Clinical trial NCT01827384
Conditions: Advanced Malignant Solid Neoplasm
Sponsor: National Cancer Institute (NCI)
Start date: 2014-01-07; Completion date: 2021-10-08
Enrollment: 208 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies molecular profiling-based assignment of cancer therapy (MPACT) in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Adavosertib, everolimus, and trametinib are drugs that each target a specific variation in tumors by blocking different proteins needed for cell growth. Veliparib blocks an enzyme that helps repair deoxyribonucleic acid (DNA) damaged by chemotherapy, which may help chemotherapy drugs work better. It is not yet known whether testing patients for variations in their tumor and assigning treatment targeting the variation is more effective than standard non-targeted therapy in treating advanced solid tumors.

Detailed description:
PRIMARY OBJECTIVE:

I. Evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers.

OUTLINE: Patients are assigned to 1 of 4 treatment regimens corresponding to one of their mutation/amplification categories.

REGIMEN I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7 and temozolomide PO once daily (QD) on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

REGIMEN II: Patients receive adavosertib PO BID for 5 doses starting on day 1 and carboplatin intravenously (IV) over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. (No longer an active study drug as of March 2018)

REGIMEN III: Patients receive everolimus PO every day (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (No longer an active study drug as of March 2018)

REGIMEN IV: Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (No longer an active study drug as of March 2018)

After completion of study treatment, patients are followed up for 30 days. Patients with unacceptable toxicities that have not resolved by day 30 are followed up biweekly until stabilization or resolution.

Arms: arm 1: Patients receive veliparib by mouth (PO) twice a day (BID) on days 1-7 and temozolomide PO every day (QD) on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive adavosertib by mouth (PO) twice a day (BID) for 5 doses starting on day 1 and carboplatin intravenous (IV) over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive everolimus by mouth (PO) every day (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 4: Patients receive trametinib by mouth (PO) every day (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Adavosertib intervention 2: Carboplatin intervention 3: Everolimus intervention 4: Temozolomide intervention 5: Trametinib intervention 6: Veliparib
Intervention descriptions: intervention 1: Given by mouth (PO) intervention 2: Given intravenous (IV) intervention 3: Given by mouth (PO) intervention 4: Given by mouth (PO) intervention 5: Given by mouth (PO) intervention 6: Given by mouth (PO)

Protocol documents:
Prot_SAP_000.pdf: 
i 
 
To: 
CTEP Protocol and Information Office 
From: 
Alice Chen, MD, DTC, NCI 
Date: 
January 7, 2019 
Re: 
Amendment to Protocol 9149: Molecular Profiling-based Assignment of Cancer 
Therapy for Patients With Advanced Solid Tumors 
With this amendment, we are incorporating recommendations from CTEP’s review of protocol 
version 02/06/2019, and making some administrative changes. 
 
We would also like to update the protocol to allow the sole patient who continues to receive 
randomized Trametinib DMSO treatment (22+ cycles) to consent to having her mutational status 
and arm assignment (i.e., experimental or control) disclosed to herself and/or her treating 
physician now, rather than wait until disease progression, given the new non-randomized study 
design and statistical analysis plan.  We would also like to allow this patient to consent to sample 
unlinking while she remains on study, in order to enable research-use analysis of her sample in 
parallel with the other results from the randomized portion of the study.  Thank you for your 
consideration. 
 
I. 
Recommendations from CTEP review of Amendment #37 (pv 02/06/2019) 
# 
Section 
Comments 
1. 
12.1 
Please revise the following paragraph as indicated. 
Data collection for this study will be done exclusively through Medidata Rave.  
Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in the Regulatory Support System 
(RSS).  To access Rave via iMedidata, the site user must have an active CTEP 
IAM account (check at https://ctepcore.nci.nih.gov/iam) and the appropriate Rave 
role (Rave CRA, Rave Read-Only, Rave CRA (Lab Admin), Rave SLA, or Rave 
Investigator) (Rave CRA, Read-Only, CRA, Lab Admin, SLA, or Site 
Investigator) on either the LPO or participating organization roster at the enrolling 
site. To hold the Rave CRA role or Rave CRA (Lab Admin) Rave CRA role or 
CRA Lab Admin role, the user must hold a minimum of an AP registration type.  
To hold the Rave Site Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in Rave.   
PI Response:  We have revised the paragraph as indicated. 
 
II. Other Protocol Changes 
# 
Section 
Comments 
2. 
Cover Page 
Updated the protocol version date and letters. 


ii 
 
# 
Section 
Comments 
3. 
Cover Page 
Updated the list of Associate Investigators. 
4. 
2 
5.2 
Given the new non-randomized study design and statistical analysis 
plan, we would like to revise and update the protocol to allow the sole 
patient who continues to receive randomized Trametinib DMSO 
treatment (22+ cycles) to consent to having her mutational status and 
arm assignment (i.e., experimental or control) disclosed to herself and/or 
her treating physician now, rather than wait until disease progression to 
find out per the original study plan.  The patient, in discussion with the 
treating physician, will have the same on-study treatment options at 
progression as before, but because she is unblinded we think she will 
have better information sooner about her future treatment options.   
5. 
9.4.1 
Revised the sample unlinking procedure to allow sample unlinking for 
the sole remaining randomized patient to occur while the patient remains 
on study, in order to enable research-use analysis of her sample in 
parallel with the other results from the randomized portion of the study. 
6. 
Appendix F 
Replaced the Biopsy Sequencing Results and Analysis Form with an 
updated form supplied by the MoCha lab.  . 


CTEP #9149 (01-07-2020) 
 
1 
 
Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced 
Solid Tumors 
 
Abbreviated Title: MPACT 
 
Coordinating Center: 
LAO-NCI/National Cancer Institute LAO 
 
 
National Cancer Institute  
 
 
10 Center Drive, 12N226 
 
 
Bethesda, MD 20892 
 
 
Principal Investigator: 
A. P. Chen, MDA-E 
 
 
Developmental Therapeutics Clinic (NCI DTC MM) 
 
 
31 Center Drive, Bldg 31, Room 3A44  
 
 
 
 
Bethesda, MD 20892 
 
 
Phone: (240) 781-3320 
 
 
Fax: (240) 541-4515 
 
 
 
 
 
 
 
 
 
 
 
 chenali@mail.nih.gov 
 
NCI Co-Investigators: 
James H. Doroshow, MD, DCTDA-E 
 
Richard Piekarz, MD, PhD, DCTDA-E 
 
Geraldine O’Sullivan Coyne, MD, PhD, DCTDA-E 
 
Howard Streicher, MD, DCTDA-E 
 
Naoko Takebe, MD, PhD, DCTDA-E 
 
Arjun Mittra, MD, DCTDA-E 
Sheila Prindiville, MD, MPH, DCTDA-E 
Rafeh Naqash, MD, DCTD/ NCIA-E 
Jessica Mukherjee, MS, CRNP, DCTD/NCIA,B,E 
 
Non-NCI Co-Investigators: 
Lamin Juwara CRNP, Leidos Biomed., FNLCRA,B,E 
 
P. Mickey Williams, PhD, Leidos Biomed., FNLCRF  
 
Referral Contact: 
 
Nancy Moore, RN, DCTDA,B,E  
Bldg 10/Rm 13N-214  
(240) 760-6045 
Fax: (301) 451-5625 
nancy.moore@nih.gov 
 
 
Roles: Aobtains information by intervening or interacting with living individuals for research purposes; 
Bobtains identifiable private information about living individuals; Cobtains the voluntary informed 
consent of individuals to be subjects; Dmakes decisions about subject eligibility; Estudies, interprets, or 
analyzes identifiable private information or data/specimens for research purposes; Freviews patient 
genetic sequencing data but is not involved in clinical care  
 


CTEP #9149 (01-07-2020) 
 
2 
 
Participating Organizations:  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
 
Statisticians: 
 
Larry Rubinstein, PhDE  
9609 Medical Center Dr. 
Rockville, MD  20850 
Phone: (240) 276 6026  
rubinsteinl@ctep.nci.nih.gov 
 
Jared Foster, PhD 
9609 Medical Center Dr. 
Rockville, MD  20850 
Phone: (240) 276 7385  
fosterjc@nih.gov 
 
NCI-supplied Agents: 
AZD1775 (NSC 751084) 
 
Veliparib (NSC 737664) 
 
Trametinib DMSO (NSC 763093) 
 
Everolimus (NSC 733504)  
Temozolomide (NSC 362856) 
Carboplatin (NSC 241240) 
 
   
IND Number:  
116976 
 
Version Date:  
January 7, 2020 (Amendment Y, iRIS V) 
 


CTEP #9149 (01-07-2020) 
 
3 
 
PRÉCIS 
Background:  
• Targeted therapy based on identifying underlying genetic aberrations within the tumor is the 
goal of personalized medicine.  This pilot trial aims to establish whether advanced cancer 
patients who have no treatment options with proven benefit, and with tumor mutations in one 
of 3 genetic pathways (DNA repair, PI3K, or RAS/RAF/MEK) are more likely to derive 
clinical benefit if treated with agents targeting that pathway than if treated with agents that do 
not.  Each patient will be randomly assigned to receive the recommended Phase II dose of 
either a study drug identified to work on their tumor’s mutation/aberrant pathway, or an agent 
from the complementary set not identified to work on the mutations of interest.  As of 
Amendment U, only the DNA repair arm remains open to accrual.  
Objectives: 
• Evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in 
patients with advanced refractory cancers. 
Eligibility: 
• Adult patients with histologically documented solid tumors whose disease has progressed 
following at least one line of standard therapy and/or for which no standard treatment is 
available that has been shown to improve survival. 
• Tumor amenable to percutaneous biopsy, and willingness to undergo tumor biopsy.  
Study Design:  
• Patients enrolled on study will have a tumor biopsy sequenced in a CLIA-certified lab for 
specific mutations of interest in DNA repair pathways.  If such mutations are not detected, the 
patient will be taken off study.  Eligibility may also be determined from existing CLIA 
genetic testing reports from a MATCH-designated CLIA lab.  
•  Patients who have received PARPi in combination with temozolomide are not eligible. 
• Patients in whom a mutation of interest is detected will receive an agent prospectively 
identified to target that mutation/pathway  
• Targeted drugs will be administered at recommended Phase II doses and schedules: (1) 
Veliparib (PARP inhibitor) with temozolomide for defects in the DNA repair pathway; (2) 
AZD1775 (Wee1 inhibitor) plus carboplatin for defects in DNA repair pathway; (3) 
Everolimus (mTOR inhibitor) for mutations in the PI3K pathway; or (4) Trametinib DMSO 
(MEK inhibitor) for mutations in the RAS/RAF/MEK pathway.  As of Amendment U, only the 
Veliparib with temozolomide arm remains open to accrual. 
• Given the relative frequencies of the mutations, up to 100 patients will need to be enrolled to 
acquire 30 evaluable patients per open arm. 
 
