NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- A Phase 2 Subprotocol of Olaparib in Patients With Tumors Harboring Defects in DNA Damage Repair Genes
Phase: PHASE2
Conditions: Advanced Malignant Solid Neoplasm, Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma, Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma, Low Grade Glioma, Malignant Glioma, Recurrent Childhood Central Nervous System Neoplasm, Recurrent Childhood Ependymoma, Recurrent Childhood Malignant Germ Cell Tumor, Recurrent Childhood Non-Hodgkin Lymphoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Osteosarcoma, Refractory Childhood Malignant Germ Cell Tumor, Refractory Ependymoma, Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Refractory Glioma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Rhabdoid Tumor, Wilms Tumor
Sponsor: National Cancer Institute (NCI)



 
    
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TABLE OF CONTENTS 
SECTION 
PAGE 
CHILDREN’S ONCOLOGY GROUP 
4 
STUDY COMMITTEE 
5 
STUDY COMMITTEE, CONT. 
6 
COG OPERATIONS STAFF 
6 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
 
Primary Aims 
8 
 
Secondary Aims 
8 
 
Exploratory Aims 
8 
2.0 
BACKGROUND 
8 
 
Introduction/Rationale for Development 
8 
 
Preclinical Studies of Olaparib 
11 
 
Adult Studies 
12 
 
Pediatric Studies 
14 
 
Overview of Proposed Pediatric Study 
14 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
15 
 
Genetic Screening Procedures for Eligibility 
15 
 
IRB Approval 
15 
 
Informed Consent/Assent 
16 
 
Screening Procedures 
16 
 
Eligibility Checklist 
16 
 
Study Enrollment 
16 
 
Institutional Pathology Report 
17 
 
Dose Assignment 
17 
4.0 
PATIENT ELIGIBILITY 
17 
 
Inclusion Criteria 
17 
 
Exclusion Criteria 
20 
5.0 
TREATMENT PROGRAM 
22 
 
Overview of Treatment Plan 
22 
 
Criteria for Starting Subsequent Cycles 
23 
 
Grading of Adverse Events 
23 
 
Definition of Dose-Limiting Toxicity (DLT) 
23 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
24 
 
Dose Modifications for Hematological Toxicity 
24 
 
Dose Modifications for Non-Hematological Toxicity 
24 
 
Dose Modifications for Pulmonary Toxicity 
25 
 
Dose Modification for Surgery 
25 
 
Dose Interruption for Conditions Other than Toxicity 
25 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
25 
 
Concurrent Anticancer Therapy 
25 
 
Investigational Agents 
25 

 
    
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Supportive Care 
25 
 
Growth Factors 
26 
 
Concomitant Medications 
26 
 
Nausea and Vomiting 
27 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
27 
 
Required Clinical, Laboratory and Disease Evaluation 
27 
 
Radiology Studies 
28 
 
Pharmacology (optional) 
30 
 
Circulating Tumor DNA Study (optional) 
31 
9.0 
AGENT INFORMATION 
33 
 
Olaparib 
33 
 
Agent Ordering and Agent Accountability 
38 
 
Clinical Drug Request and Investigator Brochure Availability 
38 
 
Agent Inventory Records 
38 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
39 
 
Criteria for Removal from Protocol Therapy 
39 
 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
39 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
40 
 
Sample Size and Study Duration 
40 
 
Dosing Considerations 
40 
 
Study Design 
41 
 
Methods of Analysis 
42 
 
Evaluability for Response 
43 
 
Evaluability for Toxicity 
43 
 
Progression free survival (PFS) 
43 
 
Correlative Studies 
43 
 
Gender and Minority Accrual Estimates 
44 
12.0 
EVALUATION CRITERIA 
44 
 
Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
44 
 
Progression-Free Survival 
44 
 
Response Criteria for Patients with Solid Tumors 
44 
 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
48 
 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
50 
 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
52 
 
Response Criteria for Patients with CNS Tumors 
53 
 
Response Criteria for Patients with non-Hodgkin Lymphoma/Histiocytosis 
55 
 
Best Response 
56 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
57 
 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
58 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
59 
 Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements: 60 
 
Definition of Onset and Resolution of Adverse Events 
61 
 
Other Recipients of Adverse Event Reports 
61 
 
Specific Examples for Expedited Reporting 
62 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
64 
 
Categories of Research Records 
64 

 
    
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CDUS 
64 
 
CRADA/CTA/CSA 
64 
 
Data and Safety Monitoring Plan 
66 
REFERENCES 
67 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
69 
APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
70 
APPENDIX III:  PAITIENT DIARY FOR OLAPARIB 
72 
 
75 
APPENDIX V: APEC1621H THERAPY DELIVERY MAP 
77 
APPENDIX VI: TARGET HISTOLOGIES FOR APEC1621H EXPANSION COHORTS 
81 
APPENDIX VII CORRELATIVE STUDIES 
82 
APPENDIX VIII: APEC1621H ACTIONABLE MUTATIONS OF INTEREST 
83 
APPENDIX IX APEC1621H PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 84 
APPENDIX X: YOUTH INFORMATION SHEETS 
86 
APPENDIX XI: CTEP AND CTSU REGISTRATION PROCEDURES 
88 
APPENDIX XII: TOXICITY-SPECIFIC GRADING 
91 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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STUDY COMMITTEE, CONT. 
 
 
 
Study CRA 
 
Study Pharmacist 
Seattle Children’s Hospital 
Children's Hospital Los Angeles 
1900 9th Ave 
4650 Sunset Blvd. 
Seattle, WA 98101 
Los Angeles, CA  90027 
 
 
COG OPERATIONS STAFF 
 
 
Research Coordinator 
Master Statistician  
222 East Huntington Dr. Suite 100  
Children’s Oncology Group – Operations Center 
Monrovia, CA 91016 
222 E. Huntington Drive, Suite 100 
 
Monrovia, CA  91016 
 
 
 
 
 
 
 
 
 
Scientific Writer/Protocol Coordinator 
 
Children’s Oncology Group – Operations Center 
 
222 E. Huntington Drive, Suite 100 
 
Monrovia, CA  91016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Group Operations (GOC) and 
 
Statistics & Data Center (SDC) contacts see: 
 
http:members.childrensoncologygroup.org  
 
 
 
AGENT NSC# AND IND#’s 
 
NCI-Supplied Agents: 
Olaparib (Lynparza) 
 
(NSC#747856 , 
) 
 
 
IND Sponsor: DCTD, NCI 
 
 
 
 

  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
 
Primary Aims 
 
 
To determine the objective response rate (ORR; complete response + partial 
response) in pediatric patients treated with olaparib with advanced solid tumors 
(including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that 
harbor activating genetic alterations in the deleterious genetic alterations in the 
DNA damage repair (DDR) pathway,  
 
 
Secondary Aims 
 
 
To estimate the progression free survival in pediatric patients treated with olaparib 
with advanced solid tumors including non-Hodgkin lymphomas, CNS tumors, and 
histiocytosis that harbor deleterious genetic alterations in the DDR pathway. 
 
 
To obtain information about the tolerability of olaparib in children and adolescents 
with relapsed or refractory cancer. 
 
 
To provide preliminary estimates of the pharmacokinetics of olaparib in children 
and adolescents with relapsed or refractory cancer 
 
 
Exploratory Aims 
 
 
To explore approaches to profiling changes in tumor genomics over time through 
the evaluation of circulating tumor DNA. 
 
 
2.0 
BACKGROUND 
 
 
Introduction/Rationale for Development 
Under normal circumstances, loss of DNA integrity triggers cell-cycle checkpoints, cell-
cycle arrest, genomic survey and activation of high fidelity DNA damage repair (DDR) 
mechanisms. Defects in DDR have been identified as one of the hallmarks of cancer, 
causing genomic instability and favoring tumor progression and metastasis. Inherited 
inactivating alterations of DDR genes such as BRCA1 and BRCA2 (breast cancer 
susceptibility genes 1 and 2) are associated with cancer predisposition. Nevertheless, 
defects in DRR genes can be exploited for cancer therapy by rendering DDR mutant cells 
selectively vulnerable to pharmacological inhibition of a parallel pathway, a process known 
as “synthetic lethality,” where either one condition might be tolerable, but the combination 
is lethal.1  More explicitly, cancer cells which harbor defects in double- strand break repair 
can be specifically targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, which 
blocks the repair of single-strand breaks, leaving cells with comparatively intact DDR 
mechanisms relatively unharmed. Olaparib (Lynparza) is an oral PARP inhibitor FDA- 
approved as monotherapy for the treatment of patients with advanced, heavily pretreated 
ovarian cancer who carry deleterious, or suspected deleterious, germline BRCA1/2-
mutations leading to the accumulation of double strand breaks. 
 
Defects in double- strand DNA damage repair and synthetic lethality with PARP 
inhibition: 
DNA damage induced by exposure to environmental, endogenous or pharmacologic toxins 

  
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can interfere with critical cellular processes and stimulate the DNA damage response. 
Single-strand breaks rely on the base excision repair (BER) and nucleotide excision repair 
(NER) pathways whereas double-stranded breaks are dependent on the high fidelity, 
homologous recombination (HR) or the less accurate, nonhomologous end joining (NHEJ) 
mechanism.2 PARP proteins bind to nicks and breaks in DNA, interact with histones, 
recruit scaffolding proteins and activate complexes of enzymes essential to single-strand 
repair via the BER pathway. Normal or DDR sufficient cells can tolerate PARP inhibition 
by using HR, the complementary double-strand break repair mechanism. Efficient double-
strand break repair by HR, however requires functional BRCA1 and BRCA2 proteins [and 
partner proteins RAD51 and PALB2 (partner and localizer of BRCA2)].3-5 
 
Germline inactivating mutations in BRCA1 or BRCA2 lead to the use of alternative repair 
pathways, such as NHEJ, resulting in imprecise repair, genomic instability, cell death, or 
survival with genomic alteration and cancer predisposition, mainly breast and ovarian.6 
However, the presence of a germline inactivating mutation in BRCA1 or BRCA2 has also 
been found to sensitize cancer cells to PARP inhibition7,8 and identifies an enriched subset 
of patients with ovarian and breast carcinoma likely to respond to therapeutic PARP 
inhibition.9-12  Likewise, deleterious alteration of ATM (ataxia-telangiectasia mutated), a 
key regulator of double-strand break repair, cell cycle checkpoint signaling and telomere 
homeostasis can cause ataxia telangiectasia, a disease characterized by genomic instability, 
premature aging, neurologic degeneration, immunodeficiency and predisposition to 
cancer.13 Nevertheless, in vitro, pharmacologic inhibition of ATM activation or ATM 
deficiency induces PARP inhibitor sensitivity.14,15 Similar vulnerabilities to PARP 
inhibition have been demonstrated in cell lines with deficiency or silencing of additional 
proteins integral to HR including: RAD51; FANCA, FANCC or FANCD2 (Fanconi 
anemia proteins); ATR (ataxia telangiectasia and Rad3-related) kinase; and other DNA 
repair factors such as MRE11A (Meiotic Recombination 11), NBS1(Nijmegen breakage 
syndrome 1) and RAD50.14 These data suggest that treatment with PARP inhibitors may 
have broad clinical utility across tumor histologies, including pediatric cancers, which 
harbor inactivating mutations in BRCA1, BRCA2, ATM and other deleterious genomic 
alterations leading to impaired double-strand break repair. 
 
