Clinical trial NCT02116777
Conditions: Adult Solid Neoplasm Childhood Solid Neoplasm Recurrent Childhood Central Nervous System Neoplasm Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Recurrent Malignant Solid Neoplasm Refractory Central Nervous System Neoplasm
Sponsor: National Cancer Institute (NCI)
Start date: 2014-05-16; Completion date: 2018-12-31
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase I/II trial studies the side effects and best dose of talazoparib and temozolomide and to see how well they work in treating younger patients with tumors that have not responded to previous treatment (refractory) or have come back (recurrent). Talazoparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving talazoparib together with temozolomide may work better in treating younger patients with refractory or recurrent malignancies.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of temozolomide when combined with a dose of talazoparib (BMN 673) given once daily for 5 days after a one day dose of BMN 673 administered orally (either once daily or twice daily), every 28 days to children with refractory or recurrent solid tumors. (Phase I) II. To define and describe the toxicities of BMN 673 given with temozolomide administered on this schedule. (Phase I) III. To characterize the pharmacokinetics of BMN 673 and temozolomide when given in combination to children with refractory or recurrent cancer. (Phase I) IV. To define the antitumor activity of BMN 673 when given with temozolomide in recurrent/refractory Ewing sarcoma.(Phase II)

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of BMN 673 and temozolomide in pediatric patients with recurrent or refractory solid tumors within the confines of a phase I study.

II. To explore possible predictive biomarkers in archival tumor tissue from Ewing sarcoma patients in Phase II.

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

Patients receive talazoparib orally (PO) once daily (QD) or twice daily (BID) on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Arms: arm 1: (Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. arm 2: (Part B): Relapse/Refractory EWS or PNET Patients receive MTD from Phase 1 portion of study. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Pharmacological Study intervention 3: Talazoparib intervention 4: Temozolomide
Intervention descriptions: intervention 1: Correlative studies intervention 2: Correlative studies intervention 3: Given PO intervention 4: Given PO

Protocol documents:
Prot_SAP_001.pdf: 
Phase 1/Pilot Consortium and  
Developmental Therapeutics (DVL) 
Chair 
Brenda J. Weigel, M.D. 
weige007@umn.edu 
 
Phase 1/Pilot Consortium and  
Developmental Therapeutics (DVL) 
Vice Chair  
Elizabeth Fox, M.D. 
foxe@email.chop.edu 
 
Phase 1 Operations Director 
Thalia Beeles, MPH 
tbeeles@childrensoncologygroup.org 
 
Phase 1 Statistician  
Charles G. Minard, Ph.D. 
minard@bcm.edu 
 
 
Phase 1/Pilot Consortium and  
DVL Chair’s Office 
University of Minnesota/ 
Masonic Cancer Center 
Masonic Children’s Hospital 
420 Delaware Street, SE 
MMC 366 
Minneapolis, MN  55455 
 
P 612 626 5501 
F 612 624 3913 
 
 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100  
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100  
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
 
A National Cancer Institute  
supported clinical cooperative 
group and Equal Opportunity 
Affirmative Action Institutions 
 
 
 
 
 
i 
 
F
 
 
March 23rd, 2017 
 
Martha Kruhm, M.S., RAC 
Head, Protocol and Information Office (PIO) 
National Institutes of Health/NCI/DCTD/CTEP/OIB/PIO 
9609 Medical Center Drive, OIB MSC 9742, Room #5W246 
Bethesda, MD 20892-9742 
 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #4 to ADVL1411, A Phase 1/2 Study of 
BMN 673 (IND #121510), an Oral Poly(ADP-ribose) Polymerase Inhibitor, 
Plus Temozolomide in Children with Refractory or Recurrent Malignancies. 
 
The Protocol has been amended to reflect modified risk information for 
BMN 673 (talazoparib). The CAEPR and risk profile have been updated to 
CAEPR Version 2.1, December 29, 2016. 
The amendment is being submitted in response to an RRA from Dr. 
Richard Piekarz (piekarzr@mail.nih.gov). 
 
Additional administrative changes were made for clarity and consistency. 
 
 
SUMMARY OF CHANGES 
 
The following specific revisions have been made to the protocol and 
informed consent document. 
 
 


 
 
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I. 
Changes to the Protocol: 
 
# 
Section 
Comments 
1.  
Title 
The version date and amendment # have been updated. 
2.  
Title 
The additional participating sites have been updated. 
3.  
TOC 
The Table of Contents has been updated. 
4.  
9.1.7 
The CAEPR has been updated to Version 2.1, December 29, 2016. 
 
• 
Added New Risk: 
• 
Less Likely: Dyspepsia; Epistaxis; Pain 
• 
Rare but Serious: Typhlitis 
• 
Also Reported on Talazoparib Trials But With Insufficient 
Evidence for Attribution: Abdominal distension; Dry skin; 
Dysgeusia; Hepatic failure; Insomnia; Neck pain; Non-
cardiac chest pain; Respiratory, thoracic and mediastinal 
disorders - Other (oropharyngeal pain); Small intestinal 
obstruction; Weight loss 
 
• 
Increase in Risk Attribution: 
• 
Changed to Likely from Less Likely: Anemia; Diarrhea; 
Platelet count decreased 
• 
Changed to Less Likely from Rare but Serious: Febrile 
neutropenia 
• 
Changed to Likely from Also Reported on Talazoparib Trials 
But With Insufficient Evidence for Attribution: Abdominal pain 
• 
Changed to Less Likely from Also Reported on Talazoparib 
Trials But With Insufficient Evidence for Attribution: 
Anorexia; Fever; Headache; Hypokalemia; Infection; 
Nervous system disorders - Other (neuropathy peripheral); 
Rash maculo-papular; White blood cell decreased 
 
• 
Modified Specific Protocol Exceptions to Expedited Reporting 
(SPEER) reporting requirements: 
• 
Added: Abdominal pain; Alopecia; Anorexia; Dizziness; 
Fever; Headache; Infection; Pain; Vomiting 
 
• 
Provided Further Clarification: 
• 
Peripheral sensory neuropathy (previously under Also 
Reported on Talazoparib Trials But With Insufficient 
Evidence for Attribution) is now reported as Nervous system 
disorders - Other (neuropathy peripheral) (under Less 
Likely). 
• 
Lung infection and Sepsis (previously under Also Reported 
on Talazoparib Trials But With Insufficient Evidence for 
Attribution) is now reported as Infection (under Less Likely). 


 
 
ADVL1411 
 
 
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# 
Section 
Comments 
• 
A new footnote #2 has been added as follows: “Infection 
may include any of the 75 infection sites under the 
INFECTIONS AND INFESTATIONS SOC.” 
• 
A new footnote #3 has been added as follows: “Neuropathy 
peripheral may include both Peripheral sensory neuropathy 
and Peripheral motor neuropathy under the NERVOUS 
SYSTEM DISORDERS.” 
 
 
II. 
Changes to the Informed Consent Document: 
 
# 
Section 
Comments 
1.  
ICD 
The version date has been updated. 
2.  
What side 
effects…? 
(Part A) 
The Risk List has been updated according to CAEPR Version 2.1, December 
29, 2016. 
 
• 
Added New Risk: 
• 
Occasional: Heartburn; Nose bleed  
• 
Rare but Serious: Swelling of the bowels which may require 
surgery 
• 
 
• 
Increase in Risk Attribution: 
• 
Changed to Common from Occasional: Anemia which may 
require blood transfusion; Diarrhea; Bruising, bleeding  
• 
Changed to Occasional from Rare: Infection, especially 
when white blood cell count is low 
• 
Changed to Common from Also Reported on Talazoparib 
Trials But With Insufficient Evidence for Attribution (i.e., 
added to the Risk Profile): Pain 
Changed to Occasional from Also Reported on Talazoparib Trials But With 
Insufficient Evidence for Attribution (i.e., added to the Risk Profile): Loss of 
appetite; Fever; Headache; Muscle weakness; Numbness, tingling or pain of 
the arms and legs; Rash 
3.  
What side 
effects…? 
(Part B) 
The Risk List has been updated according to CAEPR Version 2.1, December 
29, 2016. 
 
• 
Added New Risk: 
• 
Occasional: Heartburn; Nose bleed  
• 
Rare but Serious: Swelling of the bowels which may require 
surgery 
• 
 
• 
Increase in Risk Attribution: 


 
 
ADVL1411 
 
 
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iv 
 
# 
Section 
Comments 
• 
Changed to Common from Occasional: Anemia which may 
require blood transfusion; Diarrhea; Bruising, bleeding  
• 
Changed to Occasional from Rare: Infection, especially 
when white blood cell count is low 
• 
Changed to Common from Also Reported on Talazoparib 
Trials But With Insufficient Evidence for Attribution (i.e., 
added to the Risk Profile): Pain 
Changed to Occasional from Also Reported on Talazoparib Trials But With 
Insufficient Evidence for Attribution (i.e., added to the Risk Profile): Loss of 
appetite; Fever; Headache; Muscle weakness; Numbness, tingling or pain of 
the arms and legs; Rash 
 
 
 
Sincerely, 
Michael Weiss, Ph.D., Protocol Coordinator, for 
Eric Schafer, M.D., ADVL1411 Study Chair, and 
Brenda Weigel, M.D., PI, COG Phase 1/Pilot Consortium


 
 
 
ADVL1411 
03/23/17 
 
1 
 
 
Activated: 
April 21, 2014 
           Version Date: 
03/23/17 
Closed: 
 
Amendment:  
4 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
ADVL1411 
 
A PHASE 1/ 2 STUDY OF BMN 673 (IND# 121510), AN ORAL POLY(ADP-RIBOSE) 
POLYMERASE INHIBITOR, PLUS TEMOZOLOMIDE IN CHILDREN WITH REFRACTORY 
OR RECURRENT MALIGNANCIES  
 
Lead Organization: COG Phase 1/Pilot Consortium (COGC) 
 
Participating Organization: COG 
** Participation is limited to the following COG sites and credit will be assigned to COGC in OPEN: ** 
OR010 / Oregon Health and Science University 
WI053 / Children’s Hospital of Wisconsin 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED 
OR USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN 
THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY 
ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  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.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT 
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL 
HOSPITAL OR HEALTHCARE INSTITUTION. 
 
STUDY CHAIR 
 
Eric S. Schafer, MD, MHS  
Baylor College of Medicine 
Pediatrics/ Oncology 
1102 Bates Avenue, Suite 1590 
Houston, TX 77030 
Phone: (832) 824-4241  
Fax:      (832) 825-4107  
Email:esschafe@txch.org 
 
For COG Phase 1/Pilot Consortium Operations Contacts See: 
http://members.childrensoncologygroup.org 
 
 


 
 
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TABLE OF CONTENTS 
SECTION 
 
PAGE 
 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Aims for Phase 1 
8 
1.2 
Primary Aim for Phase 2 
8 
1.3 
Secondary Aims 
8 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Preclinical Studies 
13 
2.3 
Adult Studies 
16 
2.4 
Pediatric Studies 
17 
2.5 
Overview of Proposed Pediatric Study 
20 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
21 
3.1 
Current Study Status 
21 
3.2 
IRB Approval 
21 
3.3 
Patient Registration 
21 
3.4 
Reservation and Contact Requirements 
21 
3.5 
Informed Consent/Assent 
22 
3.6 
Screening Procedures 
22 
3.7 
Eligibility Checklist 
22 
3.8 
Institutional Pathology Report 
22 
3.9 
Study Enrollment 
22 
3.10 
Dose Assignment 
22 
4.0 
PATIENT ELIGIBILITY 
23 
4.1 
Inclusion Criteria 
23 
4.2 
Exclusion Criteria 
27 
4.3 
Leukemia Definitions 
28 
5.0 
TREATMENT PROGRAM 
31 
5.1 
Overview of Treatment Plan 
31 
5.2 
Criteria for Starting Subsequent Cycles 
32 
5.3 
Dose Escalation Schema 
32 
5.4 
Grading of Adverse Events 
34 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
34 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
35 
6.1 
Dose Modifications for Hematological Toxicity 
35 
6.2 
Dose Modifications for Non-Hematological Toxicity 
36 
6.3 
Dose Modifications for Intra-patient Dose Escalation Part B 
36 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
36 
7.1 
Concurrent Anticancer Therapy 
36 
7.2 
Investigational Agents 
36 
7.3 
Supportive Care 
36 


 
 
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7.4 
Growth Factors 
36 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
38 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
38 
8.2 
Radiology Studies 
39 
8.3 
Pharmacology Studies (Required for Cycle 1) (Part A ONLY) 
40 
8.4 
Tumor Tissue Studies (Required, Part B ONLY) 
43 
9.0 
AGENT INFORMATION 
44 
9.1 
BMN 673 
44 
9.2 
Agent Ordering and Agent Accountability 
46 
9.3 
Clinical Drug Request 
47 
9.4 
Agent Inventory Records 
47 
9.5 
Temozolomide-Oral 
47 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
50 
10.1 
Criteria for Removal from Protocol Therapy 
50 
10.2 
Off Study Criteria 
50 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
51 
11.1 
Sample Size and Study Duration 
51 
11.2 
Definitions [Phase 1 (Part A1)] 
52 
11.3 
Dose Escalation and Determination of MTD [Phase 1 (Part A1)] 
54 
11.4 
Pharmacokinetic Studies and Response Analysis [Phase 1 (Part A)] 
55 
11.5 
Study Design [Phase 2 (Parts B and C)] 
55 
11.6 
Method of Analysis [Phase 2 (Parts B and C)] 
56 
11.7 
Inclusion of Children, Women and Minorities 
56 
12.0 
EVALUATION CRITERIA 
57 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
57 
12.2 
Response Criteria for Patients with Solid Tumors 
57 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
62 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
62 
12.5 
Response Criteria for Patients with Relapsed Acute Lymphoblastic Leukemia 
64 
12.6 
Response Criteria for Patients with CNS Tumors 
64 
12.7 
Best Response 
66 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
69 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
69 
13.2 
When to Report an Event in an Expedited Manner 
71 
13.3 
Expedited Reporting Methods 
72 
13.4 
Definition of Onset and Resolution of Adverse Events 
72 
13.5 
Other Recipients of Adverse Event Reports 
73 
13.6 
Reporting Secondary AML/MDS 
73 
13.7 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
73 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
75 
14.1 
Categories of Research Records 
75 
14.2 
CDUS 
75 
14.3 
CRADA/CTA/CSA 
75 
14.4 
Data and Safety Monitoring Plan 
77 
REFERENCES 
78 
APPENDIX I: PERFORMANCE STATUS SCALES/ SCORES 
81 


 
 
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APPENDIX II-A: BMN 673 DOSING NOMOGRAM 
82 
APPENDIX II-B: TEMOZOLOMIDE DOSING NOMOGRAM 
84 
APPENDIX III-A: PATIENT DIARY INSTRUCTIONS FOR BMN 673 AND TEMOZOLOMIDE 
(FOR DOSE LEVELS -1 TO 1) 
86 
APPENDIX III-B: PATIENT DIARY FOR BMN 673 AND TEMOZOLOMIDE (FOR DOSE LEVELS -
1 TO 1) 87 
APPENDIX III-C: PATIENT DIARY INSTRUCTIONS FOR BMN 673 AND TEMOZOLOMIDE (FOR 
DOSE LEVELS 2 TO 6) 
88 
APPENDIX III-D: PATIENT DIARY FOR BMN 673 AND TEMOZOLOMIDE (FOR DOSE LEVELS 
2 TO 6) 89 
APPENDIX IV: CORRELATIVE STUDIES GUIDE 
90 
APPENDIX V: PHASE 1 PHARMACOKINETIC STUDY FORM FOR BMN 673 AND 
TEMOZOLOMIDE (PART A ONLY) 
91 
APPENDIX VI: GUIDELINES FOR SHIPPING PK SAMPLES TO ALLIANCE PHARMA 
92 
APPENDIX VII: GUIDELINES FOR SHIPPING PK SAMPLES TO THE MAYO CLINIC 
93 
APPENDIX VIII: PHASE 2 TUMOR TISSUE STUDY FORM (PART B ONLY) 
94 
APPENDIX IX: PREGNANCY INFORMATION FORM 
95 
 
 
 
 
 


 
 
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STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Eric S. Schafer, MD, MHS 
Brenda Weigel, MD 
Pediatrics/ Oncology 
Chair, Developmental Therapeutics 
Baylor College of Medicine 
University of Minnesota Medical Center – 
Fairview 
1102 Bates Avenue, Suite 1590 
Department of Pediatrics 
Houston, TX 77030 
420 Delaware Street, SE  MMC 366 
Phone:  (832) 824-4241 
Minneapolis, MN 55455 
Fax:      (832) 825-4107 
Phone:   (612) 626-5501 
Email: esschafe@txch.org 
Fax:  
 (612) 624-3913 
 
E-mail: weige007@umn.edu 
STUDY VICE CHAIR 
 
Rachel Rau, MD 
Elizabeth Fox, MD 
Pediatrics/ Oncology 
Vice Chair, Developmental Therapeutics 
Baylor College of Medicine 
Children’s Hospital of Philadelphia 
1102 Bates Avenue, Suite 1220 
Pediatrics/Division of Oncology 
Houston, TX 77030 
3501 Civic Center Blvd 
Phone:  (832) 822-4242 
CTRB-4016 
Fax:      (832) 825-4039 
Philadelphia, PA 19104 
Email: Rachel.Rau@bcm.edu 
Phone:   (267) 425-3010 
 
Fax:  
 (267) 425-0113 
SENIOR STATISTICIAN  
Email: foxe@email.chop.edu 
Charles Minard, PhD 
Baylor College of Medicine  
One Baylor Plaza, Suite 100D, BCM 122 
Houston, TX 77030 
Phone:   713-798-2353 
Fax:  
 713-798-2816 
Email: minard@bcm.edu  
 
 
Susan M. Blaney, MD 
Group Vice Chair 
Hematology/Oncology 
Baylor College of Medicine 
6621 Fannin Street, Suite 1410 
 
CC1410.00 
STUDY PHARMACIST 
Houston, TX  77030-2399 
Olga Militano, PharmD 
Children’s Oncology Group – Operations Center 
222 E. Huntington Drive, Suite 100 
Monrovia, CA  91016 
Phone: (626) 241-1517 
Fax: 
(626) 445-4334 
E-mail: omilitano@childrensoncologygroup.org  
Phone: (832) 822-1482 
Fax: 
(832) 825-4299 
E-mail: smblaney@txch.org 
 
STUDY PHARMACOLOGIST 
Joel M. Reid, PhD  
Mayo Clinic 
19-365 Gonda Building 
 
200 First Street SW 
PROTOCOL COORDINATOR 
Rochester, MN 55905 
Catalina Martinez 
Phone:   (507) 284-0822 
Children’s Oncology Group – Operations Center 
Fax:  
 (507) 284-3906 
222 E. Huntington Drive, Suite 100 
E-mail: reid.joel@mayo.edu    
Monrovia, CA  91016 
 
Phone: (626) 241-1543 
 
Fax: 
(626) 445-4334 
 
E-mail: cmartinez@childrensoncologygroup.org  
 
 
 
 
 


 
 
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STUDY NURSE 
STUDY CRA 
Susan Ehling, MN ARNP 
Seattle Children's Hospital 
Hematology/Oncology 
4800 Sand Point Way NE 
PO Box C5371 Hem/Onc. Mail Stop B6553 
Seattle, WA 98105 
Phone: (206) 987-2043 
Fax: 
(206) 987-3946 
E-mail: susan.ehling@seattlechildrens.org  
Susan Milligan, BA CCRC 
Pediatric Hematology/ Oncology 
Baylor College of Medicine 
Texas Children's Feigin Center, Suite 1220 
1102 Bates Street 
Houston, TX 77030-2399  
Phone: 832-824-2138 
Fax: 
832-825-4039 
E-mail: sdmillig@txch.org 
 
 
 
STATISTICIAN  
Xiaowei Liu, MS 
Children’s Oncology Group – Operations Center 
222 E. Huntington Drive, Suite 100 
Monrovia, CA  91016 
Phone: (626) 241-1535 
Fax: 
(626) 445-4334 
E-mail: xwliu@childrensoncologygroup.org 
 
 
 
 
 
 
 
 
For COG Phase 1/Pilot Consortium Contacts see: 
http:members.childrensoncologygroup.org 
 
 
AGENT NSC# AND IND#’s 
 
NCI-Supplied Agent: 
BMN 673 (BMN 673ts, talazoparib, MDV3800) 
NSC#771561 IND# 121510 
 
Commercial Agent: 
Temozolomide (Temodar, Temodal) NSC #362856 
 
 
IND Sponsor: CTEP 
 
 
SEE APPENDICES VI, VII AND VIII FOR SPECIMEN SHIPPING ADDRESSES. 
 


 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
ADVL1411 
03/23/17 
 
 
7 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about subjects collected during the course of our covered studies.  The 
researchers involved in the studies cannot be forced to disclose the identity or any information collected in 
the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
ABSTRACT 
Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes involved in DNA repair through the 
recruitment and activation of proteins that primarily utilize the base excision repair (BER) pathway.  
PARP1, the family’s founding member, binds to damaged DNA through its N-terminal zinc finger motifs; 
binding activates its catalytic C-terminal domain to hydrolyze NAD+ and produce linear and branched 
poly(ADP-ribose) (PAR) chains.  These PAR chains have a net negative charge, which promotes 
recruitment of DNA repair proteins involved in the BER pathway to the site of DNA damage, and facilitates 
removal of PARP1 from damaged sites allowing access to other repair proteins.  PARP2 is essential for the 
viability of PARP1.  BMN 673 is a novel, highly potent orally administered PARP 1/2 inhibitor which was 
shown to be well tolerated and have great therapeutic promise in adult patients harboring intrinsic DNA 
repair deficits, such as germline BRCA1/2, in an early phase 1 clinical trial.  Preclinical studies have strongly 
suggested that PARP inhibitors have additional mechanisms of action against certain cancers. For example, 
it has been shown that PARP1 is a key co-factor in ETS positive tumors such as EWS-FLI1 and EWS-ERG 
chimera Ewing sarcoma which in vitro is exquisitely sensitive to available PARP inhibitors.  
Temozolomide, an orally administered monofunctional SN-1 alkylating agent, which is used in the 
treatment of a variety of pediatric tumors, has been theorized to potentiate PARP inhibition through the 
creation of persistent single nucleotide gaps in double stranded DNA which would normally be repaired by 
endogenous PARP enzymes.  When BMN 673 in combination with low-dose short duration temozolomide 
was modeled through in vitro and mouse human tumor xenograft models, the treatment showed impressive 
activity in a broad range of pediatric cancers including Ewing sarcoma, Wilms tumor, medulloblastoma 
and acute lymphoblastic leukemia (ALL).   
 