 
 
 


CTEP #9149 (01-07-2020) 
 
4 
 
SCHEMA 
 
 
 
 
 
 
 
a Tumor biopsy (mandatory) will be performed on all patients enrolled on study; tissue will be 
sequenced for the presence of specific mutations of interest.  Patients with qualifying MATCH-
designated lab genetic testing reports may also be eligible. 
 
b Only patients with specified mutations of interest will be administered targeted drug at recommended 
Phase II doses and schedules (see page 5).  
 
One additional optional tumor biopsy may be performed at time of disease progression on study to 
assess for new mutations.  (This biopsy may instead be collected on day 1 (± 2 days) of the cycle 
following any restaging at which a 10-19% increase in tumor volume is observed (per RECIST criteria) 
if the patient has been on study for at least 4 cycles).  
Tumor 
biopsy  
from all 
patients for 
sequencing 
or qualifying 
mutation a 
Mutation  
not detected 
Assign treatment 
identified to target 
mutation 
OR 
Mutation 
detectedb
Off Study 
Patients with specified mutations of interest will be assigned to receive the following study drug 
combination at the assigned dose.  Cycle length is +/- 1 day for scheduling:  
 
 
Veliparib 40 mg orally BID qd days 1-7 plus temozolomide 150 mg/m2 orally qd 
days 1-5 (no food restrictions) in 28-day cycles 
Temozolomide 
Veliparib 
D1  
  
 D5 D7 
 D21 
D28 
Cycle 1 and Subsequent Cycles  
Veliparib plus 
Temozolomide 


CTEP #9149 (01-07-2020) 
 
5 
 
TABLE OF CONTENTS 
 
PRÉCIS ................................................................................................................................... 3 
SCHEMA ................................................................................................................................. 4 
TABLE OF CONTENTS ............................................................................................................ 5 
1. 
OBJECTIVES ....................................................................................................... 7 
1.1 
Primary .................................................................................................................7 
2. 
BACKGROUND ................................................................................................... 7 
2.1 
Targeted Mutations and Pathways..............................................................................9 
2.2 
Targeted Genes/Locus Selection.............................................................................. 14 
2.3 
Study Agents ........................................................................................................ 17 
2.4 
Study Disease ....................................................................................................... 18 
2.5 
Genetic Sequencing Research Ethics and NIH Genomic Data Sharing Policy ................. 18 
2.6 
Rationale for the Study .......................................................................................... 20 
3. 
PATIENT SELECTION (TUMOR SEQUENCING/DRUG TREATMENT)..................20 
3.1 
Eligibility Criteria: Tumor Biopsy Sequencing .......................................................... 21 
3.2 
Exclusion Criteria: Tumor Biopsy Sequencing........................................................... 22 
3.3 
Eligibility Criteria: Targeted Treatment .................................................................... 23 
3.4 
Exclusion Criteria: Targeted Treatment .................................................................... 25 
3.5 
Evaluation for Enrollment for Tumor Biopsy Screening .............................................. 26 
3.6 
Evaluation for Treatment on Study .......................................................................... 26 
4. 
REGISTRATION PROCEDURES ..........................................................................27 
4.1 
Investigator and Research Associate Registration with CTEP....................................... 27 
4.2 
Site Registration ................................................................................................... 27 
4.3 
General Guidelines................................................................................................ 30 
4.4 
Randomization Procedures (N/A) ............................................................................ 30 
5. 
TREATMENT PLAN............................................................................................30 
5.1 
Study Design ........................................................................................................ 30 
5.2 
Targeted Therapy Arms ......................................................................................... 31 
5.3 
Agent Administration ............................................................................................ 33 
5.4 
General Concomitant Medication and Supportive Care Guidelines:............................... 34 
5.5 
Definition of Off-Study Parameters.......................................................................... 35 
5.6 
Duration of Follow-Up .......................................................................................... 36 
5.7 
Criteria for Removal From Study............................................................................. 36 
6. 
DOSING DELAYS/DOSE MODIFICATIONS .........................................................36 
6.1 
Dose Modifications ............................................................................................... 36 
6.2 
Agent-specific Dose Modifications: Trametinib DMSO .............................................. 37 
6.3 
Agent-specific Dose Modifications: Everolimus ........................................................ 47 
6.4 
Agent-specific Dose Modifications: Veliparib ........................................................... 51 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS............................52 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ............................ 53 
7.2 
Adverse Event Characteristics ................................................................................. 66 
7.3 
Expedited Adverse Event Reporting......................................................................... 66 
7.4 
Routine Adverse Event Reporting............................................................................ 68 
7.5 
Secondary Malignancy........................................................................................... 69 
7.6 
Second Malignancy ............................................................................................... 69 
8. 
PHARMACEUTICAL INFORMATION ..................................................................69 
8.1 
Temozolomide (NSC 362856)................................................................................. 69 
8.2 
Carboplatin (NSC 241240) ..................................................................................... 70 


CTEP #9149 (01-07-2020) 
 
6 
 
8.3 
Everolimus (NSC 733504)...................................................................................... 72 
8.4 
Veliparib (NSC 737664) ........................................................................................ 73 
8.5 
AZD1775 (NSC 751084) ....................................................................................... 74 
8.6 
Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) ................................... 76 
8.7 
Agent Ordering..................................................................................................... 77 
9. 
GENETIC ANALYSIS ..........................................................................................78 
9.1 
Tumor Biopsies .................................................................................................... 78 
9.2 
Screening Eligibility Sample Collection and Processing .............................................. 80 
9.3 
Shipping for Genetic Analysis................................................................................. 81 
9.4 
Sample Handling and Unlinking Procedures.............................................................. 82 
10. 
STUDY CALENDAR: ..........................................................................................83 
11. 
MEASUREMENT OF EFFECT..............................................................................86 
11.1 
Antitumor Effect – Solid Tumors............................................................................. 86 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS
 
92 
12.1 
Data Reporting ..................................................................................................... 92 
12.2 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA) ................................................................................................................. 94 
12.3 
Publication Policy ................................................................................................. 96 
13. 
STATISTICAL CONSIDERATIONS ......................................................................97 
13.1 
Sample Size/Accrual Rate ...................................................................................... 97 
13.2 
Analysis of Additional Endpoints ............................................................................ 97 
14. 
HUMAN SUBJECTS PROTECTIONS ....................................................................98 
14.1 
Rationale for Subject Selection................................................................................ 98 
14.2 
Justification for Exclusions ..................................................................................... 99 
14.3 
Evaluation of Benefits and Risks/Discomforts ........................................................... 99 
14.4 
Consent and Assent Process and Documentation ........................................................ 99 
14.5 
Procedure for Protecting Against or Minimizing Any Potential Risks .......................... 100 
15. 
REFERENCES ................................................................................................... 101 
APPENDIX A: Performance Status Criteria ................................................................................ 106 
APPENDIX B: Potential Drug Interactions and Drug Information Handouts .................................... 107 
APPENDIX C: Medications That May Cause QTc Prolongation .................................................... 116 
APPENDIX D: Patient Study Diaries ......................................................................................... 118 
APPENDIX E: MPACT (9149) Sample Shipping Instructions and Manifest .................................... 131 
APPENDIX F: Biopsy Sequencing Results and Analysis Form ...................................................... 133 
APPENDIX G: Molecular Tumor Board Members....................................................................... 136 
APPENDIX H: Example Tumor Variant Patient Report................................................................ 137 
APPENDIX I: Veliparib plus Temozolomide (Proprietary Information)........................................... 138 
APPENDIX J: AZD1775 (Proprietary Information) ..................................................................... 141 
APPENDIX K: Trametinib DMSO (Proprietary Information) ........................................................ 145 
APPENDIX L: NCI Correlative Imaging Studies ......................................................................... 150 


CTEP #9149 (01-07-2020) 
 
7 
 
1. OBJECTIVES 
1.1 
Primary 
Evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in 
patients with advanced refractory cancers. 
 
2. BACKGROUND 
The initial design of this targeted pilot trial was to establish whether patients with tumor 
mutations in one of the genetic pathways of interest (DNA repair, PI3K, or RAS/RAF/MEK) are 
more likely to derive clinical benefit (defined as objective response or progression-free survival) 
if treated with agents targeting that specific pathway than with agents that do not.  The study 
design was developed in conjunction with experts in clinical trial design, genetic sequencing, 
molecular oncology, cell biology, and statistics, who developed an algorithm that defines clinical 
action based on genetic variants reported in the genes of interest (Table 1 and Section 2.2).  
Aberrations in the PI3K-Akt, KRAS and RAF/MEK/ERK pathways and defects in the DNA 
repair pathways are common in several cancers.  Each of these pathways and the selected 
targeted agents are discussed below.  The genes of interest and mutations to be analyzed have 
been prospectively defined based on the recommendations of the multidisciplinary Molecular 
Tumor Board convened for this study (membership list included in Appendix G). 
 
