
185 
2.09 
2.11 
420 
0.94 
0.96 
190 
2.12 
2.13 
425 
0.97 
0.98 
195 
2.14 
2.16 
430 
0.99 
1.01 
200 
2.17 
2.18 
435 
1.02 
1.03 
205 
2.19 
2.21 
440 
1.04 
1.06 
210 
2.22 
2.23 
445 
1.07 
1.08 
215 
2.24 
2.26 
450 
1.09 
1.11 
220 
2.27 
2.28 
455 
1.12 
1.13 
225 
2.29 
2.31 
460 
1.14 
1.16 
230 
2.32 
2.33 
465 
1.17 
1.18 
235 
2.34 
2.36 
470 
1.19 
1.21 
240 
2.37 
2.38 
475 
1.22 
1.23 
245 
2.39 
2.41 
480 
1.24 
1.26 
250 
2.42 
2.43 
485 
1.27 
1.28 
255 
2.44 
2.46 
490 
1.29 
1.31 
260 
2.47 
2.48 
495 
1.32 
1.33 
265 
2.49 
2.50 
500 
1.34 
1.36 
270 
 
 
 
 
 
 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
91 
Appendix G  
 
Design Input Parameters and Resulting Stopping Boundaries 
 
Input Parameters 
Parameter 
Value 
Alpha S 
128 
Beta S 
1759.8 
Alpha E 
3 
Beta E 
27.7134 
Delta 
5.5 
pL 
0.00807171 
Type of Event 
Bad 
Max patients 
60 
 
 


NCI Protocol #: PBTC-033 
Version Date: February 4, 2014 
Updated Date: February 4, 2014 
92 
 
Stopping Boundaries 
Number of 
events 
Minimum total 
time-on-test  
(in days) to 
continue 
Number of 
events 
Minimum total 
time-on-test  
(in days) to 
continue 
Number of 
events 
Minimum total 
time-on-test  
(in days) to 
continue 
1 
0 
21 
10279 
41 
23262 
2 
0 
22 
10904 
42 
23931 
3 
216 
23 
11531 
43 
24601 
4 
661 
24 
12163 
44 
25273 
5 
1131 
25 
12797 
45 
25946 
6 
1623 
26 
13434 
46 
26619 
7 
2133 
27 
14075 
47 
27295 
8 
2658 
28 
14717 
48 
27971 
9 
3196 
29 
15363 
49 
28648 
10 
3745 
30 
16010 
50 
29326 
11 
4305 
31 
16660 
51 
30005 
12 
4873 
32 
17312 
52 
30686 
13 
5450 
33 
17966 
53 
31367 
14 
6034 
34 
18622 
54 
32049 
15 
6624 
35 
19280 
55 
32732 
16 
7221 
36 
19940 
56 
33416 
17 
7823 
37 
20601 
57 
34100 
18 
8430 
38 
21264 
58 
34786 
19 
9042 
39 
21929 
59 
35472 
20 
9659 
40 
22595