Inactivating mutations of DDR genes as biomarkers of response to olaparib 
monotherapy: 
Olaparib (Lynparza) is an oral PARP inhibitor capable of trapping inactivated PARP at 
single strand nicks, blocking BER, leading to the collapse of DNA replication forks, the 
accumulation of DNA double-strand breaks and dependency on HR. In 2014, Olaparib was 
FDA approved as monotherapy for the treatment of patients with advanced, heavily 
pretreated ovarian cancer who carry deleterious, or suspected deleterious, germline 
BRCA1/2-mutations (gBRCAm) based on single arm phase 2 study demonstrating an 
objective response rate (ORR) of 31%.12,16 Clinical data from the same study, although in 
smaller numbers, also supported single agent activity in gBRCAm patients with recurrent 
breast, pancreatic and prostate cancer.17 However, there has been a growing understanding 
that other genetic aberrations may produce a phenocopy of the HR defect produced by 
presumptive biallelic somatic loss of BRCA1/2, so-called tumor “BRCAness,” that may 
also render cancers sensitive to PARP inhibition.18 Recently, a clinical trial of patients with 
sporadic, metastatic, castration-resistant prostate cancers used a next generation targeted 
sequencing platform of DDR genes to study germline and fresh biopsy tissue and explore 
biomarkers of response to olaparib.19 Of 49 evaluable patients, 16 (33%) had DNA-repair 
defects which were not only detected as genomic aberrations in BRCA2 (7), and BRCA1 
(1), but also ATM (5), PALB2 (2), CHEK2 (2), FANCA (3), and HDAC2 (1), all genes 

  
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previously reported to exhibit a synthetic lethal interaction with PARP inhibition in 
vitro.14,19  Fourteen of these 16 patients (88%) responded to olaparib, including all patients 
with BRCA2 inactivation and 4 of 5 patients with ATM loss. While tumors with BRCA2 
mutation uniformly demonstrated biallelic loss (4 with biallelic somatic loss, and 3 with 
germline mutations), strikingly, there were patients with monoallelic ATM aberrations 
affecting the kinase catalytic domain who also responded to therapy, suggesting either a 
dominant negative effect of the truncated protein or haploinsufficiency.  Additionally, there 
was a prolonged response in a patient who harbored a combined monoallelic loss of BRCA2 
and PALB2.19 Of late, a phase 2 trial in relapsed, platinum-sensitive high-grade ovarian 
carcinoma of a different PARP inhibitor, rucaparib (ARIEL 2) has identified RAD51C 
mutation or promoter hypermethylation as another potential predictive biomarker of 
response to PARP inhibition.20  
  
Inactivating mutations of DDR genes and PARP inhibition in pediatric cancer: 
The frequency of double-strand DNA repair defects in pediatric tumors is not well 
characterized. To date, studies in suggest that there is an 8.5- 10% risk of germline cancer 
predisposition in patients with childhood malignancy, the vast majority being TP53 
mutations, with only 14-27% of these in putative DDR genes, for an overall estimated 
frequency of 1-3%.21,22  In addition, not all aberrations in DDR genes will result in pathway 
inactivation and monoallelic loss may be insufficient. For example, protein-truncating 
mutations, missense mutations and large segmental rearrangements within the BRCA genes 
are expected to be deleterious, however in one recent study by Parsons et al, there was no 
evidence of somatic loss of heterozygosity in the tumors of patients with germline BRCA1 
or BRCA2 mutations.22 Of note, germline (n=3) or somatic (n=2) BRCA1 or BRCA2 
mutations have been identified in this study cohort (total frequency of 2-3%).22  
Nevertheless, the principle of synthetic lethality has been demonstrated in the context of a 
pediatric tumor model. During the preclinical testing of the potent PARP inhibitor BMN 
673, KT10, a Wilms tumor cell line showed exquisite sensitivity to PARP inhibition both 
in vitro and in vivo with a sustained complete responses in tumor xenografts. KT10 was 
subsequently demonstrated to have a frameshift mutation in PALB2 resulting in a 
premature stop codon and a truncated protein at the C-terminal end and loss of the BRCA2 
binding site. Sequence read frequency almost exclusively favored the mutated over the 
wild type allele providing evidence the cell line was either homozygous or hemizygous for 
the PALB2 mutation.23 
The PARP inhibitor BMN 673 has undergone phase 1 clinical testing in an unselected 
pediatric population in combination with temozolomide, where the maximum tolerated 
dose of BMN 673 in combination with temozolomide in children was equivalent to the 
recommended phase 2/3 dose for BMN 673 monotherapy in adults, 1 mg daily.  Dose 
limiting toxicities of the combination included myelosuppression with neutropenia (Grade 
4 x ≥ 7 days), thrombocytopenia (≥ 2 platelet transfusions in 7 days), Grade 4 abdominal 
hemorrhage, Grade 4 sepsis and prolonged Grade 3 ALT elevation.   
This will be the first clinical trial of olaparib (Lynparza) in children, and the first phase 2 
clinical trial of a PARP inhibitor in a pediatric population enriched for patients whose 
malignancies harbor deleterious alterations in DDR genes. 
 
 
 
 
 

  
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Preclinical Studies of Olaparib 
 
 
Antitumor Activity 
Olaparib was tested against a KU95, a mixed panel of 95 cancer cell lines derived 
from breast, ovarian, colorectal, head and neck, lung and pancreatic tumors. 
Olaparib exhibited a broad range of growth inhibitory (IC50) activity (ranging 
from 0.018 μM through to >10 μM), but a clear association with enhanced olaparib 
sensitivity (IC50 <1 μM) was observed in cell lines with known BRCA1 or BRCA2 
mutations, BRCA1 promoter methylation, or low expression of DDR genes/ 
proteins, notably ATM, ATR and MRE11.24 In vivo, genetically engineered mice 
with spontaneous murine mammary tumors have been used to model BRCA1 -/- and 
BRCA2-/- conditions and show prolonged survival and tumor regression, 
respectively, when compared to BRCA wild type controls.25,26  
 
An olaparib sensitive, homozygous BRCA2 deleted, triple negative breast cancer 
patient derived xenograft has also been utilized to model the pharmacokinetics and 
pharmacodynamics required for efficacy. This model predicts that a large enough 
increase in single- stranded breaks to generate cell death in HR deficient tumors 
requires maintaining >90% inhibition of PAR at steady state.24 
 
In an Ames bacterial mutation test, olaparib was not mutagenic, but chromosomal 
breakage was observed in a Chinese Hamster Ovary chromosome aberration test 
consistent with the mechanism of action of PARP inhibition.24 
 
Pharmacology 
At concentrations 6-fold the human mean free Cmax at the clinical dose of 300 mg 
bid (3.65 μM), olaparib showed no significant off-target activity against a diverse 
panel of molecular targets including enzymes, receptors, transporters and ion 
channels; concentrations 60-fold greater than the human mean free Cmax were 
required to inhibit the hERG encoded potassium channel.24 
 
In vitro, olaparib is actively taken up by isolated human hepatocytes and CYP3A4 
and CYP3A5 are the major isozymes responsible for its metabolism. It is a direct 
inhibitor of CYP3A (IC50 119 μM), a time dependent inhibitor of CYP3A (Kinact 
0.0675 min-1; KI 72.2 μM) and can induce expression of messenger RNA for 
CYPs 1A2, 2B6 and 3A4. Olaparib can inhibit UGT1A1 (IC5096.7 μM) but had 
no appreciable effect against UGT2B7.24 
 
Animal Toxicology 
Nonclinical animal pharmacology and toxicology data for olaparib is based a 
variety of single and repeat dose studies. It should be noted that in repeat dosing 
studies, the exposures achieved were lower than those anticipated at the clinical 
dose of 400mg BID (capsule) or 300mg PO BID (tablet). The absolute 
bioavailability of olaparib following po dosing to mice, rats and dogs, was 
approximately 60%, 20% and 80%, respectively. In vitro, plasma protein binding, 
showed some variation between species. Unbound fraction was ~31% in mice and 
29% in rat (between 0.023 and 46 μM), 38% to 48% in dog and 9% to 30% human 
(concentration dependent between 0.023 μM and 92.1 μM). Drug distribution was 
rapid in the rat, but with little or no distribution to brain, spinal cord or the lens of 
the eye. Whole-body autoradiography of xenograft bearing nude mice, suggested 
increased concentration an slower clearance of radiolabelled drug in the tumor 
versus the blood.24 

  
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In rats and dogs, receiving olaparib daily for 1 to 6 months, the principal toxicity 
was reversible myelosuppression, as demonstrated by anemia, neutropenia, 
lymphopenia and thrombocytopenia with full or partial recovery following 
cessation of the agent. Olaparib also induced micronuclei in bone marrow of rats, 
consistent with the induction of genomic instability. In rats but not dogs, daily 
therapy was also associated with anorexia and decreased weight gain. There were 
no significant effects on either dog cardiovascular and respiratory functions or rat 
Irwin (behavioural) tests.24 
 
In reproductive toxicology studies in rats, olaparib produced no adverse effects on 
male or female fertility. However, pre, peri or post-conception treatment with 
olaparib caused reductions in early embryofetal survival and fetal weights.  
Treatment during pregnancy was also associated with increases incidence of 
visceral and skeletal abnormalities including major eye and vertebral/rib 
malformations at dose levels that were not toxic to the mother. These findings are 
felt to be consistent with the mechanism of action of olaparib.24 
 
 
Adult Studies 
As of December 15, 2016, an estimated 4475 patients patients with ovarian, breast, 
pancreatic, gastric and a variety of other solid tumors are estimated to have received 
treatment with olaparib in AstraZeneca-sponsored, interventional studies (3799 patients) 
and the Managed Access Program (676 patients).  Of the 4475 patients, 2109 received the 
capsule formulation, 2341 received the tablet formulation, and 25 received both capsule 
and tablet. The bioavailability of the two preparations are not equivalent. This trial will 
use the tablet formulation of olaparib. 
 
 
Phase 1 Studies 
Initially, the capsule formulation of olaparib was studied in phase 1 adult solid 
tumors. The dose and schedule began at 10 mg daily for 2 of every 3 weeks, and 
escalated to 600 mg twice daily on a continuous basis using a modified accelerated-
titration 
design. 
Reversible 
dose- 
limiting 
toxicities 
included 
mood 
alteration/fatigue (Grade 3 400 mg BID), somnolence (Grade 3 600 mg BID) and 
myelosuppression (Grade 4 thrombocytopenia, 600 mg BID). The maximum 
tolerated dose of olaparib capsule was determined to be 400 mg PO twice daily. 
The most commonly reported adverse events related to drug include low-grade 
nausea (32%), fatigue (30%), vomiting (20%), taste alteration (13%), and anorexia 
(12%); Anemia (5%) and thrombocytopenia (3%) were the most common grade ≥ 
3 hematologic events. Olaparib capsule exhibited a terminal-elimination half-life 
of 5 to 7 hours with less than proportional increases in exposure with dose 
escalation, but maximized by the twice daily schedule. 400 mg BID (capsule) was 
associated with a maximum plasma concentration (Cmax) of 18 µM. Maximum 
PARP inhibition (>90%; as evidence by decreased PAR signal and the formation 
of γH2AX foci in hair follicles), was achieved at the lower dose of 100mg PO BID 
capsule, and associated with Cmin of 1µM and Cmax of 8.5 µM.9  Clinical 
responses were seen only in gBRCAm patients with breast, ovarian or prostate 
tumors. No obvious increases in adverse effects have been reported in mutation 
carriers. All doses exceeding 100mg PO (capsule) BID have been associated with 
clinical response in gBRCAm patients. 9-12,17 
 

  
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The tablet formulation developed by AstraZeneca for ease of administration will 
be used in this trial. The tablet demonstrates higher bioavailability than the 
capsular formulation. Based on single dose data, olaparib tablet is rapidly absorbed 
with peak plasma concentrations typically observed at 1.5 hours. The population 
PK analysis are consistent with sequential zero- and first-order absorption and 
show a significant impact of olaparib tablet strength on the absorption rate 
constant. Following Tmax, plasma concentrations of olaparib declined in a 
biphasic manner with an average terminal elimination half-life (t½) of 14.9 hours 
(standard deviation 8.2 hours). Exposure (AUC0-12) increased approximately 
proportionally with dose for the dose range 25 to 450 mg; while maximum plasma 
concentration (Cmax) increased slightly less than proportionally. The observed 
geometric mean steady state maximum plasma concentration (Cmax ss), area 
under the plasma concentration-time curve for the dosing interval (AUC0-τ) and 
minimum plasma concentration (Cmin ss) following multiple dosing of 300 mg 
PO BID tablet formulation are approximately 53%, 17% and 32% higher than 
those, respectively, for the capsule formulation (400 mg BID pooled population 
analysis). At 300 mg BID dosing, the estimated geometric mean Cmax ss, AUC0-
12 and Cmin were 8.76 μg/mL, 56.45 μg.h/mL and 1.67 μg/mL, respectively 
(equivalent to unbound concentrations of 1.59 μg/mL, 10.22 μg.h/mL and 0.302 
μg.h/mL, respectively). The inter-individual variability was moderate to high.  
Food slowed the rate of absorption (Tmax delayed by 2.5 hours and Cmax reduced 
by 20%), however there was no significant food effect on the extent of absorption 
(AUC), therefore olaparib tablets can be administered without regard to food.24 
Based on an efficacy and toxicity matching trial, the MTD and recommended 
phase 2 dose the tablet formulation is 300mg PO twice daily. Dose limiting 
toxicities were mainly hematologic.27 
 
 
Phase 2 Studies 
Subsequent Phase 2 studies of olaparib have confirmed the sustained antitumor 
activity in patients with gBRCAm breast cancer,11,12,17 high-grade serous epithelial 
ovarian cancer 10,12,16,17,28 and other tumor types including pancreatic17 and 
castration resistant prostate cancer.17,19 The FDA approval for olaparib 
monotherapy in patients with heavily pretreated ovarian cancer and gBRCAm was 
based on a group of 193 patients, of which 137 had measurable disease and had 
received at least three prior lines of chemotherapy. The objective response rate 
(ORR) was 34% with median duration of response (DOR) of 7.9 month. A subset 
of 59 patients had retrospectively confirmed gBRCAm by a companion diagnostic 
test. This subgroup had an ORR of 41% (95% CI, 28–54), with a median DOR of 
8.0 months.29 The phase 2 safety cohort reviewed by the FDA included 223 
patients from 6 studies with olaparib monotherapy. The most common adverse 
reactions of any grade in ≥ 20% of patients were anemia, nausea, fatigue, vomiting, 
diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/ 
pharyngitis/ upper respiratory infection, cough, arthralgia/musculoskeletal pain, 
myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort. Despite the 
heavily pretreated population, the most common grade 3-4 toxicity was anemia 
(18%). However, myelodysplastic syndrome and/or acute myeloid leukemia 
occurred in 2% of the olaparib treated patients as compared with 0.8% of those 
treated with placebo.29 Olaparib antitumour activity has also been observed in 
sporadic ovarian cancers,12 and castration resistant prostate cancer where biallelic 
somatic BRCA2 mutation, germline truncating ATM mutations and monoallelic 
ATM mutations affecting the kinase catalytic domain, as well as aberrations in 

  
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PALB2 and HDAC2 emerged as tractable DDR defects associated with olaparib 
response. No new safety signals emerged from this trial. A dose reduction was 
required in 26%; anemia was the most common indication for the dose reduction.19 
 
 
Pediatric Studies 
 
 
Prior Experience in Children  
There is no prior experience with olaparib in children.  
 