This study was placed on hold in January 2018 for interim futility analysis of the AZD1775 plus 
carboplatin and Trametinib DMSO arms (see Section 13), at which time a total of 193 patients 
had biopsies collected for screening and 99 (51%) had an actionable mutation of interest for 
randomizing to study drug.  The major conclusions from this analysis are summarized below; a 
manuscript describing study results is in progress: 
 
1. No confirmed objective responses were measured among the initial 18 patients of the 
AZD1775 plus carboplatin cohort; this cohort was terminated in March 2018.   
2. One confirmed response was measured among 20 patients starting treatment on the 
Trametinib DMSO experimental cohort (accrual beyond 12 patients was due to delayed 
outcome reporting from participating sites); this cohort was terminated in March 2018. 
3. There were insufficient numbers of patients treated on the everolimus experimental cohort to 
assess response rate, but no responses were measured; this cohort was terminated in March 
2018.   
4. There were insufficient numbers of patients treated on the veliparib plus temozolomide arm 
to assess response rate, but no responses were measured; however, the study team have 
revised the eligibility criteria to include BRCA mutations, which is projected to increase the 
hit rate.   
5. Using the percentage of patients who started their assigned treatment as a measure of 
compliance, the overall percentage of patients assigned to experimental arm B who elected 
not to receive treatment was 47%, unexpectedly higher than the rate for patients assigned to 
experimental arm A (23%) (p=.02, 1-sided, by Fisher exact test).  Interim analysis therefore 
suggests that patients at participating sites were choosing not to participate on the assigned 


CTEP #9149 (01-07-2020) 
 
8 
 
control arm because a priori knowledge of their mutations of interest (e.g., from 
FoundationOne reports) led to expectation of treatment assignment.  Our hypothesis, that 
conducting genetic analysis and choosing targeted therapy based on genomic analysis will 
result in improved response rate and PFS, cannot be evaluated in light of this—indeed, the 
utility of the randomized phase 2 design to determine whether targeted therapy based on 
presence of drug-susceptible tumor mutations will result in improved response rate is clearly 
in doubt [1].  Based on these data it was determined that the study will reopen without 
randomization; patients with actionable mutations of interest will be assigned to targeted 
treatment arm(s) to assess the proportion of patients with objective response.  The 
performance of each individual mutational status cohort will be compared to that of historical 
controls. 
 
With the current non-randomized study design and statistical analysis plan, there is less of a 
rationale for blinding randomized patients, treating physicians, and the study team to the actual 
sequencing data until disease progression.  As of Amendment Y (January 7, 2020) one patient 
who was randomized to the Trametinib DMSO cohort under the original study design remains on 
treatment with prolonged stable disease (22+ cycles), blinded to sequencing results and arm 
assignment.  Amendment Y allows this patient to consent to having her mutational status and 
arm assignment (i.e., experimental or control) disclosed to herself and/or her treating physician 
now, rather than waiting until disease progression.  The study team would also be informed.  The 
patient, in discussion with the treating physician, will continue to have the option to receive the 
other study treatment prospectively identified to work on the identified mutation/pathway per the 
original study design if she is currently on the control arm.  As noted above, the responses in the 
experimental cohorts were insufficient to indicate that a patient is more likely to derive clinical 
benefit if treated with agents targeting that pathway than if treated with agents that do not. 
 
The agents and respective pathways being evaluated in this study are:  
1. Veliparib (PARP inhibitor) with temozolomide for defects in DNA repair pathways 
2. AZD1775 (Wee1 inhibitor) plus carboplatin for defects in DNA repair pathways (closed 
March 2018) 
3. Everolimus (mTOR inhibitor) for mutations in the PI3K pathway (closed March 2018) 
4. Trametinib DMSO (MEK inhibitor) for mutations in the RAS/RAF/MEK pathway 
(closed March 2018) 
 
Genetic sequencing will be performed in the CLIA-certified Molecular Characterization 
Laboratory at the Frederick National Laboratory for Cancer Research (FNLCR).  In view of the 
complexity of information collected, each patient’s data will be reviewed by investigators 
indicated with an F on the cover page or (in their absence), their designees for internal 
consistency.  The genetic variants to be assessed and treatment algorithms have been 
prospectively defined to proceed with assigning specific treatments to the patients on study.  The 
potential risks associated with obtaining genetic information are discussed in Section 2.5.  
 
Patients with CLIA tumor reports from Foundation Medicine (FoundationOne), CARIS 
(Molecular Intelligence), or other EAY131 MATCH-Designated Laboratories (https://ecog-
acrin.org/nci-match-eay131-designated-labs) may be eligible if they have a study actionable 
mutation. 


CTEP #9149 (01-07-2020) 
 
9 
 
 
At the NCI only, every attempt will be made to collect standard-of-care images (CT or MRI) that 
qualified the patient for inclusion in this trial, along with the images taken during image-guided 
biopsy, and any follow up imaging studies during restaging (optional), will be collected to allow 
research into correlation of the image phenotypic features with the genomic analyses, an area of 
active research in radiology [2] [3].  All images will be de-identified of personal health 
information at the CCR Molecular Imaging Program before leaving the NIH Clinical Center site 
and will be stored in The Cancer Imaging Archive (http://www.cancerimagingarchive.net/), an 
NIH policy-compliant internet-accessible collection, with controlled access.  The process is 
defined in Appendix L.  
 
2.1 
Targeted Mutations and Pathways 
2.1.1 Mutations in DNA Repair Pathways and PARP Inhibitors 
DNA damage by traditional chemotherapeutic agents does not always result in cell death 
due to complex DNA repair pathways.  Recent research has suggested that directly 
targeting DNA repair pathways may result in effective killing of tumor cells, particularly 
in patients with pre-existing defects in DNA repair pathways.  There are 6 major DNA 
repair pathways: direct repair (DR), base excision repair (BER), nucleotide excision 
repair (NER), mismatch repair (MMR), homologous recombination (HR), and non-
homologous end-joining (NHEJ) [4].  Each pathway consists of a complex interaction of 
different molecular characteristics (Figure 1).   
 
 


CTEP #9149 (01-07-2020) 
 
10 
 
 
Figure 1. DNA repair pathways and potential analytes for assessment of DNA repair [4]. 
 
The BER pathway exerts its biological role by removing bases that have been damaged 
and plays a vital role in repairing DNA single-strand breaks (SSBs) caused by DNA-
damaging factors such as anticancer agents [5].  This pathway includes the poly(ADP-
ribose) polymerase (PARP) family of enzymes.  PARP-1 and -2 are the most abundant of 
the PARPs and are essential nuclear enzymes that play a role in recognition of DNA 
damage and facilitation of DNA repair [6, 7].  PARP-1 and -2 bind rapidly to sites of 
DNA SSBs, which leads to the separation of PARP from DNA.  This leads to modulation 
of DNA damage response proteins (XRCC1/ligase III complex, Polβ) that bind to sites of 
DNA damage.  Double-strand breaks (DSBs) are also strong activators of PARP-1, 
resulting in PARP-1–mediated activation of DNA-PK and Ku80, important components 
of NHEJ repair pathway [8, 9].  Inhibition of PARP sensitizes tumor cells to cytotoxic 
agents (e.g., temozolomide) which induce DNA damage that would normally be repaired 
through the BER system.  PARP inhibitors do not potentiate agents that do not cause 
DNA damage. 
 
Expression of PARP is higher in tumor cells than normal cells.  This overexpression has 
been linked to drug resistance and the ability of tumor cells to withstand genotoxic stress.  
In knockout mouse models, deletion of PARP-1 is sufficient to impair DNA repair [10-
12].  Hence, it is anticipated that PARP inhibitors will function as sensitizing agents for 


CTEP #9149 (01-07-2020) 
 
11 
 
chemotherapy and radiation therapy administered to induce DNA damage.  Recent data 
preclinical data that isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations induce a 
homologous recombination defect and a sensitivity to PARP inhibition suggest that these 
targets may have may have therapeutic relevance [13].  
 
Wee1 is a tyrosine kinase implicated in the inhibitory phosphorylation of CDK1/CDC2-
bound cyclin B complex responsible for G2 arrest [14].  Originally identified in fission 
yeast [15], wee 1 deficiency resulted in premature mitotic entry and replication of 
smaller-sized yeast.  Wee1 belongs to a family of protein kinases involved in the terminal 
phosphorylation and inactivation of (CDK1/CDC2)-bound cyclin B via phosphorylation 
of its Tyr15 residue near the ATP-binding pocket, resulting in G2 cell cycle arrest in 
response to DNA damage.  Wee1 overexpression has been demonstrated in hepatocellular 
carcinoma [16], luminal and HER-2 positive breast cancers [17], colon, lung carcinoma, 
and seminoma tumor samples [18]. 
2.1.2 Mutations in the RAS Pathway: KRAS, NRAS, BRAF  
MEK is a critical kinase in the mitogen-activated protein (MAP) kinase signal 
transduction pathway for many growth factor receptors that provide growth signals to 
cancer cells, including epidermal growth factor receptor (EGFR), insulin-like growth 
factor-1 receptor (IGFR1), and platelet-derived growth factor receptor.  Cell signaling 
through growth factor receptors and protein kinases plays an essential role in cell 
survival, proliferation, and differentiation.  The RAS/RAF kinase pathway is one of the 
most important and best understood MAP kinase pathways involved in normal and 
uncontrolled cell growth.  In proliferative diseases, genetic mutations and/or over 
expression of growth factor receptors, downstream signaling proteins, or protein kinases 
involved in the RAS/RAF MAP kinase pathway lead to uncontrolled cell proliferation 
and, eventually, tumor formation.   
 
RAS:RAF association promotes translocation of the normally cytoplasmic RAF protein 
to the plasma membrane, resulting in activation of its kinase function.  Constitutive 
activation of the RAS pathways occurs through mutation activation of the RAS oncogene 
or of downstream effectors of RAS [19].  Mutated, oncogenic forms of RAS are found in 
50% of colon and >90% of pancreatic cancers [20], as well as many others types of 
cancers [21], including 15 to 30% of non-small cell lung cancer (NSCLC) [22].   
 


CTEP #9149 (01-07-2020) 
 
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Figure 2: RAS Pathway (Figure from SABiosciences.com) 
 
KRAS mutations, specifically in codon 12, have been shown to be important for cancer 
progression and may predispose to more aggressive biological behavior in patients with 
advanced colorectal cancer [23].  Recently, BRAF (a member of the RAF kinase family) 
gene mutations, which result in a constitutively active MAP kinase cascade, have been 
identified in more than 60% of malignant melanomas [24].  Studies of primary tumor 
samples and cell lines have also shown constitutive activation or overactivation of the 
MAP kinase pathway in cancers of the pancreas, colon, lung, ovary, and kidney [25].  
Thus, there is a strong correlation between cancers and an overactive MAP kinase 
pathway resulting from genetic mutations. 
 
