NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Tipifarnib in Patients With Tumors Harboring HRAS Genomic Alterations
Phase: PHASE2
Conditions: Malignant Solid Neoplasm, Recurrent Adrenal Gland Pheochromocytoma, Recurrent Ectomesenchymoma, Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Hepatoblastoma, Recurrent Kidney Wilms Tumor, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Medulloblastoma, Recurrent Melanoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Rhabdoid Tumor, Recurrent Rhabdoid Tumor of the Kidney, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Recurrent Thyroid Gland Carcinoma, Recurrent WHO Grade 2 Glioma, Refractory Adrenal Gland Pheochromocytoma, Refractory Ependymoma, Refractory Ewing Sarcoma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Medulloblastoma, Refractory Melanoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Rhabdoid Tumor, Refractory Rhabdoid Tumor of the Kidney, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Refractory Thyroid Gland Carcinoma, Refractory WHO Grade 2 Glioma
Sponsor: National Cancer Institute (NCI)



 
 
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Contact Information 
For Regulatory Requirements 
For patient enrollments: 
For Data Submission 
Regulatory documentation must be 
submitted to the Cancer Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal. 
 (Sign in at www.ctsu.org, and 
select the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately by phone or 
email:  at 1-866-651-CTSU (2878), 
or CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment section 
of the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://open.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or email:  
1-888-823-5923, or  ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. Please 
see the Data Submission 
Schedule in the CRF packet for 
further instructions. 
The most current version of the study protocol must be downloaded from the protocol-specific page located on the 
CTSU members’ website (https://www.ctsu.org). Access to the CTSU members’ website is managed through the 
Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and 
requires log in with a CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the CTSU Regulatory 
Support System (RSS). 
For clinical questions (ie, patient eligibility or treatment-related)  
Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (ie, unrelated to patient eligibility, treatment, or clinical data submission)  
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will be 
triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 
 
 

 
 
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
31 
 
Required Clinical, Laboratory and Disease Evaluation 
31 
 
Radiology Studies 
32 
 
Circulating Tumor DNA Study (optional) 
33 
9.0 
AGENT INFORMATION 
35 
 
Tipifarnib        (12/22/2021) 
35 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
42 
 
Criteria for Removal from Protocol Therapy 
42 
 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
42 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
42 
 
Sample Size and Study Duration 
42 
 
Dosing Considerations 
42 
 
Study Design 
43 
 
Methods of Analysis 
44 
 
Evaluability for Response 
44 
 
Evaluability for Toxicity 
44 
 
Progression free survival (PFS) 
44 
 
Gender and Minority Accrual Estimates 
45 
12.0 
EVALUATION CRITERIA 
45 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
45 
 
Progression-Free Survival 
45 
 
Response Criteria for Patients with Solid Tumors 
45 
 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
49 
 
Response Criteria for Neuroblastoma Patients 
51 
 
Response Criteria for Patients with CNS Tumors 
57 
 
Response Criteria for Patients with Non- Hodgkin Lymphoma/Histiocytosis 
59 
 
Best Response 
61 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
62 
 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
62 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
63 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements:
 
65 
 
Definition of Onset and Resolution of Adverse Events 
65 
 
Other Recipients of Adverse Event Reports 
66 
 
Specific Examples for Expedited Reporting 
66 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
68 
 
Categories of Research Records 
68 
 
CDUS 
68 
 
CRADA/CTA/CSA 
69 
 
Data and Safety Monitoring Plan 
70 
REFERENCES 
72 
 
 
 
 
 
 
 
 

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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about subjects collected during the course of our covered studies.  The 
researchers involved in the studies cannot be forced to disclose the identity or any information collected in 
the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
ABSTRACT 
This subprotocol is a component of the Pediatric MATCH trial APEC1621. The APEC1621SC screening 
protocol details the process used to identify actionable mutations in patient tumor samples which will 
determine eligibility for this subprotocol. This is a phase 2 trial of tipifarnib in children with relapsed or 
refractory solid tumors (including lymphomas, histiocytoses and CNS) harboring specified activating 
mutations in the HRAS gene. 
 
Tipifarnib will be administered with food at 
mg/m2/dose PO BID (maximum 600 mg/dose) for 7 days  
followed by 7 day rest period, alternating on a 28 day cycle. Eligibility for this trial includes a relapsed or 
refractory pediatric solid tumor that harbors an activating mutation in HRAS (at codons G12, G13, Q61, or 
A146), as determined by the Pediatric-MATCH screening protocol, APEC1621SC. The trial’s primary 
objective is to determine the antitumor activity of tipifarnib, using objective response rate (CR +PR) as a 
primary endpoint.  Secondary objectives include ongoing assessment of tipifarnib-associated toxicities. 
 
EXPERIMENTAL DESIGN SCHEMA 
 
Treatment Schedule Table 
Days 1-7 
Tipifarnib orally or via NG- or 
G- tube twice daily 
Days 8-14 
Rest 
Days 15-21 
Tipifarnib orally or via NG- or 
G- tube twice daily 
Days 22-28 
Rest 
Day 28 
Evaluation 
 
Tipifarnib will be administered with food at 
 mg/m2/dose PO BID (maximum 600 mg/dose) for 7 days  
followed by 7 day rest period alternating on a 28 day cycle (i.e., Days 1-7 and 15-21 of a 28 day cycle). 
The  available formulations of tipifarnib are 100 mg and 300 mg tablets. These tablets may be swallowed 
whole or crushed and mixed in water, orange juice, apple juice, tomato juice, protein shake, or a dietary 
supplement drink (such as Ensure®). Evaluations will occur every other cycle (8 weeks) for three 
occurrences, then every three cycles (12 weeks). It is recommended to consume the mixture within 2 hours 
of preparation. The mixing container should be rinsed and the rinse consumed as well.  
 

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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. 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).  
 
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 tipifarnib with advanced solid tumors 
(including CNS tumors), lymphomas or histiocytic disorders that harbor activating 
genetic alterations in HRAS. 
 
 
Secondary Aims 
 
 
To estimate the progression free survival in pediatric patients treated with 
tipifarnib with advanced solid tumors (including CNS tumors), lymphomas or 
histiocytic disorders that harbor activating genetic alterations in HRAS. 
 
 
To obtain information about the tolerability of tipifarnib in children and 
adolescents with relapsed or refractory cancer. 
 
 
 
Exploratory Aims 
 
 
To evaluate other biomarkers as predictors of response to tipifarnib and 
specifically, whether tumors that harbor different missense mutations or variant 
allele frequency  will demonstrate differential response to tipifarnib treatment 
 
 
To explore approaches to profiling changes in tumor genomics over time through 
evaluation of circulating tumor DNA. 
 
 
2.0 
BACKGROUND 
 
 
Introduction/Rationale for Development 
 
A large number of malignancies are driven by oncogenic RAS isoforms, including 
pancreatic, colorectal and lung cancer, head and neck cancer, melanoma and hematologic 
malignancies.1  Despite this knowledge, clinically effective therapies targeting the RAS 
pathway have yet to be developed.  Direct targeting of mutant RAS with small molecules 
has proven to be difficult and current strategies are focused on inhibition of downstream 
signaling pathways.2 RAS signals through multiple effectors, including but not limited to 
BRAF, PI3-kinase, TIAM1, RAL-GEFs, PLCε and NORE1 and effector pathways driving 
tumorigenesis in each RAS-driven tumor type are often not defined.3  Tumors also rapidly 
acquire resistance to targeted inhibitors, such as inhibitors of the RAF/MEK/ERK pathway.  
In many cases, acquired resistance to MEK inhibition in NRAS-mutated melanoma is due 
to MEK1 or MEK2 mutation.4  In addition, mechanisms of intrinsic resistance to MEK 
inhibition in KRAS-mutant cells include rebound MEK and ERK phosphorylation5 and 
activation of AKT.6  Therefore, combinations of RAS effector pathway inhibitors, or novel 

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inhibitors of RAS function, may be required for clinically effective treatment. 
 
Current clinical trials for RAS-driven adult tumors commonly include combinations of a 
MEK inhibitor and a PI3-kinase or AKT  inhibitor.  Some limitations of this approach 
include overlapping toxicities of the targeted agents, incomplete dual pathway inhibition 
and impaired apoptotic response, which ultimately leads to rapid emergence of acquired 
resistance to the targeted agents.  Addition of targeted agents aimed at inhibiting a third 
RAS effector pathway or combining targeted agents with traditional cytotoxic 
chemotherapeutics to boost the apoptotic response may overcome these limitations.7  
Preclinical and clinical studies of these combinations in adult tumor types are currently 
ongoing. The advantage of a drug that inhibits RAS activation, such as tipifarnib, in this 
setting, is the ability to inhibit multiple effector pathways with one drug.   
 