This study is a Phase 1/2 trial of BMN 673 in combination with low-dose short duration temozolomide in 
children with relapsed or refractory malignancies.  This trial will be the first assessment of BMN 673 in 
children.  In addition, it is testing a novel mechanism of temozolomide in combination such that it is almost 
exclusively used as a potentiating agent; not in a manner that would be classically “synergistic.” 
Temozolomide will be given, at early dose levels, in low doses that are individually sub-therapeutic and 
therefore, minimally toxic. This allows for BMN 673 to be given on an intermittent schedule in combination 
with temozolomide, at or near the maximum tolerated dose (MTD) when given as a single agent on a 
continuous, daily schedule in adults.  Part A of the trial (Phase 1) will be a traditional dose escalation study 
using a 3+3 design to find the MTD and/or recommended Phase 2 dose (RP2D), in each 28 day cycle, of 
once daily temozolomide given for 5 days when combined with a dose of BMN 673 (400 mcg/m2/dose or 
600 mcg/m2/dose) given once daily for 5 days after a one day dose of BMN 673 (400 mcg/m2/dose or 600 
mcg/m2/dose). The Day 1 dose for BMN 673 will be administered either once daily or twice daily. Part B 
and Part C of the trial (Phase 2) will examine the efficacy of this combination at the MTD/ RP2D in Ewing 


 
 
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sarcoma/Peripheral primitive neuroectodermal tumor (PNET) and ALL patients using a Simon’s optimal 
two stage design.  For the first time, the pharmacokinetics of BMN 673 when administered in combination 
with temozolomide will be examined in children with recurrent or refractory malignancies.  In the Phase 2 
portion of the study, potential biomarkers of treatment response will be explored in Ewing sarcoma archived 
tumor samples. 
 
EXPERIMENTAL DESIGN SCHEMA 
 
 
Therapy will be discontinued if there is evidence of progressive disease or drug related dose-limiting 
toxicity that requires removal from therapy (Section 6.0). Therapy may otherwise continue for up to 24 
cycles for an approximate total treatment course of two years provided the patient meets the criteria for 
starting subsequent cycles (Section 5.2) and does not meet any of the criteria for removal from protocol 
therapy or off study criteria (Section 10.0).  
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims for Phase 1 
 
1.1.1 
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose (RP2D) of temozolomide when combined with a dose of BMN 673 given 
once daily for 5 days after a one day dose of BMN 673 administered orally (either 
once daily or twice daily), every 28 days to children with refractory or recurrent 
solid tumors. 
 
1.1.2 
To define and describe the toxicities of BMN 673 given with temozolomide 
administered on this schedule. 
 
1.1.3 
To characterize the pharmacokinetics of BMN 673 and temozolomide when given 
in combination to children with refractory or recurrent cancer. 
 
1.2 
Primary Aim for Phase 2 
 
1.2.1 
To define the antitumor activity of BMN 673 when given with temozolomide in 
recurrent/ refractory Ewing sarcoma and recurrent acute lymphoblastic leukemia 
(ALL). 
REMOVED 
1.3 
Secondary Aims  
 
1.3.1 
To preliminarily define the antitumor activity of BMN 673 and temozolomide in 
pediatric patients with recurrent or refractory solid tumors within the confines of a 
Phase 1 study. 
 
Repeat Every 
28 Days 


 
 
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1.3.2 
To explore possible predictive biomarkers in archival tumor tissue from Ewing 
sarcoma patients in Phase 2.    
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
BMN 673 is a new, orally available, highly potent and specific inhibitor of PARP 1 and 2 
designed to have an improved therapeutic index relative to existing PARP inhibitors in 
development. 
 
2.1.1 
Poly(ADP-ribose) Polymerase (PARP)  
DNA damage caused by toxins, including both naturally occurring environmental 
poisons and chemotherapy, is repaired by a number of mechanisms including base 
excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), 
single strand annealing (SSA), homologous recombination (HR) and 
nonhomologous end joining (NHEJ).  Poly(ADP-ribose) polymerases (PARPs) are 
a family of enzymes involved in DNA repair through the recruitment and 
activation of proteins that utilize primarily the BER pathway,2 but also the NHEJ3 
and HR4 pathways.  PARP1, the family’s founding member, binds to damaged 
DNA through its N-terminal zinc finger motifs; binding activates its catalytic C-
terminal domain to hydrolyze NAD+ and produce linear and branched poly(ADP-
ribose) (PAR) chains.  These PAR chains have a net negative charge, which 
promotes recruitment of DNA repair proteins, involved in the BER pathway, to the 
site of DNA damage, and facilitates removal of PARP1 from damaged sites 
allowing access to other repair proteins.5  PARP2 is essential for the viability of 
PARP1 knockout mice.5  PARP inhibitors mimic NAD+ and bind to the protein’s 
catalytic domain.6  This both inhibits necessary NAD+ binding and inhibits the 
auto-modification needed for PARP to eventually release from its complex with 
DNA6.  Both catalytic inhibition and trapping of PARP-DNA complexes lead to 
replication fork damage and cellular apoptosis.6 
 
It has been noted, that in several tumor types, that PARP1 is over expressed and 
that its overexpression is associated with an overall poor prognosis. Most recently, 
it was noted that certain tumors, such as those harboring BRCA1/2 and PTEN 
mutations have a high rate of defects in the HR pathway of DNA repair and 
therefore, by using a PARP inhibitor, salvage pathways of DNA repair are blocked 
and apoptosis results.7  Several PARP inhibitors have been developed and in pre-
clinical models have not only shown powerful cytotoxicity in BRCA1/2 and PTEN 
aberrant cell lines but have also had proof of targeting concept confirmed through 
demonstration that these compounds are in fact inhibitors of PARP enzymes 1 and 
2.8,9  For tumors that carry BRCA1/2 and PTEN mutations, PARP inhibition with 
first generation PARP inhibitors such as veliparib and olaparib are being 
investigated and thus far show much promise in terms of anti-cancer activity.10,11              
 
2.1.2 
Enhancing PARP inhibitory effects through its combination with temozolomide 
Temozolomide is an orally administered monofunctional SN-1 alkylating agent 
that creates DNA damage by adding methyl adducts to nitrogen atoms in the DNA 
ring and the extracyclic oxygen group.12  After being converted to MTIC (5-3-
methyltriazen-1-yl) imidazole-4-carboximide) at physiologic pH, methyl groups 
are transferred preferentially to the N7 position of guanine followed by the N3 


 
 
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position of adenine and O6 position of guanine.12  Although it is the least 
frequently methylated adduct, O6 methylguanine is regarded as responsible for the 
direct cytotoxicity of temozolomide13 because it initiates MutSα and MutLα 
dependent mismatch repair during second or later cell cycles (after the methylation 
insult) leading to double-strand break formation and apoptosis.14   
 
Temozolomide has been shown to have limited activity as a single agent in 
pediatric early phase clinical trials.  Estlin, et al. reported responses (complete 
response [CR] and partial response [PR]) in the single agent phase 1 setting, in 2 
out of 5 patients with high grade astrocytomas and long term stable disease (SD) 
in one out of 10 patients with diffuse intrinsic pontine glioma15 while a similar 
study by Nicholson, et al. reported, out of 59 evaluable patients, 10 with SD, 2 
with a PR and 1 with a CR.16  In the single agent phase 2 setting, DeSio, et al., 
reported a 13.4% CR+PR+minor response (MR) rate and a 38.5% SD rate among 
52 pediatric patients with relapsed solid tumors using 215 mg/m2/day x 5 days in 
patients with no history of craniospinal irradiation (CSI) and 180 mg/m2/day x 5 
days in those with a history of CSI.17  The median survival was 7.8 months.17  
Responding tumors were mostly CNS tumors and neuroblastomas with no 
responses seen in those with Ewing sarcoma family of tumors.17  In a similar phase 
2 single agent setting, Nicholson, et al. noted 5 PRs and 1 CR among 113 children 
with relapsed/refractory CNS tumors.18  In leukemias, Horton, et al., reported a PR 
in 2 of 16 pediatric patients with relapsed/refractory acute lymphoblastic leukemia 
(ALL) or acute myeloid leukemia (AML) receiving temozolomide single agent 
once daily for 5 days at either 200 mg/m2/dose or 270 mg/m2/dose.19   
 
Temozolomide has been far more effective in combination with additional agents.  
Activity in this setting has been seen in a broad range of tumors including CNS 
tumors, Ewing20 and other sarcomas,21 neuroblastoma22 and CNS lymphoma.23  
The concept of combining temozolomide with PARP inhibitors has recently been 
particularly attractive.  Methylated DNA bases, created with temozolomide 
treatment, are repaired through the BER pathway.24 An intermediate of this process 
has a single nucleotide gap in double stranded DNA containing the 5’-deoxyribose 
phosphate (dRP) group at one margin.24 PARP1 binds to and is activated by the 
dRP group and is important in an efficient repair.24  Therefore, when combined 
with PARP inhibitors, which would block BER, temozolomide induced 
cytotoxicity would result not only directly from O6 methylguanine but also 
indirectly from N7 methylguanine and N3 methyladenine.24 Several early studies 
have suggested in vitro legitimacy of this theory as temozolomide has shown an 
impressive ability to sensitize Pol β-null mouse fibroblasts,24 lymphoid and 
myeloid leukemias25 and neuroblastoma26 to PARP inhibitors in model systems. 
 
2.1.3 
PARP inhibition in Pediatric Tumors 
As outlined below, there is a role for the use of PARP inhibitors, particularly 
administered in combination with DNA damaging agents, in a variety of pediatric 
malignancies, including CNS and solid tumors as well as hematologic 
malignancies. 
 
Medulloblastoma: BRCA1/2 aberrant tumors have not been reported to occur in 
childhood.27,28  However, like BRCA1/2, PTEN is a tumor suppressor gene known 
to play a critical role in the DNA damage response and DNA repair.  Because 
PTEN inactivation spontaneously causes double stranded DNA breaks and 


 
 
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diminishes the NER, HR and NHEJ DNA repair mechanisms29 PARP inhibition 
would be a rational therapy in tumors with aberrant PTEN activity such as 
medulloblastoma,  the most common malignant CNS tumor of childhood.  Roughly 
40% of patients with medulloblastoma will die from their disease and therefore, it 
accounts for almost 10% of all pediatric cancer deaths.30  Through both loss of 
heterozygosity of chromosome 10q (where PTEN is located)31 and through 
promoter hypermethylation, PTEN mRNA and protein levels are known to be 
significantly lower in medulloblastoma when compared to normal cerebellar 
tissue.32  For this reason PARP inhibitors are already being explored in 
medulloblastoma although mainly as a sensitizing agent concomitant with 
chemotherapy or radiation therapy.33   
 
Germ Cell Tumors: PARP inhibitors may also serve as a rational targeted agent 
in testicular germ cell tumors. While these tumors generally have an excellent 
survival rate, an estimated 350 people die of testicular germ cell tumors per year 
in the United States.34  Recent evidence shows that testicular germ cell tumors have 
high levels of PARP and a high rate of DNA repair mechanism defects.35 Proof of 
concept has been shown in vitro as germ cell tumor lines proved to be sensitive to 
the PARP inhibitor olaparib both as monotherapy and in combination with 
cisplatin.36    
 
Ewing sarcoma: Ewing sarcoma is a primitive tumor, likely of mesenchymal stem 
cells, which when clinically localized at diagnosis has a 5-year overall survival 
(OS) of approximately 70%, but when metastatic, has an overall survival rate 
between 20-30%.37,38 Patients with recurrent Ewing sarcoma also have a dismal 
prognosis, with a 5-year OS of 30% when the disease recurs after 2 years and 7% 
when the disease recurs within 2 years.39 The most recent Phase 3 Children’s 
Oncology Group study in Ewing sarcoma demonstrated that compressed delivery 
(every 2 weeks) of cycles of vincristine, adriamycin and cyclophosphamide 
(VAdrC) alternating with cycles of ifosfamide and etoposide (IE) had superior 
outcome with minimal additional toxicity when compared to the same therapy 
given every 3 weeks.40 Nevertheless, major advances in outcome using standard 
chemotherapeutic approaches have been elusive. Even maximizing cytotoxicity in 
the setting of hematopoietic stem cell transplant has failed to show improved 
outcome for Ewing sarcoma, with the risk of death approaching 8%41 from 
treatment-related complications (i.e. treatment related AML/MDS, graft-versus-
host disease, infection) indicating that a limit of effectiveness of standard 
chemotherapy has been reached as a result of offsetting increases in toxicity.42,43 
 
Despite the fact that the cancer stem cell or cell of origin continues to be enigmatic, 
unlike survival advances using standard chemotherapy, the biological 
understanding of Ewing’s sarcoma has improved in recent years.  It is now known 
that Ewing sarcoma is a classic example of a malignancy driven by a fusion 
oncogene. Oncogenic fusions in Ewing sarcoma arise from specific chromosomal 
translocations that yield an in-frame fusion of the amino terminus of the EWS gene 
on chromosome 22 and the carboxyl terminus, including the DNA binding domain, 
of an ETS family gene.  The ETS gene is FLI1 in 85% of cases, ERG in 10% of 
cases and ETV1, ETV4 or FEV in the remaining 5% of cases.44  In-frame fusion of 
EWS to an ETS factor in Ewing sarcoma, yields a highly expressed non-
physiologic transcription factor, which activates an oncogenic program in the cell 
of origin.45  In vitro, the down regulation of the EWS-FLI1 fusion via antisense 


 
 
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oligonucleotides, dominant-negative transcripts and RNAi has been shown to 
dramatically limit malignant transformation and reduce cell growth.46,47  However, 
translation of these basic science findings to the clinical setting has been 
challenging, limited in part by the inability of these agents to enter the cell as 
required to exert their respective effects.48  Early phase trials have begun with 
agents thought to indirectly interfere with the EWS-ETS translocations in Ewing 
sarcoma such as IGF1-R inhibitors and ET-743 (trabectedin).49,50  However, recent 
pre-clinical data has demonstrated that a powerful inhibitor of EWS-ETS fusion 
can be found in PARP inhibition. 
 
In 2011, Brenner, et al., showed that PARP1 along with DNA-dependent protein 
kinase (DNA-PKcs) are key co-factors in ETS positive prostate cancer mediated 
by the ETS DNA binding domain.51 This finding suggested that PARP inhibition 
might have key implications in treating cancer outside of their negative influence 
on DNA damage repair.  They demonstrated proof of concept by showing that 
therapeutic inhibition of PARP1 disrupted the growth of ETS positive but not ETS 
negative prostate cancer xenografts.  Secondary to the fact that the ETS interaction 
site is also present in EWS-FLI1 and EWS-ERG chimeras, they hypothesized that 
PARP1 is also critical in the oncogenesis of Ewing sarcoma.  It was subsequently 
shown that, in fact, the EWS-FLI1 and EWS-ERG fusion proteins do interact with 
and are dependent on PARP1 and that Ewing cell lines are exquisitely sensitive to 
the PARP1/2 inhibitor olaparib in vitro.52  Furthermore, olaparib drastically 
decreased the rate of metastasis in murine Ewing sarcoma xenograft models.52 
Contemporaneously and independently, a large screen of 130 drugs on 639 human 
cell lines unexpectedly found a highly significant association between the EWS-
FLI1 rearrangement and sensitivity to olaparib.53 Screening of a structurally 
distinct PARP inhibitor, AG-014699, across a large panel of cell lines confirmed 
overwhelming sensitivity of Ewing sarcoma cell lines to PARP inhibition.  
Furthermore, the same screen found that sensitivity of Ewing cell lines to AG-
014699 were comparable to BRCA1/2 cell lines over 6 days and more sensitive 
than BRCA1/2 lines when tested over 3 days.  In summary, PARP inhibition 
appears to be a potential strategy in Ewing sarcoma not only secondary to its ability 
to potentiate DNA damage but also in its ability to inhibit the EWS-ETS-PARP1 
positive feedback loop in oncogenic transcriptional activation.       
 
Hematologic malignancies: Recent work has shown that PARP inhibition is a 
logical strategy to test in hematologic malignancies in addition to solid tumors.  It 
has been shown that myeloid leukemia cells exhibit constitutive DNA damage and 
pronounced error-prone double stranded break DNA repair, which in part, explain 
the genomic instability of acute myelogenous leukemia (AML).54,55  Follow-up 
experiments demonstrated that exposure to PARP inhibitors can induce cell cycle 
arrest and apoptosis of primary AML samples and AML cell lines in vitro; further 
analysis revealed that PARP inhibitor sensitivity was due to a defect in 
homologous recombination DNA repair.56  In a similar manner, certain lymphoid 
malignancies have been shown to be susceptible to PARP inhibition.  Ataxia 
Telangiectasia Mutated (ATM) gene mutant cells are known to exhibit impaired 
DNA double stranded break repair. Weston, et al. consequently showed that ATM 
deficient chronic lymphocytic leukemia cells, T-prolymphocytic leukemia cells 
and mantle cell lymphoma cells were sensitive to the PARP inhibitor olaparib in 
vitro.57  In addition, PARP inhibition may be logical in T-cell acute lymphoblastic 
leukemia (T-ALL).  It is well known that over 50% of cases of childhood and adult 


 
 
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T-ALL harbor activating mutations of NOTCH1, a regulatory transmembrane 
receptor that plays a crucial developmental role in cell fate determination and 
pattern formation, and in hematopoietic stem cell maintenance and T cell fate 
specification in the mature organism.58,59  Silva, et al., recently showed that T-ALL 
cells with NOTCH1 mutations had decreased PTEN mRNA expression.60  This 
decreased PTEN expression may make T-ALL cells susceptible to PARP 
inhibition. 
 
2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity of BMN 673 
BMN 673 is a new, highly potent and specific inhibitor of PARP 1 and 2 designed 
to have an improved therapeutic index relative to existing PARP inhibitors in 
development.  BMN 673 has been shown to have comparable inhibition of PARP 
1 and 2 both in cell culture and in MX-1 mammary tumor xenograft models and in 
vitro at a lower concentration (IC50=0.57nM) than PARP inhibitors ABT 888 
(IC50=4.73nM), AG 14447 (IC50=1.98nM) and olaparib (IC50=1.94nM).  
Assessment of BMN 673 was performed on human cell lines harboring mutations 
that compromise DNA repair pathways.  Gene mutations that confer selective 
tumor cell cytotoxicity included BRCA1 (MX-1 mammary tumor cells), BRCA2 
(Capan-1 pancreatic tumor cells), PTEN (MDA-MB-468 mammary, LNCaP and 
PC-3 prostate tumor cells) and MLH-1 mutations (HCT-116 colorectal tumor 
cells).  The IC50 values of BMN 673 in these tumor cell lines were in the single 
digit nanomolar or sub-nanomolar range.  In contrast, the IC50 of BMN 673 against 
normal human primary cell MRC-5 and several tumor cell lines that do not have 
reported DNA repair related mutations was significantly greater (250 nM to >1000 
nM).61  
 
In BRCA1 deficient MX-1 mouse xenograft models, oral administration of BMN 
673 at 0.33 mg/kg once daily for 28 days resulted in significant antitumor activity 
(tumor growth delay/tumor regression).  Dose-related inhibition of tumor growth 
was observed at lower doses until doses higher than 1 mg/kg/day induced not only 
tumor suppression but also significant body weight loss with associated mortality.  
Consistent with the anti-tumor effect in this model, profound reduction in 
poly(ADP-ribose) (PAR) levels (the product of PARP1/2 and therefore, a measure 
of PARP activity) was observed in the MX-1 xenografts when mice were treated 
with BMN 673 orally.  Oral administration of BMN 673 also demonstrated anti-
tumor activity in the PTEN-deficient LNCaP, MDA-MD-468 and PC-3 mouse 
xenograft models.  In addition, twice-a-day oral administration of BMN 673 
delayed the growth of the MLH-1 deficient HCT-116 xenograft tumor in nude 
mice.  Assessment of various dosing schedules in the mouse xenograft models 
indicated that continuous suppression of PARP activity is required for optimal anti-
tumor activity.61   
 
 


 
 
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2.2.2 
Animal Toxicology of BMN 673 
Five day repeat dose toxicity and toxicokinetic (TK) studies with a 28-day 
recovery were conducted in rats and dogs.  In dogs (the most sensitive species) 
BMN 673 was administered at several dose levels with severe pancytopenia being 
observed at the two highest dose levels (0.03 and 0.1 mg/kg/day).  At these doses 
the mean reticulocyte nadir occurred on Day 6 and the platelet and WBC nadirs 
were on Day 11.  These changes were reversed in the 0.03 mg/kg/day group on 
Days 17-18 (i.e. 12-13 days after the last administration of drug).  Several dogs 
treated at the highest dose level (0.1 mg/kg/day) died secondary to bacterial sepsis 
and others experienced hypoactivity, hyperthermia and fecal abnormalities on day 
12-13. Coagulation parameters were unaffected.  Therefore, at 5 day repeat dosing 
the highest non-severely toxic dose (HNSTD) was 0.03 mg/kg/day.  Twenty-eight 
day repeat dose toxicity and TK studies were also performed on rats and dogs.  In 
dogs (the most sensitive species) the only major toxicity at the doses studied were 
hematologic in nature at 0.005 and 0.01 mg/kg/day.  Mildly lowered red cell mass, 
mildly lowered platelet and absolute reticulocyte counts were noted but all 
recovered during the 28 day recovery phase.  Therefore, the HNSTD was 
determined to be 0.01 mg/kg/day.  From this the estimated safe clinical starting 
dose in humans was determined to be 1 µg/kg/day.61  
 
2.2.3 
Preclinical Pharmacokinetic Studies of BMN 673 
Pharmacokinetic studies have been performed in rats and dogs.  The oral 
bioavailability, calculated from AUC following oral administration relative to 
AUC following IV administration was 42.7% in rats and 50.5% in dogs.  The 
terminal half-life of BMN 673 was between 28.5-30.2 hours in rats and between 
69.7-91.2 hours in dogs that allows for once daily dosing.  [14C]-labeled BMN 673 
studies indicated that the drug was rapidly (but incompletely) absorbed within 15-
30 minutes post dose.  Maximum plasma radioactivity was reached within 2-4 
hours and declined to non-detectable levels within 48 hours in rats and within 72-
96 hours in dogs.  Steady state concentrations were reached on Day 15 in rats and 
on Day 20 in dogs using daily administration of BMN 673.  Excluding the GI tract, 
the highest levels of BMN 673 were observed in the kidney and liver.  Distribution 
to target organs of toxicity (thymus, bone marrow, lymph nodes, spleen) BMN 673 
was at levels higher than blood at 8 hours and continued to be detected at 24-72 
hours when blood levels were below limits of quantitation.  Radioactivity in the 
brain was generally below the level of quantitation except in the choroid plexus.  
All [14C]-BMN 673 decreased to baseline by 168 hours post dose.  Elimination of 
BMN 673 was 90% at 24 hours post dose in the rat and 84% at 72 hours post dose 
in the dog.  Fecal elimination was the major route of excretion.  In vitro metabolism 
studies demonstrated that BMN 673 has > 90% stability over 2 hours in hepatic 
microsomes.  However, in human hepatic tissues at concentrations up to 10 µM 
BMN 673 did not inhibit any of the five major human hepatic CYP isoenzymes 
(CYP1A2, 2C9, 2C19, 2D6 and 3A4).61 
 