Because activation of the RAS/RAF MAP kinase cascade plays a pivotal role in cell 
proliferation, inhibition of this pathway is believed to be beneficial in hyperproliferative 
diseases.  It is anticipated that inhibition of MEK activity should inhibit transduction of 
the mitogenic signals from multiple pathways, resulting in an effect on tumor 
proliferation, differentiation, and survival.  Inhibition of MEK has been shown to have 
potential therapeutic benefit in several studies [26, 27].   


CTEP #9149 (01-07-2020) 
 
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2.1.3 Mutations in the PI3K-AKT-mTOR Pathway  
The phosphatidylinositol 3-kinase (PI3K) family of lipid kinases converts 
phosphatidylinositol-4,5-bisphosphate to phosphatidylinositol-3,4,5-trisphosphate, which 
initiates a signaling cascade that promotes cell growth, proliferation, motility, and 
survival [28].  PI3 kinases activate AKT.  The PI3K-AKT pathway is downstream of the 
common growth factor receptor tyrosine kinases (RTKs), including EGFR, HER2, and 
IGFR, and is a likely driver of tumor progression in most carcinomas [29-31].  AKT 
promotes cell survival, growth, proliferation, migration; as well as angiogenesis and 
invasion by acting on multiple downstream pathways.   
 
AKT protein kinase is activated in a substantial proportion of human solid tumors, 
including breast, endometrial, ovarian, prostate, pancreatic, colon, gastric, and NSCLC.  
Upregulation of AKT can be caused by direct amplification/mutation of AKT, or by 
overexpression of RTKs, PI3K, and RAS, and/or by inactivation of the tumor suppressor 
PTEN [32, 33].  AKT activates and/or inhibits other proteins including BAD, FOXO, and 
mTOR [34].   
 
Activation of AKT is an important mechanism of chemotherapy/radiotherapy resistance, 
and is therefore of great interest as a potential pathway to overcome resistance.  
Numerous references provide support for AKT inhibitors in the treatment of various 
malignancies [29-31, 35-65].  AKT phosphorylation as a pharmacodynamic (PD) marker 
has also been explored in early phase clinical trials [34].   
 
Inactivation or hypoactivation of PTEN causes overactivation of the PI3K-AKT pathway 
[34].  PTEN inactivation is caused by a variety of mechanisms including somatic 
mutations, deletions, promoter methylation, and/or loss of heterozygosity.  These changes 
are commonly found in many cancers including prostate cancer, endometrial cancer, and 
glioblastoma and are often associated with advanced disease stage.  mTOR is a 
serine/threonine kinase that is structurally related to PI3K.  When mTOR binds to other 
intracellular proteins; there are two distinct complexes formed known as mTORC1 and 
mTORC2 [34].  The currently approved mTOR inhibitors: rapamycin (sirolimus), 
everolimus, and temsirolimus only block mTORC1.  mTORC1 is made up of mTOR, 
regulatory-associated protein of mTOR (raptor), and mLST8/GβL.  Results from a recent 
Phase I study of doxorubicin, bevacizumab, and temsirolimus in patients with advanced 
gynecologic and breast malignancies indicated that a high percentage of responders had 
PI3K aberrations [66]. 
 


CTEP #9149 (01-07-2020) 
 
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Figure 3: AKT/PI3K signaling cascade (SABiosciences.com). 
 
2.2 
Targeted Genes/Locus Selection 
Patients enrolled on study will have a tumor biopsy sequenced for one or more of the specific 
mutations of interest listed in Table 1.  This sequencing may be performed prior to enrollment, to 
determine eligibility, or once the patient has started treatment, to confirm the results from 
previous CLIA sequencing. 
 
A minimum of two biopsy specimens will be shipped directly to the Laboratory of Molecular 
Characterization (MoCha), located at FNLCR.  Biopsy samples (FFPE blocks) collected as part 
of another study or from a procedure performed due to medical necessity may be acceptable if 
the samples were collected within 6 months prior to registration on MPACT and the patient has 
not received any investigational or targeted treatment since that time.  Upon receipt of 
specimens, a visual examination will be performed for acceptance.  If all acceptance criteria are 
met, the specimen will be logged into the laboratory database for processing.  Biopsy cores will 


CTEP #9149 (01-07-2020) 
 
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be processed and embedded in paraffin using routine histological procedures.  A tissue section 
will be stained for histological examination for tumor content.  Samples with a tumor content of 
at least 50% (with minimal necrosis and stromal tissue) will be subjected to nucleic acid 
extraction using Qiagen’s AllPrep FFPET nucleic acid extraction methodology.  Samples with 
tumor content less than 50% will undergo tumor enrichment (described below).  Resultant DNA 
and RNA will be quantified by, but not limited to, NanoDrop spectroscopy.  If sufficient DNA is 
obtained, 20 ng will be used for library preparation using a custom AmpliSeq kit, “MATCHv3” 
(until Amendment P, the assay used MPACTv2.0).   This custom panel was designed and 
developed by MoCha to support this clinical study.  The panel employs AmpliSeq multiplex 
PCR technology to amplify and prepare clinical specimens for sequencing of genetic loci 
(targets) used for therapy selection in this trial.  The panel currently includes 13 DNA damage 
repair actionable genes (Table 1).  The genes were selected using several criteria:  
• 
Genes within the DNA damage repair pathway were selected based on demonstrating a 
minimum frequency (5%) of somatic variants as listed in the COSMIC [catalogue of 
somatic mutation in cancer] database1 version #86. 
• 
Additional genes were added, including the targets of the study drugs.   
• 
The Molecular Tumor Board further assessed the genes selected and agreed upon a final 
reportable variant protocol based on reported frequency as well as preclinical and clinical 
literature associated with a given gene and its variant.  
All sequencing will be performed in a Clinical Laboratory Improvement Amendments (CLIA)-
certified laboratory.  All of the DNA damage repair genes covered by the panel are tumor 
suppressor genes and will be assessed for loss of function mutations (Table 1).  These loss of 
function mutations have been previously reported in the COSMIC database (version 86) or 
ClinVar.  In addition to the hotspot aMOIs, the panel will also report on novel loss of function 
mutations that create a frameshift of premature stop codon in the predicted protein. 
 
The sequencing data for these genes will be shared with the patient (Appendix H) once the 
results are available.  Targeted analysis will not include analyzing for known mutations in 
receptor tyrosine kinases or TP53.   
  
The clinical specimen will be sequenced using the Ion Torrent Personal Genome Machine.  A 
variety of specimen and assay quality checks are built into the assay process and detailed in the 
SOPs.  MoCha has prepared an analytical validation plan with assay performance testing, 
validation, and quality control metrics.  These metrics include DNA yield and quality, minimum 
percentage tumor nuclei per specimen, read depth, and positive and negative controls (see 
summary below) to ensure valid assay performance and result reporting.   
 
 
 
 
1 http://www.sanger.ac.uk/genetics/CGP/cosmic/ 


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Table 1.  Genes and Pathways of Interest (DNA repair genes only after Amendment U) 
 
Gene Name 
Pathways/Function 
Gain or Loss of Function?  
ATM 
DNA repair pathway 
Loss 
NBN 
DNA repair pathway 
Loss 
RAD51 
DNA repair pathway 
Loss 
RAD51B 
DNA repair pathway 
Loss 
RAD51C 
DNA repair pathway 
Loss 
RAD51D 
DNA repair pathway 
Loss 
PALB2 
DNA repair pathway 
Loss 
BRCA1 
DNA repair pathway 
Loss 
BRCA2 
DNA repair pathway 
Loss 
CHEK1 
DNA repair pathway 
Loss 
CHEK2 
DNA repair pathway 
Loss 
FANCA 
DNA repair pathway 
Loss 
MRE11A 
DNA repair pathway 
Loss 
IDH1 
DNA repair pathway 
Loss 
IDH2 
DNA repair pathway 
Loss 
 
 
Quality Metrics 
Threshold 
Tissue Specimen Review 
>50% non-necrotic tumor nuclei present in section 
DNA Recovery 
> 20 ng 
Library Yield 
> 10 pM 
Testing Fragments 
TF-A/D > 80% AQ17, Read Length Histogram >90 bp 
Reads per Sample 
>350,000 
Amplicon Coverage  
> 80% of amplicons coverage >450x 
Positive (CPSC) Control 
Detect and call all plasmid variants 
Negative Control CEPH 
Detect no false-positive aMOIs  
LibNTC Sequence Data 
Total reads < 2% read libraries OR <120 bp mean read length 
 
After a clinical specimen has completed sequencing and passed all quality checks and filters, the 
data will be analyzed.  The report will be reviewed (by investigators indicated with an F on the 
cover page) and treatment assignments made based on the locked down algorithm defined in the 
protocol.    All delinked RNA and DNA will be stored under appropriate conditions until further 
sample studies are indicated.  Delinking of patient identifiers will be performed in a secure 
manner prior to use performing, but not limited to, whole exome sequencing and circulating 
tumor DNA (ctDNA) for research purposes. 
 
Mutations will be reported based on their presence in tumor cells and the percent of cells 
demonstrating the predefined mutation.   
 