RAS as a driver of pediatric cancer: 
Mutation of the RAS isoforms, and other alterations leading to aberrant ERK signaling, are also 
important drivers of many pediatric malignancies.  For example, recent comprehensive genomic 
analyses of human rhabdomyosarcoma tumors indicate that the most common somatic mutation in 
embryonal rhabdomyosarcoma is an oncogenic change in one of the RAS isoforms.8,9   
Neuroblastomas, especially in the relapsed setting, harbor mutations in HRAS, NRAS and KRAS.10  
Pediatric melanomas arising from large or very large congenital nevi are almost exclusively driven 
by oncogenic mutations in NRAS.11 Malignant ectomesenchymomas were recently discovered to 
harbor driver mutations in HRAS.12 RAS is aberrantly active in neurofibromatosis type 1 (NF1)-
related tumors including plexiform neurofibromas, atypical plexiform neurofibromas and 
malignant peripheral nerve sheath tumors (MPNST) through loss of function mutations in the RAS 
GTPase activating protein, NF1.13 Some pilocytic astrocytomas are driven by an activating fusion 
of BRAF, KIAA1549-BRAF, while some pleomorphic xanthoastrocytomas are driven by the 
classical mutation in BRAF, V600E.14 Recent next-generation sequencing studies of pediatric 
cancers have revealed that RAS mutations are also observed in high- and low-grade gliomas as well 
as Wilms tumor.15 Pediatric hematological malignancies are also driven by aberrant activation of 
RAS-RAF-MEK-ERK signaling, including Langerhans cell histiocytosis (BRAF)16, acute myeloid 
leukemia and acute lymphoblastic leukemia17,18, and juvenile myelomonocytic leukemia (KRAS, 
NRAS, NF1, PTPN11 and CBL).19   
 
In preliminary analysis of Pediatric MATCH trial data performed on 3/18/20, a total of 37 
activating RAS mutations were identified in 769 patients screened, including 6 HRAS mutations 
in rhabdomyosarcomas. Other sequencing efforts have also identified a small number of cases of 
HRAS mutations in pediatric solid tumors. These include: 1) the Foundation Medicine Pediatric 
Portal20 has 4 total cases of HRAS mutation (of total 1215), and of these, 3 are in embryonal RMS; 
2) cBioPortal has a total of 109 cases of HRAS mutations21 (of total 10,000 cases, frequency 1.1%), 
and of these, 2 were embryonal RMS and 1 was neuroblastoma; 3) the TARGET neuroblastoma 
data set22  has 3 cases of HRAS CNG (out of 1089 total), but no SNV detected in this cohort; 4) the 
GAIN/ iCAT2 cohort has identified 2 cases of HRAS mutant RMS (out of total 250 total tumors, 
Janeway, personal communication); and 5) a comprehensive genomic profiling study of RMS23 
revealed HRAS mutations in 2 of 43 total RMS cases.  
 
The three classical RAS genes encode four highly related guanine nucleotide binding proteins: 
HRAS, KRAS4A, KRAS4B and NRAS.  RAS proteins function as guanine nucleotide-regulated 
binary on-off switches. In normal quiescent cells, RAS is predominantly GDP-bound and inactive. 
Growth factors activate RAS-selective guanine nucleotide exchange factors (RAS-GEFs; e.g., 
SOS1, SOS2) to promote nucleotide exchange and formation of active RAS-GTP, a reaction that 
requires RAS be localized to the plasma membrane.  Once in the active, GTP-bound conformation, 

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RAS can bind to a variety of effector proteins to transmit its downstream signals, including the 
RAF kinases and PI3 kinase.  Engagement of effector proteins also requires RAS and the effectors 
to be localized to the plasma membrane.  RAS-selective GTPase accelerating proteins (RAS-
GAPs; e.g., NF1, RASA1, RASA2, SYNGAP1) normally promote GTP hydrolysis to return RAS 
to its GDP-bound resting state 2,3,24.  In sporadic pediatric or adult malignancies, RAS isoforms are 
typically somatically mutated at three main hotspots (G12, G13 and Q61); these mutations render 
RAS GAP-insensitive, and thus persistently GTP-bound and active.  RAS mutation at A146, in 
contrast, increases the fraction of GTP-bound, activated RAS by enabling RAS to spontaneously 
exchange GDP for GTP in the absence of a RAS-GEF 2,3,24.  Efforts to target RAS signaling in 
benign pediatric tumors recently have been successful clinically, leading to the breakthrough 
therapy designation for the MEK inhibitor, selumetinib, in patients with NF1-related plexiform 
neurofibromas.  Clinical trials for agents targeting RAS signaling in pediatric malignancies are 
ongoing.   
 
 
Tipifarnib: 
Localization to the plasma membrane is required for RAS activation and function.  For the RAS 
proteins, anchorage to the plasma membrane requires addition of a farnesyl moiety to the conserved 
C-terminal cysteine.  This farnesylation is catalyzed by farnesyltransferase.  Over 140 proteins have 
been identified as substrates of farnesyltransferase, including each of the RAS isoforms.  Tipifarnib 
is a potent and selective inhibitor of farnesyltransferase. Inhibitors of farnesyltransferase have an 
advantage over inhibitors of RAS effectors as cancer therapeutics because they inhibit RAS 
membrane localization, and thus inhibit the activation of all of the RAS effector pathways, not just 
one pathway. Tipifarnib inhibits tumor growth by inhibiting angiogenesis, inducing apoptosis, and 
preventing tumor cell proliferation in multiple animal models of adult malignancies.  NRAS and 
KRAS, like many other farnesyltransferase targets, are able to bypass the requirement for 
farnesylation through alternative prenylation (geranyl-geranylation), and membrane localization of 
these molecules is therefore unaffected in the presence of a farnesyltransferase inhibitor (FTI). 
HRAS, however, is unable to utilize alternative prenylation, and its membrane localization and 
cellular function are therefore suppressed by FTI such as tipifarnib 25.  As discussed above, mutant 
HRAS is a driver of both adult and pediatric solid tumors and hematological malignancies.  While 
multiple clinical trials evaluating the efficacy of tipifarnib in adults and pediatric patients with solid 
tumors or hematological malignancies have been conducted, none have been conducted to date in 
a genomically-selected patient population.   
 
 
Preclinical Studies 
 
 
Antitumor Activity 
 
Post-translation modification of proteins critical to cell signaling, proliferation, and 
differentiation is linked to lipid metabolism.26 The best-characterized example is the family 
of Ras proteins, whose anchorage to the cell membrane requires most commonly a farnesyl 
moiety, which is a derivative of the mevalonate pathway of cholesterol synthesis.27 
Farnesylation is catalyzed by a 48 kd metallo-enzyme, farnesyltransferase. More than 140 
proteins have now been identified as potential substrates for farnesyltransferase inhibitors 
(FTI). However, the function of many of these proteins is kept intact due to compensative 
prenylation through type 1 geranylgeranyl transferase.28 Among RAS isoforms, inhibition 
of the farnesylation of KRAS and NRAS leads to their geranylgeranylation and unchanged 
membrane localization.29 HRAS cannot be geranylgeranylated, and therefore its membrane 
localization and cellular function is suppressed by FTIs.28  
 

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2.3.3.1 3 weeks on/1 week off Dosing (BID on Days 1 – 21 in 28-day treatment cycles)  
In the majority of its phase 2 program, tipifarnib was given orally at a dose of 300 
mg bid for 21 days, followed by 1 week of rest, in 28 day treatment cycles (3 weeks 
on/1 week off schedule). Prior studies have shown that this treatment schedule 
results in drug exposures equivalent or above those shown to demonstrate anti-
tumor activity in preclinical tumor models. In the AML studies which administered 
tipifarnib at doses up to 600 mg bid for 21 days in 28-day treatment cycles, the 
most common adverse events were myelosuppression, gastrointestinal disorders, 
fever, fatigue, hypokalemia, rash, renal impairment, and dyspnea. The most 
common drug-related grade 3 or 4 events were myelosuppression, hypokalemia, 
fatigue, and rash. Thrombocytopenia, renal impairment, rash, and sepsis were the 
most common adverse events that led to discontinuation. In the completed MDS 
study (INT-28) which administered tipifarnib at a dose of 300 mg bid for 21 days 
in 28-day treatment cycles, the most common adverse events were 
myelosuppression, fatigue, diarrhea, nausea, and rash. The most common drug-
related grade 3 or 4 events were myelosuppression, fever, pneumonia, bacterial 
infection, and rash. The most common adverse events that lead to discontinuation 
were thrombocytopenia and rash. 26 
 
2.3.3.2 Alternative Week Dosing (BID on Days 1 – 7 and Days 15 – 21 in 28-day 
treatment cycles)  
The effect of intermittent schedules of tipifarnib was tested in several adult phase 
1 studies, including a 5-day bid dosing followed by 9-day rest (5-day schedule)49 
and two trials investigating a 7-day bid dosing followed by 7-day rest (7-day 
schedule).50,51 In the 5-day schedule phase 1 trial in patients with non-
hematological malignancies, doses from 25 to 1300 mg bid were explored. No 
MTD was identified. Dose-limiting toxicity of grade 3 neuropathy was observed 
in one patient and grade 2 fatigue in 4 of 6 patients treated with 1300 mg bid. 
Fatigue that was not dose-limiting was observed at the prior dose level (800 mg 
bid). Of note, myelosuppression which was the most common toxicity in the 21-
day schedule, was limited with the 5-day schedule and included a grade 3 
neutropenia in a patient with a prior history of myelosuppression treated with 50 
mg bid and a grade 2 thrombocytopenia in a patient treated at the 1300 mg bid dose 
level. No objective responses were noted. 26 
 