 


 
 
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2.2.4 
The Preclinical testing of BMN 673 and temozolomide from the Pediatric 
Preclinical Testing Program (PPTP) 
In order to test the hypothesis that temozolomide would create a DNA environment 
which would not only invite “classic” PARP inhibitor mechanisms in tumors 
deficient in HR DNA repair when treated with such drugs, but be able to expand 
the portfolio of malignancies which may respond to PARP inhibition by creating 
DNA adducts, the Pediatric Preclinical Testing Program (PPTP) evaluated BMN 
673 alone and in combination with temozolomide.62  Temozolomide doses of 0, 8, 
12, 30, 35 and 100 mg/kg/day were combined with doses of BMN 673 of 0, 0.1, 
0.2, 0.25, 0.33 and 0.5 mg/kg/day in tolerability (weight loss) experiments in mice.  
Determined tolerable, temozolomide at 30 mg/kg/day and BMN 673 at 0.1 
mg/kg/day x 5 days was compared to temozolomide at 12 mg/kg/day and BMN 
673 at 0.25 mg/kg/day x 5 days along with single agents and vehicles in mouse 
explant experiments.  Single agent in vitro testing of BMN 673 against the PPTP 
cell lines were consistent with earlier reported sensitivity of Ewing sarcoma.  The 
median relative IC50 (rIC50) value for the PPTP cell lines to BMN 673 was 28.4 
nM with the Ewing cell lines being the most sensitive (rIC50 = 6.4 nM) and 
significantly more sensitive than non-Ewing sarcoma cell lines (rIC50 = 40.1 nM, 
p=0.048).  However, in xenograft models, while BMN 673 showed some activity 
in Wilms tumor (KT-10) and medulloblastoma (BT-45), there was complete lack 
of activity in the Ewing sarcoma xenografts SK-NEP-1 and EW8 at 0.33 
mg/kg/day x 28 days.  An interesting observation during this phase of testing is 
that there appeared to be sensitivity phenocopy between BMN 673 and cisplatin.  
Repeat in vitro testing was performed using temozolomide from 0.3 µM to 1000 
mM in the presence of 10 nM BMN 673 with the median rIC50 value for 
temozolomide being 19.8 µM.  The cell lines with the lowest rIC50 values were 
those of Ewing sarcoma and acute lymphoblastic leukemia (ALL).  In addition, it 
was noted that the level of potentiation with temozolomide exceeded that described 
for other PARP inhibitors and exceeded that described for the combination of 
PARP inhibitors and topotecan.  Mouse xenograft models recapitulated 
combination in vitro testing and with treatment consisting of low dose 
temozolomide (12 mg/kg/dose daily) and BMN 673 (0.25mg/kg/dose twice daily) 
for 5 days responses were seen in Ewing, glioblastoma and Wilms tumor models 
with high level synergy demonstrated in 2 Ewing sarcoma xenografts (CHLA-258 
and TC-71) and synergy in 1 additional Ewing sarcoma xenograft (EW5).  These 
responses were noted with minimal animal weight loss and other general toxicities.  
In mice, the single agent MTD of temozolomide is known to be 60 mg/kg.  Because 
the tolerability of temozolomide in the presence of BMN 673 was 12 mg/kg and 
the adult clinical dose of temozolomide administered daily x 5 is 150-200 mg/m2, 
the clinical dose of temozolomide likely to be tolerated with a “high” dose of BMN 
673 is 30-40 mg/m2/day.61  
 
 


 
 
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2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies of BMN 673 
At the American Society of Clinical Oncology Annual Meeting 2013, de Bono, et 
al., presented data for the first-in-human trial of BMN 673 performed in patients 
with solid tumors with known or suspected DNA repair abnormalities (e.g. 
germline BRCA mutations, PTEN loss).  The trial was performed in patients ≥ 18 
years of age with a standard 3+3 dose escalation design and included an expansion 
in ovarian, breast, prostate and pancreas cancers with germline BRCA mutations 
and additionally included patients with Ewing sarcoma family tumors and small 
cell lung cancer. Dosing was once daily, continuously, in 28-day cycles and began 
with a dose of 25 µg/day.  Thirty-nine patients were enrolled in the escalation and 
31 patients into the expansion.  Overall, BMN 673 was well tolerated.  The 
recommended Phase 2 dose was 1000 µg with dose limiting toxicity (DLT) being 
thrombocytopenia. Myelosuppression occurred in 10-20% of patients with chronic 
dosing requiring 11 patients to have dose reductions. Fatigue, nausea and alopecia 
occurred in 20-30% of patients with no discontinuations necessary for adverse 
events. Elimination appeared to be bi-exponential with a t½, at the upper end of 
the dose range (900-1100 µg) ranging from 53.5 to 66.1 hours and from 40.4 to 
51.8 hours on Days 1 and 35, respectively. Steady state was apparent in most 
patients by two weeks with daily dosing. Inhibition of PARP activity in peripheral 
blood mononuclear cells was detected in patients dosed at ≥100 µg/day leading to 
substantial single agent anti-tumor activity in deleterious germline BRCA ovarian 
and breast cancer. Germline BRCA ovarian RECIST response rate was 44%, CA-
125 response rate was 70% and clinical benefit response rate was 82%, while 
germline BRCA breast response rate was 39% and clinical benefit response rate 
was 67%.63  Updates on the expansion cohort were provided at the 2013 AACR-
NCI-EORTC International Conference on Molecular Targets and Cancer 
Therapeutics and the ESMO/ECCO European Cancer Congress.  No additional 
toxicities of treatment were noted.  With a total of 28 BRCA aberrant ovarian 
cancer patients the clinical benefit response was 82% and with a total of 18 BRCA 
aberrant breast cancer patients the clinical benefit response was 78%.  Treatment 
was reported as on-going in 5/7 small cell lung cancer patients and 2 of 8 Ewing 
sarcoma patients with no objective responses noted as of the time of the report.64,65  
A second trial in adults with advanced hematologic malignancies with 
demonstrated or potential defects in DNA-repair pathways, including RAD51 foci 
formation or ATM deletions is also ongoing.  Pharmacokinetic and 
pharmacodynamic (PD) results are thus far similar, as are the adverse events; 
however, dose-limiting neutropenia has occurred in 2 of 5 patients with chronic 
lymphocytic leukemia or chronic myeloid leukemia at 900 µg/day with one patient 
experiencing neutropenic sepsis and both patients missing > 4 days of dosing due 
to Grade 4 neutropenia.  In 3 patients with MDS/AML, 1350 μg/day was well 
tolerated although 2000 μg/day resulted in dose limiting toxicities in 2/4 
MDS/AML patients (personal communication, Andrew Dorr, BioMarin).  
 
 


 
 
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17 
 
2.4 
Pediatric Studies 
 
2.4.1 
PARP inhibitors in combination with temozolomide in children 
 
There is no experience with BMN 673 in children.  There is, however, recent phase 
1 experience with the PARP inhibitor veliparib (ABT-888), which was studied in 
combination with intermediate and standard dose temozolomide, in Pediatric Brain 
Tumor Consortium study PBTC-027.  Temozolomide was given once daily and 
ABT-888 given twice daily by mouth for 5 days every 28 day cycle to pediatric 
patients 
with 
recurrent 
central nervous 
system 
tumors. 
Five 
ABT-
888/temozolomide dose levels were studied: 20/180, 15/180, 15/150, 20/135 and 
25/135 mg/m2/dose, respectively.  Dose limiting toxicities included Grade 4 
neutropenia and thrombocytopenia at the 20/180 and 15/180 mg/m2/dose levels. 
The Phase 2 recommended dose was 15 mg/m2/dose of ABT-888 with 135 
mg/m2/dose for 5 days in 28 day cycles. No objective responses were seen although 
4 subjects had stable disease > 6 months.66   
 
2.4.2 
Rationale for the first in children combination Phase 1 study 
BMN 673 shows potent single agent in vitro activity in pediatric tumors, 
particularly against Ewing sarcoma cell lines. Preclinical evaluation in mouse 
xenograft models performed by the PPTP demonstrated a dramatic reduction of 
tumor burden in a variety of pediatric solid tumor models (e.g., Ewing sarcoma, 
Wilms tumor, glioblastoma multiforme) when the PARP inhibitor BMN 673 was 
combined with a low dose, 5 day course of temozolomide.  The level of 
potentiation with temozolomide exceeds that described with many other PARP 
inhibitors or combinations of PARP inhibitors with other cytotoxic agents. The 
preclinical results are consistent with the hypothesis that BMN 673 is converting 
relatively nontoxic N7 and N3 methylation adducts induced by temozolomide into 
toxic lesions.  In addition, there is the reasonable expectation that this combination 
will be safe.  The proposed starting dose for BMN 673 is less than 25% of its single 
agent recommended Phase 2 dose, per course, and the starting dose of 
temozolomide is only 10% of its single agent recommended Phase 2 dose.  
Furthermore, there is considerable clinical experience with other PARP inhibitors 
administered with temozolomide and other than the expected enhancement of 
myelosuppression, unanticipated adverse events appear uncommon.  Thus, this 
combination represents a novel strategy for the treatment of a variety of pediatric 
solid (including CNS) and hematologic malignancies.  
 
In the first in human study of BMN 673, PAR activity decrease was seen within 
hours even after a single dose of 100 µg.67 PAR activity decrease was consistently 
and predictably seen at 2 and 4 hours after the first dose of BMN 676 and then pre-
dose on Days 2, 3 and 5.  Therefore, steady state did not have to be reached in 
order to see significant decreases in PAR levels with BMN 673.  In addition, 
significant PAR levels were decreased at drug trough levels on Days 2, 3 and 5 
even when well below MTD dosing (personal communication, Andrew. Dorr, 
BioMarin).  However, optimal cell kill would be postulated when BMN 673 and 
temozolomide are close to steady state in plasma.  Because BMN 673 has a long 
half-life, pharmacokinetic modeling was performed to determine most efficiently 
to achieve a steady state of BMN 673.  A lead in phase of one day of twice daily 
BMN 673 prior to the 5 day course of once daily BMN 673 with once daily 
temozolomide was determined to provide optimal exposure base on 
pharmacokinetic modeling.  In addition, this modeling predicts that even with day 


 
 
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18 
 
1 twice daily administration, plasma drug levels should not exceed that achieved 
by adults during phase 1 trials
 
 
 
 
 
 
Intra-patient dose escalation in part B (Amendment #3): Patients enrolled in Part 
B of the trial will receive Cycle 1 treatment at the RP2D defined in Part A. 
Following completion of Cycle 1, up to two intra-patient dose escalations may 
proceed in subsequent cycles if the patients have had no more than minimal 
toxicities (as defined in Section 5.3.3.2) and the criteria to advance to the next 
cycle have been met.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4.3 
Potential biomarkers to predict response in Ewing sarcoma patients 
The identification of prognostic biomarkers will be important for the future 
development of BMN673 in Ewing sarcoma.  Several studies of PARP inhibitors 
have explored both baseline PAR levels and PAR level dynamics in peripheral blood 
mononuclear cells (PBMCs) as an easily accessible tumor-surrogate tissue which 
could provide outcome predictions. While PAR levels have uniformly decreased with 
PARP inhibitor treatment, no correlation has been made between PAR levels or PAR 
level changes in PBMCs and levels seen in tumor tissue or with disease response66,68,69 
However, potential predictive biomarkers from disease tissue may correlate with 
response and should be explored.  Because of the importance placed on the discovery 


 
 
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19 
 
of reliable biomarkers as a predictor of response in developmental therapeutics, the 
submission of archival tissue will be required for patients in the Ewing sarcoma 
stratum of Phase 2.  Archival tissue will be assayed for potential biomarkers by 
immunohistochemistry. Since PARP and PARP inhibitors play a critical role in DNA 
repair, markers such as BRCA1, XPA and Chk2 will be explored.70 In addition, 
markers of interest, which have been correlated with disease outcome in Ewing 
sarcoma such as Cx43 and desmoplakin will be explored.71  Of particular interest will 
be exploring PARP-1 which has been noted to be highly expressed in Ewing sarcoma 
samples72 and those markers which have both been shown to correlate with outcome 
in Ewing sarcoma and are cell cycle regulators such as CDKN2A and TP53.70,71 
 
 


 
 
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2.5 
Overview of Proposed Pediatric Study 
This is a Phase 1 study of BMN 673 in combination with low dose temozolomide in patients 
with recurrent or refractory solid tumors including CNS tumors, and a Phase 2 study of 
BMN 673 in combination with low dose temozolomide in recurrent or refractory Ewing 
sarcoma and recurrent acute lymphoblastic leukemia (ALL). BMN 673 will be given orally 
on Day 1 (either once or twice daily) followed by BMN 673 and low dose temozolomide 
given together once per day on Days 2-6 of each 28-day cycle. This study will aim to 
describe the pharmacokinetics and the toxicities of BMN 673 when given with low dose 
temozolomide with the goal of determining the MTD or recommended Phase 2 dose of this 
regimen. The antitumor effect of this combination will also be described, more specifically 
in the Phase 2 portion of the study in pediatric patients with Ewing sarcoma and ALL. 
Additionally, during Phase 2 in patients with Ewing sarcoma, this study will explore 
potential predictive biomarkers using archival tumor tissue.   
 
 
 
 
 


 
 
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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
 
 
3.1 
Current Study Status  
Investigators should refer to the COG website to determine if the study is currently open 
for accrual. If the study is listed as active, investigators should then access the page CTSU 
OPEN (Oncology Patient Enrollment Network) to ensure that a reservation for the study is 
available. To access the Slot Availability page:  
1.  Log in to https://open.ctsu.org/open/  
2.  Click the Slot Reservation Tab. The Site Patient page opens.  
3.  Click the Report Tab. The Slot Reservation Report opens. Available Slots are 
detailed per study strata.   
 
3.2 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling patients. 
Sites must submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit (CTSU) 
Regulatory Office and allow 3 business days for processing. The submission must include 
a fax coversheet (or optional CTSU IRB Transmittal Sheet) and the IRB approval 
document(s). The CTSU IRB Certification Form may be submitted in lieu of the signed 
IRB approval letter.  All CTSU forms can be located on the CTSU web page 
(www.ctsu.org). Any other regulatory documents needed for access to the study enrollment 
screens will be listed for the study on the CTSU Member’s Website under the RSS Tab.   
 
IRB/REB 
approval 
documents 
may 
be 
faxed 
(1-215-569-0206), 
emailed 
(CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.   
 
When a site has a pending patient enrollment within the next 24 hours, this is considered a 
“Time of Need” registration. For Time of Need registrations, in addition to marking your 
submissions as ‘URGENT’ and faxing the regulatory documents, call the CTSU 
Regulatory Helpdesk at: 1-866-651-CTSU. For general (non-regulatory) questions, call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
3.3 
Patient Registration 
Prior to enrollment on study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry system once authorization for the release of 
protected health information (PHI) has been obtained. 
 
3.4 
Reservation and Contact Requirements 
Before enrolling a patient on study, a reservation must be made in OPEN and the Study 
Chair or Vice Chair should be notified. (The patient will need a COG patient ID number in 
order to obtain a reservation). Patients must be enrolled within 7 calendar days of making 
a reservation.  
 
Reservations may be obtained 24-hours a day through the OPEN website.  
 


 
 
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3.5 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
3.6 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent. This can be accomplished 
through one of the following mechanisms: a) the COG screening protocol, b) an IRB-
approved institutional screening protocol or c) the study-specific protocol.  Documentation 
of the informed consent for screening will be maintained in the patient’s research chart. 
Studies or procedures that were performed for clinical indications (not exclusively to 
determine eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
3.7 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 
into RAVE immediately following enrollment. 
 
3.8 
Institutional Pathology Report 
Immediately following enrollment, the institutional pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into RAVE. The report must 
include the associated study number and COG patient registration and accession numbers. 
Personal identifiers, including the patient’s name and initials must be removed from the 
institutional pathology report prior to submission. 
 
3.9 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Patients who give informed consent for the protocol in order to undergo 
screening for eligibility are not considered enrolled and should not be enrolled until the 
screening is completed and they are determined to meet all eligibility criteria. Study 
enrollment is accomplished by going to the CTSU OPEN (Oncology Patient Enrollment 
Network) https://open.ctsu.org/open/. For questions, please contact the CTSU OPEN 
helpdesk at https://www.ctsu.org/CTSUContact.aspx or the ADVL1411 COG Study 
Assigned Research Coordinator.  Patients must be enrolled before treatment begins.  The 
date protocol therapy is projected to start must be no later than five (5) calendar days after 
the date of study enrollment. Patients must not receive any protocol therapy prior to 
enrollment. 
 
3.10 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
 


 
 
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4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum  creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Bone marrow 
aspiration or biopsy should be performed within 14 days prior to start of protocol therapy for Phase 
2 patients with bone marrow involvement (Part B and Part C). Imaging studies must be obtained 
within 14 days prior to start of protocol therapy (repeat the tumor imaging if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01).  All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the 
time of audit. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age:   
4.1.1.1 Phase 1 (Part A) 
Patients must be > than 12 months and ≤ 21 years of age at the time of 
study enrollment.  
 
4.1.1.2 Phase 2 (Part B and Part C) 
Patients must be > than 12 months and ≤ 30 years of age at the time of 
study enrollment.  
 
4.1.2 
Body Surface Area (For Parts A, B and C): 
Patients must have a BSA of ≥ 0.42 m2 at the time of study enrollment. 
 
4.1.3 
Diagnosis:  
4.1.3.1 Phase 1 (Part A) 
i. Solid tumors (Part A1): Patients with relapsed or refractory solid tumors 
including CNS tumors without bone marrow involvement are eligible. 
Patients must have had histologic verification of malignancy at original 
diagnosis or relapse except in patients with intrinsic brain stem tumors, 
optic pathway gliomas, or patients with pineal tumors and elevations of 
CSF or serum tumor markers including alpha-fetoprotein or beta-HCG.  
 
ii. Ewing sarcoma or Peripheral PNET (Part A2): Patients with relapsed or 
refractory Ewing sarcoma or Peripheral PNET without bone marrow 
involvement will be eligible for Part A2 if there are no available slots on 
Part A1. These patients will be enrolled at one dose level below the dose 


 
 
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24 
 
level at which patients on Part A1 are actively enrolling, or at the starting 
dose level (Dose Level 1) if dose escalation has not yet occurred. Patients 
must have had histologic verification of malignancy at original diagnosis 
or relapse.  
 
4.1.3.2 Phase 2 (Part B) 
Ewing Sarcoma or Peripheral PNET: Patients with relapsed or refractory 
Ewing sarcoma or Peripheral PNET are eligible. Patients must have had 
histologic verification of malignancy at original diagnosis or relapse.  
 
4.1.3.3 Phase 2 (Part C) 
Acute Lymphoblastic Leukemias (ALL): Patients must have 2nd or greater 
relapse of pre-B ALL or T-cell ALL. Patients may not have refractory 
disease. 
 
Patients with ALL must have had histologic verification of the malignancy 
at the most recent relapse, including immunophenotyping to confirm 
diagnosis. 
 
 
 
 
 
 
 
REMOVED 
 
4.1.4 
Disease Status:  
4.1.4.1 Phase 1 (Part A): 
Patients must have either measurable or evaluable disease (see Section 
12.2 and Section 12.3 for definitions).  
 
4.1.4.2 Phase 2 (Part B ): 
Ewing sarcoma or Peripheral PNET: Patients must have measurable 
disease (see Section 12.2). See also Section 4.1.10. 
 
4.1.4.3 Phase 2 (Part C ): 
Acute Lymphoblastic Leukemias (ALL): Patients with ALL must have an 
M3 marrow with or without extramedullary site of relapse OR an M2 bone 
marrow with an extramedullary site of relapse. Patients with CNS 3 status 
are not eligible for enrollment (See Section 4.3). 
 
 
 
 
 
 
 
 
REMOVED 
 
4.1.5 
Therapeutic Options: Patient’s current disease state must be one for which there 
is no known curative therapy or therapy proven to prolong survival with an 
acceptable quality of life. 
  
4.1.6 
Performance Level:  Karnofsky ≥ 50% for patients > 16 years of age and Lansky 
≥ 50 for patients ≤ 16 years of age (See Appendix I).  Note: Neurologic deficits 
in patients with CNS tumors must have been relatively stable for at least 7 days 
prior to study enrollment.  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. 
 
4.1.7 
Prior Therapy 
 
4.1.7.1 Patients who have received prior therapy with a temozolomide-based 
regimen are eligible. Note: Patients who have progressed on a PARP 


 
 
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25 
 
inhibitor and temozolomide regimen are not eligible for Part A of the study 
(see also Section 4.2.10). 
 
4.1.7.2 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer chemotherapy. 
 
a. Myelosuppressive chemotherapy:   
i. 
Solid Tumors (Part A and Part B): At least 21 days after the last 
dose of myelosuppressive chemotherapy (42 days if prior 
nitrosourea).  
ii. Acute Lymphoblastic Leukemias (ALL) (Part C):  
• 
Patients with leukemia who relapse while receiving standard 
maintenance chemotherapy will not be required to have a 
waiting period before enrollment onto this study. 
• 
Patients who relapse while they are not receiving standard 
maintenance therapy, must have fully recovered from all 
acute toxic effects of prior therapy. At least 14 days must 
have elapsed after the completion of cytotoxic therapy, with 
the exception of hydroxyurea.  
• 
Note: Cytoreduction with hydroxyurea can be initiated and 
continued for up to 24 hours prior to the start of BMN 673. 
• 
Note: Patients with leukemia are permitted to receive 
intrathecal chemotherapy, including methotrexate or 
cytarabine. Intrathecal therapy should be restricted to Days 
15 and 22 of each 28 day cycle (see also Section 5.1.1). 
 
 
 
 
 
 
REMOVED 
 
b. Hematopoietic growth factors: At least 14 days after the last dose of a 
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting 
growth factor.  For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair. 
  
c. Biologic (anti-neoplastic agent):  At least 7 days after the last dose of 
a biologic agent.  For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair. 
 
d. Immunotherapy: At least 42 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines. 
 
e. Monoclonal antibodies: At least 3 half-lives of the antibody after the 
last dose of a monoclonal antibody. (See table on DVL homepage 
listing monoclonal antibody half-lives.) 
 
f. XRT:  At least 14 days after local palliative XRT (small port); At least 
42 days must have elapsed if other substantial BM radiation. Patients 
with prior TBI, craniospinal XRT and/or ≥ 50% radiation of the pelvis 
are not eligible. 