An adequate tumor biopsy sample will contain at least 50% tumor with minimal necrosis and 
stromal tissue; samples with less than 50% tumor will be reflexed for tumor enrichment using a 
standardized macrodissection protocol.  In case of samples with insufficient tumor content or 
DNA yield, the patient will be given the option to undergo a repeat tumor biopsy to obtain more 


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tissue.  Patients from whom sufficient tumor DNA material cannot be obtained for targeted 
analysis will be taken off-study.  
2.3 
Study Agents 
Proprietary information about each of the study agents is included in this protocol document as 
an appendix.  Veliparib will be administered with temozolomide.  
2.3.1 Veliparib  
Veliparib is an orally available, small molecule inhibitor of PARP.  Preclinical and clinical 
data show that inhibition of PARP potentiates the effects of DNA-damaging 
chemotherapeutic drugs such as the alkylating agent temozolomide [67].  In this study, 
Veliparib and temozolomide will be administered to patients with defects in DNA repair 
pathways.  Please refer to Appendix I for more information.    
2.3.2 Temozolomide 
Temozolomide is an oral alkylating agent approved by the FDA for the treatment of 
certain cancerous tumors in the brain of adult patients.  Temozolomide is spontaneously 
hydrolyzed at physiologic pH to the active species, 3-methyl-(triazen-1-yl)imidazole-4-
carboxamide (MTIC).  MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide 
(AIC) which is known to be an intermediate in purine and nucleic acid biosynthesis and 
to methylhydrazine, which is believed to be the active alkylating species. 
2.3.3 Trametinib dimethyl sulfoxide (GSK1120212) (This arm was closed to new 
accrual with Amendment U) 
Trametinib DMSO is a reversible, highly selective allosteric inhibitor of MEK1/MEK2 
activation and kinase activity.  The safety, pharmacokinetic (PK), and pharmacodynamic 
(PD) profiles, and activity of trametinib DMSO are currently being evaluated in 13 
ongoing monotherapy and combination therapy clinical trials involving subjects with a 
variety of cancers.  Trametinib DMSO was recently approved for the treatment of patients 
with unresectable or metastatic melanoma with BRAFV600E or BRAFV600K mutations based 
on a statistically significant prolongation of progression free survival over chemotherapy 
(4.8 months vs. 1.5 months) in 322 patients on a randomized active-control trial. 
2.3.4 AZD1775 (This arm was closed to new accrual with Amendment U) 
AZD1775 is a selective, adenosine-triphosphate (ATP) competitive, small molecule 
inhibitor of Wee1 kinase that directly inhibits phosphorylation of CDC2.  In vitro 
experiments have demonstrated that AZD1775 has synergistic antitumor effects when 
administered in combination with various DNA damaging agents that have divergent 
mechanisms of action.  In this study, AZD1775 will be administered with carboplatin.  
Results from preclinical and clinical studies suggest that the combination of AZD1775 
with carboplatin has antitumor efficacy and is well tolerated; refer to Appendix J for more 
information.   
2.3.5 Carboplatin (This arm was closed to new accrual with Amendment U) 
The alkylating agent carboplatin acts by binding DNA to form interstrand DNA cross-


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links that interrupt cell division.  It is approved by the FDA for the treatment of patients 
with ovarian cancer and non-small cell lung cancer, and is also used for the treatment of 
patients with small cell lung cancer, head and neck cancer, endometrial cancer, metastatic 
seminoma, and breast cancer.  Carboplatin is eliminated by renal excretion; clearance is 
related to the glomerular filtration rate (GFR), therefore the drug is dosed based on the 
GFR and the target area under the concentration versus time curve (AUC).  The main side 
effects of carboplatin are myelosuppression, nausea, vomiting, renal toxicity, and 
neurotoxicity.   
2.3.6 Everolimus (This arm was closed to new accrual with Amendment U) 
The mTOR inhibitor everolimus was approved by the FDA for patients with advanced 
renal cell carcinoma (RCC)  based on results from a multicenter, randomized, double-
blind Phase III trial comparing everolimus (10 mg daily) and placebo in 416 patients with 
metastatic RCC whose disease had progressed despite prior treatment with vascular 
endothelial growth factor-targeted therapy (sunitinib, sorafenib, or both sequentially) [68, 
69].  Median progression-free survival was 4.9 months in the everolimus arm and 1.9 
months in the placebo arm; objective response rates were 2% and 0%, respectively.  As 
described in Section 2.1.3, the serine-threonine kinase mTOR is an essential component 
of the multiprotein mTOR complex 1 (mTORC1), along with regulatory-associated 
protein of mTOR (raptor).  Once activated through PI3K activation of AKT, mTORC1 
functions as a key regulator of cell growth by phosphorylating 4E-binding protein 1 (4E-
BP1) and p70S6K (S6K), translation initiation factors required for protein synthesis [70, 
71].  Everolimus binds to the intracellular protein, FKBP-12, which in turn binds mTOR, 
impairing its activity and inhibiting translation of proteins essential for cell cycle 
progression and survival.  The main side effects of everolimus reported in patients with 
RCC are stomatitis, infections, asthenia, fatigue, cough, and diarrhea.  The recommended 
dose of everolimus for the treatment of patients with advanced RCC is 10 mg, to be taken 
once daily; this dose will be administered on this trial.   
2.4 
Study Disease  
Patients with histologically documented solid tumors whose disease has progressed following at 
least one line of standard therapy and/or there are no standard therapies available that are known 
to prolong survival will be enrolled on study and undergo mandatory tumor biopsy.  This tumor 
biopsy will be sequenced for presence of specific mutations of interest in a CLIA-certified 
laboratory.  The following specific mutations in pathways will be assessed: 
1. Mutations in DNA repair pathways  
2. Mutations in the PI3K pathway (Not currently accruing) 
3. Mutations in the RAS/RAF/MEK pathway (Not currently accruing) 
2.5 
Genetic Sequencing Research Ethics and NIH Genomic Data Sharing Policy 
This trial will collect identifiable genetic data from all patients enrolled to determine whether or 
not their tumors have a mutation(s) in one or more of the pathway of interest.  We will screen for 
pre-defined variations in genes in a CLIA-certified laboratory for assignment of patient treatment 
on study.  As treatment options and data analyses will be based on this information, de-
identifying the samples is not feasible.  Designing the study therefore poses challenging 


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questions about informed consent, the privacy of the patient and the patient’s family, the 
researchers’ obligation to disclose genetic information to the patient, and the use and storage of 
research data, as well as of the selection and interpretation of gene variants [72-74].  In the vast 
majority of cases we do not know the medical significance of genetic variants [75, 76].  These 
challenges will continue to be evaluated to maintain the rigor and integrity of the study and the 
wellbeing of our patients.  A Certificate of Confidentiality has been obtained from the NIH to 
help protect the privacy of all study participants.   
 
The protocol includes separate informed consent forms for the screening biopsy and treatment 
parts of the study; each patient will know whether or not their tumor has a variation in a gene of 
interest.  Patients with actionable mutations that may establish eligibility for other clinical trials 
or targeted agents, including MATCH (Targeted Therapy Directed by Genetic Testing in 
Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma, 
NCT02465060), which uses the same custom AmpliSeq screening panel as MPACT, will be 
informed that they may have other treatment options.  Information on tumor gene variants that 
form the basis of treatment assignment will be stored in the patient’s medical records.  
 
Whole exome sequencing (performed for research purposes) of tumor and blood can detect 
nonambiguous germline variants, which may raise health and privacy implications for the patient 
and his or her family.  Whole exome sequencing will not be validated for clinical use and no 
clinical decisions can be made based on its results.  In addition, given the uncertain clinical 
significance of some of these variants and the ethical implications, we will perform such research 
analysis on de-identified samples only.  Once each patient has completed treatment on study and 
is taken off study, patient identifiers will be de-linked and we will perform whole exome 
sequencing on the de-identified samples.  No genetic data will be shared with the patient other 
than the data from the targeted sequencing panel.  All other analysis will be performed on de-
identified samples.  The process for de-identifying the samples is described in Section 9.4.1.  
 
This study affords a unique opportunity to collect information about the prevalence of mutations 
in genes associated with cancer, as well as how patients’ tumors respond to targeted therapy in 
the refractory tumor setting; DNA variants and changes in RNA expression from tumors 
collected when patients progress on study drugs is anticipated to illuminate resistance 
mechanisms that will inform subsequent studies and improve patient outcomes.   
2.5.1 NIH Genomic Data Sharing Policy 
The NIH Genomic Data Sharing (GDS) Policy ensures broad and responsible sharing of 
genomic research data from all NIH-funded research2.  Providing that patient consent has 
been obtained, whole-exome sequencing data generated for research purposes from 
samples unlinked from patient identifiers will be submitted to the Database of Genotypes 
and Phenotypes (dbGaP) for controlled-access use within a time frame consistent with 
study CRADAs and data publication.  The identities of research participants will not be 
disclosed to dbGaP or to secondary users of the data.  Genomic data generated from 
 
2 https://gds.nih.gov/index.html 


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patients before this trial became a multicenter study will not be subject to GDS policy as 
adequate consent was not obtained from these individuals.    
2.6 
Rationale for the Study 
The original proposal was designed to address, in a randomized trial, whether patients with 
underlying mutations in a given pathway in their tumor are more likely to derive clinical benefit 
if treated with agents that target that pathway than if treated with agents that do not, as well as to 
address this question, in a non-randomized fashion, for each separate cohort defined by mutation 
status.  Randomization was taken out of the study design with Amendment U.  
 
Patients will receive one of the agents/regimens defined to work on one of their identified 
mutations.  In the absence of a randomized control arm, the performance of each individual 
mutational status cohort will be compared to that of historical controls.  If no objective responses 
are observed among the initial 12 patients of a 30-patient Arm A agent cohort, the cohort will be 
terminated early.  An optional tumor biopsy will be performed at the time of disease progression 
to assess for new acquired mutations; this biopsy may, if feasible, be collected on day 1 (± 2 
days) of the cycle following any restaging at which a 10-19% increase in tumor volume is 
observed (per RECIST criteria) if the patient has been on study for at least 4 cycles.   
 
The treatment regimens and number of treatment regimens may change over time as long as the 
same set of regimens is offered to a given set of patients.  The doses that will be administered are 
Phase II-recommended doses.   
2.6.1 Veliparib plus Temozolomide arm 
As of Amendment U, this is the only arm open to accrual.  Seven patients had been 
assigned to this arm prior to the study being placed on hold for futility analysis (targeted 
plus control arms).   
 
The combination of veliparib with temozolomide in patients with DNA damage 
mutations is supported by preclinical data in patient-derived xenograft (PDX) mouse 
models.  Overall, 32 PDX models have been treated with this combination; 8 have 
demonstrated delayed tumor growth (unpublished data).  Complete or partial response, as 
well as an increase in relative median event-free survival, has been observed with 
veliparib plus temozolomide in tumors with a range of DNA damage mutations.  Based 
on these data, we have revised the list of actionable mutations of interest for the veliparib 
plus temozolomide arm.  We expect that the new eligibility criteria, including variants in 
DNA repair genes BRCA1, BRCA2, CHK2, and ATM, will allow more patients with 
potential to benefit from this combination to enroll on this treatment arm. 
 