 
Overview of Proposed Pediatric Study 
We will conduct a phase 2 trial of olaparib in children with relapsed or refractory solid 
tumors (including non-Hodgkin lymphomas, histiocytoses and CNS involvement) 
harboring specified defects in DNA damage repair genes. The primary endpoint will be 
objective response rate (ORR; complete response + partial response) as determined by 
RECIST. Progression free survival (PFS) will be assessed as a secondary endpoint. 
Olaparib tablet formulation will be given twice daily continuously, without break. A cycle 
will be 28 days. Because the pediatric dose of olaparib has not been established, there will 
be a limited dose finding phase consisting of the first 12 evaluable patients enrolled on 
study. Toxicity will be assessed and the pharmacokinetics of olaparib will be evaluated in 
the dose finding cohorts. 
 
 
  
 
 
 
 
 
  
 
  
 

  
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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Oncology Patient Enrollment Network 
(OPEN), a web-based registration system available on a 24/7 basis. It is integrated with the NCI 
Cancer Trials Support Unit (CTSU) Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient position in the RAVE database. 
 
Access requirements for OPEN:  
Investigators and site staff will need to be registered with CTEP and have a valid and active Cancer 
Therapy Evaluation Program-Identity and Access Management (CTEP-IAM) account (check at < 
https://ctepcore.nci.nih.gov/iam/ >). This is the same account (user id and password) used for 
credentialing in the CTSU members' web site. To perform registrations in OPEN, the site user must 
have been assigned the 'Registrar' role on the relevant Group or CTSU roster. OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. Registrars must hold a minimum of an AP registration type.   
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise 
System for regulatory and roster data and, upon enrollment, initializes the patient position in the 
Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in OPEN, the 
IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on the site’s IRB 
approval.  Please see Appendix XI for detailed CTEP and CTSU Registration Procedures including: 
registration in Registration and Credential Repository (RCR), requirements for site registration, 
submission of regulatory documents and how to check your site’s registration status. 
 
 
Genetic Screening Procedures for Eligibility  
Patient enrollment onto the APEC1621SC screening protocol is required. Tumor and blood 
samples will be obtained and the results of the evaluation of the tumor specimens will 
determine if the patient's tumor has an actionable Mutation of Interest (aMOI) for which a 
MATCH treatment subprotocol is available. 
 
The treatment assignment to MATCH to a subprotocol will be communicated to the 
enrolling institution via the COG or MATCHBox treatment assignment mechanism at the 
time the results of MATCH are returned, upon which a reservation to APEC1621H will be 
secured by COG. Reservations should be withdrawn by the institution if at any point the 
patient indicates they do NOT intend to consent to participation or the site investigator 
indicates the patient will never be eligible for APEC1621H. 
 
 
IRB Approval 
In order to participate in Pediatric MATCH, an institution must participate in the NCI 
Pediatric CIRB. NCI Pediatric CIRB approval of this study must be obtained by a site prior 
to enrolling patients.  
 
Submitting Regulatory Documents:  Submit required forms and documents to the CTSU 
Regulatory Office, where they will be entered and tracked in the CTSU RSS.   
 
Online: www.ctsu.org (members’ section) → Regulatory Submission Portal 
 
Regulatory Help Desk: 866-651-2878 
                             
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU Regulatory 
Office for initial, continuing, or amendment review.  However, sites must submit a Study 

  
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Specific Worksheet for Local Context (SSW) to the CIRB (via IRBManager) to indicate 
their intention to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office for compliance in the RSS.  The Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study so that the study approval can be applied 
to those institutions.  Other site registration requirements (e.g., laboratory certifications, 
protocol-specific training certifications, or modality credentialing) must be submitted to 
the CTSU Regulatory Office or compliance communicated per protocol instructions. 
 
 
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. 
 
 
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 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. 
 
 
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. 
 
 
Study Enrollment 
Following a MATCH treatment assignment to a protocol, patients may be enrolled on the 
study once all eligibility requirements for the study have been met. Before enrolling a 
patient on study, the Study Chair or Vice Chair should be notified. 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 COG Study Research Coordinator, or the CTSU OPEN 
helpdesk at https://www.ctsu.org/CTSUContact.aspx.  Patients must be enrolled before 
treatment begins.  Patients must not receive any protocol therapy prior to enrollment. 
 
Patients must be enrolled within 8 weeks (56 days) of treatment assignment. Protocol 
therapy must start no later than 7 calendar days after the date of enrollment. Patients 
enrolling onto APEC1621H will have a COG ID obtained through their prior enrollment 
onto the screening protocol or from a prior COG study. 
 
Note:  No starter supplies will be provided. Drug orders of olaparib should be placed 
with CTEP after enrollment and treatment assignment to APEC1621H with 
consideration for timing of processing and shipping to ensure receipt of drug supply 
prior to start of protocol therapy. 
 

  
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Institutional Pathology Report 
The institutional pathology report from the tumor specimen submitted for sequencing will 
have been uploaded into RAVE immediately following enrollment on the APEC1621SC 
screening protocol.  
 
 
Dose Assignment 
The dose will be assigned via OPEN at the time of study enrollment. 
 
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. Imaging 
studies, bone marrow biopsy and/or aspirate (when applicable) 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.  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. 
 
 
Inclusion Criteria 
 
 
APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been 
given a treatment assignment to MATCH to APEC1621H based on the presence 
of an actionable mutation as outlined in Appendix VIII. 
  
 
Age:  Patients must be  than 12 months and  21 years of age at the time of 
study enrollment. 
 
 
BSA:  Patients must have a body surface area ≥ 0.65 m2 at enrollment. 
 
 
Disease Status:  
Patients must have radiographically measurable disease (see Section 12) at the 
time of study enrollment. Patients with neuroblastoma who do not have measurable 
disease but have MIBG+ evaluable disease are eligible. Measurable disease in 
patients with CNS involvement is defined as tumor that is measurable in two 
perpendicular diameters on MRI and visible on more than one slice. 
Note:  The following do not qualify as measurable disease:  
- 
malignant fluid collections (e.g., ascites, pleural effusions) 
- 
bone marrow infiltration except that detected by MIBG scan for 

  
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neuroblastoma 
- 
lesions only detected by nuclear medicine studies (e.g., bone, gallium or 
PET scans) except as noted for neuroblastoma 
- 
elevated tumor markers in plasma or CSF  
- 
previously radiated lesions that have not demonstrated clear progression 
post radiation  
- 
leptomeningeal lesions that do not meet the measurement requirements for 
RECIST 1.1. 
 
 
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. 
 
 
Prior Therapy 
 
4.1.6.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g. blood count 
criteria, the patient is considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive.See:https://www.cogmembers.org/site/disc/devthe
rapeutics/default.aspx  for commercial and Phase 1 investigational 
agent classifications. For agents not listed, the duration of this interval 
must be discussed with the study chair and the study-assigned 
Research Coordinator prior to enrollment. 
i. 
 ≥ 21 days after the last dose of cytotoxic or myelosuppressive 
chemotherapy (42 days if prior nitrosourea).  
 
 
 
b. Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days after the 
last dose of agent.  See   https://www.cogmembers.org/site/disc/devt
herapeutics/default.aspx  for commercial and Phase 1 investigational 
agent classifications. For agents not listed, the duration of this interval 
must be discussed with the study chair and the study-assigned 
Research Coordinator prior to enrollment.  
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. 
 
d. Corticosteroids: See Section 4.2.2.1. If used to modify immune 
adverse events related to prior therapy, ≥ 14 days must have elapsed 
since last dose of corticosteroid. 
 
e. Hematopoietic growth factors: ≥ 14 days after the last dose of a long-
acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting 

  
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growth factor. For growth factors 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 and the study-assigned Research Coordinator. 
 
f. Interleukins, Interferons and Cytokines (other than hematopoietic 
growth factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than hematopoietic growth factors) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 
days after infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 
days. 
 
h. Cellular Therapy: ≥ 42 days after the completion of any type of 
cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.) 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days after 
local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to 
 50% of the pelvis; ≥ 42 days if other substantial BM radiation. 
 
Note: Radiation may not be delivered to “measurable disease” tumor 
site(s) being used to follow response to subprotocol treatment. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG): ≥ 42 days after systemically administered 
radiopharmaceutical therapy. 
 
k. Patients must not have received prior exposure to olaparib, veliparib, 
niraparib, rucaparib, talazoparib or other PARPi. 
 
 
Organ Function Requirements 
 
4.1.7.1 
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) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.1.7.1.a 
(may receive platelet or pRBC transfusions provided they are not 
known to be refractory to red cell or platelet transfusions). These 

  
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patients will not be evaluable for hematologic toxicity.  
 
4.1.7.2 
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 (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
4.1.7.3 
Adequate Liver Function Defined as: 
 
i. 
Patients with solid tumors: 
- 
Bilirubin (sum of conjugated + unconjugated)  1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT)  135 U/L.  (For the purpose of this study, the ULN 
for SGPT is 45 U/L.)  
- 
Serum albumin  2 g/dL. 
 
4.1.7.4 
Adequate Coagulation Defined as: 
- 
Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN 
- 
INR ≤ 1.5. 
 
 
Patients must be able to swallow intact tablets.  
 
 
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.  
 
 
Exclusion Criteria 
 
 
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. Pregnancy 
tests must be obtained in girls who are post-menarchal. Women of child-bearing 
potential and their partners should agree to use two (2) highly effective forms of 
contraception throughout study participation and for at least one (1) month after the 
last dose of olaparib.  Male study participants should avoid fathering a child or 
donating sperm during the study and for three (3) months after the last dose of 
olaparib. 
 
 

  
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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. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of 
corticosteroid (See Section 4.1.6.1.d). 
 
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. 
 
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. 
 
4.2.2.5  
CYP3A/ CYP3A4 Agents: Patients who are currently receiving drugs that 
are strong and moderate inducers or inhibitors of CYP3A or CYP3A4 are 
not eligible. Strong inducers or inhibitors of CYP3A4 should be avoided 
from 21 days prior to enrollment to the end of the study. See Appendix II 
for a list of CYP3A4 agents.   
 
 
 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
 
Patient who are known to be serologically positive for human immunodeficiency 
virus (HIV). 
 
 
Patients with known active hepatitis (i.e. Hepatitis B or C).  
 
 
Patients who have received a prior solid organ transplantation are not eligible. 
 
 
Patients with symptomatic uncontrolled brain metastases. A scan to confirm the 
absence of brain metastases is not required. The patient can receive a stable dose 
of corticosteroids before and during the study as long as these were started at least 
4 weeks prior to enrollment. Patients with spinal cord compression unless 
considered to have received definitive treatment for this and evidence of clinically 
stable disease for 28 days. 
 
 
Patients with known symptomatic Fanconi Anemia (FA), Ataxia-telangiectasia 
(A-T) Syndrome, Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) 
are not eligible (Asymptomatic carriers are acceptable). 
 
 
Major surgery must not have occurred within 2 weeks prior to enrollment and 
patients must have recovered from any effects of any major surgery. 
 
 Patients who in the opinion of the investigator may not be able to comply with the 

  
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safety monitoring requirements of the study are not eligible. 
5.0 
TREATMENT PROGRAM 
 
 
Overview of Treatment Plan 
 
Treatment Schedule Table 
Days 1-28 
Olaparib BID 
Day 28 
Evaluation 
 
Olaparib will be given orally twice daily 
. A 
cycle of therapy is considered to be 28 days.  A cycle may be repeated up to a total duration 
of therapy of 2 years (maximum 26 cycles). Olaparib must only be used in accordance with 
the dosing recommendations in this protocol. Any dose or frequency of dosing that exceeds 
the dosing regimen specified in this protocol should be reported as an overdose. Adverse 
reactions associated with overdose should be treated symptomatically and should be 
managed appropriately. 
 
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 2 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 criteria (Section 10.0).  
 