 
 
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g. Stem Cell Infusion without TBI:  No evidence of active graft vs. host 
disease and at least 84 days must have elapsed after transplant or stem 
cell infusion. 
 
4.1.7.3 PARP Inhibitor Exposure: 
a. Part A: Patients who have received prior therapy with a PARP 
inhibitor, with the exception of BMN 673, are eligible; however, 
patients who have progressed on a PARP inhibitor and temozolomide 
regimen are not eligible.  
 
b. Part B and Part C: Patients who have previously been exposed to a 
PARP inhibitor are not eligible. 
 
4.1.8 
Organ Function Requirements 
 
4.1.8.1 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
• 
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 
• 
Platelet count ≥ 100,000/mm3 (transfusion independent, defined as 
not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
• 
Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions) 
 
All patients enrolled on Part A of the study must be evaluable 
for hematologic toxicity. 
 
b. Patients on Part B of the study with known bone marrow metastatic 
disease will be eligible for the study provided they meet the blood 
counts in 4.1.8.1.a (may receive transfusions provided they are not 
known to be refractory to red cell or platelet transfusions). These 
patients will not be evaluable for hematologic toxicity. 
 
c. Patients on Part C with acute lymphoblastic leukemia: 
• 
Platelet count ≥ 20,000/mm3 (may receive platelet transfusions). 
These patients must not be known to be refractory to red cell or 
platelet transfusion. 
REMOVED 
 
4.1.8.2 Adequate Renal Function Defined as: 
• 
Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or 
• 
A serum creatinine based on age/gender as follows: 
 
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 


 
 
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27 
 
(Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC. 
 
4.1.8.3 Adequate Liver Function Defined as: 
 
i. Patients on Part A and Part B: 
• 
Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of 
normal (ULN) for age  
• 
SGPT (ALT) ≤ 110 U/L.  For the purpose of this study, the ULN for 
SGPT is 45 U/L.  
• 
Serum albumin ≥ 2 g/dL. 
 
ii. Patients on Part C with Acute Lymphoblastic Leukemias (ALL): 
• 
Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of 
normal (ULN) for age  
• 
SGPT (ALT) ≤ 225 U/L.  For the purpose of this study, the ULN for 
SGPT is 45 U/L.  
• 
Serum albumin ≥ 2 g/dL. 
 
 
 
 
 
 
 
 
REMOVED 
 
4.1.9 
Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines. 
 
4.1.10 For patients enrolling on Part B: Tissue blocks or slides must be sent per Section 
8.4. If tissue blocks or slides are unavailable, the study chair must be notified 
prior to enrollment. 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks of 
fetal and teratogenic adverse events as seen in animal/human studies with 
temozolomide; the teratogenic potential is unknown with BMN 673. Pregnancy 
tests must be obtained in girls who are post-menarchal. Males or females of 
reproductive potential may not participate unless they have agreed to use an 
effective contraceptive method. 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. 
 
4.2.2.2 Investigational Drugs: Patients who are currently receiving another 
investigational drug are not eligible. 
 
4.2.2.3 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible [except leukemia patients receiving hydroxyurea, 
which may be continued until 24 hours prior to start of protocol therapy]. 
Patients with acute lymphoblastic leukemia may receive intrathecal 


 
 
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28 
 
therapy as outlined in Section 5.1.1. 
 
4.2.2.4 Anti-GVHD agents post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial. 
 
4.2.3 
Patients must be able to swallow capsules whole.  
 
4.2.4 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.5 
For Part C (Phase 2): Recurrent acute lymphoblastic leukemia (ALL) patients 
with CNS 3 status are not eligible (See Section 4.3). 
REMOVED 
 
4.2.6 
Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.7 
Patients with prior TBI, craniospinal XRT and/or those with ≥ 50% radiation of 
the pelvis are not eligible. 
 
4.2.8 
Patients who in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study are not eligible. 
 
4.2.9 
Patients with known hypersensitivity to temozolomide or dacarbazine are not 
eligible. 
 
4.2.10 Phase 1 (Part A): Patients who have progressed on a PARP inhibitor and 
temozolomide regimen are not eligible. 
 
4.2.11 Phase 2 (Part B and Part C): Patients who have previously been exposed to a 
PARP inhibitor are not eligible. 
 
4.2.12 Phase 1 (Part A): Patients with known bone marrow involvement are not eligible 
(see Section 4.1.8.1). 
 
4.3 
Leukemia Definitions 
 
4.3.1 
Bone marrow status 
M1 
< 5% lymphoblasts 
M2 
5 - 25% lymphoblasts 
M3 
> 25% lymphoblasts 
 
4.3.2 
Leukemia Relapse 
• Isolated Bone Marrow Relapse: M3 marrow confirmed by bone marrow aspirate or 
biopsy. 
• Isolated CNS Relapse: Positive cytomorphology and WBC ≥ 5/μL OR positive 
cytomorphology with CSF WBC 0-4/μL on 2 successive occasions 1 month apart. If 
any CSF evaluation shows positive cytomorphology and WBC < 5/μL, a second CSF 
evaluation is required in greater or equal to 4 weeks. Identification of leukemic clone 
in CSF by flow cytometry (TdT, CD19, CD10, etc.) or FISH for diagnostic karyotypic 
abnormality is encouraged. 
• Isolated Testicular Relapse: Confirmation by testicular biopsy preferred but not 
required. 


 
 
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• Combined Relapse: Documented extramedullary relapse and an M2 or M3 bone 
marrow. 
 
 


 
 
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4.3.3 
Central nervous system (CNS) involvement of leukemia at relapse diagnosis 
• CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, 
regardless of the number of WBCs. 
 
• CNS 2: In CSF, presence < 5/μL WBCs and cytospin positive for blasts, or ≥ 5/μL 
WBCs but negative by Steinherz/Bleyer algorithm: 
o 
CNS 2a: < 10/μL red blood cells (RBCs); < 5/μL WBCs and cytospin positive 
for blasts; 
o 
CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; and 
o 
CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but 
negative by Steinherz/Bleyer algorithm (see below); 
 
• CNS 3: In CSF, presence of ≥ 5/μL WBCs and cytospin positive for blasts and/or 
clinical signs of CNS leukemia or lymphoma: 
o 
CNS 3a: < 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts; 
o 
CNS 3b: ≥ 10/μL RBCs, ≥ 5/μL WBCs and positive by Steinherz/Bleyer 
algorithm (see below); 
o 
CNS 3c: Clinical signs of CNS leukemia or lymphoma (such as facial nerve 
palsy, brain/eye involvement or hypothalamic syndrome). 
 
4.3.4 
Method of evaluating initial traumatic lumbar punctures (LPs) 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is 
traumatic and contains ≥ 5 WBC/μL and blasts, the following Steinherz/Bleyer algorithm 
should be used to distinguish between CNS2 and CNS3 disease: 
 
CSF WBC > 2X  Blood WBC 
CSF RBC             Blood RBC 
 
A patient with CSF WBC ≥ 5/μL blasts, whose CSF WBC/RBC ratio is 2X greater than 
the blood WBC/RBC ratio, has CNS disease at diagnosis. 
 
Example: CSF WBC = 60/μL; CSF RBC = 1,500/μL; blood WBC = 46000/μL; blood 
RBC = 3.0 X 106/μL: 
  60      =  0.04 >  2X  46,000  =  0.015 
1,500 
                     3.0 X 106 
 
 


 
 
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5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
 
 
Day 1 
Days 2-6 
Day 28 
Dose Levels 
-1 & 1 
BMN 673 
(once daily) 
BMN 673 (once daily), and 
Temozolomide (once daily) 
Evaluation 
Dose Levels 
2 to 6 
BMN 673 
(twice daily) 
BMN 673 (once daily), and 
Temozolomide (once daily) 
Evaluation 
 
BMN 673 will be administered orally once daily or twice daily on Day 1. The second dose 
of BMN 673 on Day 1 for Dose Levels 2-6 will be administered 12 hours after the first 
dose. On Days 2-6, BMN 673 will be administered orally once daily (immediately before 
the temozolomide dose in the morning.  
 
NOTE:  BMN 673 dose and capsule strengths are in MICROGRAMS (mcg). 
 
Temozolomide will be administered orally once daily in the morning on Days 2-6 
immediately after the BMN 673 dose. At the discretion of the treating physician, the use 
of antiemetic therapy is allowed prior to low-dose temozolomide administration. For PCP 
prophylaxis guidelines refer to Section 7.3.1. 
 
On days on which pharmacokinetic samples are collected, BMN 673 (during Cycle 1 on 
Day 1, and on Day 5 or 6) and temozolomide (during Cycle 1 on Day 5 or 6) should be 
administered on an empty stomach (1 hour before or 2 hours after food or drink except 
water). Note: Day 2 BMN 673 and temozolomide do not need to be administered on an 
empty stomach during Cycle 1. On non-pharmacokinetic study days, BMN 673 and 
temozolomide can be administered without food or drink restrictions (i.e., with or without 
food).  
 
A cycle of therapy is considered to be 28 days. A cycle may be repeated for a total of 24 
times, up to a total duration of therapy of approximately 24 months. 
 
Drug doses should be adjusted based on the BSA calculated from height and weight 
measured within 7 days prior to the beginning of each cycle (see Appendix II-A and 
Appendix II-B).   
 
The capsules should not be opened or crushed but should be swallowed whole. 
 
If a patient vomits within 30 minutes after the dose of BMN 673 and/or temozolomide is 
administered, that dose of BMN 673 and/or temozolomide may be repeated. Otherwise, 
that dose of BMN 673 or temozolomide will not be repeated. 
 
If the dose of BMN 673 or temozolomide is missed and less than 6 hours have passed 
since the scheduled dosing time, the BMN 673 or temozolomide dose should be taken 
immediately. If more than 6 hours have passed since the scheduled dosing time, the patient 
should not take the missed dose but should wait and take the next regularly scheduled dose. 
 
Update: The MTD/RP2D of Part A1 was determined to be: Day 1: 600 
mcg/m2/dose BMN 673 PO BID; Days 2-6: 600 mcg/m2/dose BMN 673 
and 30 mg/m2/dose temozolomide PO; on a 28-day cycle, maximum BMN 


 
 
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32 
 
673 dose: 1000 mcg/day. 
 
 
5.1.1 
Intrathecal Therapy for Relapsed Acute Lymphoblastic Leukemia (ALL) Patients 
Patients may receive intrathecal chemotherapy in the second and subsequent cycles 
at the treating physician’s discretion. Intrathecal therapy, if given, should be restricted 
to Days 15 and 22 of each 28 day cycle and its administration should be reflected on 
the respective roadmaps and reporting period case report forms. 
 
 
 
 
 
 
 
 
REMOVED 
 
5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0.  
 
5.3 
Dose Escalation Schema 
 
5.3.1 
Inter-Patient Escalation [Phase 1 (Part A1) only]  
The starting dose of BMN 673 will be 400 mcg/m2/dose (maximum daily dose is 
800 mcg/day). Subsequently, the BMN 673 dose for Dose Levels 3-6 will be 
fixed at 600 mcg/m2/dose (maximum daily dose is 1000 mcg/day). The starting 
dose of temozolomide will be 20 mg/m2/dose (Dose Level 1) with dose levels for 
subsequent groups of patients as follows. 
 
NOTE:  BMN 673 dose and capsule strengths are in MICROGRAMS (mcg). 
 
Dose Level 
BMN 673 Dose 
Temozolomide 
Dose  
(mg/m2/dose) 
mcg/m2/dose 
Max. Daily 
Dose 
(mcg/Day) 
         -1 
 400# 
800 
15 
  1* 
 400# 
800 
20 
2 
 400& 
800 
20 
3 
 600& 
1000 
20 
4 
 600& 
1000 
30 
5 
 600& 
1000 
40 
6 
 600& 
1000 
  55^ 
* Starting Dose Level 
#  Once daily on Days 1-6.  
& Twice daily on Day 1, and then once daily on Days 2-6.  
^ In the event that the recommended Phase 2 dose has not been reached by Dose Level 6, 
additional dose levels may be added with BMN 673 dosed at 600 mcg/m2/dose and 
temozolomide escalated in 30% increments to a maximum of 150 mg/m2/dose (i.e. 70 
mg/m2/dose, 90 mg/m2/dose, 120 mg/m2/dose and 150 mg/m2/dose). 
 
If the MTD has been exceeded at the first dose level, then the subsequent cohort 
of patients will be treated at a BMN 673 dose of 400 mcg/m2/dose and a 
temozolomide dose of 15 mg/m2/dose (Dose Level -1).  
 
If Dose Level -1 is not well tolerated, further de-escalation will not occur. The 
study will be closed to accrual. 
 
5.3.2 
Ewing sarcoma or Peripheral PNET [Phase 1 (Part A2) only]: If an objective 


 
 
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33 
 
response is observed in a patient with Ewing sarcoma or Peripheral PNET on Part 
A1 of the study, Part A2 of the study will open so that patients with Ewing sarcoma 
or Peripheral PNET may actively enroll at any time.  Patients with Ewing sarcoma 
or Peripheral PNET may enroll onto Part A2 if there are no available patient slots 
at the current dose level on Part A1.  These patients may enroll one dose level 
below the current dose level at which patients on Part A1 are actively enrolling, or 
at the starting dose level (Dose Level 1) if dose escalation has not yet occurred.  
 
5.3.3 
Intra-Patient Escalation 
 
5.3.3.1 Phase 1 (Part A2) only 
Intra-patient dose escalation to a higher dose level will be allowed for Part 
A2 patients on study in cycles of therapy subsequent to Cycle 1, provided 
the patient has not experienced dose-limiting toxicity (DLT) at the dose at 
which they began therapy. Part A2 patients who are more than one dose 
level below the actively enrolling dose level in Part A1 can escalate one 
dose level per cycle until they reach the actively enrolling dose level, 
provided they do not experience a DLT when escalating. 
 
5.3.3.2 Phase 2 (Part B – Ewing sarcoma and peripheral PNET) only 
Patients enrolled onto Part B of this study will receive study drug at the 
R2PD in Cycle 1. Intra-patient dose escalation, to the next highest Dose 
Level (as defined in Section 5.3.1) will be allowed in cycles of therapy 
subsequent to Cycle 1, only for patients who do not have PD and have 
experienced no more than minimal toxicities (defined below), considered 
at least possibly related to study drug. These patients may be dose 
escalated (per Section 5.3.1) to RP2D + 1 Dose Level for at least one cycle, 
and subsequently may be escalated to RP2D + 2 Dose Levels if the subject 
continues to have never experienced more than minimal toxicities during 
therapy. A patient may not dose escalate beyond RP2D + 2 Dose Levels. 
In patients not eligible for dose escalation after any course due to greater 
than minimal toxicities, there will be no further attempt to dose escalate. 
Patients eligible to dose escalate after cycle 1, who are not dose escalated 
due to site related issues may start dose escalation in a subsequent cycle 
provided they meet all criteria for dose escalation. For patients who 
experience any dose limiting toxicity (DLT), as defined in Section 5.5, 
after a dose escalation, dose modification rules defined in Section 6 should 
be followed. Once a patient has required a single dose modification, no 
further dose escalations are permitted in that patient and the patient will 
receive the remaining therapy at the highest Dose Level at which no dose-
limiting toxicities were observed in the patient. 
 
Minimal toxicity for intra-patient dose escalation: Dose escalation is not allowed 
if any of the following conditions occur during a cycle: 
 
Hematological Toxicity 
• 
>Grade 2 thrombocytopenia 
• 
>Grade 3 neutropenia 
Non-hematological Toxicity 
• 
Any Grade 3 or 4 non-hematological toxicity with the specific 
exclusion of: 
o Grade 3 nausea and vomiting < 3 days duration 


 
 
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34 
 
o Grade 
3 
liver 
enzyme 
elevation, 
including 
ALT/AST/GGT elevation that returns to Grade ≤ 1 or 
baseline prior to the time for the next treatment cycle. 
Note:  For the purposes of this study the ULN for ALT is 
defined as 45 U/L. 
o Grade 3 fever  
o Grade 3 infection 
o Grade 3 hypophosphatemia, hypokalemia, hypocalcemia 
or hypomagnesemia responsive to oral supplementation. 
• 
Any grade 2 non-hematological toxicity that persists for > 7 days 
and is considered medically significant or sufficiently intolerable 
by patients that requires treatment interruption. 
 
5.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can 
be downloaded from the CTEP website (http://ctep.cancer.gov). Any suspected or 
confirmed dose-limiting toxicity should be reported immediately (within 24 hours) to the 
Study Chair. 
 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to protocol therapy.  The DLT observation period for the purposes of dose-
escalation will be the first cycle of therapy. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.   
 
5.5.1 
Non-hematological dose-limiting toxicity 
5.5.1.1 Any Grade 3 or Grade 4 non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
• Grade 3 nausea and vomiting < 3 days duration 
• Grade 3 liver enzyme elevation, including ALT/AST/GGT elevation 
that returns to Grade ≤ 1 or baseline prior to the time for the next 
treatment cycle. Note:  For the purposes of this study the ULN for 
ALT is defined as 45 U/L. 
• Grade 3 fever  
• Grade 3 infection 
• Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to oral supplementation. 
 
5.5.1.2 Non-hematological toxicity that causes a delay of ≥ 14 days between 
treatment cycles. 
 
5.5.1.3 Note: Allergic reactions that necessitate discontinuation of study drug will 
not be considered a dose-limiting toxicity. 
 
 


 
 
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35 
 
5.5.2 
Hematological dose limiting toxicity 
 
5.5.2.1 Hematological dose limiting toxicity is defined as: 
 
• 
In patients evaluable for hematological toxicity (see Section 4.1.8.1),   
• 
Grade 4 neutropenia for > 7 days 
• 
Platelet count < 20,000/mm3 on 2 separate days, or requiring a 
platelet transfusion on 2 separate days, within a 7 day period  
• 
Myelosuppression that causes a delay of > 14 days between 
treatment cycles.  
 
• 
In patients with acute lymphoblastic leukemia, DLT will be defined 
as failure to recover a peripheral ANC > 500/mm3 and platelets > 
20,000/mm3 by 42 days after the first treatment day, not due to 
malignant infiltration. 
 
5.5.2.2 Note:  Grade 4 febrile neutropenia will not be considered a dose-limiting 
toxicity. 
 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
 
Note: Patients with dose limiting toxicity should receive subsequent cycles at the next lower 
dose level (See Section 5.3.1). See Appendix II-A and Appendix II-B for dosing nomogram.  
 
NOTE:  BMN 673 dose and capsule strengths are in MICROGRAMS (mcg). 
 
6.1 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
Patients who have dose-limiting thrombocytopenia should receive subsequent 
cycles at the next lower dose level. Patients who experience dose-limiting 
thrombocytopenia after two dose reductions must be removed from protocol 
therapy. If a patient who was originally assigned to Dose Level 1 experiences dose-
limiting thrombocytopenia after a dose reduction to Dose Level -1 then that patient 
must be removed from protocol therapy. 
 
6.1.2 
Patients who have dose-limiting neutropenia (Grade 4 neutropenia of > 7 days 
duration or delay in the start of the next cycle for > 14 days due to neutropenia) 
with no other dose-limiting toxicity should receive the same dose in the next cycle 
with myeloid growth factor support. Note: Patients MUST NOT receive 
prophylactic myeloid growth factor in the first cycle of therapy (See Section 7.4). 
If Grade 4 neutropenia recurs after myeloid growth factor is added, then the patient 
should receive treatment at the next lower dose level for subsequent cycles, and G-
CSF 5 mcg/kg/day SC or IV should be administered, starting 24 hours after the last 
dose of chemotherapy and continuing until the post-nadir ANC is ≥ 2,000/µl. 
Patients who experience dose-limiting neutropenia after addition of myeloid 
growth factor and one dose reduction must be removed from protocol therapy. 
 
 


 
 
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36 
 
6.1.3 
Patients who have a dose-limiting hematological toxicity that does not resolve to 
meet eligibility or baseline parameters within 21 days after the planned start of the 
next treatment cycle must be removed from protocol therapy. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
6.2.1 
Patients who have any dose-limiting non-hematological toxicity (as defined in 
Section 5.5.1) may continue on protocol therapy upon meeting eligibility lab 
requirements (or baseline if not specifically defined in the eligibility criteria in 
Section 4.0) but should receive subsequent doses at the next lower dose level.  
 
6.2.2 
If non-hematological dose-limiting toxicity recurs after one dose reduction, the 
patient must be removed from protocol therapy. 
 
6.2.3 
Patients who have a dose-limiting non-hematological toxicity that does not resolve 
to meet eligibility or baseline parameters within 21 days after the planned start of 
the next treatment cycle must be removed from protocol therapy. 
 
6.3 
Dose Modifications for Intra-patient Dose Escalation Part B 
 
For patients who experience any dose limiting toxicity (DLT), as defined in Section 5.5, 
after a dose escalation, dose modification rules defined in Section 6.1 and Section 6.2 
should be followed. Once a patient has required a single dose modification, no further dose 
escalations are permitted and the patient will receive the remaining therapy at the highest 
Dose Level at which no dose-limiting toxicities were observed in the patient. 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. See Section 
4.1.7.2.a and Section 5.1.1 for the exception related to intrathecal chemotherapy for 
patients with acute lymphoblastic leukemia.  
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary (see Section 6.0).  
 
7.3.1 
Pneumocystis Pneumonia (PCP) Prophylaxis (Recommended) 
There have been multiple episodes of PCP reported in patients receiving 
temozolomide. For this reason, patients should receive PCP prophylaxis during 
treatment. TMP/SMX is recommended; monthly pentamidine or other appropriate 
alternative antibiotic are also acceptable. PCP prophylaxis should be discontinued 
3 months after chemotherapy has been discontinued. 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 


 
 
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37 
 
administered in accordance with Section 6.1 or for culture proven bacteremia or invasive 
fungal infection. The Study Chair should be notified before growth factors are initiated. 
 