3. PATIENT SELECTION (TUMOR SEQUENCING/DRUG TREATMENT) 
Patients meeting the criteria defined below will be enrolled on study, then undergo a tumor 
biopsy.  The tumor will be sequenced for specific mutations of interest defined in Section 
2.2; only if such mutations are detected will the patient continue on study to the 
randomization/treatment part of this protocol.  The eligibility criteria for both the tumor 


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sequencing and treatment parts of this protocol are similar, such that in general, a patient 
eligible for tumor sequencing will be eligible for the subsequent treatment part of the 
protocol if his/her tumor contains a mutation of interest.  Additional agent-specific 
treatment exclusions are listed in Section 3.4; agent-specific exclusions are to ensure 
patient safety.   
3.1 
Eligibility Criteria: Tumor Biopsy Sequencing 
3.1.1 Patients with histologically documented solid tumors whose disease has 
progressed following at least one line of standard therapy and/or no standard of 
treatment exists that has been shown to prolong survival. 
3.1.2 Patient must have tumor amenable to percutaneous or excisional skin biopsy and 
be willing to undergo a tumor biopsy, or  
Biopsy samples (FFPE blocks) collected on another study or from a procedure 
performed due to medical necessity may be acceptable if collected within 6 
months prior to registration on MPACT and providing that the patient has not 
received any investigational or targeted treatment since that time, or 
A report from an MATCH study designated CLIA laboratory (see https://ecog-
acrin.org/nci-match-eay131-designated-labs) that a patient has a variant in the 
genes of interest.   
3.1.3 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan. 
3.1.4 Patients with bone metastases or hypercalcemia on intravenous bisphosphonate 
treatment, denosumab, or similar agents are eligible to participate and may 
continue this treatment.  Patients with prostate cancer may continue LHRH 
agonists or antagonists.  
3.1.5 Age ≥ 18 years.  Children are excluded from this study, but may be eligible for 
future pediatric trials. 
3.1.6 Karnofsky performance status ≥ 70%, see Appendix A. 
3.1.7 Life expectancy > 3 months. 
3.1.8 Patients must have adequate organ and marrow function as defined below: 
− absolute neutrophil count  
≥1,000/L (mcL) 
− platelets  
 
 
 
 
 
≥100,000L (mcL) 
− total bilirubin 
 
 
 
 
< 1.5 X institutional upper limit of normal 
− AST(SGOT)/ALT(SGPT)  
≤ 3 X institutional upper limit of normal 
− creatinine 
 
 
 
 
 
< 1.5 X institutional upper limit of normal 
OR 


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− creatinine clearance  
 
 
≥ 60 mL/min for patients with creatinine 
levels ≥1.5 X institutional upper limit of 
normal. 
3.1.9 The effects of these targeted agents on the developing human fetus are unknown 
or anticipated to cause fetal harm based on their mechanism of action.  For this 
reason, women of childbearing potential and men must agree to use highly 
effective contraception prior to study entry, for the duration of study participation, 
and for 3 months after completion of study.  Because there may be a risk for 
adverse events in nursing infants secondary to treatment of the mother with these 
agents, breastfeeding should be discontinued while the patient is on this trial and 
for 30 days following last dose of study drug.   
3.1.10 Patients with history of CNS metastases who have received treatment and who 
either have not had seizures or have been on stable doses of anti-seizure medicine 
and had no seizures for 4 weeks will be eligible.  Enzyme-inducing 
anticonvulsants are contraindicated.  
3.1.11 Ability to understand and the willingness to sign a written informed consent 
document (subjects with impaired decision-making capacity are not eligible). 
3.2 
Exclusion Criteria: Tumor Biopsy Sequencing  
3.2.1 Women who are pregnant or breastfeeding. 
3.2.2 Patients who are receiving any other investigational agents.  Patients on other 
trials will be eligible as long as they are no longer receiving study treatment. 
3.2.3 Patients with uncontrolled intercurrent illness including, but not limited to 
psychiatric illness/social situations that would limit compliance with study 
requirements, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, myocardial infarction in the past 6 months, invasive fungal 
infections, or active (acute or chronic) or uncontrolled severe infection, liver 
disease such as cirrhosis, decompensated liver disease, and active and chronic 
hepatitis (i.e., quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-
RNA) are not eligible to participate.  Testing for hepatitis B or other infections for 
eligibility will be performed only if clinically indicated.  
3.2.4 Patients with gastrointestinal conditions that might predispose for drug 
intolerability or poor drug absorption (e.g., inability to take oral medication or a 
requirement for IV alimentation, prior surgical procedures affecting absorption, 
malabsorption syndrome, and active peptic ulcer disease) are excluded.  Subjects 
with Crohn’s disease or a partial or complete small bowel obstruction are also 
excluded, as are any patients who cannot swallow tablets or capsules whole.  
Tablets or capsules must not be crushed or chewed; nasogastric or G-tube 
administration is not allowed.   


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3.2.5 HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for PK interactions.   
3.2.6 Patients who require use of coumarin-derivative anticoagulants such as warfarin 
are excluded.  Low molecular weight heparin is permitted for prophylactic or 
therapeutic use. 
3.2.7 Patients who have previously been treated with the combination of temozolomide 
plus a PARP inhibitor should not be considered eligible for a biopsy given that 
these patients would not be eligible for the active Veliparib plus temozolomide 
arm.  
Patients who meet the screening criteria and have a tumor biopsy determined to have one 
of the specific mutations of interest (defined in Section 2.2) will be eligible to participate 
in the treatment part of this protocol.  If the patient does not meet the criteria in Section 
3.3 or the patient has any of the conditions listed in Section 3.4, the patient is not 
eligible for this trial.   
3.3 
Eligibility Criteria: Targeted Treatment 
3.3.1 Patient must have predefined targeted mutation in tumor biopsy as defined in 
Section 2.2.  
3.3.2 Patients with histologically documented solid tumors whose disease has 
progressed following at least one line of standard therapy or for which no 
standard therapy exists that has been shown to prolong survival. 
3.3.3 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan. 
3.3.4 Any prior therapy, radiotherapy, or major surgery must have been completed 
≥ 3 weeks (> 6 weeks for nitrosoureas or mitomycin C) or 5 half-lives of the agent 
(whichever is shorter) prior to enrollment on protocol, and the participant must 
have recovered to eligibility levels from prior toxicity.  RFA of localized lesions 
should have been performed ≥ 2 weeks prior to starting treatment.  
3.3.5 Patients with bone metastases or hypercalcemia on intravenous bisphosphonate 
treatment, denosumab, or similar agents are eligible to participate and may 
continue this treatment.  Patients with prostate cancer may continue LHRH 
agonists or antagonists. 
3.3.6 Age ≥ 18 years.  Because no dosing or adverse event data are currently available 
on the use of study investigational agents in patients < 18 years of age, children 
are excluded from this study, but may be eligible for future pediatric trials. 
3.3.7 Karnofsky performance status ≥ 70%, see Appendix A. 
3.3.8 Adequate organ and marrow function as defined in Section 3.1.8 


CTEP #9149 (01-07-2020) 
 
24 
 
3.3.9 Life expectancy > 3 months. 
3.3.10 The effects of these targeted agents on the developing human fetus are unknown 
or anticipated to cause fetal harm based on their mechanism of action.  For this 
reason, women of childbearing potential and men must agree to use highly 
effective contraception (see list below) prior to study entry, for the duration of 
study participation, and for 3 months after completion of study.  
Total abstinence: When this is in line with the preferred and usual lifestyle of 
the subject.  (Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception). 
Sterilization: have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  
In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment 
Male partner sterilization (with the appropriate post-vasectomy documentation 
of the absence of sperm in the ejaculate).  (For female subjects on the study, 
the vasectomised male partner should be the sole partner for that subject). 
Use of a combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected, implanted or other hormonal methods of 
contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal 
suppository 
In case of use of oral contraception, women should have been stable on the oral 
agent before taking study treatment. 
 
Sexually active males must use a condom during intercourse 
3.3.11 Because there may be a risk for adverse events in nursing infants secondary to 
treatment of the mother with these agents, breastfeeding should be discontinued 
while the patient is on this trial and for 30 days following last dose of study drug.   
3.3.12 Patients with ovarian cancer or metastatic breast cancer and BRCA mutations 
must have received approved PARP inhibitor therapy; these patients are eligible 
for the Veliparib plus temozolomide arm unless the PARP inhibitor was 
administered with temozolomide.   
3.3.13 Patients with a history of seizures are not eligible to receive Veliparib,  
3.3.14 Patients who have had prior treatment with any PARP inhibitor in combination 
with temozolomide are not eligible to receive treatment with Veliparib on this 
study.  Patients who have received prior temozolomide or PARP inhibitor with or 
without other chemotherapy/targeted agent should not be excluded.   
3.3.15   Patients must have ≥10.0 g/dL Hb and no blood transfusion in the past 28 days to 


CTEP #9149 (01-07-2020) 
 
25 
 
receive Veliparib. 
3.4 
Exclusion Criteria: Targeted Treatment 
3.4.1 Women who are pregnant or breastfeeding. 
3.4.2 Patients who are receiving any other investigational agents.  Patients on other trials 
will be eligible as long as they are no longer receiving study treatment. 
3.4.3 Patients with active brain metastases or carcinomatous meningitis are excluded 
from this clinical trial.  Patients who have a history of seizures are not eligible to 
receive Veliparib 
3.4.4 Patients with uncontrolled intercurrent illness including, but not limited to  
psychiatric illness/social situations that would limit compliance with study 
requirements, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, myocardial infarction in the past 6 months, invasive fungal 
infections, or active (acute or chronic) or uncontrolled severe infection, liver 
disease such as cirrhosis, decompensated liver disease, and active and chronic 
hepatitis (i.e., quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-
RNA) are not eligible to participate.  Testing for hepatitis B or other infections for 
eligibility will be performed only if clinically indicated. 
3.4.5 Patients with gastrointestinal conditions that might predispose for drug 
intolerability or poor drug absorption (e.g., inability to take oral medication or a 
requirement for IV alimentation, prior surgical procedures affecting absorption, 
malabsorption syndrome, and active peptic ulcer disease) are excluded.  Subjects 
with Crohn’s disease or a partial or complete small bowel obstruction are also 
excluded, as are any patients who cannot swallow tablets or capsules whole.  
Tablets or capsules must not be crushed or chewed; nasogastric or G-tube 
administration is not allowed.   
3.4.6 HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for PK interactions.   
3.4.7 Eligibility of subjects receiving any medications or substances known to affect or 
with the potential to affect the activity or pharmacokinetics (i.e., CYP450, PgP) of 
any of the study drugs will be determined following review of their cases by the 
PI.  Patients on strong and moderate cytochrome P450 system inducers or 
inhibitors (Appendix B) are ineligible.  Every effort would be made to switch 
patients off medications that are known substrates of CYP450; if it is medically 
important for the patient to remain on such medications, these patients can still be 
eligible to participate based on PI discretion.  Refer to Section 8 for more detailed 
information.   
3.4.8 Patients who require use of coumarin-derivative anticoagulants such as warfarin 
are excluded.  Low molecular weight heparin is permitted for prophylactic or 
therapeutic use.   