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 and according to the dosing 
nomogram in Appendix IV. Patients should swallow the tablets as a whole and should not 
chew or crush them. If a patient vomits within 30 minutes after the dose of olaparib is 
administered, and all the tablets are intact and can be accounted for, that dose may be 
repeated once. Otherwise, the dose will be missed.  
 
 
Determination of Recommended Phase 2 Dose (RP2D)/Tolerable Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

  
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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 2 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 criteria (Section 10.0). 
 
 
Intra-Patient Escalation 
Intrapatient dose escalation is not allowed. 
 
 
Therapy Delivery Map 
See Appendix V for APEC1621H Therapy Delivery Map  
 
 
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 and 
eligible to continue agent administration per the requirements in section 6.0.  
  
 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the current version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE).  All appropriate treatment 
areas should have access to a copy of the current version of the CTCAE V5.0.  A copy of 
the CTCAE V5.0 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. 
 
 
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. Dose limiting hematological and non-hematological 
toxicities are defined differently. The DLT evaluation period for the purpose of dose 
escalation will be cycle 1 of therapy. 
 
 
Non-Hematological Dose-Limiting Toxicity 
5.4.1.1 Any Grade 3 or greater non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of less < 3 days duration 
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to 
levels that meet initial eligibility criteria or baseline within 7 days See 
Appendix XII for values that represent thresholds between CTCAE 
grades.  
Note: For the purposes of this study the ULN for ALT is defined as 45 U/L 
regardless of baseline. 
- 
Grade 3 or 4 fever < 5 days duration. 
- 
Grade 3 infection < 5 days duration. 

  
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- 
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to supplementation 
• 
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires treatment interruption. 
• 
Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 
 
Hematological dose limiting toxicity  
5.4.2.1 Hematological dose limiting toxicity is defined as: 
 
a) In patients evaluable for hematological toxicity (see Section 4.1.7.1),   
• 
Grade 4 thrombocytopenia or neutropenia, not due to malignant 
infiltration. 
• 
Grade 3 thrombocytopenia that persists for ≥ 7 days 
• 
Grade 3 thrombocytopenia requiring a platelet transfusion on two 
separate days within a 7-day period 
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Neutropenia or thrombocytopenia that causes a delay of > 14 days 
between treatment cycles" (e.g. platelets <100K or ANC<1000). 
 
5.4.2.2 Note: Grade 3 or 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. 
 
 
Dose Modifications for Hematological Toxicity 
 
 
If a patient experiences hematological dose-limiting toxicity as defined in Section 
5.4.2.1, the treatment will be held.  Counts should be checked every 3-4 days for 
thrombocytopenia and every other day for neutropenia during this time. If the 
toxicity resolves to meet eligibility parameters within 14 days of drug 
discontinuation, the patient may resume treatment at a reduced dose as outlined in 
the dosing nomogram (See Appendix IV).  Doses reduced for toxicity will not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.  
 
 
If toxicity does not resolve to meet eligibility parameters within 14 days of drug 
discontinuation, the patient must be removed from protocol therapy. 
 
 
If hematological dose-limiting toxicity recurs in a patient who has resumed 
treatment at the reduced dose, the patient must be removed from protocol therapy. 
 
 
Dose Modifications for Non-Hematological Toxicity 
 
 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.4.1, the treatment will be held. When the toxicity resolves to meet 

  
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eligibility parameters or baseline within 14 days of drug discontinuation, the 
patient may resume treatment at a reduced dose as outlined in the dosing 
nomogram (See Appendix IV). Doses reduced for toxicity will not be re-escalated, 
even if there is minimal or no toxicity with the reduced dose. 
 
 
If toxicity does not resolve to meet eligibility or baseline parameters within 14 
days of drug discontinuation, the patient must be removed from protocol therapy. 
 
 
If the same dose-limiting toxicity recurs in a patient who has resumed treatment at 
the reduced dose, the patient must be removed from protocol therapy. 
 
 
Dose Modifications for Pulmonary Toxicity 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities 
occur in the absence of a clear diagnosis, an interruption in study treatment dosing is 
recommended and further diagnostic workup (including a high resolution CT scan) should 
be performed to exclude pneumonitis. 
 
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study treatment can be restarted, if deemed appropriate by the 
investigator. If significant pulmonary abnormalities are identified, these need to be 
discussed with the Study Physician. 
 
 
Dose Modification for Surgery 
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery 
study treatment can be restarted when the wound has healed. No stoppage of study 
treatment is required for any needle biopsy procedure. 
 
 
Dose Interruption for Conditions Other than Toxicity  
Interruptions should be kept as short as possible. If a patient cannot restart study treatment 
within 14 days for resolution of an intercurrent condition not related to disease progression 
or toxicity, the patient must be removed from protocol therapy.  
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
 
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. 
 
 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. Please see COG Supportive Care guidelines at 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. See Section 
7.5 for drugs that should not be used concomitantly due to potential interactions with olaparib. 
See below for recommendations on management of specific toxicities associated with 
olaparib. 
 
 

  
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Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. The Study Chair 
should be notified before growth factors are initiated. 
 
 
Concomitant Medications 
 
 
CYP3A4/5 inhibitors or inducers: In vivo data indicate that CYP3A4/5 is important 
for olaparib metabolism and clearance in humans. For this reason, avoid concomitant 
administration of strong and moderate CYP 3A4/5 inducers and inhibitors. Strong 
CYP3A4/5 inhibitors such as ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
and voriconazole are not permitted on study. Strong CYP3A4/5 inducers (such as 
rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentine, 
phenobarbital, and St John’s wort), grapefruit, and grapefruit juice are not 
permitted on study. (See Appendix II). Note: Dexamethasone for CNS tumors or 
metastases, on a stable dose, is allowed. 
 
 
Strong or moderate CYP3A inhibitors: Known strong CYP3A inhibitors (e.g., 
itraconazole, telithromycin, clarithromycin, boosted protease inhibitors, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors 
(ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) should not be 
taken with olaparib. 
 
If there is no suitable alternative concomitant medication then the dose of olaparib 
should be reduced by at least 25% and rounded down to the nearest tablet size for 
the period of concomitant administration. 
 
 
Strong or moderate CYP3A inducers: Strong  and moderate CYP3A inducers 
should not be taken with olaparib. (See Appendix II for list of agents) 
 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp). 
Administration of strong P-gp inhibitors and inducers should be avoided with 
concurrent olaparib.  
 
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems 
and induces CYP 1A2, 2B6, and 3A4 and potentially induces CYP 2C9, 2C19 and 
P-gp. Therefore, avoid concomitant administration of sensitive substrates, 
particularly those with narrow therapeutic ranges.   
 
7.5.4 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug 
and toxin extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP. 
In vitro studies suggest that olaparib may increase exposure of substrates of these 
transport systems, although the clinical relevance is not clear. The manufacturer 
recommends that statins, in particular, should be administered with caution when 
given concomitantly with olaparib. 
 
 
Patients who are taking warfarin may participate in this trial; however, it is 
recommended that international normalized ratio (INR) be monitored carefully at 
least once per week for the first month, then monthly if the INR is stable. 
Subcutaneous heparin and low molecular weight heparin are permitted. 

  
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Nausea and Vomiting 
No routine prophylactic anti-emetic treatment is required at the start of study treatment, 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines.  
Alternatively, olaparib tablets can be taken with a light meal/snack. 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
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. Imaging studies, bone 
marrow aspirate and/or biopsy, 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^ 
History 
X 
Weekly 
X 
Physical Exam  with vital signs 
X 
Weekly 
X 
Neurologic Exam 
X 
 
 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
Pregnancy Test1 
X 
 
 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 days)2,3 
Weekly2,3 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
 
X 
aPTT/INR 
X 
 
 
Tumor Disease Evaluation4-A,4-B, 4-C 
X 
 
Every other cycle x 3 then q 
3 cycles 4 
Bone Marrow Aspirate and/or biopsy5,6 
X6 
 
 
Patient Diary7 
 
Weekly 
X 
Pharmacokinetics (Optional) 8 
X 
X 
 
Circulating Tumor DNA (ctDNA-
optional)9 
 
 
Cycle 5, Day 1 and End of 
Protocol Therapy OR 
disease progression  
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
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. 
2 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery 

  
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Page 28 
to Grade 3 or until meeting the criteria for dose limiting toxicity. 
3 
If patients develop Grade 3 or greater thrombocytopenia then CBCs should be checked every 3 to 4 days 
until recovery per section 6.1. 
4 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 
of either a PR or CR.  Subsequent scans may restart 2 cycles after the confirmatory scan. 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. 
4-A     Neurological exam is also required for CNS patients.  
4-B  Non- Hodgkin Lymphoma/ Histiocytosis patients are required to have PET scans within 2 weeks prior 
to start of therapy and should also be followed with PET scans if positive at diagnosis. Refer to Section 
12.8    
4-c   Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy prior to enrollment if the 
patient was enrolled with or has a history of having MIBG avid tumor. Otherwise the patient must have 
both CT/MRI and bone scan prior to enrollment. For patients with neuroblastoma and measurable disease 
by CT or MRI, lesions should be measured and followed using the same modality (CT or MRI) in 
addition to MIBG or bone scan. For patients with neuroblastoma and evaluable disease by MIBG 
scintigraphy or bone scan, use the same modality (MIBG scintigraphy or bone scan) to image and follow 
patients; CT/MRI are not required but may be performed as clinically indicated. Refer to Section 12.5.4 
and Section 12.9. 
5 
Bone marrow aspirate and/or biopsy only required in patients with known bone marrow metastasis on 
the basis of history, symptoms, laboratory evaluation or other clinical data. Should only be performed 
on patients with known bone marrow involvement at baseline.   
6 
Bone marrow aspirate and/or biopsy should only be performed only when complete response or partial 
response is identified in target disease or when progression in bone marrow is suspected.  
7.  Patient diary (see Appendix III) should be reviewed weekly during cycle 1, after completion of each 
treatment cycle and uploaded into RAVE. 
8. 
See Section 8.3 for details of PK studies. 
9. 
With consent, two samples will be collected on this protocol (Cycle 5 Day 1; at progression or end of 
protocol therapy) see Section 8.4 for details of the ctDNA studies. Note that a ctDNA sample is 
scheduled to be obtained on the APEC1621SC screening protocol prior to the initiation of treatment on 
this subprotocol. 
 
 
 
Radiology Studies 
 
 
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. The Operations center will notify the site when a 
patient has met the criteria for review. The tumor disease evaluations to be 
submitted for review include baseline (prestudy) evaluations as well as all end of 
cycle tumor disease evaluations which occurred while the patient was on the 
subprotocol therapy study. 
  
 
Technical Details of Submission:  
To ensure an adequate interpretation of FDG-PET and CT with contrast scans, 
scans transferred between the treating institutions and the Imaging and Radiation 
Oncology Core Group IROC RI (QARC) must be submitted in Digital Imaging 
and Communications in Medicine (DICOM) format. BMP ﬁles, JPG ﬁles, or hard 
copies (ﬁlms) are unacceptable for adequate interpretation of PET and CT with 
contrast scans. Imaging studies must be submitted electronically as outlined in the 
following paragraph. The images will be made available to study radiologists and 
nuclear medicine physicians for central review. 
 

  
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Submission of Diagnostic Imaging data in DICOM format is required.  
Submission of the digital files and reports via TRIAD is preferred.  Instructions for 
TRIAD set up are below. 
 
Alternatively, the images and reports may be submitted via sFTP to IROC Rhode 
Island. Digital data submission instructions including instructions for obtaining a 
sFTP account, can be found at http://irocri.qarc.org. Follow the link labeled digital 
data.  Sites using the Dicommunicator software to submit imaging may continue 
to use that application. 
 
Corresponding Radiology reports may be submitted along with the electronic 
submission 
via 
TRIAD 
or 
sFTP 
or 
may 
be 
emailed 
to 
DataSubmission@QARC.org.  The COG operations center and IROC are available 
to assist with any queries regarding the corresponding radiology reports which 
should be included when the scans are submitted 
 
Questions may be directed to DataSubmission@QARC.org or 401.753.7600. 
  
Digital RT Data Submission Using TRIAD (if TRIAD is available at your site): 
TRIAD is the American College of Radiology’s (ACR) image exchange 
application.  TRIAD provides sites participating in clinical trials a secure method 
to transmit DICOM and DICOM RT files and other digital objects, such as reports. 
TRIAD de-identifies and validates the images as they are transferred. 
 
TRIAD Access Requirements: 
Site physics staff who will submit images through TRIAD will need to be 
registered with the Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management (IAM) account.  Please refer to 
CTEP Registration Procedures of the protocol for instructions on how to request a 
CTEP-IAM account. 
To submit images, the site TRIAD user must be on the site roster and be assigned 
the 'TRIAD site user' role on the CTSU roster.  Users should contact the site’s 
CTSU Administrator or Data Administrator to request assignment of the TRIAD 
site user role.   
 