In the first of the weekly schedule studies,50 the starting dose was 300 mg bid with 
300 mg dose escalations to a maximum planned dose of 1800 mg bid. Two of 6 
patients with non-hematological tumors in dose level 3 (900 mg bid) developed 
grade 3 fatigue attributable to study drug, and 600 mg bid on alternate weeks was 
identified as the recommended phase 2 dose. There were no objective responses 
but 4 out of 21 patients, 3 of whom had NSCLC, remained on study for at least 1 
year with stable disease (12, 13, 16 and 17 months). Five grade 3 events of 
myelosuppression (out of 21 patients) were described by the authors (doses not 
indicated) that were not considered dose limiting toxicities (DLTs) and 
hematological toxicity was described as moderate and manageable. 26 
 
The second weekly schedule study was conducted in patients with 
relapsed/refractory AML.51 Tipifarnib was administered bid on days 1–7 and days 
15–21 of 28-day cycles at doses up to 1600 mg bid. At the 400 mg bid dose level, 
a grade 5 hepatorenal failure occurred, potentially related to the study drug. There 

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IRB Approval 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. For CTEP and Division 
of Cancer Prevention (DCP) studies open to the National Clinical Trials Network (NCTN) 
and NCI Community Oncology Research Program (NCORP) Research Bases after March 
1, 2019, all U.S.-based sites must be members of the NCI Central Institutional Review 
Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open 
at the site under the local IRB. International sites should continue to submit Research Ethics 
Board (REB) approval to the CTSU Regulatory Office following country-specific 
regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU 
Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 

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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 
Patient may be enrolled on the study once all eligibility requirements for the study have 
been met. 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 in Stage 2 of Pediatric 
MATCH (effective with Amendment #4 of APEC1621SC for patients enrolling on 
screening protocol) is outlined in section 3.1.3. 
 
Patients enrolling onto APEC1621M will have a COG ID obtained through their prior 
enrollment onto the APEC1621SC screening protocol or a prior COG study. Patients must 
be enrolled within 2 weeks (14 days) of treatment assignment. Protocol therapy must start 
no later than 7 calendar days after the date of enrollment. Patients enrolling onto 
APEC1621M will have a COG ID obtained through their prior enrollment onto the 
screening protocol or from a prior COG study. Patients who are started on protocol therapy 
prior to study enrollment will be considered ineligible.  
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated in the eligibility section below. 
 
 
Reassignment Request through APEC1621SC (if unable to enroll within 8 week 
timeframe) 
The treating team may email PedsMATCHOps@childrensoncologygroup.org and 
the APEC1621SC study co-chairs (dwparson@txch.org seibelnl@mail.nih.gov) 
with a request for a single treatment re-assignment for any patient who was 
previously matched to a therapeutic subprotocol arm, but were unable to enroll 
during the original specified reservations window. The request can be made within 
a year of the ‘Pediatric MATCH-Reservation expiration date’ stipulated in the 
original treatment assignment email when the patient was assigned. The treatment 
re-assignment request is subject to slot availability on the therapeutic subprotocol at 
the time of the request. 
 
Note:  No starter supplies will be provided. Drug orders of tipifarnib should be placed 
with CTEP after enrollment and treatment assignment to APEC1621M 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 APEC1621 
master 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 APEC1621M based on the presence 
of an actionable mutation as defined in APEC1621SC. Examples of actionable 
mutations for APEC1621SC are listed 
 
  
 
Age:  Patients must be ≥ 12 months and ≤ 21 years of age at the time of study 
enrollment. 
 
 
BSA:  Patients must have a body surface area ≥ 0.29 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 any lesion that 
is at minimum 10 mm in one dimension on standard MRI or CT. 
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 (
 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/devther
apeutics/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. 
 

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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 
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 hematopoetic 
growth factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than hematopoetic 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 radio-
pharmaceutical therapy. 
 
k. Patients must not have received prior exposure to tipifarnib. 
 
 
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 transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 

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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 utilizing child length and stature data published 
by the CDC. 
 
4.1.7.3 Adequate Liver Function Defined as: 
- 
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 Neurologic Function Defined as: 
- 
Patients with seizure disorder may be enrolled if on anticonvulsants 
and well controlled. 
- 
Nervous system disorders (CTCAEv5.0) resulting from prior therapy 
must be ≤ Grade 2. 
 
 
Patients must be able to swallow intact tablets or crushed tablets mixed in water, 
orange juice, apple juice, tomato juice, ginger ale,  applesauce, yogurt, protein 
shake, or a dietary supplement drink (such as Ensure®). PEG-tube or nasogastric 
tube administration is permitted. 
 
 
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. Males or females of 
reproductive potential may not participate unless they have agreed to use  two 
effective contraceptive method for the duration of study treatment. Both female 
subjects and male subjects with female partners of child-bearing potential must 
agree to use a highly effective method of contraception for 2 weeks prior to 
protocol therapy, during, and at least 4 weeks after last dose of tipifarnib.  

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In addition, since tipifarnib could induce toxicity of male reproductive organs and 
cause impairment of fertility, sperm cryopreservation should be recommended for 
male subjects wishing to preserve their fertility following tipifarnib treatment.  
 
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 Patients who are currently receiving drugs that are strong inducers or 
inhibitors of CYP3A4/5 or UGT are not eligible. Strong inducers or 
inhibitors of CYP3A4/5 or UGT should be avoided from 14 days 
prior to the 1st dose of tipifarnib to the end of the study. In addition, 
patients receiving agents that are sensitive or narrow therapeutic 
range substrates of CYP3A4/5 are not eligible.   
 
  Note: CYP3A4/5 inducing anti-epileptic drugs and 
dexamethasone for CNS tumors or metastases, on a stable dose, are 
allowed. 
 
 
Patients with known hypersensitivity to tipifarnib or any components of the tablet 
are not eligible. 
 
Patients with hypersensitivity to imidazoles, such as clotrimazole, ketoconazole, 
miconazole and others in this drug class are not eligible. 
 
 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
 
Patients who have received a prior solid organ transplantation are not eligible. 
 
 
Patients who in the opinion of the investigator may not be able to comply with the 
safety monitoring requirements of the study are not eligible. 
 
 

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5.0 
TREATMENT PROGRAM 
 
 
Overview of Treatment Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tipifarnib will be given orally with food twice daily (approximately 12 hours apart) on 
Days 1-7 and Days 15-21 (
). 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 of 26 cycles). 
 
Tablets should be swallowed whole with water. Tablets may be chewed or crushed if 
necessary.  Crushed tablets can be mixed with water, orange juice, apple juice, apple sauce, 
ginger ale, yogurt, tomato juice, a protein shake or a dietary supplement drink (such as 
Ensure®) for oral administration. Use of a percutaneous endoscopic gastrostomy tube (G-
tube) or nasogastric (NG) tube is allowed (crushed tablets may be mixed with water with 
NG or G-tube administration). Patients should be advised to be appropriately hydrated 
during the course of the study (e.g. drinking at least 8 glasses of water/day for an adolescent 
or young adult). Refer to 
 
  
 
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.  If a patient vomits after the 
dose of tipifarnib is administered, that dose  should not be repeated. Missed doses should 
not be taken if it is more than 4 hours past the scheduled time. 
 
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 (maximum 26 cylces) 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). 
 
 
Therapy Delivery Map 
See 
 for Cycle 1 and subsequent cycles. 
 
Intra-Patient Escalation 
Intrapatient dose escalation is not allowed. 
 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and has 
Treatment Schedule Table 
Days 1-7 
Tipifarnib 
 mg/m2/dose orally or 
via NG- or G- tube  twice daily 
(maximum 600 mg/dose BID) 
Days 8-14 
Rest 
Days 15-21 
Tipifarnib 
mg/m2/dose orally or 
via NG- or G- tube  twice daily 
(maximum 600 mg/dose BID) 
Days 22-28 
Rest 
Day 28 
Evaluation 

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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 CTCAEv5.0.  A copy of 
the CTCAEv5.0 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. 
 
 
Non-hematological dose-limiting toxicity 
5.4.1.1 Any Grade 3 or greater non-hematological toxicity attributable to 
protocol therapy with the specific exclusion of: 
 
• Grade 3 nausea and vomiting < 3 days duration 
• Grade 3 liver enzyme elevation, including ALT/AST/GGT, that 
returns to Grade ≤ 1 or baseline prior to the time for the next 
treatment cycle. Note: For the purposes of this study the ULN for 
ALT is defined as 45 U/L. See 
 
  
• Grade 3 fever  
• Grade 3 infection 
• Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to supplementation. 
• Grade 3 rash 
 
5.4.1.2 Non-hematological toxicity that causes a delay of ≥ 14 days between 
treatment cycles. 
 
Note: Allergic reactions that necessitate discontinuation of study drug will 
not be considered a dose-limiting toxicity. 
 