 
 


 
 
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38 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility (see 
Section 4.0) must be no older than seven (7) days at the start of therapy.  Laboratory tests need 
not be repeated if therapy starts within seven (7) days of obtaining labs to assess eligibility.  If 
a post-enrollment lab value is outside the limits of eligibility, or laboratory values are older 
than 7 days, then the following laboratory evaluations must be re-checked within 48 hours prior 
to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) and serum  creatinine.  If 
the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and 
will be considered off protocol therapy. Bone marrow aspiration or biopsy should be performed 
within 14 days prior to start of protocol therapy for Phase 2 patients with bone marrow 
involvement (Part B and Part C). Imaging studies must be obtained within 14 days prior to start 
of protocol therapy (repeat the tumor imaging if necessary). 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^,* 
End of Study^^ 
History 
X 
Weekly 
X 
X 
Physical Exam  with vital signs 
X 
Weekly 
X 
X 
Height, weight, BSA 
X 
 
X 
X 
Performance Status 
X 
 
 
 
Pregnancy Test1 
X 
 
Every other cycle x 2 
then q 3 cycles 
X 
CBC, differential, platelets 
X 
Twice Weekly  
(every 3 to 4 days)2 
Weekly3 
X 
Pharmacokinetics4 
X 
X 
 
 
Urinalysis 
X 
 
 
 
Electrolytes including Ca++, PO4, 
Mg++ 
X 
Weekly 
X 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
X 
Albumin 
X 
 
X 
X 
Tumor Disease Evaluation5 
X 
  End of Cycle 1 
Every other cycle x 2 
then q 3 cycles 
X 
Patient Diary6 
 
End of Cycle 1 
End of Cycle 
 
Bone marrow aspirate or biopsy7 
X 
End of Cycle 1 
Every other cycle x 2 
then q 3 cycles 
X 
CSF cytology8 
X 
End of Cycle 1 
X 
X 
Tumor Tissue (Required)9 
X 
Clinically indicated 
 
 
^ Studies may be obtained within 72 hours prior to the start of the subsequent cycle.  
* For patients who progress on study, the imaging that confirmed progression, if obtained, will be documented, but full “Prior to 
Subsequent Cycle” imaging studies will not be performed unless these studies were the ones that documented progression. To 
the extent possible, the “Prior to Subsequent Cycle” laboratory evaluations should be obtained in patients with progressive 
disease. 
^^ “End of Study” evaluations are to be performed 30 days after the last dose of the investigational agent(s) for patients who 
complete 24 cycles of therapy. 
1 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually active patients must use 
an acceptable method of birth control. Abstinence is an acceptable method of birth control.  Pregnancy testing is required prior 
to tumor imaging as per institutional guidelines. 
2 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery to Grade 3 or until 
meeting the criteria for dose limiting toxicity (see Section 6.1). 
3 
If patients develop Grade 4 neutropenia then CBCs should be checked every 3 to 4 days until recovery to Grade 3. 
4 
This applies to all Part A patients. See Section 8.3 for timing of PK studies. 


 
 
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39 
 
5 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation of either a PR or CR.  
Please note that for solid tumor patients, if the institutional investigator determines that the patient has progressed based on 
clinical or laboratory evidence, he/she may opt not to confirm this finding radiographically. 
6 
Patient diary (see Appendix III) should be reviewed after completion of each treatment cycle and uploaded into RAVE. 
7 
This only applies to Part B and Part C patients with bone marrow involvement. Bone marrow aspirates or biopsies must be done 
for diagnostic and staging purposes prior to enrollment on study and as indicated in the table above. 
8 
For Part C acute lymphoblastic leukemia patients only. 
9 
For Part B patients (See Section 8.4). Archival tumor tissue should be submitted if available for all patients. If a patient does not 
have tissue available, the study chair must be notified prior to enrollment. 
  
 
 
 
 
8.2 
Radiology Studies 
 
8.2.1 
Central Radiology Review for Response:   
Patients who respond (CR, PR) to therapy or have long term stable disease (SD) 
(≥ 6 cycles) on protocol therapy will be centrally reviewed. COG Operations 
Center will notify the Imaging Center of any patient requiring central review. The 
Imaging Center will then request that the treating institution forward the requested 
images for central review. The central image evaluation results will be entered into 
RAVE for review by the COG Operations Center and for data analysis.  
 
The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the ImageInBox.   
 
COG institutions that are not connected via the ImageInBox can send the images 
on hard copy film, CD ROM, USB flash drive or by FTP.  Submitted imaging 
studies should be clearly marked with the COG patient ID, study number 
(ADVL1411) and date and shipped to Syed Aamer at the address below: 
 
Syed Aamer, MBBS, CRP 
Administrator, Imaging Research Center 
Data Administrator  
Children’s Hospital Los Angeles  
4650 Sunset Boulevard, MS # 81 
Los Angeles, CA 90027 
Phone: 
(323) 361-3898 
Fax: 
(323) 361-3054 
E-mail: 
saamer@chla.usc.edu 
 
 


 
 
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40 
 
8.3 
Pharmacology Studies (Required for Cycle 1) (Part A ONLY) 
 
8.3.1 
Description of Studies and Assay 
 
8.3.1.1 Pharmacokinetic analysis for BMN 673 will be conducted by Alliance 
Pharma using validated assays by HPLC with MS/MS detection in plasma 
samples.  
 
8.3.1.2 Pharmacokinetic analysis for temozolomide will be conducted by Dr. Joel 
Reid at the Mayo Clinic using validated assays by HPLC with MS/MS 
detection in plasma samples.  
 
8.3.2 
Sampling Schedule (See Appendix V) 
 
8.3.2.1 Blood samples (2-3 mL per sample) will be collected at the following time 
points during Cycle 1:  
 
o Day 1 (Required from all patients): Pre-dose, and then at 1, 2, 4 and 8 hours 
after the first BMN 673 dose.   
o Day 2 (Optional): In consenting patients, a pre-dose Day 2 sample will be 
collected (24 hours after the first BMN 673 dose).  
o Day 5 or 6 (Required from all patients): Pre-dose, and then at 1, 2, 4 and 
8 hours after BMN 673 and temozolomide administration.  
 
NOTE: On days on which pharmacokinetic samples are collected, BMN 673 
(during Cycle 1 on Day 1, and on Day 5 or 6) and temozolomide (during 
Cycle 1 on Day 5 or 6), should be administered on an empty stomach (1 hour 
before or 2 hours after food or drink except water).  Day 2 BMN 673 and 
temozolomide do not need to be administered on an empty stomach. 
 
o Days 8 and 15 (Required from patients > 10 kg): These samples are 
collected at time of CBC evaluation.  
 
8.3.3 
Sample Collection and Handling Instructions 
Each blood sample must be centrifuged within 30-60 minutes of draw and frozen at 
– 70 oC until shipment.  
 
Keep BMN 673 samples at room temperature during the blood collection and 
samples should be processed as described in Section 8.3.4.1.   
 
Keep temozolomide samples at 4 oC during the blood collection and samples should 
be processed as described in Section 8.3.4.2. 
 
o Day 1, Pre-dose: Two consecutive 2 mL blood samples (a total of 4 mL) 
will be collected from the patient’s vein (peripheral or central) before BMN 
673 administration. 
• 
Sample 1 for BMN 673 pharmacokinetic studies: The first 2 mL 
blood sample should be collected into a room temperature 4 mL 
K3EDTA vacutainer tube containing anticoagulant and processed as 
described in Section 8.3.4.1.  
 
• 
Sample 2 for temozolomide pharmacokinetic studies: The second 


 
 
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41 
 
2 mL blood sample should be collected into a pre-chilled vacutainer 
tube containing sodium heparin and processed as described in Section 
8.3.4.2.  
 
o Day 1 and 2: Blood samples (3 mL per sample) will be collected from the 
patient’s vein (peripheral or central) at each designated time point (1, 2, 4, 
8, and 24 hours) post-first BMN 673 administration into room 
temperature 4 mL K3EDTA vacutainer tubes containing anticoagulant 
for the preparation of plasma. See Section 8.3.4.1 for BMN 673 processing 
instructions.   
 
o Day 5 or 6: For each designated time point, two consecutive 2 mL blood 
samples (a total of 4 mL per time point) will be collected from the patient’s 
vein (peripheral or central). 
 
• 
Sample 1 for BMN 673 pharmacokinetic studies: The first 2 mL 
blood sample should be collected into a room temperature 4 mL 
K3EDTA vacutainer tube containing anticoagulant and processed as 
described in Section 8.3.4.1.  
 
• 
Sample 2 for temozolomide pharmacokinetic studies: The second 
2 mL blood sample should be collected into a pre-chilled vacutainer 
tube containing sodium heparin and processed as described in Section 
8.3.4.2.  
 
o Days 8 and 15 (only from patients > 10 kg): Blood samples (3 mL per 
sample) will be collected from the patient’s vein (peripheral or central) 
into room temperature 4 mL K3EDTA vacutainer tubes containing 
anticoagulant for the preparation of plasma. See Section 8.3.4.1 for BMN 
673 processing instructions.   
 
Record the exact time that the sample is drawn along with the exact time that the 
drug is administered (Appendix V).  
 
8.3.4 
Sample Processing 
 
8.3.4.1 Sample processing for BMN 673 pharmacology studies 
 
1. Invert vacutainer gently 8 to 10 times.  
2. Separate plasma by centrifugation at 1500 x g for 10 minutes at room 
temperature. 
3. Transfer the plasma (about 1.0 mL) into a 2 mL-cryovial. To avoid 
contamination always use a new transfer pipette for each sample, and do 
not remove the plasma near the precipitate. 
4. Transfer plasma samples to -70 oC freezer (within 1 hour of collection) 
and store until shipment. 
5. Ship plasma samples on dry ice to Alliance Pharma (see Section 8.3.6.1 
and Appendix VI). 
8.3.4.2 Sample processing for temozolomide pharmacology studies 
 


 
 
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42 
 
1. Blood samples (2 mL) will be collected in pre-chilled heparinized tubes. 
2. Invert tube 8-12 times and place in an ice water bath.  
3. Centrifuge at 2,000 rpm for 10 min in a refrigerated centrifuge set at 4°C. 
4. Following centrifugation, transfer 1 mL of plasma to a microcentrifuge 
tube containing 0.1 mL 1 M HCl.  
5. Vortex briefly and transfer to a -70 oC freezer (within 30 minutes of 
collection). 
8.3.5 
See Section 8.3.6.2 and Appendix VII for shipping instructions.Sample Labeling 
Each tube must be labeled with the COG patient ID and accession number, the 
study I.D. (ADVL1411), and the date and time the sample was drawn.  Data 
should be recorded on the Pharmacokinetic Study Form (Appendix V), which 
must accompany the sample(s). 
 
8.3.6 
Sample Shipping Instructions 
 
8.3.6.1 Sample Shipping Instructions for BMN 673: 
The BMN 673 samples must be batched, and maintained at -70 oC until 
shipment. Ship samples for each patient together.  See Appendix VI for 
guidelines and the mailing address for shipping samples to Alliance 
Pharma.  
 
8.3.6.2 Sample Shipping Instructions for temozolomide: 
Day 1 pre-dose, and Day 5 or 6 temozolomide samples should be batched, 
and maintained at -70 oC until shipment. Ship samples together for each 
patient. See Appendix VII for guidelines and the mailing address for 
shipping samples to Dr. Joel Reid at the Mayo Clinic. 
 
 


 
 
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8.4 
Tumor Tissue Studies (Required, Part B ONLY)  
 
Note: Archival tumor tissue should be submitted if available for all Phase 2 Ewing 
sarcoma or Peripheral PNET patients. If a patient does not have tissue available, the 
study chair must be notified prior to enrollment. 
 
8.4.1 
Description of Studies   
If multiple biopsies have been performed, tissue from the most recent biopsy is 
preferred. Tumor tissue will be analyzed by immunohistochemistry.  
 
8.4.2 
Sampling Schedule  
Either paraffin-embedded tissue block or unstained slides are required for 
enrollment.  
• 
Tumor tissue or slides may be from original diagnosis or from any 
resections or biopsies that occurred prior to enrollment. Samples from the 
most recent procedure are desired.  
 
• 
A block or slides from any resections or biopsies occurring after the start 
of ADVL1411 protocol therapy are also requested.  
  
8.4.3 
Sample Collection Instructions 
A paraffin-embedded tissue block should be submitted. If a tissue block is 
unavailable, at least 10 unstained standard sections of 3 to 4 μM thickness must be 
sent (15 slides are recommended). 
 
8.4.4 
Sample Labeling 
Each tube must be labeled with the COG patient ID and accession number, the study 
I.D. (ADVL1411), the collection date and the collection time point of the sample. 
Data should be recorded on the Tumor Tissue Study Form (Appendix VIII), which 
must accompany the sample(s). The Tumor Tissue Study Form (Appendix VIII) must 
be completed for each time point. 
 
8.4.5 
Sample Shipping Instructions 
See Appendix VIII for guidelines and the mailing address for shipping samples to 
Dr. Alex Bishop’s laboratory. Samples must be shipped at room temperature 
via overnight FedEx. Shipments should be sent Monday through Thursday 
only. 
 
 
 


 
 
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9.0 
AGENT INFORMATION 
 
9.1 
BMN 673 
(BMN 673ts, talazoparib, MDV3800) NSC#771561 IND# 121510 
9.1.1 
Structure and molecular weight  
The chemical name of BMN 673 is 3H-Pyrido[4,3,2-de]phthalazin-3-one, 5-fluoro-
8-(4-fluorophenyl)-2,7,8,9-tetrahydro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-, 
(8S,9R)-, 4-methylbenzenesulfonate (1:1).  The structure and molecular weight of 
BMN 673ts are C26H22F2N6O4S and 552.5624, respectively.  BMN 673 is a potent 
and specific inhibitor of poly(ADP-ribose) polymerase (PARP) inhibitors (i.e., 
PARP1 and PARP2), which prevents PARP-mediated DNA repair of single strand 
DNA breaks via the base-excision repair pathway.  It has demonstrated synthetic 
lethality in tumors with defects in DNA repair pathways, such as BRCA mutations 
and PTEN dysfunction. BMN 673 free base is the active moiety of the BMN 673ts 
(tosylate salt) formulation. 
 
9.1.2 
Supplied by: 
BMN 673 capsules are supplied by Medivation, Inc, and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI. 
 
9.1.3 
Formulation 
BMN 673 is supplied as 100 mcg (opaque ivory, size 4) and 250 mcg capsules 
(opaque white, size 4) packaged in 30-count HDPE bottles with an induction seal 
and child-resistant cap.  The hypromellose capsules contain a blend of BMN 673 
drug substance, silicified microcrystalline cellulose, titanium dioxide, red iron 
oxide, and yellow iron oxide. 
 
9.1.4 
Storage 
Store BMN 673 capsules at room temperature (15-30 °C/ 59-86 °F), protected from 
light, in the original container. BMN 673 capsules may be repackaged from the 
manufacturer-supplied HDPE bottle into a pharmacy-supplied HDPE bottle for 
dispensing purposes. 
 
9.1.5 
Stability 
Shelf-life stability studies of BMN 673 capsules are ongoing. 
 
9.1.6 
Administration 
Give/take BMN 673 by mouth on an empty stomach either one hour before or two 
hours after a meal on pharmacokinetic study days (during Cycle 1 on Day 1, and on 
Day 5 or 6). Note: Day 2 BMN 673 do not need to be administered on an empty 
stomach during Cycle 1. On non-pharmacokinetic study days, BMN 673 can be 
administered without food or drink restrictions (see Section 5.1).  BMN 673 should 
be taken immediately prior to temozolomide on Days 2 through 6 of each cycle.  
 
Based on in vitro data, BMN 673 is not likely to inhibit metabolism via human 
cytochrome P450 (CYP 450) enzymes. Effects of co-administration of repeat dosing 
of BMN 673 with other drugs are unknown. 
 
The capsules should not be opened or crushed but should be swallowed whole.  
 
9.1.7 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 


 
 
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The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting 
(SPEER), appears in a separate column and is identified with bold and italicized text. 
This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to 
expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelin
es.pdf for further clarification. Frequency is provided based on 232 patients. Below 
is the CAEPR for talazoparib (BMN 673). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER. If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.1, December 29, 20161 
 
 Adverse Events with Possible  
 Relationship to Talazoparib (BMN 673) 
 (CTCAE 4.0 Term) 
[n= 232] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
 
Febrile neutropenia 
 
  
GASTROINTESTINAL DISORDERS 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Typhlitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
 
Pain 
 
 Pain (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
 Infection 2 (Gr 2) 
INVESTIGATIONS 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 2) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 2) 
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hypokalemia 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
Nervous system disorders - 
Other (neuropathy peripheral)3 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  


 
 
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 Adverse Events with Possible  
 Relationship to Talazoparib (BMN 673) 
 (CTCAE 4.0 Term) 
[n= 232] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Epistaxis 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Rash maculo-papular 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
3Neuropathy peripheral may  include both Peripheral sensory neuropathy and Peripheral motor neuropathy 
under the NERVOURS SYSTEM DISORDERS. 
 
 
Adverse events reported on talazoparib (BMN 673) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that talazoparib (BMN 673) caused the adverse 
event: 
 
CARDIAC DISORDERS - Atrial flutter 
GASTROINTESTINAL DISORDERS - Abdominal distension; Flatulence; Small intestinal obstruction; 
Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Non-cardiac chest 
pain HEPATOBILIARY DISORDERS - Hepatic failure 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Weight 
loss 
MUSCULOSKELETAL 
AND 
CONNECTIVE 
TISSUE 
DISORDERS 
- 
Arthralgia; 
Back 
pain; 
Musculoskeletal and connective tissue disorder - Other (muscle cramps); Musculoskeletal and connective 
tissue disorder - Other (muscle spasm); Neck pain; Pain in extremity 
NERVOUS SYSTEM DISORDERS - Dysgeusia 
PSYCHIATRIC DISORDERS - Anxiety; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Pleural effusion; 
Respiratory, thoracic and mediastinal disorders - Other (oropharyngeal pain) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin 
 
Note: Talazoparib (BMN 673) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 
 
 
9.2 
Agent Ordering and Agent Accountability 
BMN 673 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 


 
 
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47 
 
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. 
 
9.3 
Clinical Drug Request 
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 at https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password. For questions about drug orders, transfers, returns, 
or accountability call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 
pm (ET) or email pmbafterhours@mail.nih.gov anytime. 
 
9.4 
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 (DAR) Form (See the NCI Investigator’s Handbook for 
Procedures for Drug Accountability and Storage). 
 
9.5 
Temozolomide-Oral   
 
 
 
 
 
 (Temodar, Temodal) NSC #362856  
 
 
 
           (09/09/13) 
 
9.5.1 
Source and Pharmacology  
An orally administered alkylating agent, a second generation imidazotetrazine. A 
prodrug of MTIC, temozolomide spontaneously decomposes to MTIC at physiologic 
pH. Exerts its effect by cross-linking DNA. This is likely a site specific alkylation at 
the O6-position of guanine with some effect at the N7 position. Temozolomide 
reaches its peak concentration in 1 hour. Food reduces the rate and extent of 
absorption. It has an elimination half-life of 1.13 hr (intraperitoneally) and 1.29 hr 
(orally) with an oral bioavailability of 0.98. Total apparent body clearance is 
100 mL/min/m2 and plasma elimination half-life is ~ 100 minutes. 
 
9.5.2 
The table below lists the anticipated toxicity profile of temozolomide (oral): 
Incidence 
Toxicities 
Common 
(>20% of patients) 
Constipation, nausea, vomiting, diarrhea, anorexia, alopecia, alanine aminotransferase 
increased, aspartate aminotransferase increased, ataxia, anxiety, depression, insomnia, 
nervous system disorders – other: hemiparesis or paresis, dizziness, gait disturbance, 
amnesia, paresthesia, somnolence, headache, seizure, fatigue 
Occasional 
(4-20% of patients) 
Edema limbs, localized edema, rash maculopapular, dysphagia, mucositis oral, anemia, 
platelet count decreased, white blood cell count decreased, lymphocyte count 
decreased, aplastic anemia, blood bilirubin increased, urinary frequency, cough, upper 
respiratory infection, sinusitis 
Rare 
(≤ 3% of patients) 
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, 
hypercalcemia, lower gastrointestinal hemorrhage, upper gastrointestinal hemorrhage, 
cholecystitis, alkaline phosphatase increased, myelodysplastic syndrome, leukemia 
secondary to oncology chemotherapy, infections and infestations – other: Pneumocystis 
pneumonia, pulmonary fibrosis, anaphylaxis, allergic reaction, hepatic failure 


 
 
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Incidence 
Toxicities 
Pregnancy & 
Lactation 
Pregnancy Category  
Adequate, well-controlled studies have not been conducted in humans. Women of 
childbearing potential should be advised against becoming pregnant while taking 
temozolomide and for at least 6 months following the end of therapy. Temozolomide 
administration to rats and rabbits at 3/8 and 3/4 the human dose resulted in the 
development of malformations of the external organs, soft tissues, and skeleton. These 
animal studies also demonstrated embryolethality (increased resorptions) at similar 
doses. There is no information available regarding the transmission of temozolomide 
during lactation; women should avoid breastfeeding while receiving temozolomide. 
 
9.5.3 
Formulation and Stability:  
Temozolomide capsules are available in six different strengths (5, 20, 100 mg). The 
capsules vary in size, color, and imprint according to strength. In the US, capsules are 
packaged in 5-count and 14-count bottles. In other countries temozolomide may be 
packaged in 5-count, 14-count or 20-count bottles. Temozolomide capsules are 
stored at controlled room temperature. 
 
9.5.4 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol (See Section 5.0 and 
Section 6.0). The capsules should not be opened or crushed but should be swallowed 
whole.  
 
There is a potential for medication errors involving temozolomide capsules resulting 
in drug overdosages, which may have been caused by dispensing/taking the wrong 
number of capsules per day and/or product usage exceeding the prescribed dosing 
schedule. 
 
When dispensing, it is extremely important that prescribing and dispensing include 
clear instructions on which capsules, and how many of each capsule(s) are to be taken 
per day. Only dispense what is needed for the course, and clearly indicate how many 
days of dosing the patient will have and how many days are without temozolomide 
dosing. When counseling patients, it is important for each patient/parent to understand 
the number of capsules per day and the number of days that they take temozolomide. 
It is also important for the patient/parent to understand the number of days that they 
will be off the medication.  
 
Each strength of temozolomide must be dispensed in a separate vial or in its original 
container (e.g., bottle or sachet). Based on the dose prescribed, determine the number 
of each strength of temozolomide capsules needed for the full course as prescribed by 
the physician. For example, 25 mg/day for 5 days would be dispensed as five 20 mg 
capsules and five 5 mg capsules. Label each container with the appropriate number 
of capsules to be taken each day. Dispense to the patient/parent, making sure each 
container lists the strength (mg) per capsule and that he or she understands to take the 
appropriate number of capsules of temozolomide from each bottle or vial to equal the 
total daily dose prescribed by the physician. Institutions that have the capability to 
dispense temozolomide as daily doses in a blister pack may do so, taking specific 
precautions to ensure that the appropriate dose is provided and that the patient is 
educated to understand the daily dosing regimen. 
 
 


 
 
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9.5.5 
Supplier:  
Commercially available. See package insert for further information. 
 
 


 
 
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10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12.0). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6.0). 
c) 
Refusal of further protocol therapy by patient/parent/guardian. 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of 24 cycles of therapy. 
f) 
Physician determines it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of BMN 673 (See Section 4.0 and Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy. 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent. Patients who are removed from protocol therapy in subsequent cycles should 
have the necessary observations to ensure adequate clinical care.  
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Ongoing adverse events, or adverse events that emerge after the patient 
is removed from protocol therapy, but within 30 days of the last dose of investigational 
agent, must be followed and reported via RAVE and CTEP-AERS (if applicable).  Follow-
up data will be required unless consent is withdrawn. 
 