TRIAD Installations: 
 
When a user applies for a CTEP-IAM account with the proper user role, he/she 
will need to have the TRIAD application installed on his/her workstation to be able 
to submit images. TRIAD installation documentation can be found by following 
this link https://triadinstall.acr.org/triadclient/   
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
 
If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
IROC Rhode Island (formerly QARC) will facilitate the central reviews. 
 
For FDG-PET imaging, the transferred imaging data should include uncorrected 

  
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time that the sample is drawn along with the exact time that the drug is 
administered. 
 
Sites are expected to use their own standard materials for PK sample collection as 
kits will not be provided for the PK studies for this study. 
 
 
Sample Processing 
Following collection, the sample will be immediately gently mixed by inversion 
8-10 times.  The sample will be stored on wet ice until centrifugation.  Within 30 
minutes of blood collection. The sample will be centrifuged at 1500 x g for 10 
minutes at 4° C. From each blood sample, transfer roughly equal volumes into a 
total of two 1.8ml polypropylene cryovials using a disposable polypropylene 
pipette.  
 
Store plasma samples at -20°C in an upright position within 30 minutes of plasma 
preparation and keep frozen at this temperature until shipment. 
 
 
Sample Labeling 
Each sample must be labeled with the patient’s study registration number, the study 
I.D# (APEC1621H), and the date and time the sample was drawn.  Data should be 
recorded appropriate transmittal form found in RAVE. 
 
 
Sample Shipping Instructions 
Ship the aliquots frozen on dry ice. The samples must be securely packed in boxes 
to avoid breakage during transit, double-bagged to contain leaks, and where 
applicable, packed with a sufficient quantity of dry ice to ensure they remain frozen 
for at least 72 hours.  
Sample Receiver:  
Trish Hansen  
Covance Laboratories 
8211 SciCor Drive, Suite B 
Indianapolis, IN46214 
Phone: 317.715.3985 
Fax: 317.616.2301 
Email: Patricia.Hansen@covance.com 
and IndyBioSA@Covance.com 
 
Circulating Tumor DNA Study (optional)  
 
 
Sampling Schedule   
An initial sample was previously required at time of enrollment onto the pediatric 
MATCH screening protocol. Two additional samples (optional) will be collected 
into Streck Cell-Free DNA BCT tubes at the timepoints: (1) Cycle 5 Day 1 
(2) At disease progression or end of protocol therapy  
 
Peripheral blood samples for circulating tumor DNA should be obtained as 
follows:  
• 
For patients ≥ 10 kg collect 20 mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg collect 10 mL (one tube)  
• 
For patients < 5 kg research samples will not be collected  
 

  
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In all cases, blood draw volumes should strictly adhere to institutional limitations, 
taking other blood draws into consideration. However, if a reduction in volume is 
required, samples should be collected in 10 mL increments (ie. 0, 10, or 20 mL 
should be collected such that each Streck Cell-Free DNA BCT is completely 
filled). 
 
Established institutional guidelines should be followed for blood collection via 
vascular access devices. Heparin should be avoided in pre-collection flush 
procedures. If therapeutic heparin dosing contamination is a possibility, 
venipuncture is recommended as a first choice collection method. If a Streck Cell-
Free DNA BCT tube immediately follows a heparin tube in the draw order, we 
recommend collecting an EDTA tube as a waste tube prior to collection in the 
Streck Cell-Free DNA BCT. 
 
For patients who do not have indwelling catheters, blood should be collected via 
venipuncture. To guard against backflow, observe the following precautions: 
• 
Keep patient’s arm in the downward position during the collection 
procedure. 
• 
Hold the tube with the stopper in the uppermost position so that the tube 
contents do not touch the stopper or the end of the needle during sample 
collection. 
• 
Release tourniquet once blood starts to flow in the tube, or within 2 
minutes of application. 
• 
Fill tube completely. 
• 
Remove tube from adapter and immediately mix by gentle inversion 8 to 
10 times. Inadequate or delayed mixing may result in inaccurate test 
results. 
• 
Store blood in Streck tube at room temperature until shipment 
 
 
Sample Processing 
Samples do not need to be processed at the collection site. 
 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D (APEC1621H), and the date and time the sample was drawn.  Data should be 
recorded on the appropriate transmittal form found in RAVE. 
 
 
Sample Shipping Instructions 
Specimen should be shipped at room temperature to the BPC (address below). 
Upon arrival separation, extraction, and storage of plasma and cellular DNA will 
be performed. Samples should be shipped from Monday through Friday for 
Tuesday through Saturday delivery. If blood is collected over the weekend or on 
the day before a holiday, the sample should be stored in a refrigerator until shipped 
on the next business day.  Ship by FedEx Priority Overnight using the COG FedEx 
account. Blood samples should be shipped the same day as collection, ship blood 
for Saturday delivery if shipped on Friday. 
 
 
 
 
 
 

  
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Ship specimens to the following address: 
 
 
 
Biopathology Center 
 
 
Nationwide Children’s Hospital 
 
 
Protocol APEC1621H– Peds MATCH* 
 
 
700 Children’s Drive, WA1340 
 
 
Columbus, OH 43205 
 
 
Phone: (614) 722-2865 
 
 
Fax: (614) 722-2897 
Email:BPCBank@nationwidechildrens.org 
 
*Packages must be labeled “Peds MATCH” in order to expedite processing at the 
BPC. 
 
Ship samples by FedEx Priority Overnight using a FedEx shipping label obtained 
through the COG FedEx account.  
 
9.0 
 AGENT INFORMATION 
 
 
Olaparib 
(Lynparza, AZD2281, KU-0059436; CO-CE 42) 
NSC# 747856 
 
  
 
Structure and molecular weight  
Chemical name: 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Molecular Formula: 
 C24H23FN4O3  
Molecular Weight: 434.46 
 
 
Supplied by: Astrazeneca supplies and PMB, CTEP, DCTD, NCI distributes 
Olaparib. 
 
 
Formulation 
Olaparib is supplied as film-coated tablets in 25 mg, 100 mg and 150 mg strengths.  
 
• 25 mg tablets are 6 mm round-shaped 
• 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 150 mg are 14.5 mm x 7.25 mm oval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) 
bottles with child-resistant closures. Each bottle contains 32 tablets with desiccant.  
 
Tablet core components include active drug substance, copovidone, colloidal silicon 
dioxide, mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl 
methylcellulose (hypromellose), macrogol 400 (polyethylene glycol 400), titanium 
dioxide, iron oxide yellow and iron oxide black. 
 
 
Storage 

  
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Store in a secure location below 30° C (86° F).  
 
If a storage temperature excursion is identified, promptly return olaparib to 
controlled room temperature and quarantine the supplies.  Provide a detailed report 
of the excursion (including documentation of temperature monitoring and duration 
of the excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability.   
 
 
Stability 
Shelf-life studies are ongoing. Sites are not permitted to re-package tablets. Once 
the bottle is opened, olaparib tablets must be used within 3 months of the opening 
date; unused tablets should be discarded. Use as few tablet sizes as possible. 
Instruct patients not to open a bottle until they are ready to use it. 
 
 
Administration  
See Treatment (Section 5.0) and Dose Modification (Section 6.0) sections of the 
protocol.  
 
Olaparib tablets should be administered orally twice a day without regard to meals. 
If a patient vomits within 30 minutes after the dose of olaparib is administered, and 
all the tablets are intact and can be accounted for, that dose may be repeated once. 
Otherwise, the dose will be missed. 
 
 
Potential Drug Interactions 
In vivo data indicate that CYP3A4/5 is important for olaparib metabolism and 
clearance in humans. For this reason, avoid concomitant administration of strong and 
moderate CYP 3A4/5 inducers and inhibitors.  Consult the protocol document or 
study investigator prior to making any dose adjustments related to potential drug-
drug interactions. 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for 
organic anion-transporting polypeptides (OATP1B1 and OATP1B3), organic cation 
transporter 1 (OCT1), multi-drug resistance protein 2 (MRP-2) efflux transporter or 
breast cancer resistance protein (BCRP). Administration of strong P-gp inhibitors and 
inducers should be avoided with concurrent olaparib.   
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and 
induces CYP 1A2, 2B6, and 3A4 and potentially induces CYP 2C9, 2C19 and P-gp. 
Therefore, avoid concomitant administration of sensitive substrates, particularly those 
with narrow therapeutic ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug 
and toxin extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, 
but not an inhibitor of OATP1B3 or MRP-2. In vitro studies suggest that olaparib 
may increase exposure of substrates of these transport systems, although the clinical 
relevance is not clear. The manufacturer recommends that statins, in particular, should 
be administered with caution when given concomitantly with olaparib. 
 
 
Patient Care Implications: 
Pre-clinical data indicate that olaparib adversely affects embryofetal survival and 
development. Therefore, women of child-bearing potential and their partners should 

  
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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. 
 
 
Adverse events reported on olaparib (AZD2281) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that olaparib (AZD2281) caused the adverse event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (nodal rhythm); Chest pain - 
cardiac; Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Colonic obstruction; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal stenosis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders 
- Other (gastrointestinal hemorrhage); Gastrointestinal disorders - Other (intestinal obstruction); 
Gastrointestinal disorders - Other (intestinal perforation); Ileus; Jejunal perforation; Obstruction gastric; 
Pancreatitis; Periodontal disease; Rectal hemorrhage; Small intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Fever; 
Malaise; Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response 
syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Dermatitis radiation; Fracture; 
Gastrointestinal anastomotic leak; Injury, poisoning and procedural complications - Other (vena cava 
injury); Wound dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood 
bilirubin increased; GGT increased; Hemoglobin increased; Lipase increased; Lymphocyte count 
decreased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypermagnesemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Avascular necrosis; Bone 
pain; Generalized muscle weakness; Muscle weakness lower limb; Muscle weakness upper limb; Neck 
pain; Rotator cuff injury; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Treatment related secondary malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration 
impairment; Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; Reversible posterior 
leukoencephalopathy syndrome; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(decreased glomerular filtration rate); Renal and urinary disorders - Other (hydronephrosis); Urinary tract 
obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Hypoxia; Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Arterial thromboembolism; Flushing; Hot flashes; Hypertension; 
Hypotension; Peripheral ischemia; Thromboembolic event 
 

  
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Note: Olaparib (AZD2281) 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. 
 
 
 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents. The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied investigational agents 
for the study should be ordered under the name of one lead participating investigator at that 
institution. 
                           
Note: No starter supplies will be provided Drug orders of olaparib should be placed 
with CTEP after enrollment and treatment assignment to APEC1621H with 
consideration for timing of processing and shipping to ensure receipt of drug supply 
prior to start of protocol therapy.  If expedited shipment is required, sites should provide 
an express courier account through the Online Agent Order Processing (OAOP) 
application. Provide the patient ID number in the comment box when submitting an order 
request. 
 
 
Clinical Drug Request and Investigator Brochure Availability 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. The current versions of the IBs for the agents will also be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, “current” 
password, and active person registration status. For questions about drug orders, transfers, 
returns, or accountability call or email PMB anytime. Refer to the PMB’s website for 
specific policies and guidelines related to agent management. Questions about IB access 
may be directed to the PMB IB coordinator via email. 
 
 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
 
Useful Links and Contacts  
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Registration: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
 
 
http://ctep.cancer.gov/branches/pmb/agent management.htm    

  
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• PMB Online Agent Order Processing (OAOP) application:  
 
 
https://ctepcore.nci.nih.gov/OAOP  
• CTEP Identity and Access Management (IAM) account:  
      https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: 
 
ctepreghelp@ctep.nci.nih.gov  
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575  
Monday through Friday between 8:30 am and 4:30 pm (ET) 
• PMB IB Coordinator: IBcoordinator@mail.nih.gov 
• Registration and Credential Repository (RCR): 
https://ctepcore.nci.nih.gov/rcr/  
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6). 
c) 
Refusal of 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 26 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 protocol therapy (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
j) 
Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute 
myeloid leukaemia (AML) 
k) 
Patient did not receive protocol treatment after study enrollment. 
 
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 from the APEC1621SC screening protocol. Patients who are removed from 
protocol therapy in subsequent cycles should have the necessary observations to 
ensure adequate clinical care.  
 
 
 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
Patients who are off subprotocol therapy will continue to be followed on the APEC1621SC 
screening protocol. Follow-up data submission will occur until one of the APEC1621SC 
Off Study Criteria is met (See Section 10 of APEC1621SC for details). 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 

  
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via RAVE and CTEP-AERS (if applicable).  Follow-up data will be required until off study 
criteria are met unless consent is withdrawn or the patient dies or is lost to follow-up. 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
 
Sample Size and Study Duration 
 
 Assuming an enrollment rate of 4-6 biomarker 
positive patients per year, this subprotocol is expected to be completed within 8-12 years. 
 
 
Dosing Considerations  
 
 Pediatric MATCH Sub-arm Dosing in the Absence of Pediatric Phase 1 Data 
Please see Section 5.1 for a specific discussion of the dosing of olaparib to be used 
in this study.  As there is no prior pediatric phase 1 data for olaparib, study 
investigators have reviewed relevant data with the pharmaceutical partner to 
identify a drug specific dosing plan for testing in children with relapsed/refractory 
cancer, and trial participants will be closely monitored to ensure tolerability of the 
selected dose. Limited pharmacokinetic sampling may be done for patients 
enrolled on these arms. 
 