 
Hematological dose limiting toxicity 
In patients evaluable for hematological toxicity (see Section 4.1.7.1), hematological dose limiting toxicity 
is defined as: 
• Grade 4 neutropenia for > 7 days 
• Platelet count < 25,000/mm3  for > 7 days, or requiring a platelet 
transfusion on 2 separate days, within a 7 day period 
• Myelosuppression that causes a delay of > 14 days between 
treatment cycles.  
 
 
Note: Grade 3 or 4 febrile neutropenia will not be considered a dose-limiting toxicity. 
 
 
 

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Potential Drug Interactions 
Tipifarnib is a substrate for the CYP450 enzymes (mostly CYP 3A4/5) and UDP-
glucuronosyltransferase (UGT). Due to the potential for drug-drug interactions, 
tipifarnib should not be administered with strong inhibitors or inducers of 
CYP3A4/5 or UGT. Additionally, CYP 2C19, 2D6, and 2E1 were observed to play 
a minor role in tipifarnib clearance in human liver microsomes. Population PK trials 
using different classes of common concomitant medications show that 1) enzyme-
inducing antiepileptic drugs can significantly reduce tipifarnib plasma concentrations 
and 2) antifungal azoles do not alter tipifarnib clearance. 
 
In vitro, tipifarnib inhibited the metabolism of CYP450 enzymes 2C8/9/10, 3A4/5, 
2A6, and 2D6. Although the interaction is not likely based on very low unbound 
concentrations of tipifarnib, the potential for drug-drug interactions between 
tipifarnib and drugs metabolized by these enzymes cannot be excluded. Patients 
should not receive concomitant medication with sensitive or narrow therapeutic 
range substrates of these CYP isoforms while receiving tipifarnib.  
 
Tipifarnib is extensively bound to blood albumin and is not dependent on drug 
concentration. Use caution when co-administering with other highly protein-bound 
drugs with narrow-therapeutic ranges. 
 
Pharmacokinetic trials with tipifarnib and either omeprazole or rabeprazole 
showed no clinically meaningful effect on tipifarnib exposure. The impact of 
aluminum or magnesium-containing antacids has not been evaluated. 
 
Patient Care Implications:  
Tipifarnib is contraindicated in individuals with hypersensitivities to imidazole-
containing agents (e.g. clotrimazole, ketoconazole, miconazole).  
 
Advise women of child-bearing potential and men with female partners of child-
bearing potential to use two (2) highly effective forms of contraception 2 weeks prior 
to starting study treatment, while receiving study treatment and for 1 (one) month 
after the last dose. 
  
Since tipifarnib could induce toxicity of male reproductive organs and potentially 
impair fertility, sperm cryopreservation is recommended for men study participants 
who wish to preserve their fertility following study treatment. 
 
 
Toxicity 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pd
f for further clarification. Frequency is provided based on 
patients. 
 
 

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Tablets should be swallowed whole with water. Tablets may be chewed or crushed 
if necessary. Use of a percutaneous endoscopic gastrostomy tube (G-tube) or 
nasogastric tube (NG) is allowed.  
 
Crushed Tablets for Oral, G-Tube or NG Administration 
 
•     Tablets should be crushed with a commercial tablet crusher, transferred into a 
dosing cup/glass and crusher rinsed with water.  
•     Crushed tipifarnib tablets might have a bitter flavor profile. The crushed tablets 
can be mixed with the following liquids for oral administration: water, orange 
juice, apple juice, tomato juice, a protein shake or a dietary supplement drink 
(eg., Ensure®).   
• 
Patients should be instructed to consume the mixture with a meal.  Following 
consumption, the dosing cup or glass should be rinsed with water and each 
rinse completely swallowed to ensure the entire dose is consumed.   
• 
Crushed tablets mixed with liquids intended for oral administration should be 
used within 2 hours of mixing. The mixing container should be rinsed and the 
rinse consumed as well.   
•      For NG or G-tube administration crushed tablets should be mixed with sterile 
swater.    
•      After completion of dosing, the NG or G-tube should be flushed with 10-
20mL sterile water to ensure that the entire dose is delivered.  
•      Crushed tablets mixed with water intended for nasogastric or gastric tube 
administration should be used within 16 hours of mixing.  
 
Unless otherwise contraindicated, subjects should be advised to be appropriately 
hydrated during the course of the study (e.g. drinking at least 8 glasses of 
water/day). Vomitted doses should not be made up. Missed doses should not be taken 
if it is more than 4 hours past the scheduled time. Patients should continue with the 
next scheduled dose.  
 
 
Supplier:  
Supplied by Kura Oncology and distributed by a Division of Cancer Treatment 
and Diagnosis the Pharmaceutical Management Branch (DCTD), NCI. 
 
 
Obtaining the Agent 
 
9.1.7.1 Agent Ordering  
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 tipifarnib should 
be placed with CTEP after enrollment and treatment assignment to 
APEC1621M with consideration for timing of processing and shipping to 

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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. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, “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.  
 
 
Agent Accountability 
 
9.1.8.1 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. 
 
 
Investigator Brochure Availability 
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. 
Questions about IB access may be directed to the PMB IB coordinator via email. 
 
 Useful Links and Contacts  
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  
• PMB policies and guidelines: 
 
 
http://ctep.cancer.gov/branches/pmb/agent_management.htm     
• PMB Online Agent Order Processing (OAOP) application:  
 
 
https://ctepcore.nci.nih.gov/OAOP  
• CTEP Identity and Access Management (IAM) account:  
   
  https://ctepcore.nci.nih.gov/iam/  
• 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/   
 

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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) 
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 initially be followed on the therapeutic 
subprotocol for a 30-day period. During follow-up on the therapeutic subprotocol ongoing 
adverse events, or adverse events that emerge after the patient is removed from protocol 
therapy, but within 30 days of the last dose of investigational agent, must be followed and 
reported via RAVE and CTEP-AERS (if applicable). Upon completion of subprotocol 
follow-up period, the patient 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); consent is withdrawn or the 
patient dies or is lost to follow-up. 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
 
Sample Size and Study Duration 
APEC1621M will require a minimum of 20 evaluable patients and a maximum of 49 
patients, allowing for 15% inevaluability. Assuming an enrollment rate of 2-9 biomarker 
positive patients per year, the primary cohort of this subprotocol is expected to be 
completed within 2.7-12 years. 
 
 
Dosing Considerations  
 
 Pediatric MATCH Sub-arm Dosing in the Absence of Pediatric Phase 1 Data 

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We will open up to 3 such expansion cohorts for biomarker positive patients (i.e., 
if 3 histologies have ≥ 3 responses, we will open a total of 3 expansion cohorts as 
described above). Note that this can only happen if the response rate in the primary 
cohort is at least 45% (9/20) and there cannot be more than 21 additional evaluable 
patients in total for these expansion cohorts. 
 
 
 
Methods of Analysis 
Response criteria are described in Section 12. A responder is defined as a patient who 
achieves a best response of PR or CR on the study. Response rates will be calculated as the 
percent of evaluable patients who are responders, and confidence intervals will be 
constructed using the Wilson score interval method.54 Decision making for A’Hern design 
cohorts will follow rules described above. 
 
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. Any patient who receives non-protocol anti-cancer 
therapy during the response evaluation period will be considered a non-responder for the 
purposes of the statistical rule, unless they show an objective response prior to receiving 
the non-protocol anti-cancer therapy (in which case they will be considered a responder). 
Patients who demonstrate a complete or partial response confirmed by central review will 
be considered to have experienced a response. 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 
All eligible patients who receive at least one dose of protocol therapy will be considered in 
the evaluation of 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.     
 

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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 lesions.  
 
 
 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, 

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pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
12.3.2.4 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 

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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 
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 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 

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follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
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.55 
 
 
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 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 

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reference the smallest sum diameters while on 
study 
 
 
 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
 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 

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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 
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 Marrow 
Overall 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
PD 
SD 
CR/PR/SD 
Non-PD 
SD 
PR 
CR/PR 
Non-PD 
PR 
CR/PR 
PR 
Non-PD 
PR 
CR 
CR 
Non-PD 
PR 
CR 
CR 
CR 
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  
 
This study will use the revised International Neuroblastoma Response Criteria for disease 
assessment.56 The updated response criteria incorporate current approaches to imaging of 
neuroblastoma, including functional imaging. Furthermore, a standardized approach to assessment 
of bone marrow involvement is included.  The current INRC do not include methods of disease 
assessment that are less sensitive and/or specific for neuroblastoma (99Tc bone scan and 
catecholamine levels).  
 