CTEP #9149 (01-07-2020) 
 
26 
 
3.4.9  Patients who have a history of another primary malignancy, with the exceptions 
of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast 
from which the patient has been disease free for > 3 years. 
3.4.10 Patients with treatment-related AML (t-AML)/MDS, or with features suggestive 
of AML/MDS, or who have had prior allogeneic bone marrow transplant or 
double umbilical cord blood transplantation, should not receive Veliparib due to 
reports of MDS and leukemia secondary to oncology therapy on CTEP-sponsored 
studies utilizing Veliparib.  
3.5 
Evaluation for Enrollment for Tumor Biopsy Screening  
3.5.1 Histologic confirmation of solid malignancy.   
3.5.2 History and physical examination: Complete history and physical examination 
(including height, weight, vital signs, performance score, EKG) will be conducted 
within 8 days prior to enrollment.   
3.5.3 Imaging Studies (Baseline): Imaging studies to determine biopsiable disease.  
3.5.4 Laboratory Evaluation: Baseline laboratory data are to be obtained within 8 days 
prior to enrollment (fasting blood preferred): 
• Hematological Profile: CBC with differential  
• Biochemical Profile: albumin, alkaline phosphatase, total bilirubin, BUN, 
calcium, creatinine, glucose, phosphorus, total protein, SGOT[AST], 
SGPT[ALT], magnesium, potassium, and sodium 
• Serum or urine pregnancy test for female participants of childbearing potential 
3.6 
Evaluation for Treatment on Study 
3.6.1 History and physical examination: complete history and physical examination 
(including weight, vital signs, performance score, EKG) will be conducted within 
8 days prior to enrollment.  If the patient’s condition deteriorates prior to initiation 
of treatment, evaluations should be repeated within 48 hours prior to initiating 
treatment.  
3.6.2 Imaging Studies (Baseline): Every participant should have an evaluation of 
known sites of disease as part of the baseline evaluation.  All patients will be 
required to undergo a CT scan of the chest/abdomen/pelvis to evaluate sites of 
disease within 28 days prior to starting study drugs.  MRI or CT scan with 
contrast of the brain, MRI liver, MRI for other disease sites, ECHO/MUGA or 
bone scan may be done as clinically indicated before starting study drugs (ECHO/ 
MUGA required for patients receiving trametinib or everolimus). 
3.6.3 Laboratory Evaluation: Baseline laboratory data are to be obtained within 8 days 
prior to enrollment and within 3 days prior to starting study drugs.  If the patient’s 
condition deteriorates prior to initiation of treatment, laboratory evaluations 
should be repeated within 48 hours prior to initiating treatment: 


CTEP #9149 (01-07-2020) 
 
27 
 
a. Hematological Profile: CBC with differential.  
b. Biochemical Profile: albumin, alkaline phosphatase, total bilirubin, BUN, 
calcium, creatinine, glucose, phosphorus, total protein, SGOT[AST], 
SGPT[ALT], magnesium, potassium, and sodium. 
c. Serum or urine pregnancy test for female participants of childbearing potential. 
 
4. REGISTRATION PROCEDURES 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require 
all individuals contributing to NCI-sponsored trials to register and to renew their registration 
annually.  To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).   
In addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator 
(NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE 
or acting as a primary site contact) must complete their annual registration using CTEP’s web-
based Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR AP A 
FDA Form 1572 
✔ 
✔ 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
✔ 
✔ 
✔ 
 
HSP/GCP training 
✔ 
✔ 
✔ 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
4.2 
Site Registration 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 


CTEP #9149 (01-07-2020) 
 
28 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following:  
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
In addition, the site-protocol PI must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office.  For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  For the 
SSW approval to be processed, the Signatory Institution must inform the CTSU which CIRB-
approved institutions aligned with the Signatory Institution are participating in the study. 
 
Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 9149 protocol page located on the CTSU 
Web site.  Permission to view and download this protocol is restricted and is based on person and 
site roster data housed in the CTSU RSS.  To participate, Investigators and Associates must be 
associated with the Corresponding or Participating protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, and then select LAO-NCI, 
and protocol #9149. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
Requirements for 9149 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) 
▪ Local informed consent document 


CTEP #9149 (01-07-2020) 
 
29 
 
▪ Study chair approval 
 
Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab → 
Regulatory Submission  
When applicable, original documents should be mailed to:  
CTSU Regulatory Office  
1818 Market Street, Suite 3000, Philadelphia, PA 19103  
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 to receive further instruction and support.  
 
Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU website.  
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password  
• Click on the Regulatory tab at the top of your screen  
• Click on the Site Registration tab  
• Enter your 5-character CTEP Institution Code and click on Go  
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network.  It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks.  
4.2.1 OPEN / IWRS 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
As this trial has a slot reservation requirement, OPEN will connect to IWRS at 
enrollment initiation to check slot availability.  Registration staff should ensure that a slot 
is available and secured for the patient before completing an enrollment.  Slots can be 
reserved for a maximum of 14 calendar days.  
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  


CTEP #9149 (01-07-2020) 
 
30 
 
 
 
OPEN/IWRS User Requirements 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar.  Registrars must 
hold a minimum of an AP registration type.  
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
OPEN/IWRS Questions? 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website: website 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11 This 
link to the Theradex website is also on the CTSU website OPEN tab.  For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
4.3 
General Guidelines 
Following registration, patients should be assigned to protocol treatment as specified in Section 
5.1.  Issues that would cause treatment delays should be discussed with the Principal Investigator.  
If a patient does not receive protocol therapy following registration, the patient’s registration on 
the study may be canceled.  The Study Coordinator should be notified of cancellations as soon as 
possible.  Please make every effort not to schedule biopsy collections on a Friday as FNLCR 
cannot accept courier deliveries at weekends. 
4.4 
Randomization Procedures (N/A) 
 
5. TREATMENT PLAN 
5.1 
Study Design 
After signing the consent form and enrolling on the study, patients will undergo mandatory 
tumor biopsy as described in Section 9 unless a CLIA-certified tumor mutation report from an 


CTEP #9149 (01-07-2020) 
 
31 
 
MATCH study designated lab (see https://ecog-acrin.org/nci-match-eay131-designated-labs) 
indicating a study aMOI is provided.  Reports from other academic, clinical, or commercial 
testing organizations will not be accepted due to the level of evidence needed for this research 
protocol.  Genetic sequencing at the NCI will be performed in the CLIA-certified laboratory of 
Dr. Mickey Williams, Director, Molecular Characterization and Clinical Assay Development 
Laboratory (MoCha), to assess for the presence of specific, pre-defined mutations of interest.     
 
The laboratory will return notification of whether a mutation of interest has been detected in 
approximately 2 weeks, including details about the specific mutation/pathway for assignment to 
the treatment arm based on predefined criteria.  Patients in whom mutations of interest are not 
detected will be taken off study.  Patients considered eligible for the study due to results from a 
MATCH-designated lab will have a biopsy collected during cycle 1 for confirmatory testing with 
the MPACT Oncominev3 assay; patients who do not have their actionable mutation confirmed 
can choose to continue treatment but will not count towards evaluable patients and will be 
replaced for futility analysis.    
 
All treatment will be open-label in this trial.  Drugs will be administered at the recommended 
Phase II doses and schedules.  A new cycle may begin 1 day earlier or 1 day later than it would 
otherwise be scheduled to allow for flexibility for days the clinic is closed and other unexpected 
events.  CT scans will be performed at baseline, and repeat imaging scans will be performed 
every 2 cycles (8 weeks for 28-day schedules, 6 weeks for 21-day schedules).  Once a patient has 
been on a treatment for more than 1 year, the CT scans will be performed every 3 cycles for 28-
day cycles or every 4 cycles for 21-day cycles.  
 
History and physical exam, labs (CBC with differential; serum chemistries, including fasting 
glucose) will be performed at the start of each cycle (within 3 days prior to start of new cycles).  
Additional evaluations will be conducted as clinically indicated at the investigator’s discretion, 
or more frequently for patients on certain treatment arms as specified in Section 10.   
 
Lipid monitoring (triglycerides and cholesterol) will be performed at restaging (every 2 cycles or 
as defined above) and urinary protein the start of each cycle for patients on everolimus only.  
 
Patients will be asked to maintain a Study Medication Diary (Appendix D) and record each dose 
of medication.  Patients will be given instructions for completing the medication diary and will 
be asked to return it to the clinic staff at the end of each cycle.  All patients will be carefully 
monitored for side effects while on study.  Appropriate dose modifications are described in 
Section 6. 
5.2 
Targeted Therapy Arms 
Treatment assignment is made by GeneMed, an informatics system that performs treatment 
assignments based on the locked down algorithm defined in the protocol.  The assignment will 
be sent to the treating physician once it is verified within 24-48 hours.  The treating physician 
and the patient will not be blinded to the sequencing data.   
 


CTEP #9149 (01-07-2020) 
 
32 
 
Patients with tumor mutations of interest will receive an agent prospectively identified to work 
on that mutation/pathway (see below).  As long as the same set of protocols are offered to a 
given set of patients, the number and actual treatments regimens can vary over time. 
 
At the time of Amendment Y, the last patient randomized to the Trametinib DMSO cohort under 
the original study design remains on treatment with the option that she and/or her physician may 
now be informed prior to, rather than at, disease progression about her mutational status and arm 
assignment.  The study team would also be informed.  The patient, in discussion with the treating 
physician, may still crossover to a study treatment prospectively identified to work on the 
identified mutation/pathway per the original study design (see list below).  The patient may not 
switch to another treatment and then back to Trametinib DMSO. 
 