 
 
 
 
 
 
 
  
 
 Determination of Recommended Phase 2 Dose (RP2D)/Tolerable Dose 
 
 
 
 The DLT evaluation period for the purpose of dose escalation 
will be cycle 1 of therapy. Note that adverse events that begin during cycle 1 and 
specify a duration of time in order to be considered a DLT must be followed to 
resolution or until the definition of DLT has been met, regardless of the schedule 
end of cycle 1 (e.g.  grade 2 thrombocytopenia would be considered a DLT if it 
developed during cycle 1 of therapy and caused, or would have caused, a delay of 
>14 days to begin cycle 2).  
 
Enrollment of the initial cohort of up to six patients will follow the standard rules 
of the rolling six design 31 to assess safety and tolerability of cycle one of protocol 
treatment prior to extending accrual to additional patients. 
 
The rolling six phase 1 trial design will be used for the conduct of this study. Two 
to six patients can be concurrently enrolled onto a dose level, dependent upon (1) 
the number of patients enrolled at the current dose level, (2) the number of patients 
who have experienced DLT at the current dose level, and (3) the number of patients 
entered but with tolerability data pending at the current dose level.  Accrual is 
suspended when a cohort of six has enrolled or when the study endpoints have 
been met.  
 
Dose level assignment is based on the number of participants currently enrolled in 
the cohort, the number of DLTs observed, and the number of participants at risk 

  
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for developing a DLT (i.e., participants enrolled but who are not yet assessable for 
toxicity). For example, when three participants are enrolled onto a dose cohort, if 
toxicity data is available for all three when the fourth participant entered and there 
are no DLTs, the dose is escalated and the fourth participant is enrolled to the 
subsequent dose level. If data is not yet available for one or more of the first three 
participants and no DLT has been observed, or if one DLT has been observed, the 
new participant is entered at the same dose level. Lastly, if two or more DLTs have 
been observed, the dose level is de-escalated. This process is repeated for 
participants five and six. In place of suspending accrual after every three 
participants, accrual is only suspended when a cohort of six is filled. When 
participants are inevaluable for toxicity, they are replaced with the next available 
participant if escalation or de-escalation rules have not been fulfilled at the time 
the next available participant is enrolled onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the 
current dose level (ii) at an escalated dose level, (iii) at a de-escalated dose level, 
or whether the study is suspended to accrual: 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
3 
0 
3 
0 
Escalate** 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
4 
0 
4 
0 
Escalate** 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
5 
0 
5 
0 
Escalate** 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
dose escalation will be stopped. 
 
In addition to determination of the RP2D, a descriptive summary of all toxicities will be 
reported. 
 
 
Study Design 
The primary cohort will employ a single stage A’Hern design of N=20. The agent will be 

  
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Recommended Phase 2 Dose (dose finding phase) will count toward the objective response 
rate in their respective cohort. 
 
Toxicity tables will be constructed to summarize the observed incidence by type of toxicity 
and grade. A patient will be counted only once for a given toxicity for the worst grade of 
that toxicity reported for that patient. Toxicity information recorded will include the type, 
severity, time of onset, time of resolution, and the probable association with the study 
regimen.   
 
 
Evaluability for Response 
Any eligible patient who is enrolled and receives at least one dose of protocol therapy will 
be considered evaluable for response Patients who are not evaluable for response 
evaluation may be replaced for the purposes of the statistical rule. Patients who 
demonstrate a complete or partial response confirmed by central review will be considered 
to have experienced a response. When opening expansion cohorts, the evaluation period 
for determination of best response will be 6 treatment cycles. All other patients will be 
considered non-responders. Patients who are not evaluable for response evaluation may be 
replaced for the purposes of the statistical rule. All patients considered to have a response 
(CR or PR) must have imaging studies reviewed centrally at the COG. Centers will be 
notified by the COG about requests for scans of patients with stable disease. Preliminary 
assessment of activity using institutionally provided tumor measurements will be entered 
into CDUS quarterly. The central review by COG will be provided as the final reviewed 
assessment of response when such becomes available. 
 
 
Evaluability for Toxicity 
Any eligible patient who receives at least one dose of the study drug(s) or who experiences 
a dose-limiting toxicity is considered evaluable for Adverse Events. In addition, for the 
dose-escalation portion during Cycle 1, patients without DLT who receive at least 85% of 
the prescribed dose per protocol guidelines and must have the appropriate toxicity 
monitoring studies performed during cycle 1 to be considered evaluable for toxicity. 
 
Progression free survival (PFS) 
Progression free survival will be defined as time from the initiation of protocol treatment 
to the occurrence of any of the following events: disease progression or disease recurrence 
or death from any cause. All patients surviving at the time of analyses without events will 
be censored at their last follow-up date. 
 
PFS along with the confidence intervals will be estimated using the Kaplan-Meier method. 
Patients with local calls of disease progression (i.e. calls made by the treating institution), 
will be counted as having had an event, even if the central review does not declare 
progression. We will also report PFS based on central radiology review as a secondary 
analysis, if adequate number of disagreements in progressions exist between the treating 
institutions and the central radiology review to make such an analysis meaningful.     
 
 
Correlative Studies 
A descriptive analysis of pharmacokinetic (PK) parameters 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).   
 

  
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response:  a) solid tumor (non-CNS) and measurable disease (Section 12.4); b) 
neuroblastoma with MIBG positive lesions (Section 12.5); c) CNS tumor (Section 12.7); 
and d) non-Hodgkin lymphoma/hystiocytosis (Section 12.8). Note: Neuroblastoma patients 
who do not have MIBG positive lesions should be assessed for response as solid tumor 
patients with measurable disease. 
 
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. 
 
 Definitions 
 
12.3.1.1 
Evaluable for objective response:  
Eligible patients who receive at least one dose of protocol therapy will be 
considered evaluable for response. Evaluable patients who demonstrate a 
complete or partial response confirmed by central review before receiving 
non-protocol anti-cancer therapy will be considered a responder. All other 
evaluable patients will be considered non-responders 
12.3.1.2 
Evaluable Non-Target Disease Response: 
Eligible patients who have lesions present at baseline that are evaluable 
but do not meet the definitions of measurable disease and have received 
at least one dose of protocol therapy will be considered evaluable for 
non-target disease response. The response assessment is based on the 
presence, absence, or unequivocal progression of the  
 
 Disease Parameters 
 
12.3.2.1 
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. 
 
12.3.2.2 
Malignant lymph nodes: To be considered pathologically enlarged and 
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. 
 
12.3.2.3 
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 

  
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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. 
 
12.3.2.4 
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. 
 
12.3.2.5 
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.  
 
 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. 
 
12.3.3.1 
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.  
 
12.3.3.2 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 

  
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when they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
 
12.3.3.3 
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.  
 
12.3.3.4 
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 or International Pediatric non-Hodgkin 
Lymphoma Response Criteria 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.   
 
12.3.3.5 
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.  
 
12.3.3.6 
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. 
 
12.3.3.7 
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 

  
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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. 
              
            For patients with a positive PET scan at diagnosis, PET can be 
used to follow response in addition to a CT scan using the 
International Pediatric non-Hodgkin Lymphoma Response 
Criteria.34 
 
 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
 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 
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 
 
 Evaluation of Non-Target Lesions 

  
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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.     
 
 Overall Response Assessment 
 
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. 
**  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. 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 

  
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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: 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 
 
 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 
12.9  from a sequence of overall response assessments. 
 
 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
 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. 
 
 
 
 
 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 
 
 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 

  
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for study endpoint. See Section 8.2 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
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. 
 
 Overall Response Assessment 
 
Table 4: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease 

  
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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 
 
 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 Section 12.9. 
 
 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
 Bone Marrow Involvement  
Note: patients with bone marrow as the ONLY site of disease are not eligible for 
this study. Response criteria in this section are intended to be used when 
assessing marrow involvement as a component of overall response.  
 
Histologic analysis at the local institution of marrow tumor cell involvement is 
required for patients with a history of marrow involvement. Marrow aspirate and 
biopsy should be evaluated at baseline and every 2 cycles thereafter. Note: If 
progressive disease is documented by RECIST criteria using tumor measurements 
or by MIBG scan, then a repeat BM is not needed to confirm PD.  
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 
morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 

  
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tumor is detected in 2 consecutive bone marrow biopsies 
or aspirations done at least 21 days apart. 
 
Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
 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 Section 12.9. 
 
 
Response Criteria for Patients with CNS Tumors 
 
 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
 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. 
 
 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). 
 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
 
 
 
 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. Off all steroids 
with stable or improving neurologic examination. 
 

  
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• 
Partial response (PR): A greater than 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; on a stable or decreasing 
dose of steroids with a stable or improving neurologic examination. 
 
• 
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; on a stable or 
decreasing dose of steroids with a stable or improving neurologic examination. 
 
• 
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. 
 
Increasing doses of corticosteroids required to maintain stable neurological 
status should be strongly considered as a sign of clinical progression unless in 
the context of recent wean or transient neurologic change due e.g. to radiation 
effects. 
 
 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. 
 
 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
 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.   
 
 
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 

  
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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 
12.9 from a sequence of overall response assessments. 
 
 
 
Response Criteria for Patients with non-Hodgkin Lymphoma/Histiocytosis 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Pediatric non-Hodgkin 
Lymphoma Criteria, with modification from the Lugano classification. 35 33 35 34 
 
 Disease Parameters 
 
12.8.1.1 Measurable disease: A measurable node must have an LDi (longest 
diameter) greater than 1.5 cm. A measurable extranodal lesion should 
have an LDi greater than 1.0 cm. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
12.8.1.2 Non-measured disease: All other lesions (including nodal, extranodal, and 
assessable disease) should be followed as nonmeasured disease (e.g., 
cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial 
effusions, ascites).   
 
12.8.1.3 Target lesions: For patients staged with CT, up to six of the largest target 
nodes, nodal masses, or other lymphomatous lesions that are measurable 
in two diameters (longest diameter [LDi] and shortest diameter) should 
be identified from different body regions representative of the patient’s 
overall disease burden and include mediastinal and retroperitoneal 
disease, if involved. 
 
 
 
 
 
 
 
 
 Evaluation of Measurable Disease 
 
Complete Response (CR) 
Disappearance of all disease. CT or MRI should be free of residual mass or 
evidence of new disease. FDG-PET should be negative. 
 
Complete Response Unconfirmed (CRu) 
Residual mass is negative by FDG-PET; no new lesions by imaging examination; 
no new and/or progressive disease elsewhere 
 

  
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Partial Response (PR) 
50% decrease in SPD (the sum of the products of the largest diameter and the 
perpendicular diameter for a tumor mass) on CT or MRI; FDG-PET may be 
positive (Deauville score or 4 or 5 with reduced lesional uptake compared with 
baseline); no new and/or PD; morphologic evidence of disease may be present in 
BM if present at diagnosis; however, there should be 50% reduction in percentage 
of lymphoma cells. 
 
No Response (Stable Disease) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
Progressive disease 
For those with > 25% increase in SPD on CT or MRI, Deauville score 4 or 5 on 
FDG-PET with increase in lesional uptake from baseline, or development of new 
morphologic evidence of disease in BM  
 
 Evaluation of Non-measured Lesions (CT-based response, PET/CT based 
response not applicable)35 
 
Complete Response (CR): 
Absent non-measured lesions.  
 
Partial response (PR): 
Absent/normal, regressed, lesions, but no increase. 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): New 
or 
clear 
progression 
of 
preexisting 
non-measured lesions. 
 
 Evaluation of organ enlargement35  
 
Complete Response (CR): 
Regress to normal  
 
Partial response (PR): 
Spleen must have regressed by >50% in length 
beyond normal 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): In the setting of splenomegaly, the splenic length 
must increase by 50% of the extent of its prior 
increase beyond baseline. If no prior splenomegaly, 
must increase by at least 2 cm from baseline.  
 
New or recurrent splenomegaly 
 
Best Response 
Two objective status determinations of disease status, obtained on two consecutive 
determinations, separated by at least a 3 week time period, are required to determine the 
patient’s overall best response. Two objective status determinations of CR before 
progression are required for best response of CR. Two determinations of PR or better 
before progression, but not qualifying for a CR, are required for a best response of PR. 
Two determinations of stable/no response or better before progression, but not qualifying 
as CR or PR, are required for a best response of stable/no response; if the first objective 
status is unknown, only one such determination is required. Patients with an objective 

  
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status of progression on or before the second evaluations (the first evaluation is the first 
radiographic evaluation after treatment has been administered) will have a best response of 
progressive disease. Best response is unknown if the patient does not qualify for a best 
response of progressive disease and if all objective statuses after the first determination and 
before progression are unknown. 
 
 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 5.  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 
 
 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.  
 
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 Case Report Forms 
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 

  
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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. 
 