Key sites and terms 
Primary site: The primary site will be identified as a measurable lesion ≥ 10 mm in diameter as 
assessed by cross sectional imaging (CT or MRI scan). Primary site measurements must be 
recorded in millimeters (or decimal fractions of centimeters). The longest diameter of the primary 
tumor will be recorded at baseline. Serial measurements of the primary tumor will include 
assessment of tumor size in the same orthogonal plane at the time of each evaluation.57 In patients 
with bilateral adrenal lesions, response will be based on the sum of the longest dimensions of both 
adrenal 
lesions 
unless 
biopsy 
proves 
one 
to 
be 
ganglioneuroma 
rather 
than 
neuroblastoma/ganglioneuroblastoma. In patients with multi-focal non-adrenal disease, the largest 

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tumor will be considered the primary tumor. Response in additional lesions will be assessed as 
described below for metastatic lesions. 
  
Tracer avidity (123I-MIBG or FDG-PET) in the primary site will be recorded at baseline. The scan 
appropriate for serial disease assessments should be used at each disease re-evaluation timepoint 
(e.g. 123I-MIBG avid primary lesions should be followed using 123I-MIBG scans during therapy). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a metastatic 
lymph node must be ≥ 15 mm in short axis when assessed by CT or MRI scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short 
axis of a discreet lymph node will be measured and followed as per RECIST criteria. Patients with 
neuroblastoma may have conglomerate masses of non-discrete lymph nodes (i.e. multiple 
contiguous retroperitoneal nodes). When a short axis of a discreet node cannot be identified, a 
lymph node conglomerate can be measured using the longest diameter of the composite lesion. 
Tracer avidity of metastatic nodes will be recorded at baseline and during disease evaluations. 
 
For the purposes of response assessment, target lesions are disease sites that are measurable (non-
nodal soft tissue mass ≥ 10 mm in longest dimension or lymph node ≥ 15 mm in short axis) and 
tracer avid OR are biopsy positive for neuroblastoma or ganglioneuroblastoma. The sum of 
diameters of target lesions is defined as the sum of the short axis of discrete lymph nodes (i.e., 
cervical, axillary nodes) added to the sum of the longest diameters of non-lymph node soft tissue 
metastases.   
 
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 are considered non-measurable. 
 
 Bone lesions: Osteomedullary disease will be assessed using 123I-MIBG scans or FDG-PET scans. 
Technetium bone scans are no longer used as part of the revised INRC and are not included as part 
of disease reassessments during this trial. The extent of tracer avid disease will be evaluated using 
the Curie scoring system (see Curie Scoring System). SPECT may be used to confirm the presence 
or absence of lesions in a given segment of the body. The absolute Curie score should be reported 
at baseline. A relative score (Curie score at the time of disease assessment divided by baseline Curie 
score) should be recorded at the time of each disease evaluation. 
 
Bone marrow disease: Bilateral bone marrow aspirates and trephine biopsies are required at disease 
assessment timepoints. The extent of marrow involvement in all four samples should be recorded. 
Use of immunohistochemical staining for evaluation of trephine biopsies is strongly encouraged. 
The percentage of tumor infiltration of bone marrow space assessed by histologic evaluation of 
trephine/biopsies or counting the number of tumor cells in aspirates by cytology or 
immunocytology 
(recommended 
if 
available) 
divided 
by 
the 
number 
of 
hematopoietic/mononuclear cells evaluated to obtain a percentage involvement (methodology 
described by Burchill et al.).58 The bone marrow sample with the highest percentage of tumor 
infiltration is used for response assessment. If > 0% to ≤ 5% tumor infiltration is the highest 
percentage seen among samples obtained, the result should be recorded as minimal marrow disease. 
 
 
 

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 Response Criteria 
 
PRIMARY (SOFT TISSUE) TUMOR RESPONSE1  
RESPONSE 
ANATOMICAL IMAGING + MIBG 
(FDG-PET2) IMAGING 
Complete 
Response 
(CR) 
• 
< 10 mm residual soft tissue at primary site, 
AND 
• 
complete resolution of MIBG or FDG-PET 
uptake (for MIBG non-avid tumors) at 
primary site 
Partial 
Response 
(PR) 
• 
≥ 30% decrease in longest diameter (LD) of 
primary site 
• 
MIBG or FDG-PET uptake at primary site 
stable, improved or resolved 
Progressive 
Disease (PD) 
• 
> 20% increase in longest diameter taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study), AND  
• 
a minimum absolute increase of 5 mm in 
longest dimension3  
Stable 
Disease (SD) 
Neither sufficient shrinkage for PR nor 
sufficient increase for PD at the primary site 
1Not for use in assessment of metastatic sites 
2 For 123I-MIBG non-avid tumors 
3 A mass that has not met PD measurement criteria but has fluctuating 123I-MIBG avidity will not 
be considered progressive disease. 
 
RESPONSE AT METASTATIC SOFT TISSUE AND BONE SITES 
RESPONSE 
ANATOMICAL IMAGING + MIBG (FDG-PET1) IMAGING 
Complete 
Response (CR) 
• 
Resolution of all sites of disease defined as: 
• 
Non-primary target and non-target lesions measure < 10 mm AND 
• 
Lymph nodes identified as target lesions decrease to a short axis < 15 
mm, AND  
• 
MIBG uptake or FDG-PET uptake (for MIBG non-avid tumors) of non-
primary lesions resolves completely 
Partial 
Response (PR) 
• 
≥ 30% decrease in sum of diameters2 of non-primary target lesions compared to 
baseline, AND all of the following: 

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• 
Non-target lesions may be stable or smaller in size AND 
• 
No new lesions AND 
• 
≥ 50% reduction in MIBG absolute bone score (Relative MIBG bone 
score ≥ 0.1 to ≤ 0.5) or ≥ 50% reduction in number of FDG-PET avid 
bone lesions3,4 
Progressive 
Disease (PD) 
Any of the following5: 
• 
Any new soft tissue lesion detected by CT or MRI that is also MIBG avid or 
FDG-PET avid; 
• 
Any new soft tissue lesion seen on anatomic imaging that is biopsied and 
confirmed to be a neuroblastoma or ganglioneuroblastoma; 
• 
Any new bone site that is MIBG avid;   
• 
A new bone site that is FDG-PET avid (for MIBG non-avid tumors) AND has 
CT or MRI findings consistent with tumor OR has been confirmed 
histologically to be neuroblastoma or ganglioneuroblastoma; 
• 
> 20% increase in longest diameter taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study), AND a 
minimum absolute increase of 5 mm in sum of diameters of target soft tissue 
lesions; 
• 
Relative MIBG score ≥ 1.24 
Stable Disease 
(SD) 
Neither sufficient shrinkage for PR nor sufficient increase for PD of non-primary lesions 
1 Used for MIBG non-avid tumors 
2Sum of diameters is defined as the sum of the short axis of discrete lymph nodes (i.e., cervical, axillary 
nodes) added to the sum of the longest diameters of non-lymph node soft tissue metastases.  Masses of 
conglomerate non-discrete lymph nodes will be measured using longest diameter. 
3 For patients with soft tissue metastatic disease, resolution of MIBG and/or FDG-PET uptake at the soft 
tissue sites is not required; all size reduction criteria must be fulfilled. 
4Relative Curie score is the absolute score for bone lesions at time of response assessment divided by 
the absolute score for bone lesions at entry onto a clinical trial. MIBG-SPECT or MIBG-SPECT/CT 
may be used for scoring purposes but the same imaging methodology should be used for all evaluations. 
5The post-infusion MIBG scan is not considered a diagnostic study for the purposes of response 
assessment. Progressive disease should NOT be designated on the basis of this scan. 
 
 
 
 

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BONE MARROW RESPONSE 
RESPONSE 
BONE MARROW STATUS1 
Complete response 
(CR) 
Bone marrow with no tumor infiltration upon reassessment, independent of 
baseline tumor involvement  
Progressive disease 
(PD) 
Any of the following: 
• 
Bone marrow without tumor infiltration that becomes > 5% tumor 
infiltration upon reassessment; or 
• Bone marrow with tumor infiltration that increases by > 2 fold and has 
> 20% tumor infiltration upon reassessment. 
Minimal disease 
(MD) 
Any of the following: 
• 
Bone marrow with ≤ 5% tumor infiltration and remains > 0-≤ 5% 
tumor infiltration upon reassessment; or 
• Bone marrow with no tumor infiltration that becomes ≤ 5% tumor 
infiltration upon reassessment; or 
• Bone marrow with >20% tumor infiltration that has > 0-≤ 5% tumor 
infiltration upon reassessment. 
Stable disease (SD) 
Bone marrow with tumor infiltration that remains positive with > 5% tumor 
infiltration upon reassessment but does not meet CR, MD or PD criteria 
1Immunohistochemistry strongly encouraged 
 
DETERMINATION OF OVERALL RESPONSE 
RESPONSE 
CRITERIA 
Complete Response (CR) 
All components meet criteria for CR 
Partial Response (PR) 
PR in at least one component and all other 
components are either CR, MD (Bone 
marrow), PR (Soft tissue or Bone) or Not 
involved (NI); no component with PD.   
Minor Response (MR) 
PR or CR in at least one component but at least 
one other component with SD; no component 
with PD. 
Stable Disease (SD) 
SD in one component with no better than SD or 
NI in any other component; no component with 
PD. 
Progressive Disease (PD) 
Any component with PD 
NI = Not involved, site not involved at study entry and remains not involved; MD = Minimal Disease, for 
bone marrow assessment only. 
 