10.2 
Off Study Criteria 
 
a) 
Thirty days after the last dose of the investigational agent. 
b) 
Death 
c) 
Lost to follow-up 
d) 
Withdrawal of consent for any further required observations or data submission. 
e) 
Enrollment onto another COG therapeutic (anti-cancer) study  
 
 


 
 
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11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
Strata: 
Part A1:    Patients with relapsed or refractory solid tumors and CNS tumors (Phase 1) 
Part A2: 
Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET (Phase 1) 
Part B:    
Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET (Phase 2) 
Part C: 
Patients with relapsed acute lymphoblastic leukemias (ALL) (Phase 2) 
 
 
 
 
 
 
 
 
 
REMOVED 
Phase 1 (Part A1):  
A minimum of 3 evaluable patients will be entered at each dose level for determination of 
MTD. Once the MTD or recommended Phase 2 dose (RP2D) has been defined, up to 6 
additional patients with relapsed or refractory solid tumors may be enrolled to acquire PK 
data in a representative number of young patients (i.e. patients < 12 years old).  Review of 
the enrollment rate into previous COG Phase 1 new agent studies indicates that 1-2 patients 
per month are available, which will permit completion of Part A of the study within 21-42 
months if six evaluable patients are studied at each of six dose levels to determine the MTD 
or RP2D.  A maximum of 94 patients is anticipated, assuming a 20% inevaluability rate.  
 
Phase 1 (Part A2):  
If an objective response is observed in a patient with Ewing sarcoma or Peripheral PNET 
on Part A1 of the study, Part A2 of the study will open so that patients with Ewing sarcoma 
or Peripheral PNET may actively enroll at any time. Patients with Ewing sarcoma or 
Peripheral PNET may enroll onto Part A2 if there are no available patient slots at the current 
dose level on Part A1.  These patients may enroll one dose level below the current dose 
level at which patients on Part A1 are actively enrolling, or at the starting dose level (dose 
level 1) if dose escalation has not yet occurred. Up to 6 patients may enroll at each lagging 
dose level, for a maximum total of 30 patients in Part A2. Once the MTD or RP2D has 
been determined in Part A1, Part A2 will be closed to accrual. 
 
Intra-patient dose escalation to a higher dose level will be allowed for Part A2 patients on 
study in cycles of therapy subsequent to cycle 1, provided the patient has not experienced 
dose-limiting toxicity (DLT) at the dose at which they began therapy. Part A2 patients who 
are more than one dose level below the actively enrolling dose level in Part A1 can escalate 
one dose level per cycle until they reach the actively enrolling dose level, provided they do 
not experience a DLT when escalating. 
 
Phase 2 (Parts B and C):  
Accrual to Parts B and C will only open once the MTD or RP2D has been determined in 
Part A1, and may open concurrently with the PK expansion described above. Review of 
patient accrual onto recent Phase 2 studies indicates the following entry rates for the 
various tumors under study can be achieved: 
 
Disease Group 
 
Patients/Year 
Ewing Sarcoma or Peripheral PNET 
  
         10 
Acute Lymphoblastic Leukemias (ALL)  
          5 
 
 
 
REMOVED 
 
 


 
 
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A minimum of 10 evaluable patients and a maximum of 24 patients are expected to enroll 
in Parts B and C combined, assuming an inevaluability rate of 20%. We anticipate that the 
entire study will require 12-29 months for enrollment and evaluation of all parts. 
 
Update: The MTD/RP2D of Part A1 was determined to be: Day 1: 600 
mcg/m2/dose BMN 673 PO BID; Days 2-6: 600 mcg/m2/dose BMN 673 
and 30 mg/m2/dose temozolomide PO; on a 28-day cycle, maximum BMN 
673 dose: 1000 mcg/day. 
 
Intra-patient dose escalation to a higher dose level will be allowed for Part B patients on 
study in cycles of therapy subsequent to cycle 1, provided the patient has not experienced 
more than minimal toxicities at the dose at which they began therapy. Part B patients may 
be dose escalated to RP2D + 1 Dose Level for at least one cycle, and subsequently may be 
escalated to RP2D + 2 Dose Levels if the patient continues to have never experienced more 
than minimal toxicities (as defined in Section 5.3.3.2) during therapy. 
 
 
11.2 
Definitions [Phase 1 (Part A1)] 
 
11.2.1 Evaluable For Adverse Effects 
Any patient who experiences DLT at any time during protocol therapy is 
considered evaluable for Adverse Effects. (Note: patients who experience dose-
limiting PCP must have received PCP prophylaxis to be considered evaluable for 
this Adverse Effect). Patients without DLT who receive at least 85% of the 
prescribed dose per protocol guidelines and had the appropriate toxicity 
monitoring studies performed are also considered evaluable for Adverse Effects. 
Patients who are not evaluable for Adverse Effects at a given dose level during 
Cycle 1 will be replaced. 
 
11.2.2 Maximum Tolerated Dose 
• 
The MTD will be the maximum dose at which fewer than one-third of patients 
on Part A1 experience DLT (See Section 5.5) during Cycle 1 of therapy.  
 
• 
In the event that two DLTs observed out of 6 evaluable patients are different 
classes of Adverse Effects (e.g. hepatotoxicity and myelosuppression), 
expansion of the cohort to 12 patients will be considered if all of the following 
conditions are met:  
 
o One of the DLTs does not appear to be dose-related 
o The Adverse Effects are readily reversible 
o The study chair, DVL statistician, DVL committee chair or vice chair, and 
IND sponsor all agree that expansion of the cohort is acceptable 
 
In Part A1, expansion will proceed according to the rules of the 3+3 design 
(see Section 11.3): Three additional patients will be studied.  If none of the 
initial three additional patients experiences DLT, the dose will be 
escalated.* If one of the initial three additional patients experiences DLT, 
expansion to a total of 12 patients will continue. If fewer than 1/3 of patients 
in the expanded cohort experience dose-limiting toxicities, the dose escalation 
can proceed.* 
 


 
 
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* If the expansion occurs in the last dose level, the recommended phase 2 dose 
has been defined and Part A1 will be closed. 
 
• 
The DLTs observed in the pharmacokinetic (PK) expansion cohort will be 
counted towards the total number of DLTs observed at the MTD during the 
dose escalation portion of the study. If ≥ 1/3 of the cohort of patients at the 
MTD (during the dose escalation plus the PK expansion) experience DLT then 
the MTD will be exceeded. 
 
 
 


 
 
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11.3 
Dose Escalation and Determination of MTD [Phase 1 (Part A1)] 
As an added safety precaution, one evaluable patient will be initially enrolled at the first 
dose level.  Additional patients may continue to enroll as described below only after this 
patient has been evaluated by the study leadership for treatment-related toxicities from 
his/her first course of therapy. 
11.3.1 Three patients are studied at the first dose level. 
 
11.3.2 If none of these three patients experience DLT, then the dose is escalated to the 
next higher level in the three subsequent patients. 
 
11.3.3 If one of three patients experiences DLT at the current dose, then up to three more 
patients are accrued at the same level. 
 
a)  If none of these three additional patients experience DLT, then the dose is 
escalated in subsequent patients. If there are no further dose escalations, then 
the RP2D has been confirmed. 
 
b)  If one or more of these three additional patients experiences DLT, then patient 
entry at that dose level is stopped.  (See Section 11.2.2 for exception to rule).  
Up to three more patients are treated at the next lower dose (unless six patients 
have already been treated at that prior dose). 
 
11.3.4 If two or more of a cohort of up to six patients experience DLT at a given dose 
level, then the MTD has been exceeded and dose escalation will be stopped (see 
Section 11.2.2 for exception to rule).  Up to three more patients are treated at the 
next lower dose (unless six or more patients have already been treated at that prior 
dose). The highest dose with less than two DLTs out of six evaluable patients will 
be the estimated MTD. 
 
11.3.5 Using this dose escalation scheme, the probability of escalating to the next dose 
level, based on the true rate of DLT at the current dose, is given by the following 
table when there are 6 evaluable patients at the current dose: 
 
 
True Adverse Effects at a Given Dose 
 
10% 
20% 
30% 
40% 
50% 
60% 
Probability of 
Escalating 
.91 
.71 
.49 
.31 
.17 
.08 
 
Thus, if the true underlying proportion of toxic events is 30% at the current dose, 
there is a 49% chance of escalating to the next dose. 
 
In addition to determination of the MTD or RP2D, a descriptive summary of all toxicities 
will be reported. 
 
Update: The MTD/RP2D of Part A1 was determined to be: Day 1: 600 
mcg/m2/dose BMN 673 PO BID; Days 2-6: 600 mcg/m2/dose BMN 673 
and 30 mg/m2/dose temozolomide PO; on a 28-day cycle, maximum BMN 
673 dose: 1000 mcg/day. 
 
 
 


 
 
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11.4 
Pharmacokinetic Studies and Response Analysis [Phase 1 (Part A)] 
 
A descriptive analysis of pharmacokinetic (PK) parameters of BMN 673 will be performed 
to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The 
PK parameters will be summarized with simple summary statistics, including means, 
medians, ranges, and standard deviations (if numbers and distribution permit).   
 
While the primary aim of this study is to evaluate the toxicity of BMN 673 in combination 
with temozolomide, patients will have disease evaluations performed as indicated in 
Section 8.1.  Disease response will be assessed according to RECIST criteria for patients 
with solid tumors (Section 12.2) and according to criteria for CNS tumors (Section 12.6). 
All disease responses will be reported descriptively. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
 
11.5 
Study Design [Phase 2 (Parts B and C)] 
 
The best response of disease to BMN 673 plus temozolomide will be examined separately 
in each of the two disease strata for Ewing sarcoma and ALL. Patients with Ewing sarcoma 
from Part A1 or A2 treated at the MTD/RP2D and who meet eligibility criteria for Part B 
of the study will be counted in the Phase 2 evaluation.  The following Simon’s optimal two 
stage design will be used in each stratum. 
 
The two stage design for Part B and Part C is illustrated below: 
 
 
Cumulative Number of 
Responses 
Decision 
Stage 1: Enter 10 evaluable 
patients 
0 
Terminate the trial because the 
agent is ineffective. 
1 or more 
Proceed to Stage 2. 
Stage 2: Enter 10 additional 
evaluable patients 
2 or less 
Terminate the trial because the 
agent is ineffective. 
3 or more 
Terminate the trial because the 
agent is effective. 
 
We will consider BMN 673 plus temozolomide not of sufficient interest for further 
evaluation in a disease category if the true response rate is 5% and of sufficient activity if 
the true response rate is 25%. If BMN 673 plus temozolomide has a true response rate of 
5%, the rule described above will identify it of sufficient activity for further study with 
probability 0.07 (type I error), and the trial will have an expected sample size of 14 with 
60% probability of early termination. If BMN 673 plus temozolomide has a true response 
rate of 25%, the rule described above will identify it of sufficient activity for further study 
with probability 0.88 (power against the alternative hypothesis P = 0.25). 
 
 


 
 
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11.6 
Method of Analysis [Phase 2 (Parts B and C)] 
 
Response in Ewing sarcoma or peripheral PNET patients will be determined according to 
RECIST as defined in Section 12.0. For patients with ALL, response criteria will be based 
on the standard definitions of complete remission (CR), partial remission (PR), partial 
remission, cytolytic (PRCL), stable disease (SD), and progressive disease (PD) using the 
leukemia rating scale and peripheral blood counts (See Section 12.5). These responses will 
be reported descriptively. A report on the efficacy assessment will be posted on the 
completed disease stratum as part of the semi-annual study committee meeting book report.  
 
Toxicities for patients will be described separately. Every effort will be made to accrue the 
number of patients needed to evaluate efficacy according to the schema in Section 11.5. 
For strata not appropriately filled, descriptive statistics will be employed to describe 
outcomes.  
 
11.7 
Inclusion of Children, Women and Minorities 
 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual 
to past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies.  Efforts will be made to extend the accrual to a 
representative population, but in a Phase 1 trial which will accrue a limited number of 
patients, a balance must be struck between patient safety considerations and limitations on 
the number of individuals exposed to potentially toxic or ineffective treatments on the one 
hand and the need to explore gender, racial, and ethnic aspects of clinical research on the 
other. If differences in outcome that correlate to gender, racial, or ethnic identity are noted, 
accrual may be expanded or additional studies may be performed to investigate those 
differences more fully. 
 
 


 
 
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12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
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 website 
(http://ctep.cancer.gov). 
 
12.2 
Response Criteria for Patients with Solid Tumors  
See the table in section 8.0 for the schedule of tumor evaluations. In addition to the 
scheduled scans, a confirmatory scan should be obtained 28 days following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].  Key points are that 5 target lesions are identified and that changes in the largest 
diameter (unidimensional measurement) of the tumor lesions but the shortest diameter of 
malignant lymph nodes are used in the RECIST v 1.1 criteria. 
 
12.2.1 Definitions 
 
12.2.1.1 Evaluable for objective response: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will be considered evaluable for 
response. For all other patients, only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, 
and have had their disease re-evaluated will be considered evaluable for 
response.  
 
12.2.1.2 Evaluable Non-Target Disease Response: Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for non-
target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
12.2.2 Disease Parameters 
 
12.2.2.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥20 mm by chest x-ray, as ≥10 mm with CT scan, or ≥10 
mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable.  If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
12.2.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 


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


 
 
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12.2.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
12.2.3.1 Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and ≥10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
12.2.3.2 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable.  
 
12.2.3.3 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 
12.2.3.4 PET-CT:  At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.2.3.5 Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
 
 


 
 
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12.2.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.2.3.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
 
12.2.4 Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.2.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 


 
 
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sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 
is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
12.2.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
12.2.5 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
 


 
 
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12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
12.3.1 Evaluable Disease 
The presence of at least one lesion, with no lesion that can be accurately measured 
in at least one dimension.  Such lesions may be evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers or other reliable 
measures.  
 
12.3.2 Complete Response 
Disappearance of all evaluable disease. 
 
12.3.3 Partial response 
Partial responses cannot be determined in patients with evaluable disease 
 
12.3.4 Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), 
or Progressive Disease. 
 
12.3.5 Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. 
 
12.3.6 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
12.4.1 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
12.4.2 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions 
 
12.4.3 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2.1 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 


 
 
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course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 
 
 
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
12.4.4 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Table 5 in Section12.7.1. 
 
 


 
 
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12.5 
Response Criteria for Patients with Relapsed Acute Lymphoblastic Leukemia 
 
12.5.1 Complete Remission (CR) 
Attainment of an M1 bone marrow (< 5% blasts in the bone marrow aspirate or 
biopsy if aspirate not available) with no evidence of circulating blasts or 
extramedullary disease and with recovery of peripheral counts (absolute neutrophil 
count (ANC) > 500/μL and platelet count > 50,000/μL).  
 
12.5.2 Partial Remission (PR) 
Complete disappearance of circulating blasts and achievement of M2 marrow 
status (≥ 5% or < 25% blast cells in the bone marrow aspirate or biopsy if aspirate 
not available). Attainment of a bone marrow CR (above) with proven persistence 
of extramedullary disease qualifies as a PR. 
 
12.5.3 Partial Remission –Cytolytic (PRCL) 
Complete disappearance of circulating blasts and achievement of at least 50% 
reduction from baseline in bone marrow blast count. 
 
12.5.4 Stable Disease (SD)  
This is present when the patient fails to qualify for either a CR, PR, PRCL or 
progressive disease. 
 
12.5.5 Progressive Disease (PD) 
An increase of at least 25% in the maximum Absolute Peripheral Blast Count 
measured pre-therapy or during the first 14 days following start of therapy; or in 
patients who achieve a PR an increase in the bone marrow blast count of ≥ 25% 
relative to the minimum bone marrow blast count; or in patients who achieve a CR 
an increase in the bone marrow blast count to ≥ 5%, the development of new 
extramedullary disease, or other clinical evidence of progressive disease. 
 
12.6 
Response Criteria for Patients with CNS Tumors 
 
12.6.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
12.6.2 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
12.6.3 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 


 
 
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Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
12.6.4 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 
• 
Complete Response (CR): Disappearance of all target lesions. 
 
• 
Partial response (PR): ≥50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements. 
 
• 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of 
the two perpendicular diameters of all target lesions to qualify for PR, nor 
sufficient increase in a single target lesion to qualify for PD. 
 
• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
12.6.5 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
12.6.6 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
12.6.7 Overall Response Assessment 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 


 
 
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Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
 
12.7 
Best Response 
 
12.7.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
   
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>28 days Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>28 days Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once 
>28 days from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
 


 
 
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Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
Table 3.  Sequences of overall response assessments with corresponding best response. 
 
1st Assessment 
2nd Assessment Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
Table 4: Overall Response for Patients with Neuroblastoma and Measurable Disease 
 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
 
 


 
 
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Table 5: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease Only 
 
If patients are enrolled without disease measurable by CT/MRI, any new or newly identified lesion by CT/MRI 
that occurs during therapy would be considered progressive disease. 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
12.7.2 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
 


 
 
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13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the data collection packet 
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source.  The NCI, rather than a commercial distributor, may on some occasions 
distribute commercial agents for a trial. 
 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 4.0.  The 
descriptions and grading scales found in the revised CTCAE version 4.0 will be 
used 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 website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
Note:  This includes all events that occur within 30 days of the last dose of protocol 
treatment.  Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the 
agent(s) must also be reported according to the instructions in the table 
below. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
 


 
 
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Table A: 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 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 
7 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 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 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 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For 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 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 


 
 
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71 
 
birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 1 
Trials Utilizing an Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not clearly due 
to progressive disease must be reported via CTEP-AERS for an agent under a CTEP or non-CTEP 
IND agent per the timelines outlined in the table above. 
 
• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), does 
not require expedited reporting, unless it is associated with hospitalization. 
Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
• Grade 1 and 2 adverse events listed in the table below do not require expedited reporting via CTEP-
AERS: 
 
Category 
Adverse Events 
GASTROINTESTINAL DISORDERS 
Nausea 
GASTROINTESTINAL DISORDERS 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
NERVOUS SYSTEM DISORDERS 
Dizziness 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Alopecia 
 
• See also the Specific Protocol Exceptions to Expedited Reporting (SPEER) in Section 9.1.7 of the 
protocol.   
 
As referenced in the CTEP Adverse Events Reporting Requirements, an AE that resolves and then recurs 
during a subsequent cycle does not require CTEP-AERS reporting unless (1) the Grade increases; or (2) 
hospitalization is associated with the recurring AE. 
 
13.2 
When to Report an Event in an Expedited Manner  
 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at: 
http://ctep.cancer.gov (telephone CTEP at: 301-897-7497 within 24 hours of becoming 
aware of the event if the CTEP-AERS 24-Hour Notification web-based application is 
unavailable) and by telephone call to the Study Chair. Once internet connectivity is 
restored, a 24-hour notification phoned in must be entered electronically into CTEP-
AERS by the original submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 


 
 
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72 
 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited 
Reporting 
System), 
accessed 
via 
the 
CTEP 
home 
page 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.h
tm. 
 
13.3 
Expedited Reporting Methods  
 
13.3.1 CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the CTEP Adverse Event 
Reporting System (CTEP-AERS) that can be found at http://ctep.cancer.gov. 
 
A CTEP-AERS report must be submitted electronically via the CTEP-AERS 
Web-based application located at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm.  If prompted to enter a sponsor email address, please type in: 
COGCADEERS@childrensoncologygroup.org. 
 
Fax supporting documentation to the NCI (fax # 301-230-0159) and send by email 
to the ADVL1411 COG Study Assigned Research Coordinator.  ALWAYS 
include the ticket number on all faxed and emailed documents. 
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG data 
submission forms and do not alter the guidelines for CTEP-AERS reporting. 
 
13.4.1 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
13.4.2 If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
13.4.3 The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
13.4.4 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than Grade 1, whichever level is higher (note that the resolution 
date may therefore be different from the date at which the grade of the AE 
decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."   
 
13.4.5 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
 


 
 
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13.5 
Other Recipients of Adverse Event Reports 
 
13.5.1 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the data 
form packet (See Section 14.1). 
 
13.5.2 COG will forward reports and supporting documentation to the Study Chair, to 
the FDA (when COG holds the IND) and to the pharmaceutical company (for 
industry sponsored trials). 
 
13.5.3 Adverse events determined to be reportable must also be reported according to 
the local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
13.6 
Reporting Secondary AML/MDS 
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 
[AML])  
• 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.  
 
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. 
 
13.7 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and faxed along with any 
additional medical information to (301) 230-0159 (see Appendix IX). Copies of all 
documents faxed to the NCI must also be emailed to the ADVL1411 COG Study Assigned 
Research Coordinator. The potential risk of exposure of the fetus to the investigational 
agent should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
 
13.7.1 Pregnancy 
• 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should be reported in an expedited manner via CTEP-AERS as 
“Pregnancy, puerperium and perinatal conditions - Other (Pregnancy) 


 
 
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under the Pregnancy, puerperium and perinatal conditions SOC and 
reported as Grade 3. 
 
• 
Pregnancy should be followed until the outcome is known at intervals 
deemed appropriate by her physicians. The “Pregnancy Information 
Form” should be used for all follow-ups. If the baby is born with a birth 
defect or other anomaly, then a second CTEP-AERS report is required. 
 
13.7.2 Fetal Death 
• 
Fetal death is defined in CTCAE as “A disorder characterized by death in 
utero; failure of the product of conception to show evidence of respiration, 
heartbeat, or definite movement of a voluntary muscle after expulsion 
from the uterus, without possibility of resuscitation.” 
 
• 
 Any fetal death should be reported expeditiously, as Grade 4 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC.  
 
• 
 A fetal death should NOT be reported as “Fetal death,” a Grade 5 event 
under the Pregnancy, puerperium and perinatal conditions SOC, as 
currently CTEP-AERS recognizes this event as a patient death. 
 
13.7.3 Death Neonatal 
• 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. 
 
• 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration- Other (neonatal loss)” under the General 
disorders and administration SOC. 
 
• 
Neonatal death should NOT be reported as “Death neonatal” under the 
General disorders and administration SOC, a Grade 5 event. If reported as 
such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
 
 


 
 
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14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories: 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the data form packet. 
 
See separate Data Form Packet, which includes submission schedule. 
 
 
 
14.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports 
are due January 31, April 30, July 31 and October 31.  This is not a responsibility of institutions 
participating in this trial. 
 
14.3 
CRADA/CTA/CSA 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement. 
 
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 investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 


 
 
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agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order 
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 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 


 
 
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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. 
 