 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
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 a serious adverse drug experience 
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. 
 
 Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair 
have the primary responsibility for AE identification, documentation, grading, and 
assignment of attribution to the investigational agent/intervention. It is the 
responsibility of the treating physician to supply the medical documentation 
needed to support the expedited AE reports in a timely manner.  
 
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via 
routine reporting. Routine reporting is accomplished via the Adverse Event (AE) 
Case Report Form (CRF) within the study database.   
 
 CTEP-AERS Expedited Reporting Methods  
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page https://ctepcore
.nci.nih.gov/ctepaers/pages/task. 
 
Send supporting documentation to the NCI by fax (fax# 301-897-7404) and by 

  
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email to both COGCAdEERS@childrensoncologygroup.org and to the APEC162
1H COG Study Assigned Research Coordinator. ALWAYS include the ticket 
number on all faxed and emailed documents. 
 
 
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 current version of the NCI CTCAE V 
5.0.  The descriptions and grading scales found in the current version of the 
CTCAE v5.0 will be used for AE reporting. All appropriate treatment areas should 
have access to a copy of the CTCAE v5.0.  A copy of the CTCAE v5.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAE v5.0. 
 
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.  
 
• 
Any medical event equivalent to CTCAE v5.0 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 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. 
• 
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. 
• 
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). 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 
calendar days of learning of the event (refer to Table A). 
 
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 ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 

  
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should be reported at the end of each cycle using the forms provided in the CRF 
packet (See Section 14.1). 
 
 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. 
 
 
Specific Examples for Expedited Reporting 
 
 Reportable Categories of Death 
• Death attributable to a CTCAE v5.0 term.  
• Death Neonatal: A disorder characterized by “Newborn deaths occurring during 
the first 28 days after birth.” 
• Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be attributed 
to a CTCAE v5.0 term associated with Grade 5.  
• Death NOS: A cessation of life that cannot be attributed to a CTCAE v5.0 term 
associated with Grade 5.  
• Death due to progressive disease should be reported as Grade 5 “Disease 
Progression” under the system organ class (SOC) of “General Disorders and 
Administration Site Conditions.” Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
• Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 
hours.  
 
• 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 per the timelines outlined in the table above. 
 
 
 
 
 Reporting Secondary Malignancy 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, 
radiation 
or 
chemotherapy). A secondary malignancy is not considered a metastasis of the 
initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  

  
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1) Leukemia secondary to oncology chemotherapy (e.g., acute 
myelocytic leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
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. 
 
 Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Neonatal loss”, the Pregnancy Information Form, available at: http://ctep.cancer.
gov/protocolDevelopment/electronic applications/docs/PregnancyReportForm.p
df, needs to be completed and faxed along with any additional medical information 
to (301)-897-7404. 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. 
 
Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the fetus to 
agents that may be teratogenic. For this reason, pregnancy needs to be reported in 
an expedited manner via CTEP-AERS as Grade 3 “Pregnancy, puerperium and 
perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and 
perinatal conditions SOC. 
 
Pregnancy needs to be followed until the outcome of the pregnancy is known at 
intervals deemed appropriate by her physicians. The “Pregnancy Information 
Form” should be used for all necessary follow-ups. If the baby is born with a birth 
defect or anomaly, then a second CTEP-AERS report is required. 
 
Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE v5.0 as “Death in utero.” 
 
Any pregnancy loss, needs to be reported expeditiously, as Grade 4 “Pregnancy 
loss” under the “Pregnancy, puerperium and perinatal conditions” SOC. Do 
NOT report a pregnancy loss as a Grade 5 event since CTEP-AERS recognizes 
any Grade 5 event as a patient death. 
 
Death Neonatal 
Neonatal death, defined in CTCAE v5.0 as “Newborn deaths occurring during 
the first 28 days after birth” that is felt by the investigator to be at least possibly 
due to the investigational agent/intervention, should be reported expeditiously, as 
Grade 4 “Death Neonatal” under the system organ class (SOC) of “General 
disorders and administration site conditions.” When the death is the result of a 
patient pregnancy or pregnancy in partners of men on study. Do NOT report 
a neonatal death resulting from a patient pregnancy or pregnancy in partners of 

  
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men on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event 
as a patient death.  
 
 Reporting of Study Drug Overdose 
Study drug overdose refers to the uses of the study drug outside of that specified 
by the protocol. 
 
• 
Overdose: Accidental or intentional use of the study drug in an amount 
higher than the protocol defined dose. 
 
Any study drug overdose should be reported on the Reporting Period-Dosing CRF. 
All AEs associated with an overdose should be entered both on the Reporting 
Period CRF and reported expeditiously using the CTEP-AERS. 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
 
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 case report form (CRF) 
packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis.  Reports are due January 31, April 30, July 31 and October 31.  
This is not a responsibility of institutions participating in this trial. 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.   
 
 
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 

  
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Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the provisions in the “Intellectual Property Option to Collaborator” (http://ctep.cancer.go
v/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 
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/industr
yCollaborations2/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. 

  
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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 
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. 
 
 
 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
 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. 
 
 Monitoring by the Study Chair and MATCH 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 
MATCH Chair, Vice Chair and Statistician on a weekly conference call. 

  
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REFERENCES 
1. 
McLornan DP, List A, Mufti GJ: Applying synthetic lethality for the selective targeting of cancer. 
N Engl J Med 371:1725-35, 2014 
2. 
Hoeijmakers JHJ: Genome maintenance mechanisms for preventing cancer. Nature 411:366-374, 
2001 
3. 
Rouleau M, Patel A, Hendzel MJ, et al: PARP inhibition: PARP1 and beyond. Nat Rev Cancer 
10:293-301, 2010 
4. 
Kurumizaka H, Ikawa S, Nakada M, et al: Homologous-pairing activity of the human DNA-repair 
proteins Xrcc3.Rad51C. Proc Natl Acad Sci U S A 98:5538-43, 2001 
5. 
Buisson R, Dion-Cote AM, Coulombe Y, et al: Cooperation of breast cancer proteins PALB2 and 
piccolo BRCA2 in stimulating homologous recombination. Nat Struct Mol Biol 17:1247-54, 2010 
6. 
Ashworth A: A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for 
the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 26:3785-90, 
2008 
7. 
Bryant HE, Schultz N, Thomas HD, et al: Specific killing of BRCA2-deficient tumours with 
inhibitors of poly(ADP-ribose) polymerase. Nature 434:913-7, 2005 
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. 
Fong PC, Boss DS, Yap TA, et al: Inhibition of poly(ADP-ribose) polymerase in tumors from 
BRCA mutation carriers. N Engl J Med 361:123-34, 2009 
10. 
Audeh MW, Carmichael J, Penson RT, et al: Oral poly(ADP-ribose) polymerase inhibitor olaparib 
in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept 
trial. Lancet 376:245-51, 2010 
11. 
Tutt A, Robson M, Garber JE, et al: Oral poly(ADP-ribose) polymerase inhibitor olaparib in 
patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. 
Lancet 376:235-44, 2010 
12. 
Gelmon KA, Tischkowitz M, Mackay H, et al: Olaparib in patients with recurrent high-grade serous 
or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, 
open-label, non-randomised study. The Lancet Oncology 12:852-861, 2011 
13. 
Lavin MF, Kozlov S: ATM activation and DNA damage response. Cell Cycle 6:931-42, 2007 
14. 
McCabe N, Turner NC, Lord CJ, et al: Deficiency in the Repair of DNA Damage by Homologous 
Recombination and Sensitivity to Poly(ADP-Ribose) Polymerase Inhibition. Cancer Research 
66:8109-8115, 2006 
15. 
Wang C, Jette N, Moussienko D, et al: ATM-Deficient Colorectal Cancer Cells Are Sensitive to 
the PARP Inhibitor Olaparib. Translational Oncology 10:190-196, 2017 
16. 
Matulonis UA, Penson RT, Domchek SM, et al: Olaparib monotherapy in patients with advanced 
relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates 
and safety. Ann Oncol 27:1013-9, 2016 
17. 
Kaufman B, Shapira-Frommer R, Schmutzler RK, et al: Olaparib monotherapy in patients with 
advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33:244-50, 2015 
18. 
Lord CJ, Ashworth A: BRCAness revisited. Nat Rev Cancer 16:110-20, 2016 
19. 
Mateo J, Carreira S, Sandhu S, et al: DNA-Repair Defects and Olaparib in Metastatic Prostate 
Cancer. N Engl J Med 373:1697-708, 2015 
20. 
Swisher EM, Lin KK, Oza AM, et al: Rucaparib in relapsed, platinum-sensitive high-grade ovarian 
carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. The Lancet 
Oncology 18:75-87, 2017 
21. 
Zhang J, Walsh MF, Wu G, et al: Germline Mutations in Predisposition Genes in Pediatric Cancer. 
New England Journal of Medicine 373:2336-2346, 2015 
22. 
Parsons DW, Roy A, Yang Y, et al: Diagnostic Yield of Clinical Tumor and Germline Whole-
Exome Sequencing for Children With Solid Tumors. JAMA Oncol 2:616-624, 2016 
23. 
Smith MA, Hampton OA, Reynolds CP, et al: Initial testing (stage 1) of the PARP inhibitor BMN 

  
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673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo 
response to BMN 673. Pediatr Blood Cancer 62:91-8, 2015 
24. 
AstraZeneca: Investigator's Brochure AZD2281, LYNPARZA™, olaparib, 2016 
25. 
Rottenberg S, Jaspers JE, Kersbergen A, et al: High sensitivity of BRCA1-deficient mammary 
tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl 
Acad Sci U S A 105:17079-84, 2008 
26. 
Hay T, Matthews JR, Pietzka L, et al: Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses 
autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in 
combination with carboplatin. Cancer Res 69:3850-5, 2009 
27. 
Mateo J, Moreno V, Gupta A, et al: An Adaptive Study to Determine the Optimal Dose of the 
Tablet Formulation of the PARP Inhibitor Olaparib. Target Oncol 11:401-15, 2016 
28. 
Domchek SM, Aghajanian C, Shapira-Frommer R, et al: Efficacy and safety of olaparib 
monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or 
more lines of prior therapy. Gynecol Oncol 140:199-203, 2016 
29. 
Kim G, Ison G, McKee AE, et al: FDA Approval Summary: Olaparib Monotherapy in Patients 
with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More 
Lines of Chemotherapy. Clin Cancer Res 21:4257-61, 2015 
31. 
Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the Timeline of Pediatric Phase I Trials: 
The Rolling Six Design. Journal of Clinical Oncology 26:190-195, 2008 
32. 
A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 20:859-66, 2001 
33. 
Agresti A, Coull BA: Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician 52:119-126, 1998 
34. 
Sandlund JT GR, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma Response 
Criteria. J Clin Oncol 33, 2015 
35. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32:3059-68, 2014 
 
 

  
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APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
 
This is not an inclusive list. Because the lists of these agents are constantly changing, it is important to 
regularly consult frequently updated medical references. 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate Inhibitors 
Strong Inducers 
Moderate Inducers 
alfentanil4,5  
acalabrutinib5 
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
ergotamine4 
erlotinib 
eplerenone5 
erlotinib 
estrogens 
etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
mifepristone 
nilotinib 
verapamil 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
dabrafenib 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifapentin 
 
 
 

  
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ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4  
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
telaprevir 
tamoxifen 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 7.5 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥ 5-fold with strong inhibitors) 

  
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Cycle 1  
See Section 6.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care 
Guidelines. 
 
         
 
 
Required Observations in Cycle 1  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below. For information related to prestudy observations please refer to Section 8.1. Studies on Day 
28/1 may be obtained within 72 hours prior to the start of the subsequent cycle. 
 
 
 
 
 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
Treatment Details: Cycle 1 
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are 
met (whichever occurs later).  
 
 
 
 
 
a. 
History/Physical Exam (including VS) 
b. 
Ht/Wt/BSA 
c. 
 
CBC/differential/platelets- 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. If patients 
develop Grade 3 or greater thrombocytopenia then CBCs should be checked every 3 to 4 days until 
recovery per section 6.1. 
d. 
Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, bilirubin 
f. 
Albumin 
g. 
 
Patient Diary- (see Appendix III) should be reviewed after completion of each treatment cycle and 
uploaded into RAVE. The patient diary should be collected weekly.  
h. 
Pharmacokinetics (optional)-see Section 8.3 for details of PK studies.  

  
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Subsequent Cycles 
* Please refer to Section 8.1 for the specific timing of these observations. Studies on Day 28/1 may be obtained 
within 72 hours prior to the start of the subsequent cycle. 
 