 

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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 12.8 from a sequence of overall response 
assessments. 
 
Primary Tumor 
Soft Tissue and Bone Metastatic Disease 
(MIBG or FDG-PET or PET/MR) 
Bone Marrow Metastatic Disease  
Overall 
CR 
CR 
CR 
CR 
CR for one response component with either CR or NI for other components 
CR 
CR 
CR 
MD 
PR 
CR 
PR 
CR 
PR 
CR 
PR 
MD 
PR 
CR 
PR 
NI 
PR 
CR 
NI 
MD 
PR 
PR 
CR 
CR 
PR 
PR 
CR 
NI 
PR 
PR 
CR 
MD 
PR 
PR 
PR 
CR 
PR 
PR 
PR 
NI 
PR 
PR 
PR 
MD 
PR 
PR 
NI 
CR 
PR 
PR 
NI 
NI 
PR 
PR 
NI 
MD 
PR 
NI 
CR 
MD 
PR 
NI 
PR 
CR 
PR 
NI 
PR 
MD 
PR 
CR 
CR 
SD 
MR 
CR 
PR 
SD 
MR 
CR 
SD 
CR 
MR 
CR 
SD 
MD 
MR 
CR 
SD 
SD 
MR 
CR 
SD 
NI 
MR 
CR 
NI 
SD 
MR 
PR 
CR 
SD 
MR 
PR 
PR 
SD 
MR 
PR 
SD 
CR 
MR 
PR 
SD 
MD 
MR 
PR 
SD 
SD 
MR 
PR 
SD 
NI 
MR 
PR 
NI 
SD 
MR 
SD 
CR 
CR 
MR 
SD 
CR 
MD 
MR 
SD 
CR 
SD 
MR 
SD 
CR 
NI 
MR 
SD 
PR 
CR 
MR 
SD 
PR 
MD 
MR 
SD 
PR 
SD 
MR 
SD 
PR 
NI 
MR 
SD 
SD 
CR 
MR 
SD 
NI 
CR 
MR 
NI 
CR 
SD 
MR 
NI 
PR 
SD 
MR 
NI 
SD 
CR 
MR 
SD 
SD 
MD 
SD 
NI 
SD 
MD 
SD 
SD 
NI 
MD 
SD 
NI 
NI 
MD 
SD 
SD 
SD 
SD 
SD 
SD 
NI 
SD 
SD 
NI 
SD 
SD 
SD 
NI 
SD 
NI 
SD 
NI 
NI 
SD 
SD 
PD in any one component 
PD 
Response of Not Evaluable for any one of the 3 components that had measurable/evaluable tumor at study enrollment and no PD for any component 
Not Evaluable 
No response evaluation performed for any of the 3 components 
Not Done 
CR: Complete Response; MD: Minimal Disease; PR: Partial Response; MR: Minor Response; SD: Stable Disease; PD: Progressive disease; NI: 
not involved; site not involved at study entry and remains not involved 

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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. 
 
• 
Partial response (PR): ≥ 50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements; 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. 
 
 

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 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 
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 Criteria55, with modification from the Lugano classification.59 
 
 
 Disease Parameters 
 
12.7.1.1 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). 
 
12.7.1.2 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).   
 
12.7.1.3 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 

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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 
 
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)59 
 
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 enlargement  
 
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 

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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 
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). 
 

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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 
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. 
 
 

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 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.  
 
Any medical documentation supporting an expedited report (eg, H & P, 
admission and/or notes, consultations, ECG results, etc.) MUST be faxed 
within 48-72 hours to the NCI. NOTE: English is required for supporting 
documentation submitted to the numbers listed below in order for the NCI to 
meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents 
supplied under a CTEP IND to: (301) 897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax# 
(310) 640-9193; email: COGAERS@childrensoncologygroup.org; Attention: 
COG AERS Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
 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://eapps-ctep.nci.nih.gov/ctepaers. 
 
Send supporting documentation to the NCI by fax (fax# 301-640-9193) and by 
email to COGCAdEERS@childrensoncologygroup.org , the APEC1621M COG 
Study 
Assigned 
Research 
Coordinator, 
and 
to 
COGAERS@childrensoncologygroup.org; Attention: COG AERS 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 CTCAEv5.0.  
The descriptions and grading scales found in the current version of the CTCAEv5.0 
will be used for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAEv5.0.  A copy of the CTCAEv5.0 can be downloaded from 
the CTEP website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAEv5.0. 
 
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 

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 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
 If an adverse event progresses through several grades during one course of therapy, 
only the most severe grade should be reported. 
 
 The duration of the AE is defined as the duration of the highest (most severe) grade 
of the Adverse Effects.  
 
 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than or equal to Grade 1, whichever level is higher (note that the 
resolution date may therefore be different from the date at which the grade of the 
AE decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."   
 
 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
 
Other Recipients of Adverse Event Reports 
 
 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the 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) should be 
submitted.  
 

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• 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:  
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 
“Death 
Neonatal”, 
the 
Pregnancy 
Information 
Form, 
available 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, 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 

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intervals deemed appropriate by her physicians. The “Pregnancy Information 
Form” should be used for all necessary follow ups. This form is available at https
://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregnancy
ReportForm.pdf.  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 
men on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event 
as a patient death. 
 
 
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. 

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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 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
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 

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FDA, as appropriate and unless additional disclosure is required by law or court 
order 
as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected , used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP for immediate delivery to Collaborator(s) for advisory review and comment 
prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and 
other media presentations must also be forwarded to CTEP prior to release. Copies 
of any manuscript, abstract and/or press release/ media presentation should be sent 
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 

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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 
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Rev Drug Discov 13:828-51, 2014 
3. 
Cox AD, Der CJ: Ras history: The saga continues. Small GTPases 1:2-27, 2010 
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Villanueva J, Infante JR, Krepler C, et al: Concurrent MEK2 mutation and BRAF amplification 
confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep 4:1090-9, 2013 
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Lito P, Saborowski A, Yue J, et al: Disruption of CRAF-mediated MEK activation is required for 
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Sos ML, Fischer S, Ullrich R, et al: Identifying genotype-dependent efficacy of single and 
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Zhu Z, Golay HG, Barbie DA: Targeting pathways downstream of KRAS in lung adenocarcinoma. 
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Shern JF, Chen L, Chmielecki J, et al: Comprehensive genomic analysis of rhabdomyosarcoma 
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10. 
Eleveld TF, Oldridge DA, Bernard V, et al: Relapsed neuroblastomas show frequent RAS-MAPK 
pathway mutations. Nat Genet 47:864-71, 2015 
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Charbel C, Fontaine RH, Malouf GG, et al: NRAS mutation is the sole recurrent somatic mutation 
in large congenital melanocytic nevi. J Invest Dermatol 134:1067-74, 2014 
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Huang SC, Alaggio R, Sung YS, et al: Frequent HRAS Mutations in Malignant 
Ectomesenchymoma: Overlapping Genetic Abnormalities With Embryonal Rhabdomyosarcoma. 
Am J Surg Pathol 40:876-85, 2016 
13. 
Zhang M, Wang Y, Jones S, et al: Somatic mutations of SUZ12 in malignant peripheral nerve 
sheath tumors. Nat Genet 46:1170-2, 2014 
14. 
Penman CL, Faulkner C, Lowis SP, et al: Current Understanding of BRAF Alterations in 
Diagnosis, Prognosis, and Therapeutic Targeting in Pediatric Low-Grade Gliomas. Front Oncol 
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Grabner A, Schramm K, Silswal N, et al: FGF23/FGFR4-mediated left ventricular hypertrophy is 
reversible. Scientific Reports 7:1993, 2017 
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Badalian-Very G, Vergilio JA, Degar BA, et al: Recurrent BRAF mutations in Langerhans cell 
histiocytosis. Blood 116:1919-23, 2010 
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Braun BS, Shannon K: Targeting Ras in myeloid leukemias. Clin Cancer Res 14:2249-52, 2008 
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Irving J, Matheson E, Minto L, et al: Ras pathway mutations are prevalent in relapsed childhood 
acute lymphoblastic leukemia and confer sensitivity to MEK inhibition. Blood 124:3420-30, 2014 
19. 
Caye A, Strullu M, Guidez F, et al: Juvenile myelomonocytic leukemia displays mutations in 
components of the RAS pathway and the PRC2 network. Nat Genet 47:1334-40, 2015 
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Chmielecki J, Bailey M, He J, et al: Genomic Profiling of a Large Set of Diverse Pediatric Cancers 
Identifies Known and Novel Mutations across Tumor Spectra. Cancer Research 77:509-519, 2017 
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Zehir A, Benayed R, Shah RH, et al: Mutational landscape of metastatic cancer revealed from 
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https://ocg.cancer.gov/programs/target: TARGET: Therapeutically Applicable Research To 
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Shern JF, Chen L, Chmielecki J, et al: Comprehensive genomic analysis of rhabdomyosarcoma 
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Cox AD, Der CJ: Ras family signaling: therapeutic targeting. Cancer Biol Ther 1:599-606, 2002 