 
14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.4.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the developmental therapy 
scientific committee; and a member from the NCI. The DSMC meets at least every 
6 months to review current study results, as well as data available to the DSMC 
from other related studies. Approximately 6 weeks before each meeting of the 
Phase 1 and 2 DSMC, study chairs will be responsible for working with the study 
statistician to prepare study reports for review by the DSMC. The DSMC will 
provide recommendations to the COG Developmental Therapeutics Chair and the 
Group Chair for each study reviewed to change the study or to continue the study 
unchanged. Data and Safety Committee reports for institutional review boards can 
be prepared using the public data monitoring report as posted on the COG Web 
site. 
 
14.4.2 Monitoring by the Study Chair and Developmental Therapeutics Leadership  
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the 
Developmental Therapeutics Chair, Vice Chair and Statistician on a weekly 
conference call. 


 
 
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REFERENCES 
1. Smith MA, Kang M, Reynolds CP, et al: Pediatric Preclinical Testing Program (PPTP) evaluation of BMN 673, 
an inhibitor of Poly-ADP Ribose Polymerase (PARP), alone and with Temozolomide (TMZ). Mol Cancer Ther 
12(11 Suppl):Abstr #C206, 2013. 
2. de Murcia JM, Niedergang C, Trucco C, et al: Requirement of poly(ADP-ribose) polymerase in recovery from 
DNA damage in mice and in cells. Proc Natl Acad Sci U S A 94:7303-7, 1997. 
3. Ruscetti T, Lehnert BE, Halbrook J, et al: Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) 
polymerase. J Biol Chem 273:14461-7, 1998. 
4. Bryant HE, Helleday T: Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for 
subsequent homologous recombination repair. Nucleic Acids Res 34:1685-91, 2006. 
5. Rouleau M, Patel A, Hendzel MJ, et al: PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10:293-301, 2010 
6. Murai J, Huang SY, Das BB, et al: Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 
72:5588-99, 2012. 
7. Kummar S, Chen A, Parchment RE, et al: Advances in using PARP inhibitors to treat cancer. BMC Med 10:25, 
2012. 
8. Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic 
strategy. Nature 434:917-21, 2005. 
9. Mendes-Pereira AM, Martin SA, Brough R, et al: Synthetic lethal targeting of PTEN mutant cells with PARP 
inhibitors. EMBO Mol Med 1:315-22, 2009. 
10. Dean E, Middleton MR, Pwint T, et al: Phase I study to assess the safety and tolerability of olaparib in combination 
with bevacizumab in patients with advanced solid tumours. Br J Cancer 106:468-74, 2012. 
11. Kummar S, Ji J, Morgan R, et al: A phase I study of veliparib in combination with metronomic cyclophosphamide 
in adults with refractory solid tumors and lymphomas. Clin Cancer Res 18:1726-34, 2012. 
12. Yoshimoto K, Mizoguchi M, Hata N, et al: Complex DNA repair pathways as possible therapeutic targets to 
overcome temozolomide resistance in glioblastoma. Front Oncol 2:186, 2012. 
13. Tentori L, Graziani G, Gilberti S, et al: Triazene compounds induce apoptosis in O6-alkylguanine-DNA 
alkyltransferase deficient leukemia cell lines. Leukemia 9:1888-95, 1995. 
14. Quiros S, Roos WP, Kaina B: Processing of O6-methylguanine into DNA double-strand breaks requires two rounds 
of replication whereas apoptosis is also induced in subsequent cell cycles. Cell Cycle 9:168-78, 2010. 
15. Estlin EJ, Lashford L, Ablett S, et al: Phase I study of temozolomide in paediatric patients with advanced cancer. 
United Kingdom Children's Cancer Study Group. Br J Cancer 78:652-61, 1998. 
16. Nicholson HS, Krailo M, Ames MM, et al: Phase I study of temozolomide in children and adolescents with 
recurrent solid tumors: a report from the Children's Cancer Group. J Clin Oncol 16:3037-43, 1998. 
17. De Sio L, Milano GM, Castellano A, et al: Temozolomide in resistant or relapsed pediatric solid tumors. Pediatr 
Blood Cancer 47:30-6, 2006. 
18. Nicholson HS, Kretschmar CS, Krailo M, et al: Phase 2 study of temozolomide in children and adolescents with 
recurrent central nervous system tumors: a report from the Children's Oncology Group. Cancer 110:1542-50, 2007. 
19. Horton TM, Thompson PA, Berg SL, et al: Phase I pharmacokinetic and pharmacodynamic study of temozolomide 
in pediatric patients with refractory or recurrent leukemia: a Children's Oncology Group Study. J Clin Oncol 
25:4922-8, 2007. 
20. Casey DA, Wexler LH, Merchant MS, et al: Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-
Kettering experience. Pediatr Blood Cancer 53:1029-34, 2009. 
21. Mixon BA, Eckrich MJ, Lowas S, et al: Vincristine, irinotecan, and temozolomide for treatment of relapsed 
alveolar rhabdomyosarcoma. J Pediatr Hematol Oncol 35:e163-6, 2013. 
22. Castel V, Segura V, Berlanga P: Emerging drugs for neuroblastoma. Expert Opin Emerg Drugs 18:155-71, 2013 
23. Schlegel U: Primary CNS lymphoma. Ther Adv Neurol Disord 2:93-104, 2009. 
24. Horton JK, Wilson SH: Predicting enhanced cell killing through PARP inhibition. Mol Cancer Res 11:13-8, 2013. 
25. Horton TM, Jenkins G, Pati D, et al: Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic 
activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA 
methyltransferase activity. Mol Cancer Ther 8:2232-42, 2009. 
26. Daniel RA, Rozanska AL, Thomas HD, et al: Inhibition of poly(ADP-ribose) polymerase-1 enhances 
temozolomide and topotecan activity against childhood neuroblastoma. Clin Cancer Res 15:1241-9, 2009. 
27. Herman JD, Appelbaum H: Hereditary breast and ovarian cancer syndrome and issues in pediatric and adolescent 
practice. J Pediatr Adolesc Gynecol 23:253-8, 2010. 
28. Martinez-Borges AR, Petty JK, Hurt G, et al: Familial small cell carcinoma of the ovary. Pediatr Blood Cancer 
53:1334-6, 2009. 
29. Ming M, He YY: PTEN in DNA damage repair. Cancer Lett 319:125-9, 2012. 


 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
ADVL1411 
03/23/17 
 
 
79 
 
30. Rutkowski S, Cohen B, Finlay J, et al: Medulloblastoma in young children. Pediatr Blood Cancer 54:635-7, 2010. 
31. Bigner SH, Mark J, Friedman HS, et al: Structural chromosomal abnormalities in human medulloblastoma. Cancer 
Genet Cytogenet 30:91-101, 1988. 
32. Hartmann W, Digon-Sontgerath B, Koch A, et al: Phosphatidylinositol 3'-kinase/AKT signaling is activated in 
medulloblastoma cell proliferation and is associated with reduced expression of PTEN. Clin Cancer Res 12:3019-
27, 2006. 
33. Daniel RA, Rozanska AL, Mulligan EA, et al: Central nervous system penetration and enhancement of 
temozolomide activity in childhood medulloblastoma models by poly(ADP-ribose) polymerase inhibitor AG-
014699. Br J Cancer 103:1588-96, 2010. 
34. Jemal A, Siegel R, Xu J, et al: Cancer statistics, 2010. CA Cancer J Clin 60:277-300, 2010. 
35. Mego M, Cierna Z, Svetovska D, et al: PARP1 expression in testicular germ cell tumors [abstract]. Journal of 
Clinical Oncology 30:e15027, 2012. 
36. Cavallo F, Graziani G, Antinozzi C, et al: Reduced proficiency in homologous recombination underlies the high 
sensitivity of embryonal carcinoma testicular germ cell tumors to Cisplatin and poly (adp-ribose) polymerase 
inhibition. PLoS One 7:e51563, 2012. 
37. Rodriguez-Galindo C, Liu T, Krasin MJ, et al: Analysis of prognostic factors in ewing sarcoma family of tumors: 
review of St. Jude Children's Research Hospital studies. Cancer 110:375-84, 2007. 
38. Rodriguez-Galindo C, Navid F, Liu T, et al: Prognostic factors for local and distant control in Ewing sarcoma 
family of tumors. Ann Oncol 19:814-20, 2008. 
39. Leavey PJ, Mascarenhas L, Marina N, et al: Prognostic factors for patients with Ewing sarcoma (EWS) at first 
recurrence following multi-modality therapy: A report from the Children's Oncology Group. Pediatr Blood Cancer 
51:334-8, 2008. 
40. Womer RB, West MD, Krailo M, et al: Randomized comparison of every-two-week v. every-three-week 
chemotherapy in Ewing sarcoma family tumors (ESFT). [abstract]. Journal of Clinical Oncology 26:abstr. 10504, 
2008. 
41. Bhatia S, Krailo MD, Chen Z, et al: Therapy-related myelodysplasia and acute myeloid leukemia after Ewing 
sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group. Blood 
109:46-51, 2007. 
42. Ladenstein R, Lasset C, Pinkerton R, et al: Impact of megatherapy in children with high-risk Ewing's tumours in 
complete remission: a report from the EBMT Solid Tumour Registry. Bone Marrow Transplant 15:697-705, 1995. 
43. Meyers PA, Krailo MD, Ladanyi M, et al: High-dose melphalan, etoposide, total-body irradiation, and autologous 
stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin 
Oncol 19:2812-20, 2001. 
44. Janknecht R: EWS-ETS oncoproteins: the linchpins of Ewing tumors. Gene 363:1-14, 2005. 
45. Jedlicka P: Ewing Sarcoma, an enigmatic malignancy of likely progenitor cell origin, driven by transcription factor 
oncogenic fusions. Int J Clin Exp Pathol 3:338-47, 2010. 
46. Kovar H, Aryee DN, Jug G, et al: EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro. 
Cell Growth Differ 7:429-37, 1996. 
47. Lambert G, Bertrand JR, Fattal E, et al: EWS fli-1 antisense nanocapsules inhibits ewing sarcoma-related tumor 
in mice. Biochem Biophys Res Commun 279:401-6, 2000. 
48. Subbiah V, Anderson P, Lazar AJ, et al: Ewing's sarcoma: standard and experimental treatment options. Curr Treat 
Options Oncol 10:126-40, 2009. 
49. Baruchel S, Pappo A, Krailo M, et al: A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, 
Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: a report from the Children's Oncology Group. 
Eur J Cancer 48:579-85, 2012. 
50. Olmos D, Martins AS, Jones RL, et al: Targeting the Insulin-Like Growth Factor 1 Receptor in Ewing's Sarcoma: 
Reality and Expectations. Sarcoma 2011:402508, 2011. 
51. Brenner JC, Ateeq B, Li Y, et al: Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS 
gene fusion-positive prostate cancer. Cancer Cell 19:664-78, 2011. 
52. Brenner JC, Feng FY, Han S, et al: PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma. Cancer Res 
72:1608-13, 2012. 
53. Garnett MJ, Edelman EJ, Heidorn SJ, et al: Systematic identification of genomic markers of drug sensitivity in 
cancer cells. Nature 483:570-5, 2012. 
54. Brady N, Gaymes TJ, Cheung M, et al: Increased error-prone NHEJ activity in myeloid leukemias is associated 
with DNA damage at sites that recruit key nonhomologous end-joining proteins. Cancer Res 63:1798-805, 2003. 
55. Gaymes TJ, North PS, Brady N, et al: Increased error-prone non homologous DNA end-joining--a proposed 
mechanism of chromosomal instability in Bloom's syndrome. Oncogene 21:2525-33, 2002. 


 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
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80 
 
56. Gaymes TJ, Shall S, Farzaneh F, et al: Chromosomal instability syndromes are sensitive to poly ADP-ribose 
polymerase inhibitors. Haematologica 93:1886-9, 2008. 
57. Weston VJ, Oldreive CE, Skowronska A, et al: The PARP inhibitor olaparib induces significant killing of ATM-
deficient lymphoid tumor cells in vitro and in vivo. Blood 116:4578-87, 2010. 
58. Grabher C, von Boehmer H, Look AT: Notch 1 activation in the molecular pathogenesis of T-cell acute 
lymphoblastic leukaemia. Nat Rev Cancer 6:347-59, 2006. 
59. Weng AP, Ferrando AA, Lee W, et al: Activating mutations of NOTCH1 in human T cell acute lymphoblastic 
leukemia. Science 306:269-71, 2004. 
60. Silva A, Jotta PY, Silveira AB, et al: Regulation of PTEN by CK2 and Notch1 in primary T-cell acute 
lymphoblastic leukemia: rationale for combined use of CK2- and gamma-secretase inhibitors. Haematologica 
95:674-8, 2010. 
61. BioMarin Pharmaceutical Inc. BMN 673 Investigator's Brochure. Version 4.0- 29 JUL, 2013. 
62. Smith MA, Kang M, Reynolds CP, et al: Pediatric Preclinical Testing Program (PPTP) Evaluation of BMN 673, 
an inhibitor of Poly-ADP Ribose Polymerase (PARP), Alone and with Temozolomide (TMZ). EORTC-NCI-
AACR Molecular Targets and Cancer Therapeutics Meeting, 2013. 
63. deBono JS, Mina LA, Gonzalez M, et al: First-in-human trial of novel oral PARP inhibitor BMN 673 in patients 
with solid tumors [abstract]. Journal of Clinical Oncology 31:2850, 2013. 
64. Ramanathan RK, Wainberg ZV, Mina LA, et al: PARP inhibition with BMN 673 in ovarian and breast cancer 
patients with deleterious mutations of BRCA1 and BRCA2. ECC Abstract 29LBA, 2013. 
65. Wainberg ZV, De Bono J, Mina LA, et al: Update on first-in-human trial of novel PARP inhibitor BMN 673 in 
patients with solid tumors. EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Meeting Abstract 
C295, 2013. 
66. Su J, Thompson PA, Adesina A, et al: A phase I clinical trial of veliparib and temozolomide in children with 
recurrent central nervous system tumors: A Pediatric Brain Tumor Consortium report. [abstract]. J Clin Oncol 
31:2036, 2013. 
67. Henshaw JH, Zhou H, Herriott A, et al: Inhibition of PBMC PARP activity with the novel PARP 1/2 inhibitor 
BMN 673 in patients with advanced solid tumors. EORTC-NCI-AACR Molecular Targets and Cancer 
Therapeutics Meeting Abstract A220, 2013. 
68. Yang SX, Kummar S, Steinberg SM, et al: Immunohistochemical detection of poly(ADP-ribose) polymerase 
inhibition by ABT-888 in patients with refractory solid tumors and lymphomas. Cancer Biol Ther 8:2004-9, 2009. 
69. Kummar S, Kinders R, Gutierrez ME, et al: Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor 
ABT-888 in patients with advanced malignancies. J Clin Oncol 27:2705-11, 2009. 
70. Wang X, Weaver DT: The ups and downs of DNA repair biomarkers for PARP inhibitor therapies. Am J Cancer 
Res 1:301-327, 2011. 
71. Shukla N, Schiffman J, Reed D, et al: Biomarkers in Ewing Sarcoma: The Promise and Challenge of Personalized 
Medicine. A Report from the Children's Oncology Group. Front Oncol 3:141, 2013. 
72. Soldatenkov VA, Albor A, Patel BK, et al: Regulation of the human poly(ADP-ribose) polymerase promoter by 
the ETS transcription factor. Oncogene 18:3954-62, 1999. 
 
 
 


 
 
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APPENDIX I: PERFORMANCE STATUS SCALES/ SCORES 
 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 


 
 
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APPENDIX II-A: BMN 673 DOSING NOMOGRAM 
 
Note: Patients must have a BSA of ≥ 0.42 m2 at the time of study enrollment.  
NOTE: All doses for BMN 673 are in MICROGRAMS (mcg) 
 
 
 
Dose Level -1 to 1: Days 1-6 (Once Daily) 
BMN 673 Dose Assignment: 400 mcg/m2/dose 
Maximum Daily Dose is 800 mcg/Day 
  
BSA (m2) 
Total Dose (mcg/day) 
Number of 100 mcg 
capsules 
Number of 250 mcg 
capsules 
0.42-0.56 
200 
2 
0 
0.57-0.68 
250 
0 
1 
0.69-0.81 
300 
3 
0 
0.82-0.93 
350 
1 
1 
0.94-1.06 
400 
4 
0 
1.07-1.18 
450 
2 
1 
1.19-1.31 
500 
0 
2 
1.32-1.43 
550 
3 
1 
1.44-1.56 
600 
1 
2 
1.57-1.68 
650 
4 
1 
1.69-1.81 
700 
2 
2 
1.82-1.93 
750 
0 
3 
≥1.94 
800 
3 
2 
 
Dose Level 2: Day 1 (Twice Daily) 
BMN 673 Dose Assignment: 400 mcg/m2/dose 
Maximum Daily Dose is 800 mcg/Day 
 
BSA (m2) 
BMN 673 
AM 
Day 1 Dose 
(mcg/dose) 
BMN 673 
PM  
Day 1 Dose 
(mcg/dose) 
Number of 
100 mcg 
capsules per 
dose 
Number of 
250 mcg 
capsules per 
dose 
Total Dose 
(mcg/day) 
0.42-0.56 
200 
200 
2 
0 
400 
0.57-0.68 
250 
250 
0 
1 
500 
0.69-0.81 
300 
300 
3 
0 
600 
0.82-0.93 
350 
350 
1 
1 
700 
≥0.94 
400 
400 
4 
0 
800 
 
 Dose Level 2: Days 2-6 (Once Daily) 
BSA (m2) 
Total Dose  
(mcg/ day) 
Number of 100 
mcg capsules 
Number of 250 
mcg capsules 
0.42-0.56 
200 
2 
0 
0.57-0.68 
250 
0 
1 
0.69-0.81 
300 
3 
0 
0.82-0.93 
350 
1 
1 
0.94-1.06 
400 
4 
0 
1.07-1.18 
450 
2 
1 
1.19-1.31 
500 
0 
2 
1.32-1.43 
550 
3 
1 
1.44-1.56 
600 
1 
2 
1.57-1.68 
650 
4 
1 
1.69-1.81 
700 
2 
2 
1.82-1.93 
750 
0 
3 
≥1.94 
800 
3 
2 


 
 
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Dose Levels 3 to 6: Day 1 (Twice Daily) 
BMN 673 Dose Assignment: 600 mcg/m2/dose 
Maximum Daily Dose is 1000 mcg/Day 
 
BSA (m2) 
BMN 673 
AM  
Day 1 Dose 
(mcg/dose) 
BMN 673 
PM  
Day 1 Dose 
(mcg/dose) 
Number of 
100 mcg 
capsules per 
dose 
Number of 
250 mcg 
capsules per 
dose 
Total Dose 
(mcg/day) 
0.42-0.45 
250 
250 
0 
1 
500 
0.46-0.54 
300 
300 
3 
0 
600 
0.55-0.62 
350 
350 
1 
1 
700 
0.63-0.70 
400 
400 
4 
0 
800 
0.71-0.79 
450 
450 
2 
1 
900 
≥0.80 
500 
500 
0 
2 
1000 
 
Dose Levels 3 to 6: Days 2-6 (Once Daily) 
BSA (m2) 
Total Dose 
(mcg/day) 
Number of 100 mcg 
capsules 
Number of 250 mcg 
capsules 
0.42-0.45 
250 
0 
1 
0.46-0.54 
300 
3 
0 
0.55-0.62 
350 
1 
1 
0.63-0.70 
400 
4 
0 
0.71-0.79 
450 
2 
1 
0.80-0.87 
500 
0 
2 
0.88-0.95 
550 
3 
1 
0.96-1.04 
600 
1 
2 
1.05-1.12 
650 
4 
1 
1.13-1.20 
700 
2 
2 
1.21-1.29 
750 
0 
3 
1.30-1.37 
800 
3 
2 
1.38-1.45 
850 
1 
3 
1.46-1.54 
900 
4 
2 
1.55-1.62 
950 
2 
3 
≥1.63 
1000 
0 
4 
 


 
 
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APPENDIX II-B: TEMOZOLOMIDE DOSING NOMOGRAM 
 
Note: Patients must have a BSA of ≥ 0.42 m2 at the time of study enrollment. 
 
Dose Level -1: Days 2-6 (Once Daily) 
Temozolomide Dose Assignment: 15 mg/m2/dose 
BSA (m2) 
Total Daily Dose (mg/day) 
0.42-0.62 
5 
0.63-0.87 
10 
0.88-1.16 
15 
1.17-1.50 
20 
1.51-1.83 
25 
1.84-2.16 
30 
2.17- ≥2.30 
35 
 
Dose Level 1, 2 and 3: Days 2-6 (Once Daily) 
Temozolomide Dose Assignment: 20 mg/m2/dose 
BSA (m2) 
Total Daily Dose (mg/day) 
0.42-0.62 
10 
0.63-0.87 
15 
0.88-1.12 
20 
1.13-1.37 
25 
1.38-1.62 
30 
1.63-1.87 
35 
1.88-2.12 
40 
2.13- ≥2.30 
45 
 
Dose Level 4: Days 2-6 (Once Daily) 
Temozolomide Dose Assignment: 30 mg/m2/dose 
BSA (m2) 
Total Daily Dose (mg/day) 
0.42-0.58 
15 
0.59-0.75 
20 
0.76-0.91 
25 
0.92-1.08 
30 
1.09-1.25 
35 
1.26-1.41 
40 
1.42-1.58 
45 
1.59-1.75 
50 
1.76-1.91 
55 
1.92-2.08 
60 
2.09-2.24 
65 
2.25- ≥2.30 
70 


 
 
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85 
 
Dose Level 5: Days 2-6 (Once Daily) 
Temozolomide Dose Assignment: 40 mg/m2/dose 
BSA (m2) 
Total Daily Dose (mg/day) 
0.42-0.56 
20 
0.57-0.68 
25 
0.69-0.81 
30 
0.82-0.93 
35 
0.94-1.06 
40 
1.07-1.18 
45 
1.19-1.31 
50 
1.32-1.43 
55 
1.44-1.56 
60 
1.57-1.68 
65 
1.69-1.81 
70 
1.82-1.93 
75 
1.94-2.06 
80 
2.07-2.18 
85 
2.19- ≥2.30 
90 
 
 
Dose Level 6: Days 2-6 (Once Daily) 
Temozolomide Dose Assignment: 55 mg/m2/dose 
BSA (m2) 
Total Daily Dose (mg/day) 
0.42-0.50 
25 
0.51-0.59 
30 
0.60-0.68 
35 
0.69-0.77 
40 
0.78-0.86 
45 
0.87-0.95 
50 
0.96-1.04 
55 
1.05-1.13 
60 
1.14-1.22 
65 
1.23-1.31 
70 
1.32-1.40 
75 
1.41-1.50 
80 
1.51-1.59 
85 
1.60-1.68 
90 
1.69-1.77 
95 
1.78-1.86 
100 
1.87-1.95 
105 
1.96-2.04 
110 
2.05-2.13 
115 
2.14-2.22 
120 
2.23- ≥2.30 
125 
  
 


 
 
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APPENDIX III-A: PATIENT DIARY INSTRUCTIONS FOR BMN 673 AND TEMOZOLOMIDE 
(FOR DOSE LEVELS -1 TO 1) 
 
COG Patient ID:___________   Acc#_________________ 
Institution:________________________________ 
Please do not write patient names on this form. 
 