Required Observations in All Subsequent Cycles 
 
a. 
History/Physical Exam (including VS) 
b. 
Ht/Wt/BSA 
c. 
CBC/differential/platelets 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. If patients develop Grade 3 or greater 
thrombocytopenia then CBCs should be checked every 3 to 4 days until recovery per 
section 6.1. 
d. 
Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, bilirubin 
f. 
Albumin 
g. 
Tumor Disease Evaluation – Every other cycle x 2 then q 3 cycles. Tumor Disease  
Evaluation should be obtained on the next consecutive cycle after initial  
documentation of either a PR or CR.  Subsequent scans may restart 2 cycles after  
the confirmatory scan. 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 
h. 
Patient Diary- (see Appendix III) should be reviewed after completion of each 
treatment cycle and uploaded into RAVE. 
i. 
Circulating Tumor DNA (ctDNA-optional)- With consent, two samples will be  
collected on this protocol (Cycle 5 Day 1; and for patients receiving ≥ 5 cycles,  at  
progression or end of protocol therapy) see Section 8.4 for details of the ctDNA 
studies.  
j. 
Bone Marrow Aspirate and/or biopsy- Bone marrow aspirate and/or biopsy should 
only be performed only when complete response or partial response is identified in 
target disease or when progression in bone marrow is suspected. 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
Treatment Details: Subsequent Cycles 
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are 
met (whichever occurs later). 

  
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APPENDIX VI: TARGET HISTOLOGIES FOR APEC1621H EXPANSION COHORTS 
 
Target tumor types considered for biomarker-positive expansion cohorts in the event of agent activity 
in a specific tumor type. 
 
 
 
 
 
Tumor type 
1. Ependymoma 
2. Ewing Sarcoma/Peripheral PNET 
3. Hepatoblastoma 
4. Glioma, high grade 
5. Glioma, low grade 
6. Langerhans Cell Histiocytosis 
7. Malignant Germ Cell Tumor 
8. Medulloblastoma  
9. Neuroblastoma 
10. Non-Hodgkin Lymphoma 
11. Non-RMS Soft Tissue Sarcoma 
12. Osteosarcoma 
13. Rhabdoid Malignancy 
14. Rhabdomyosarcoma 
15. Wilms Tumor 
16. Other Histology (based on COG/NCI-CTEP approval) 

  
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APPENDIX VII CORRELATIVE STUDIES 
 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total 
Cycle 
1 
Pharmacokinetics 
8.3 
2 mL 
12 
mL 
2 mL BD Vacutainer tubes 
containing Lithium Heparin 
Total Blood Volume in 
Cycle 1 
 
12 
mL 
 
 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total 
Cycle 5 
Day 1 
Circulating tumor 
DNA (optional) 
8.4 
• 
For patients ≥ 10 kg collect 
20 mLs (10 mL per tube x 2 
tubes)  
• 
For patients ≥ 5 kg but < 10 
kg collect 10 mL (one tube)  
• 
For patients < 5 kg research 
samples will not be collected  
 
10-20 
mL 
Streck Cell-Free DNA BCT 
tubes 
Total Blood Volume in 
Cycle 5 Day 1 
 
10-20 
mL 
 
 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total  ‘Time of 
progression’ or 
‘End of protocol 
therapy’ 
Circulating tumor 
DNA (optional) 
8.4 
• 
For patients ≥ 10 kg collect 20 
mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg 
collect 10 mL (one tube)  
• 
For patients < 5 kg research 
samples will not be collected  
 
10-20 mL 
Streck Cell-Free 
DNA BCT tubes 
Total Blood Volume in 
‘Time of progression or 
End of protocol therapy’ 
 
10-20 mL 
 
 
 
 
 
 

  
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APPENDIX VIII: APEC1621H ACTIONABLE MUTATIONS OF INTEREST 
 
NON-
HOTSPOT 
RULES 
  
  
Gene Name 
Description 
Variant Type 
LOE 
BRCA1 
Include 
Deleterious 
1 
BRCA2 
Include 
Deleterious 
1 
ATM 
Include 
Deleterious 
1 
RAD51C 
Include 
Deleterious 
2 
RAD51D 
Include 
Deleterious 
2 
 

  
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APPENDIX IX APEC1621H PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
study drug, olaparib (AZD2281).  This clinical trial is sponsored by the National Cancer Institute 
(NCI).  This form is addressed to the patient, but includes important information for others who 
care for this patient.  
 
These are the things that you as a prescriber need to know: 
  
Olaparib interacts with certain specific enzymes in the liver and certain transport proteins that 
help move drugs in and out of cells. 
 
• The enzymes in question are CYP 3A4/5, 1A2, 2B6, 2C9, 2C19 and UGT1A1. Olaparib is 
cleared by CYP3A4/5 and is affected by strong and moderate inhibitors and inducers of 
CYP3A4/5. Olaparib inhibits CYP3A4 and UGT1A1enzymes and may increase levels of 
other drugs that are cleared by these enzymes. Olaparib induces CYP 1A2, 2B6 and 3A4 
enzymes and has the possibility of inducing CYP 2C9, 2C19 enzymes that may result in 
decreased levels of other drugs that are cleared by these enzymes.   
• The transport proteins in question are P-glycoprotein (P-gp), organic anion-transporting 
polypeptides (OATP1B1 and OAT3), organic cation transporters (OCT1 and OCT2), 
multi-drug and toxin extrusion proteins (MATE1 and MATE2K) and breast cancer 
resistance protein (BCRP). Olaparib requires P-gp to move in and out of cells and 
concomitant administration of strong P-gp inhibitors and inducers should be avoided. 
Olaparib inhibits P-gp, BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K 
transporters and has the possibility of inducing P-gp and that may affect the transport of 
other drugs that depend on these proteins to move in and out of cells. Use caution when 
taking substrates of these transporters, such as statins. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
November 2015 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Olaparib may interact with many drugs which can cause side effects. Because of this, it is very 
important to tell your study doctors about all of your medicines before you enroll on this clinical 
trial.  It is also very important to tell them if you stop taking any regular medicines, or if you start 
taking a new medicine while you take part in this study.  When you talk about your medications 
with your doctors, include medicine you buy without a prescription (over-the-counter remedy), or 
any herbal supplements such as St. John’s Wort. It is helpful to bring your medication bottles or 
an updated medication list with you. 
 
Many health care prescribers can write prescriptions.  You must also tell your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical 
trial.  

  
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These are the things that you and they need to know: 
 
Olaparib must be used very carefully with other medicines that need certain liver enzymes and 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong inducers/inhibitors of CYP3A4/5 
and P-gp.” Olaparib inhibits enzymes “CYP3A4, UGT1A1, P-gp, OATP1B1, OCT1, OCT2, 
OAT3, MATE1, MATE2K and BCRP.” Olaparib possibly induces “CYP 1A2, 2B6, 3A4, 2C9, 
2C19 and P-gp.” These characteristics may change how other medicine works in your body. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctor or 
pharmacist to determine if there could be any side effects.  
• Avoid ingesting grapefruit, grapefruit juice and Seville oranges while taking olaparib. 
• You may need to be monitored more frequently if you are taking any drugs that have 
narrow therapeutic ranges. 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is ______________________________________                
and he or she can be contacted at ____________________________________. 
 
 
 
 
 
 
 
 
  
 
      November 2015 
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug olaparib 
(AZD2281).  This clinical trial is sponsored by the NCI.  Olaparib 
interacts with drugs that are processed by your liver, or use certain 
transport proteins in your body.  Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
➢ Olaparib interacts with liver enzymes, CYP3A4/5, 1A2, 2B6, 2C9, 
2C19, UGT1A1, and transport proteins, P-gp, OATP1B1, OCT1, OCT2, 
OAT3, MATE1, MATE2K and BCRP.    
 
➢ Olaparib must be used very carefully with other medicines that 
interact with these enzymes and proteins.  
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines that are considered ““strong or moderate 
inducers/inhibitors of CYP3A4/5 and P-gp.” Olaparib inhibits “CYP 
3A4, UGT1A1 and transport proteins P-gp, OATP1B1, OCT1, OCT2, 
OAT3, MATE1, MATE2K and BCRP and induces CYP 1A2, 2B6, 3A4, 
2C9, 2C19 and transport protein P-gp.” It may change how other 
medicine works in your body. 
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

  
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APPENDIX X: YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621H 
(for children from 7 through 12 years of age) 
A study of Molecular Analysis for Therapy Choice (MATCH) in children 
with a cancer that has come back after treatment or is difficult to treat 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already 
but it did not go away or it came back after treatment.  
 
2. We are asking you to take part in a research study because other treatments did not get rid of the 
cancer. A research study is when doctors work together to try out new ways to help people who are 
sick. In this study, we are trying to learn more about how to treat the kind of cancer that you have.  
 
3. You agreed to be part of a study to see if your cancer has any specific changes that could help us 
decide what medicine might “match” best to your cancer. 
 
4. We have found a medicine called olaparib that could “match” your tumor. The doctors want to see 
if olaparib will help children with your type of cancer get better. We don’t know if olaparib will 
work well to get rid of your cancer. That is why we are doing the study. 
 
5. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is that olaparib may 
cause your cancer to stop growing or to shrink for a period of time but we don’t know for sure if 
there is any benefit of being part of this study. 
 
6. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that you may have problems, or side effects 
from olaparib. There may be risks that we don’t know about. 
 
7. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your cancer that your 
doctor can tell you about.  
8. If you decide to be treated with olaparib you might have some tests and check-ups done more often 
that you might if you weren’t part of the study. 
 
9. As part of the study we are also trying to learn more about children’s cancers and how olaparib 
works in them. We will draw some extra blood samples for this if your family agrees. 
 
 

  
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Page 87 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621H 
(for teens from 13 through 17 years of age) 
A study of Molecular Analysis for Therapy Choice (MATCH) in children 
with a cancer that has come back after treatment or is difficult to treat 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already but 
the cancer did not go away or it came back after treatment.  
 
2. We are asking you to take part in a research study because other treatments did not get rid of the cancer. 
A research study is when doctors work together to try out new ways to help people who are sick. In this 
study, we are trying to learn more about how to treat the kind of cancer that you have. 
 
3. The main purpose of this study is to learn how well cancers that have specific changes (mutations) 
respond to medicines that are aimed at those changes. This combination of a tumor with a mutation and 
a medicine that aims at that mutation is called a “match”. 
 
4.  Your tumor has a mutation that matches olaparib, and so you have been assigned to olaparib. The 
doctors want to see if olaparib will make children with your type of cancer get better. We don’t know 
if olaparib will work well to get rid of your cancer. That is why we are doing the study. 
 
5.  You will get olaparib by mouth twice daily for a 28-day period. This entire 28-day period is called a 
cycle. Olaparib should be swallowed whole, not chewed or crushed. You may continue to receive 
olaparib for up to about 24 months (approximately 26 cycles) as long as you do not have bad effects 
from it and your cancer does not get any worse. If you decide to be treated with olaparib, you will also 
have exams and tests done that are part of normal cancer care. Some of these may be done more often 
while you are being treated with olaparib. The doctors want to see if olaparib will help children or 
adolescents with your type of cancer get better. We don’t know if olaparib is better than other 
medicines. That is why we are doing this study.  
 
6. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that olaparib may cause 
your cancer to stop growing or to shrink for a period of time but we don’t know for sure if there is any 
benefit of being part of this study. 
 
7. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The primary risk to you from this study is that you may have side effects, from olaparib. 
Your doctor will talk to you about the risks we know about from olaparib. There may be other risks 
from olaparib that we don’t know about yet.  
 
8. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments for your illness that your doctor can 
tell you about. Make sure to ask your doctors any questions that you have.  
 
9. As part of the study we are also trying to learn more about the mutations that occur in cancers that happen 
in children and teens, as well as how olaparib works. If your family agrees we will draw some extra 
blood samples to do these tests. 
 
 
 
 

  
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Page 89 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements for APEC1621H Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
IROC Credentialing Status Inquiry (CSI) Form  
NOTE: For studies with a radiation and/or imaging (RTI) component, the enrolling site must 
be aligned to a RTI provider.  To manage provider associations access the Provider Association 
tab on the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or 
remove associated providers.  Sites must be linked to at least one IROC credentialed provider 
to participate on trials with an RT component.   
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
 

  
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Page 90 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave 
via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab 
Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum 
of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered 
as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the 
DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner of the 
iMedidata page. Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com. 
 

  
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APPENDIX XII: TOXICITY-SPECIFIC GRADING  
 
Bilirubin 
 
Grade 1: 
≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN - 3 x ULN 
Grade 3: 
> 3 x ULN -10 x ULN 
Grade 4: 
> 10 x ULN 
 
ALT: For the purpose of this study, the ULN for SGPT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
≤ 135 U/L 
Grade 2: 
136 U/L - 225 U/L 
Grade 3: 
226 U/L - 900 U/L 
Grade 4: 
> 900 U/L 
 
AST: For the purpose of this study, the ULN for SGOT is 50 U/L regardless of baseline. 
 
Grade 1: 
≤ 150 U/L 
Grade 2: 
151 U/L -250 U/L 
Grade 3: 
251 U/L -1000 U/L 
Grade 4: 
> 1000 U/L 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 x ULN- 5 x ULN 
Grade 3: 
> 5 x ULN-20 x ULN 
Grade 4: 
> 20 x ULN