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Cox AD, Der CJ, Philips MR: Targeting RAS Membrane Association: Back to the Future for Anti-
RAS Drug Discovery? Clin Cancer Res 21:1819-27, 2015 
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Casey PJ, Solski PA, Der CJ, et al: p21ras is modified by a farnesyl isoprenoid. Proceedings of the 
National Academy of Sciences of the United States of America 86:8323-8327, 1989 
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Berndt N, Hamilton AD, Sebti SM: Targeting protein prenylation for cancer therapy. Nat Rev 
Cancer 11:775-91, 2011 
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Whyte DB, Kirschmeier P, Hockenberry TN, et al: K- and N-Ras are geranylgeranylated in cells 
treated with farnesyl protein transferase inhibitors. J Biol Chem 272:14459-64, 1997 
30. 
End D, Skrzat S, Devine A: 115777: A selective farnesyl protein transferase inhibitor with 
antitumor activity in vitro and in vivo. . Document ID No: N124052; JRF Nonclinical 
Pharmacology Report (October 1996).  
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End DW, Smets G, Todd AV, et al: Characterization of the Antitumor Effects of the Selective 
Farnesyl Protein Transferase Inhibitor R115777 &lt;em&gt;in Vivo&lt;/em&gt; and &lt;em&gt;in 
Vitro&lt;/em&gt. Cancer Research 61:131, 2001 
32. 
Kelland LR, Smith V, Valenti M, et al: Preclinical antitumor activity and pharmacodynamic studies 
with the farnesyl protein transferase inhibitor R115777 in human breast cancer. Clin Cancer Res 
7:3544-50, 2001 
33. 
Goemans BF, Zwaan CM, Harlow A, et al: In vitro profiling of the sensitivity of pediatric leukemia 
cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets. 
Blood 106:3532-7, 2005 
34. 
Cloughesy TF, Wen PY, Robins HI, et al: Phase II trial of tipifarnib in patients with recurrent 
malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North 
American Brain Tumor Consortium Study. J Clin Oncol 24:3651-6, 2006 
35. 
Karp JE, Smith BD, Gojo I, et al: Phase II trial of tipifarnib as maintenance therapy in first complete 
remission in adults with acute myelogenous leukemia and poor-risk features. Clin Cancer Res 
14:3077-82, 2008 
36. 
Li T, Christos PJ, Sparano JA, et al: Phase II trial of the farnesyltransferase inhibitor tipifarnib plus 
fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium 
Trial P6205. Ann Oncol 20:642-7, 2009 
37. 
Li T, Guo M, Gradishar WJ, et al: A phase II trial of capecitabine in combination with the 
farnesyltransferase inhibitor tipifarnib in patients with anthracycline-treated and taxane-resistant 
metastatic breast cancer: an Eastern Cooperative Oncology Group Study (E1103). Breast Cancer 
Res Treat 134:345-52, 2012 
38. 
Sparano JA, Moulder S, Kazi A, et al: Phase II trial of tipifarnib plus neoadjuvant doxorubicin-
cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer. Clin Cancer Res 15:2942-
8, 2009 
39. 
Van Cutsem E, van de Velde H, Karasek P, et al: Phase III trial of gemcitabine plus tipifarnib 
compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430-8, 
2004 
40. 
Widemann BC, Arceci RJ, Jayaprakash N, et al: Phase 1 trial and pharmacokinetic study of the 
farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a 
report from the Children's Oncology Group. Pediatr Blood Cancer 56:226-33, 2011 
41. 
Widemann BC, Salzer WL, Arceci RJ, et al: Phase I trial and pharmacokinetic study of the 
farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis 
type I and plexiform neurofibromas. J Clin Oncol 24:507-16, 2006 
42. 
Haas-Kogan DA, Banerjee A, Poussaint TY, et al: Phase II trial of tipifarnib and radiation in 
children with newly diagnosed diffuse intrinsic pontine gliomas. Neuro Oncol 13:298-306, 2011 
43. 
Kurzrock R, Kantarjian HM, Cortes JE, et al: Farnesyltransferase inhibitor R115777 in 
myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. Blood 102:4527-
34, 2003 

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44. 
Burnett AK, Russell NH, Culligan D, et al: The addition of the farnesyl transferase inhibitor, 
tipifarnib, to low dose cytarabine does not improve outcome for older patients with AML. Br J 
Haematol 158:519-22, 2012 
45. 
Stieglitz E, Ward AF, Gerbing RB, et al: Phase II/III trial of a pre-transplant farnesyl transferase 
inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group. 
Pediatr Blood Cancer 62:629-36, 2015 
46. 
Widemann BC, Dombi E, Gillespie A, et al: Phase 2 randomized, flexible crossover, double-
blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young 
adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Neuro Oncol 
16:707-18, 2014 
47. 
Thomas E. Witzig M: Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell 
Lymphoma (AITL) and CXCL12+ Peripheral T-Cell Lymphoma (PTCL): Preliminary Results 
from an Open-Label, Phase 2 Study [abstract]. In: American Society for Hematology 61st annual 
meeting in Orange County #468, 2019 
48. 
Cox AD, Der CJ, Philips MR: Targeting RAS Membrane Association: Back to the Future for Anti-
RAS Drug Discovery? Clinical Cancer Research 21:1819-1827, 2015 
49. 
Zujewski J, Horak ID, Bol CJ, et al: Phase I and pharmacokinetic study of farnesyl protein 
transferase inhibitor R115777 in advanced cancer. J Clin Oncol 18:927-41, 2000 
50. 
Lara PN, Jr., Law LY, Wright JJ, et al: Intermittent dosing of the farnesyl transferase inhibitor 
tipifarnib (R115777) in advanced malignant solid tumors: a phase I California Cancer Consortium 
Trial. Anticancer Drugs 16:317-21, 2005 
51. 
Kirschbaum MH, Synold T, Stein AS, et al: A phase 1 trial dose-escalation study of tipifarnib on a 
week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia. Leukemia 
25:1543-7, 2011 
52. 
Ho A, Chau, Nicole, Brana, Irene, Ferte, Charles, Evem, Caroline, Burrows, Francis, Kessler, 
Linda, Mishra, Vishnu, Magnuson, Kelly, Scholz, Catherine and Gualberto, Antonio: Preliminary 
Results from a Phase 2 Trial of Tipifarnib in HRAS mutant Head and Neck Squamous Cell 
Carcinomas. AACR Head and Neck Poster Presentation, 2018 
53. 
A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 20:859-66, 2001 
54. 
Agresti A, Coull BA: Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician 52:119-126, 1998 
55. 
Sandlund JT, Guillerman RP, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol 33:2106-11, 2015 
56. 
Park JR, Bagatell R, Cohn SL, et al: Revisions to the International Neuroblastoma Response 
Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning 
Meeting. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 35:2580-2587, 2017 
57. 
Bagatell R, McHugh K, Naranjo A, et al: Assessment of Primary Site Response in Children With 
High-Risk Neuroblastoma: An International Multicenter Study. J Clin Oncol 34:740-6, 2016 
58. 
Burchill SA, Beiske K, Shimada H, et al: Recommendations for the standardization of bone marrow 
disease assessment and reporting in children with neuroblastoma; on behalf of the International 
Neuroblastoma Response Criteria Bone Marrow Working Group. Cancer, 2016 
59. 
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 
acalabrutinib5 
alfentanil4,5  
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 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
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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etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
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 

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sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
telaprevir 
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 4.2.2.1 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  
              
 
 
 
 
          
Required Observations in Cycle 1  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below.  
 
 
 
 
 
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. 
   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 higher thrombocytopenia then CBCs should 
be checked every 3-4 days until recovery 
c. 
Electrolytes including Ca++, PO4, Mg++ 
d. 
Creatinine, ALT, bilirubin 
e. 
   Medication Diary (see Appendix III should be reviewed after completion of each treatment 
cycle and uploaded into RAVE. The medication diary should be collected weekly.   