 
 
 
  Part of the Study (tick one): □ A1 □ A2 □ B □ C         Body Surface Area: _____ m2       Cycle Start Date: ___/___/___ 
 
NOTE:  BMN 673 dose and capsule strengths are in MICROGRAMS (mcg). 
 
Complete each day with the time BMN 673 and temozolomide are given. Make note of other drugs and supplements 
taken under the Comments section below.  
 
On Days 2 to 6, BMN 673 should be taken immediately prior to temozolomide. Note the time you take the medication 
in the Time column next to the drug name.  
 
The prescribed medication can be taken without food or drink restrictions. The only exception to this instruction is 
during pharmacokinetic study days for Part A patients (Phase 1) during Cycle 1: Day 1, and Day 5 or 6 
medication should be taken in the clinic on an empty stomach (1 hour before or 2 hours after food).   Patients 
enrolled on Part A and who consent to Day 2 pharmacokinetic studies during Cycle 1 should take their 
medication in the clinic. 
 
The capsules should not be opened or crushed but should be swallowed whole. If the capsule is broken and the 
powder of the capsules gets on your skin, wash the exposed area with as much water as necessary.  Inform your study 
doctor or nurse immediately for additional instructions.  
 
If you vomit after taking BMN 673 and/or temozolomide within 30 minutes, that dose of BMN 673 and/or 
temozolomide may be repeated. You should contact your study doctor if you have vomiting and re-take the dose. 
If you vomit more than 30 minutes after taking either BMN 673 and /or temozolomide, that dose of BMN 673 and/or 
temozolomide will be missed.  
 
If you miss a BMN 673 or temozolomide dose and less than 6 hours have passed since the scheduled dosing time, 
that dose should be taken immediately. If you miss a BMN 673 or temozolomide dose and more than 6 hours have 
passed since the scheduled dosing time, that dose of BMN 673 or temozolomide will be missed; wait and take the next 
regularly scheduled BMN 673 or temozolomide dose. 
 
Add the dates to the calendar below and return the completed diary (Appx. III-B) to your institution after each treatment 
cycle. Your institution will upload this document into RAVE (the database to send it to the COG) after each treatment 
cycle. 
 
 
 
 
 
EXAMPLE                     *************** INSTITUTION USE ONLY *************** 
 
# of  prescribed BMN 673 capsules/ dose 
 100 mcg 
250 mcg 
1 
2 
# of prescribed temozolomide capsules/ dose 
 5 mg 
20 mg 
100 mg 
2 
1 
 
   
 
EXAMPLE 
Date 
Time 
# of BMN 673 capsules 
taken 
# temozolomide capsules 
taken  
Comments 
WEEK 1 
100 mcg 
250 mcg 
5 mg 
20 mg 
100 mg 
Day 1 
Wednesday 
1/15/14 
BMN 
673 
 
8:30 
AM 
 
1 
 
2 
 
 
He felt nauseated an hour 
after taking the drug but did 
not vomit. 
 
Day 2 
Thursday 
1/16/14 
BMN 
673 
8:30 
AM 
1 
2 
 
He felt the same as on Day 1.  
Temoz. 
8.32 
AM 
 
2 
1 
 


 
 
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87 
 
APPENDIX III-B: PATIENT DIARY FOR BMN 673 AND TEMOZOLOMIDE (FOR DOSE 
LEVELS -1 TO 1) 
  
COG Patient ID:___________   Acc#_________________ 
Institution:________________________________ 
Please do not write patient names on this form. 
 
 
 
 
Part of the Study (tick one):□ A1 □ A2 □ B □ C         Body Surface Area: _____ m2       Cycle Start Date: ___/___/___ 
 
NOTE:  BMN 673 dose and capsule strengths are in MICROGRAMS (mcg). 
 
 
 
 
 
 
 
*************** INSTITUTION USE ONLY *************** 
 
# of  prescribed BMN 673 capsules/ dose 
 100 mcg 
250 mcg 
 
 
# of prescribed temozolomide capsules/ dose 
 5 mg 
20 mg 
100 mg 
 
 
 
  
 
Cycle #: _____                                       BMN 673 Dose Level: ______mcg/m2/dose                
                                   Temozolomide Dose Level: ______mg/m2/dose   
 
WEEK 1 
Date 
Time 
# of BMN 673 
capsules taken 
# temozolomide 
capsules taken  
Comments 
100 
mcg 
250 
mcg 
5  
mg 
20  
mg 
100 
mg 
Day 1 
 
BMN 673  
 
 
 
 
 
Day 2 
 
BMN 673 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
Day 3 
 
BMN 673 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
Day 4 
 
BMN 673 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
Day 5 
 
BMN 673 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
Day 6 
 
BMN 673 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
Day 7 
 
 
 
 
WEEK 2 
(Days 8-14) 
 
 
 
 
WEEK 3 
(Days 15-21) 
 
 
 
 
WEEK 4 
(Days 22-28) 
 
 
 
 
 
 


 
 
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APPENDIX III-C: PATIENT DIARY INSTRUCTIONS FOR BMN 673 AND TEMOZOLOMIDE 
(FOR DOSE LEVELS 2 TO 6) 
 
COG Patient ID:___________   Acc#_________________ 
Institution:________________________________ 
Please do not write patient names on this form. 
 
 
 
 
  Part of the Study (tick one): □ A1 □ A2 □ B □ C         Body Surface Area: _____ m2       Cycle Start Date: ___/___/___ 
 
NOTE:  BMN 673 dose and capsule strengths are in MICROGRAMS (mcg). 
 
Complete each day with the time BMN 673 and temozolomide are given. Make note of other drugs and supplements 
taken under the Comments section below.  
 
On Day 1, the first and second dose of BMN 673 should be taken 12 hours apart. On Days 2 to 6, BMN 673 should be 
taken immediately prior to temozolomide; note the time you take the medication in the Time column next to the drug 
name.  
 
The prescribed medication can be taken without food or drink restrictions. The only exception to this instruction is 
during pharmacokinetic study days for Part A patients (Phase 1) during Cycle 1: Day 1, and Day 5 or 6 
medication should be taken in the clinic on an empty stomach (1 hour before or 2 hours after food). Patients 
enrolled on Part A and who consent to Day 2 pharmacokinetic studies during Cycle 1 should take their 
medication in the clinic. 
 
The capsules should not be opened or crushed but should be swallowed whole. If the capsule is broken and the 
powder of the capsules gets on your skin, wash the exposed area with as much water as necessary.  Inform your study 
doctor or nurse immediately for additional instructions.  
 
If you vomit after taking BMN 673 and/or temozolomide within 30 minutes, that dose of BMN 673 and/or 
temozolomide may be repeated. You should contact your study doctor if you have vomiting and re-take the dose. 
If you vomit more than 30 minutes after taking either BMN 673 and /or temozolomide, that dose of BMN 673 and/or 
temozolomide will be missed.  
 
If you miss a BMN 673 or temozolomide dose and less than 6 hours have passed since the scheduled dosing time, 
that dose should be taken immediately. If you miss a BMN 673 or temozolomide dose and more than 6 hours have 
passed since the scheduled dosing time, that dose of BMN 673 or temozolomide will be missed; wait and take the next 
regularly scheduled BMN 673 or temozolomide dose. 
 
Add the dates to the calendar below and return the completed diary (Appx. III-D) to your institution after each treatment 
cycle. Your institution will upload this document into RAVE (the database to send it to the COG) after each treatment 
cycle. 
 
 
 
 
EXAMPLE                     *************** INSTITUTION USE ONLY *************** 
 
 
# of  prescribed BMN 673 capsules/ dose 
 100 mcg 
250 mcg 
Day 1 
0 
2 
Days 2-6 
0 
3 
# of prescribed temozolomide capsules/ dose 
 5 mg 
20 mg 
100 mg 
2 
1 
 
 
 
EXAMPLE 
Date 
Time 
# of BMN 673 capsules 
taken 
# temozolomide capsules 
taken  
Comments 
WEEK 1 
100 mcg 
250 mcg 
5 mg 
20 mg 
100 mg 
 
Day 1 
Wednesday 
1/15/14 
BMN 
673 
8:30 
AM 
0 
2 
 
He felt nauseated an hour 
after taking the drug but did 
not vomit. 
BMN 
673 
8:30 
PM 
0 
2 
 
Day 2 
Thursday 
1/16/14 
BMN 
673 
8:30 
AM 
0 
3 
 
He felt the same as on Day 1.  
Temoz. 
8.32 
AM 
 
2 
1 
 


 
 
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89 
 
 
APPENDIX III-D: PATIENT DIARY FOR BMN 673 AND TEMOZOLOMIDE (FOR DOSE 
LEVELS 2 TO 6) 
  
COG Patient ID:___________   Acc#_________________ 
Institution:________________________________ 
Please do not write patient names on this form. 
 
 
 
 
Part of the Study (tick one):□ A1 □ A2 □ B □ C         Body Surface Area: _____ m2       Cycle Start Date: ___/___/___ 
 
NOTE:  BMN 673 dose and capsule strengths are in MICROGRAMS (mcg). 
 
 
 
 
 
 
 
*************** INSTITUTION USE ONLY *************** 
 
 
 
# of  prescribed BMN 673 capsules/ dose 
 100 mcg 
250 mcg 
Day 1 
 
 
Days 2-6 
 
 
 
# of prescribed temozolomide capsules/ dose 
 5 mg 
20 mg 
100 mg 
 
 
 
  
 
Cycle #: _____                                       BMN 673 Dose Level: ______mcg/m2/dose                
                                   Temozolomide Dose Level: ______mg/m2/dose   
 
WEEK 1 
Date 
Time 
# of BMN 673 
capsules taken 
# temozolomide 
capsules taken  
Comments 
100 
mcg 
250 
mcg 
5  
mg 
20  
mg 
100 
mg 
Day 1 
 
BMN 673 (AM) 
 
 
 
 
 
BMN 673 (PM) 
 
 
 
Day 2 
 
BMN 673 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
Day 3 
 
BMN 673 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
Day 4 
 
BMN 673 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
Day 5 
 
BMN 673 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
Day 6 
 
BMN 673 
 
 
 
 
 
Temozolomide 
 
 
 
 
 
Day 7 
 
 
 
 
WEEK 2 
(Days 8-14) 
 
 
 
 
WEEK 3 
(Days 15-21) 
 
 
 
 
WEEK 4 
(Days 22-28) 
 
 
 
 
 


 
 
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90 
 
 
 
APPENDIX IV: CORRELATIVE STUDIES GUIDE 
 
                              
 
For Part A (Phase 1) 
 
Correlative  
Study 
 
Appendix 
Blood Volume 
 
 
Tube Type 
Volume 
per 
sample 
Total  
Cycle 1 
≤ 10 kg 
Total  
Cycle 1 
> 10 kg 
Pharmacokineticsa 
V 
2-3 mL 
36 mL 
42 mL 
K3EDTA lavender top (BMN 673 PK studies) 
Heparinized containing sodium (temozolomide PK studies) 
Pharmacokineticsb 
3 mL 
3 mL 
3 mL 
K3EDTA lavender top (BMN 673 PK studies) 
Total Blood Volume in Cycle 1 
 
39 mL 
45 mL 
 
a Required for all patients  
b Optional for all patients  
 
                                     
For Part B (Phase 2) 
 
Correlative Study 
 
Appendix 
Tumor Tissuea 
VIII 
 
 
 
      a Required from all Part B Patients  


 
 
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91 
 
APPENDIX V: PHASE 1 PHARMACOKINETIC STUDY FORM FOR BMN 673 AND TEMOZOLOMIDE 
(PART A ONLY) 
 
COG Pt ID # ______________ 
   ACC # ___________    Cycle 1, Day 1 Date: ___/___/___ 
Body Surface Area: ______m2    
Please do not write patient names on this form or on samples.            Institution: ____________________________  Weight: ______kg                 
                   
 
 
BMN 673 Dose Level:  ______mcg/m2/ dose     Temozolomide Dose Level: ________mg/m2/dose 
Total Dose Day 1: ______mcg/day BMN 673 
 
 
Total Dose Day 5 or 6: ______mcg/day BMN 673                     
                                         
 
 
 
 
 
                        ______mg/day Temozolomide 
 
Plasma samples (2-3 mL per sample) will be collected at the following time points during Cycle 1:  
• Day 1 (Required from all patients): Pre-dose, and then at 1, 2, 4 and 8 hours after the first BMN 673 morning dose. 
• Day 2 (optional): Pre-dose on Day 2 (24 hours after the first BMN 673 dose on Day 1) from consenting patients. 
• Day 5 or 6 (Required from all patients): Pre-dose, and then at 1, 2, 4 and 8 hours after BMN 673 and temozolomide administration.  
• Day 8 and Day 15 (Required from patients > 10 kg): These samples are collected at time of CBC evaluation. 
 
Refer to Section 8.3.2 for detailed instructions regarding food and drink restrictions during pharmacokinetic study days. Record the 
exact date and time each sample is drawn. Sample handling and processing instructions for BMN 673 and temozolomide are in 
Section 8.3. Note: BMN 673 samples must be maintained at room temperature during collection and processing. Temozolomide 
samples should be maintained at 4 oC during collection and processing. 
 
Blood 
Sample 
No. 
Time Point 
 
Scheduled Collection 
Time 
 Scheduled Time 
Point  
 Actual Dose   
Administered 
To Patient 
Actual Date 
Sample 
Collected or 
Dose Given 
Actual Time 
Collected or 
Dose Given 
(24-hr clock) 
1 
Cycle 1, Day 1 
Prior to Cycle 1, Day 1@ 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, Day 1 
 
BMN 673 AM 
Dose  
________mcg 
___/___/___ 
|__|__| : |__|__| 
2 
Cycle 1, Day 1 
1 hr after 1st dose 
 
___/___/___ 
|__|__| : |__|__| 
3 
Cycle 1, Day 1 
2 hr after 1st dose 
 
___/___/___ 
|__|__| : |__|__| 
4 
Cycle 1, Day 1 
4 hrs after 1st dose 
 
___/___/___ 
|__|__| : |__|__| 
5 
Cycle 1, Day 1 
8 hrs after 1st dose 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, Day 1 
 
BMN 673 PM 
Dose + 
________mcg 
___/___/___ 
|__|__| : |__|__| 
6 
Cycle 1, Day 2 
24 hrs after 1st dose* 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1,  
Day 5 or 6 
 
7 
Cycle 1,  
Day 5 or 6 
Prior to Cycle 1, Day 5 or 
6 dose of BMN 673@ 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1,  Day 5 or 6 
BMN 673 Dose 
________mcg 
___/___/___ 
|__|__| : |__|__| 
Temozolomide 
Dose 
_________mg 
___/___/___ 
|__|__| : |__|__| 
8 
Cycle 1, Day 5 or 6 
1 hr after dose@ 
 
___/___/___ 
|__|__| : |__|__| 
9 
Cycle 1, Day 5 or 6 
2 hr after dose@ 
 
___/___/___ 
|__|__| : |__|__| 
10 
Cycle 1, Day 5 or 6 
4 hrs after dose@ 
 
___/___/___ 
|__|__| : |__|__| 
11 
Cycle 1, Day 5 or 6 
8 hrs after dose@ 
 
___/___/___ 
|__|__| : |__|__| 
 
  12^ 
Cycle 1, Day 8 
 
___/___/___ 
|__|__| : |__|__| 
  13^ 
Cycle 1, Day 15 
 
___/___/___ 
|__|__| : |__|__| 
@ Two consecutive 2 mL blood samples will be collected (a total of 4 mL). Sample 1: Follow BMN 673 PK processing and shipping 
requirements in Section 8.3.4.1. Sample 2: Follow temozolomide PK processing and shipping requirements in Section 8.3.4.2.  
+   Only applicable for Dose Levels 2 to 6. The 2nd dose of BMN 673 on Day 1 of Cycle 1 should be administered 12 hours after 
the first dose of BMN 673. 
*   Optional pre-dose sample on Day 2. 
^  Patients > 10 kg only. 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. Another copy should be sent with the samples 
to the address listed in Appendix VI and Appendix VII. See Appendix VI and Appendix VII for detailed guidelines for 
packaging and shipping PK samples to Alliance Pharma and the Mayo Clinic, respectively.   
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: ______________________________________________                    Date:__________________________ 
 
 
(site personnel who collected samples) 


 
 
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92 
 
 
APPENDIX VI: GUIDELINES FOR SHIPPING PK SAMPLES TO ALLIANCE PHARMA 
 
1. Ship PK plasma samples to Alliance Pharma when requested (see Step 6 below). The PK samples 
should be batched for shipping at the end of Cycle 1. 
2. Place samples grouped by patient in a cryobox. Ensure the cryobox is closed and remains so in 
transit using shipping tape. Place the cryobox in a shipping container with sufficient dry ice to 
maintain samples at -20 oC for at least 72 hours.  
3. Each shipment should be prepared in accordance with IATA regulations.  
4. Samples must be shipped at least 3 days prior to US National Holiday. A holiday schedule will be 
provided.  
5. Frozen samples should be shipped via overnight FedEx, Monday through Wednesday. No 
shipments should be made later than Wednesday of any given week.  
6. Before shipment: Clinical sites will arrange for the timing of the shipment with Alliance 
Pharma. For questions regarding sample shipment, contact Lara Graham via email 
(lgraham@alliancepharmaco.com) or by phone (610-296-3152). 
7. On the day of shipment: Email a copy of the completed pharmacokinetic study form (Appendix 
V) and the tracking number to Lara Graham (lgraham@alliancepharmaco.com) and copy the 
ADVL1411COG Study Assigned Research Coordinator on the email. 
8. Ship the PK samples to the following address and include a completed copy of Appendix V with 
the shipment: 
    Attention: Lara Graham 
Sample Management 
Alliance Pharma 
17 Lee Blvd. 
Malvern, PA19355 
Phone: 610-296-3152 
Email: lgraham@alliancepharmaco.com 
 
Email the sample information and tracking # to lgraham@alliancepharmaco.com and 
linh.nguyen@medivation.com at time of shipment. Use FedEx Account# 2919-4462-0 for these 
shipments. 
 
 
 
 
 


 
 
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APPENDIX VII: GUIDELINES FOR SHIPPING PK SAMPLES TO THE MAYO CLINIC 
 
1. Day 1 pre-dose, and Day 5 or 6 PK samples should be batched, maintained at -70 oC until 
shipment, and shipped together for each patient at the end of Cycle 1.   
2. Place samples in a cryobox. Ensure the cryobox is closed and remains so in transit using shipping 
tape. Place the cryobox in a shipping container with sufficient dry ice to maintain samples at -20 
oC for at least 72 hours.  
3. Each shipment should be prepared in accordance with IATA regulations.  
4. Frozen samples should be shipped via overnight FedEx, Monday through Wednesday. No 
shipments should be made later than Wednesday of any given week.  
5. On the day of shipment: Email a copy of the completed pharmacokinetic study form (Appendix 
V) and the tracking number to Dr. Joel Reid (reid.joel@mayo.edu) and copy the ADVL1411 
COG Study Assigned Research Coordinator on the email. 
6. Ship the PK samples to the following address and include a completed copy of Appendix V with 
the shipment: 
 
    Attention: Dr. Joel M. Reid 
Department of Oncology 
Mayo Clinic 
Room 19-151, Gonda Building 
200 First Street SW 
Rochester, MN 55905. 
Phone (507) 284-0822 
Fax (507) 284-3906 
Email: reid.joel@mayo.edu 
 


 
 
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94 
 
APPENDIX VIII: PHASE 2 TUMOR TISSUE STUDY FORM (PART B ONLY) 
 
 COG Pt ID # ___________ 
ACC # _______          Cycle 1, Day 1 Date: ___/___/___ 
Institution: ____________ 
     Please do not write patient names on this form or on samples. 
                 
BMN 673 Dose Level: _______mcg/m2/ dose 
Temozolomide Dose Level: ______mg/m2/dose 
Total Dose Day 1:      ______mcg/day BMN 673 
Total Dose Days 2-6:  ______mcg/day  BMN 673           
                                     ______mg/day  Temozolomide 
BSA: _____ m2   
Tumor sample scheduling and collection: 
See Section 8.4 for schedule details. A paraffin-embedded tissue block should be submitted. If a tissue 
block is unavailable, at least 10 unstained standard sections of 3 to 4 μM thickness must be sent (15 slides 
are recommended). 
 
Tumor sample labeling 
Samples should be labeled with the following information: 
 
Protocol Number: 
ADVL1411 
Institution: 
 
COG Patient ID #: 
 
Accession #: 
 
Sample Date: 
 
Site of Acquired 
Tissue: 
 
Time tissue obtained at (check one option): 
□ Diagnosis           □ Relapse 
□ After the start of ADVL1411 treatment 
 
On the day of shipment:  
Email shipment notifications (including the FedEx tracking number) along with a completed copy of this 
form to the laboratory manager, Eva Loranc (Loranc@uthscsa.edu). Dr. Alex Bishop 
(bishopa@uthscsa.edu) and the ADVL1411 COG Study Assigned Research Coordinator should also 
be copied on this email.  
For questions regarding sample shipments sites may contact Eva Loranc by phone (business hours: 210-
562-9066; after hours: 210-364-7900) or by email (Loranc@uthscsa.edu). 
Shipment of tumor tissue (Monday through Thursday via overnight FedEx):  
Please indicate above the date of the sample, site of tissue acquisition and whether it was obtained at 
diagnosis, relapse, or after the start of ADVL1411 treatment. Paraffin embedded tumor specimens must 
be packaged appropriately and shipped at room temperature to Dr. Alex Bishop’s laboratory as stated 
below.  
  Attention: Eva Loranc  
                  Dr. Alex Bishop Laboratory 
  Greehey Children's Cancer Research Institute 
  The University of Texas Health Science Center 
  8403 Floyd Curl Dr. 
  San Antonio TX, 78229 
  Phone: 210-562-9066 
 
This form must accompany the patient samples at time of shipment, and one copy of the form should be 
uploaded into RAVE. Please include one form per patient per time point in each shipment. 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: ___________________________________________             Date:______________________ 
 
 
(site personnel who collected samples).   


 
 
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APPENDIX IX: PREGNANCY INFORMATION FORM 
 
Attach to CTEP-AERS 5-Day Report 
 
 
 
NOTE: For an initial reporting fax both the Pregnancy CTEP-AERS Report and this additional Pregnancy Information Form. For follow-
up reporting, fax only this Pregnancy Information Form (See Section 13.7). Copies of all documents that are faxed to the NCI during initial 
and follow-up reporting must also be sent via email to the ADVL1411 Study Assigned Research Coordinator.