 APEC1621M 
 
88 
 
APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621M 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 tumor (includes RTK, MRT) 
14. Rhabdomyosarcoma 
15. Wilms Tumor 
16. Pheochromocytoma 
17. Thyroid carcinoma 
18. Malignant ectomesenchymoma 
19. Melanoma 
20. Other Histology (based on COG/NCI-CTEP approval) 

 
 
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APPENDIX VIII: EXAMPLES OF ACTIONABLE MUTATIONS OF INTEREST FOR 
APEC1621M 
 
INCLUSION 
VARIANTS 
  
  
  
  
  
  
  
  
NON-HOTSPOT 
RULES 
  
  
  
Gene Name 
Description 
Variant Type 
LOE 
aMOI 
HRAS 
COSM6006359 
SNV 
1.9 
p.A146T 
HRAS 
rs121917759 
SNV 
1.9 
p.A146V 
 
HOTSPOTS 
  
  
  
  
Gene Name 
Variant ID 
Variant Type 
aMOI 
LOE 
HRAS 
COSM485 
SNV 
p.G12A 
1.9 
HRAS 
COSM481 
SNV 
p.G12C 
1.9 
HRAS 
COSM484 
SNV 
p.G12D 
1.9 
HRAS 
COSM482 
SNV 
p.G12R 
1.9 
HRAS 
COSM480 
SNV 
p.G12S 
1.9 
HRAS 
COSM483 
SNV 
p.G12V 
1.9 
HRAS 
COSM488 
SNV 
p.G13C 
1.9 
HRAS 
COSM490 
SNV 
p.G13D 
1.9 
HRAS 
COSM486 
SNV 
p.G13R 
1.9 
HRAS 
COSM487 
SNV 
p.G13S 
1.9 
HRAS 
COSM489 
SNV 
p.G13V 
1.9 
HRAS 
COSM497 
SNV 
p.Q61E 
1.9 
HRAS 
COSM502 
SNV 
p.Q61H 
1.9 
HRAS 
COSM503 
SNV 
p.Q61H 
1.9 
HRAS 
COSM496 
SNV 
p.Q61K 
1.9 
HRAS 
COSM498 
SNV 
p.Q61L 
1.9 
HRAS 
COSM52978 
MNV 
p.Q61L 
1.9 
HRAS 
COSM500 
SNV 
p.Q61P 
1.9 
HRAS 
COSM33695 
MNV 
p.Q61R 
1.9 
HRAS 
COSM499 
SNV 
p.Q61R 
1.9 
HRAS 
COSM501 
MNV 
p.Q61R 
1.9 
 
 
 
 
 
 
 

 
 
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Additional information is located on the CTEP website at https://ctep.cancer.gov/investigatorRes
ources/default.htm. For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov. 
Cancer Trials Support Unit (CTSU) Registration Procedures 
This study is supported by the NCI CTSU. 
Protocol-Specific Requirements For 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) 
 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 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’s registration status on the members’ side of the CTSU website.  
• Log on to the CTSU members’ website; 
• Click on Regulatory at the top of your screen; 
• Click on Site Registration;  
• Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined above. 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 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and 
role assignments.  
Requirements to access Rave via iMedidata: 
• A valid CTEP-IAM account; and  
• Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 

 
 
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o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration 
type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
e-mail from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password 
and click on the accept link in the upper right-corner of the iMedidata page. Site staff will 
not be able to access the study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings) 
and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. 
If an eLearning is required and has not yet been taken, the link to the eLearning will appear 
under the study name in iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will be granted, 
and a Rave EDC link will display under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the 
CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com.   
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are available 
to access details and reports of unanswered queries, delinquent forms, and timeliness 
reports. Review the DQP modules on a regular basis to manage specified queries and 
delinquent forms. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization for delinquent form details and reports to be available on the 

 
 
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DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.   
 
 
 

 
 
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APPENDIX X:  TOXICITY-SPECIFIC GRADING 
 
Bilirubin 
 
Grade 1: 
> ULN- ≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN - 3.0 x ULN 
Grade 3: 
> 3.0 x ULN -10.0 x ULN 
Grade 4: 
> 10.0 x ULN 
 
ALT: For the purpose of this study, the ULN for ALT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
> 45 U/L - ≤ 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 AST is 50 U/L regardless of baseline. 
 
Grade 1: 
> 50 U/L - ≤ 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 - 5.0 x ULN 
Grade 3: 
> 5.0 x ULN -20.0 x ULN 
Grade 4: 
> 20.0 x ULN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
This protocol is for research purposes only see page 1 for usage policy. 
APEC1621M 
Version Date: 10/28/2022  
 
   Page 95 
APPENDIX XI YOUTH INFORMATION SHEETS  
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621M 
(for children from 7 through 13 years of age) 
We want to tell you all about this study. You and your family can decide if you want to be in it. 
Ask questions if you don’t understand. 
 
1. What is the name of the study? 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 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is 
being done at other hospitals. 
 
3. What is the study about? 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 you have.  
 
4. What will happen to me in the study? Children who are part of this study have been “matched” to 
a medicine. We think that this medicine will help you and other kids that have the same kind of 
cancer as you have. If you decide to be treated with this medicine, you will have some tests and 
check-ups done more often than if you weren’t part of this study. We will follow your health after 
you finish the study treatment. 
 
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 for your cancer to 
stop growing, or even shrink, but we don’t know for sure if there is any benefit of being part of this 
study. 
 
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 more problems, or side 
effects, from a medicine used in this study. There may be risks that we don’t know about yet. 
 
5. Do I have to be in the study? You and your family can choose to be part of this study or not. You 
and 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. If you have any questions 
or don’t like what is happening, please tell your parent, the doctor or nurse. 
 
6. We are asking your permission to collect additional tumor tissue. We want to see if there are ways 
to tell how the cancer will respond to treatment. These samples would be taken on tumor samples 
that we already have, so there would be no extra procedures. This would not change what medicines 
we would use to treat your tumor and would not provide any “benefits” to you. We hope that it 
might help us learn how to better treat other children’s cancers in the future. You do not have to 
participate if you do not want to.  
 
 
 
 
 

 
 
This protocol is for research purposes only see page 1 for usage policy. 
APEC1621M 
Version Date: 10/28/2022  
 
   Page 96 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621M 
(for teens from 14 through 17 years of age) 
1. What is the name of the study? 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 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is being 
done at other hospitals. 
 
3. What is the study about? 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.  
 
4.  What will happen to me on the study? Your tumor has a mutation that matches tipifarnib, and so 
you have been assigned to tipifarnib. The doctors want to see if tipifarnib will make children with 
your type of cancer get better. We don’t know if tipifarnib will work well to get rid of your cancer. 
That is why we are doing the study. 
 
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 tipifarnib 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. 
 
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 
tipifarnib. Your doctor will talk to you about the risks we know about from tipifarnib. There may 
be other risks from tipifarnib that we don’t know about yet.  
 
 
5.   Will I be paid to be in this study? You will not be paid for being in this study. 
 
6.    Do I have to be in the study? You and your family can choose to be part of this study or not. You 
and 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. If you have any questions 
or don’t like what is happening, please tell your parent, the doctor or nurse. 
 
7. We are asking your permission to collect additional tumor tissue. We want to see if there are ways 
to tell how the cancer will respond to treatment. These samples would be taken on tumor samples 
that we already have, so there would be no extra procedures. This would not change what medicines 
we would use to treat your tumor and would not provide any “benefits” to you. We hope that it 
might help us learn how to better treat other children’s cancers in the future. You do not have to 
participate if you do not want to. 
 

 
 
This protocol is for research purposes only see page 1 for usage policy. 
APEC1621M 
Version Date: 10/28/2022  
 
   Page 97 
APPENDIX XII: PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions 
with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis:  
      
Trial #: 
APEC1621M 
Study 
Doctor: 
      
Study 
Doctor 
Phone #:  
      
Study 
Drug(s): 
Tipifarnib 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse practitioners, 
pharmacists), and tell them you are taking part in a clinical trial sponsored by the National Cancer Institute.  
 
These are the things that your healthcare providers need to know: 
Tipifarnib interacts with certain enzymes in your liver and gut. 
 
 
Explanation 
CYP 
isoenzymes  
The enzymes in question are CYP 3A4/5, 2C8/9/10, 2A6 and 2D6 and UDP-
glucuronosyltransferase (UGT).  Tipifarnib is broken down by CYP3A4/5 and UGT 
enzyme pathways. Tipifarnib levels in the body are affected by strong 
inducers/inhibitors of these enzymes. Tipifarnib inhibits CYP 3A4/5, 2C8/9/10, 2A6 
and 2D6 and can affect sensitive substrates of these enzymes. 
 
 
 
These are the things that you need to know: 
The study drug tipifarnib, may interact with other drugs which can cause side effects.  For this reason, it is 
very important to tell your doctors about all your medicines, including:  (a) medicines you are taking before 
this clinical trial, (b) medicines you start or stop taking during this study, (c) medicines you buy without a 
prescription (over-the-counter remedy), (d) herbals or supplements (e.g. St. John’s Wort).  It is helpful to 
bring your medication bottles or an updated medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers 
to review any medicines and herbal supplements that are considered strong inducers/inhibitors of CYP 
3A4/5 and UGT or sensitive substrates of CYP 3A4/5, 2C8/9/10, 2A6 and 2D6. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
o Avoid ingesting grapefruit juice, grapefruit and Seville oranges while taking tipifarnib.  
• Make sure your doctor knows to avoid certain prescription medications.  
 
• 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.   
 
 
 
Version MAY/2019