The treatment regimens are as follows: 
• Veliparib plus temozolomide for defects in DNA repair pathways 
• AZD1775 (Wee1 inhibitor) plus carboplatin for defects in DNA repair pathways (no 
longer an active study drug as of March 2018) 
• Everolimus (mTOR inhibitor) for mutations in the PI3K pathway (no longer an active 
study drug as of March 2018) 
• Trametinib DMSO (MEK inhibitor) for mutations in the RAS/RAF/MEK pathway (no 
longer an active study drug as of March 2018) 
 
Treatment exceptions are also listed in Section 3.3.  The following patients will not receive 
certain treatments on this protocol: 
1) Patients with ovarian cancer and BRCA mutations must have received specific PARP 
inhibitor therapy.   
 
2) Patients with treatment-related AML (t-AML)/MDS, or with features suggestive of 
AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord 
blood transplantation, should not receive Veliparib due to reports of MDS and leukemia 
secondary to oncology therapy on CTEP-sponsored studies utilizing Veliparib.  
 
Information on whether a mutation(s) of interest was detected for a given patient as well as what 
drugs are allowed for assignment of a treatment regimen will be provided to the study team; the 
Biopsy Sequencing Results and Analysis Form (Appendix F) will be provided to the clinician.  
 
Arm A:  Targeted treatment based on the detected genetic mutation will be assigned.  
Mutations will be reported based on their presence in tumor cells and the percent of cells 
demonstrating the pre-defined mutation (as allele frequency).   
 
At the time of disease progression for all targeted therapy patients, an optional tumor biopsy may 
be collected to assess for new acquired mutations; this biopsy may instead be collected on day 1 
(± 2 days) of the cycle following any restaging at which a 10-19% increase in tumor volume is 
observed (per RECIST criteria) if the patient has been on study for at least 4 cycles. 
 
No more than 3 tumor biopsy procedures will be performed: one mandatory at baseline, one 


CTEP #9149 (01-07-2020) 
 
33 
 
optional repeat biopsy if sufficient tumor DNA cannot be isolated at baseline, and one optional 
biopsy at or near time of disease progression to assess for new acquired mutations.  
5.3 
Agent Administration 
5.3.1 Veliparib plus Temozolomide 
The Veliparib dose of 40 mg BID on days 1-7 with temozolomide administered 
150 mg/m2 po QD days 1-5 in 28-day cycles was selected based on clinical results 
presented at ASCO  [77] [78].  The dose of temozolomide is based on BSA then rounded 
off to the nearest 5 mg. Patients who receive temozolomide will have an evaluation of 
their LFTs at the time of coming off-treatment.  
5.3.2 Everolimus 
Everolimus will be administered once a day at a dose of 10 mg each day in 28-day cycles.  
Tablets should not be crushed or chewed and should be swallowed whole with a glass of 
water.  If patients miss a dose of everolimus, they may still take it up to 6 hours after the 
time they would normally take it.  If more than 6 hours have elapsed, they should be 
instructed to skip the dose for that day.  The next day, they should take everolimus at the 
usual time; patients should not take 2 doses to make up for the one that they missed.  If 
vomiting occurs, no attempt should be made to replace the vomited dose.  Caregivers 
should be advised to wash their hands thoroughly after touching the tablets.  Patients on 
everolimus should also avoid close contact with others who have received live, attenuated 
vaccines (e.g., intranasal influenza).  
5.3.3 Trametinib DMSO 
Trametinib DMSO will be administered at 2 mg each day in 28-day cycles.  Drug must 
be taken while fasting (water is permitted) 1 hour before or 2 hours after a meal. 
5.3.4 AZD1775 plus carboplatin 
AZD1775 will be administered orally at a dose of 225 mg BID for 5 doses starting on day 
1 of every cycle.  Drug must be taken at least two hours before or two hours after a meal. 
Carboplatin (AUC 5) will be administered IV on day 1 of every cycle over 30-60 minutes 
concomitantly with AZD1775; the cycle length is 21 days.  All patients must receive a 5-
HT3 antagonist, ondansetron (Zofran) 8 mg PO BID or granisetron (Kytril) 1 mg PO BID 
prior to each dose of AZD1775.  Additional doses of 5-HT3 antagonist may be used if 
needed.   In addition, dexamethasone 4 mg PO will be given with each AZD1775 dose as 
a minimum on the first day of dosing AZD1775 of every 3-5 days dosing period, unless 
contraindicated or not well-tolerated.  Dexamethasone may be continued on further days 
of dosing, potentially at a lower dose.  Dexamethasone or the 5-HT3 antagonist may be 
given by IV as needed.  Promethazine (Phenergan), prochlorperazine (Compazine), and 
benzodiazepine may still be used as additional adjunctive treatments during AZD1775 
therapy.  Please note: aprepitant (Emend) and fosaprepitant are not permitted due to 
known DDIs. 


CTEP #9149 (01-07-2020) 
 
34 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines:  
All patients will be provided with the best available supportive care.  All concurrent medications 
should be documented prior to initiation of treatment and be periodically reviewed with the 
patient.  Particular attention must be paid to medications which may prolong the QTc interval 
(Appendix C) and agents that interact with CYP450 isoenzymes or are PgP inhibitors (Appendix 
B).  
 
Nausea/Vomiting: Nausea and vomiting will be considered refractory if they do not resolve to ≤ 
Grade 1 with treatment with a combination of at least 2 antiemetics.  Concomitant treatment with 
aprepitant is not allowed for patients receiving AZD1775 because of potential drug-drug 
interaction. 
 
Diarrhea: If diarrhea develops and does not have an identifiable cause other than study drug 
administration, loperamide 4 mg po will be given after the first unformed stool with 2 mg po 
every 2 hours as long as unformed stools continue (4 mg every 4 hours while asleep).  This 
regimen can be repeated for each diarrheal episode.  Diarrhea will be considered refractory if it 
does not resolve within 24 hours to ≤ Grade 1 with the above regimen (total of 16 mg of 
loperamide a day).  If the patient develops blood or mucus in the stool, dehydration, or 
hemodynamic instability, or fever along with the diarrhea, loperamide will be discontinued and 
the patient will be treated with IV fluids and antibiotics as medically indicated.   
 
Seizures: Seizures were seen in some animal toxicology studies with Veliparib, although at 
doses much higher than those anticipated for this study.  Seizures in animals were successfully 
treated with lorazepam.  Therefore, lorazepam should be considered as a possible first choice for 
controlling seizures, should they occur on this study.  All patients experiencing a seizure on 
study need to be evaluated (e.g., imaging of the brain) to determine the cause. 
 
Anemia: Symptomatic anemia should be treated with red blood cell transfusion and is 
recommended if the hemoglobin falls below 8 mg/dL.  Use of erythropoietin is allowed per 
accepted guidelines.  
 
Thrombocytopenia: Thrombocytopenia will be treated conservatively.  In the absence of 
bleeding, fever, or a necessary invasive procedure, platelet transfusions should be given for a 
platelet count below 10,000/µL (mcL).  If the patient is febrile, platelet transfusions should be 
given for a platelet count below 20,000/µL (mcL).  If an invasive procedure is planned or the 
patient develops bleeding, platelet transfusions should be administered in accordance with 
standard of practice, usually maintaining a platelet count above 50,000/µL (mcL). 
 
Neutropenia: Febrile neutropenia is a life-threatening complication requiring hospitalization and 
urgent broad-spectrum antibiotics, as well as an aggressive search for the source and microbial 
cause of the episode.  If clinically indicated, filgastrim may be initiated for Grade 4 neutropenia 
at the study investigator’s discretion.  Study medications will not be reinitiated until at least 
24 hours after filgastrim administration. 
 


CTEP #9149 (01-07-2020) 
 
35 
 
Reflux/Gastritis: Antacids and other anti-ulcer medications such as histamine H2-receptor 
antagonists may be used if clinically indicated.  To avoid significantly altering gastric pH, when 
needed, these medications should be used 4 hours after study drug administration.   
 
Skin Rash: Appropriate clinical management of skin rash may be utilized as clinically indicated.  
Patients will be allowed to use topical emollients, topical steroids, antihistamine agents, and 
topical or oral antibiotics.  A suggested step-wise approach follows: 
• Grade 1 rash: Start with topical steroids (e.g., hydrocortisone, triamcinolone acetonide), 
topical antibiotics such as clindamycin gel, or no treatment if the patient is asymptomatic.  
Use of topical steroid cream with higher potency or oral antibiotic may be considered early 
in patients with moderate rash on the face. 
• Grade 2 rash: Topical steroid cream, consider addition of an oral antibiotic (e.g., 
minocycline 100 mg PO BID) or a similar agent. 
• Grade 3 rash that does not respond to our measures: Dose interruption and/or dose 
reduction, in addition to supportive care as above.   
• Pruritus of any grade may be treated with an antihistamine, such as diphenhydramine or 
hydroxyzine hydrochloride. 
• Xerosis can be treated with classical emollients. 
 
Hyperglycemia: Blood glucose home monitoring will be initiated in patients with persistently 
elevated fasting glucose (> 160 mg/dL, CTCAE Grade ≥ 2).  Appropriate clinical management 
including oral anti-hyperglycemic medication or insulin, and supportive care (e.g., electrolyte 
management and hydration) will be provided as clinically indicated.  
5.5 
Definition of Off-Study Parameters 
In the absence of treatment delays due to adverse events, treatment may continue per protocol 
until one of the following criteria applies: 
• Disease progression  
• Intercurrent illness that prevents further administration of treatment, 
• Patient requires more than 2 dose reductions (see Section 6.0)  
At which point, the patient is taken off that particular treatment.   
 
Duration of Therapy on MPACT Study:  
• Pre-defined mutation is not identified  
• Disease progression  
• All treatment regimens on study specific for the patient’s mutation(s) of interest have 
been exhausted  
• Intercurrent illness that prevents further administration of treatment, 
• Patient receives any other investigational agent or anticancer therapy  
• Patient decides to withdraw from the study. 
At which point, the patient is taken off the MPACT study.   


CTEP #9149 (01-07-2020) 
 
36 
 
5.6 
Duration of Follow-Up 
Patients in whom a pre-defined mutation is not identified will be taken off study, and no study-
specific follow up will be performed.  Patients who receive study drug will be followed for 30 
days after the last dose is administered or until one of the following occurs: patient enrolls on 
another protocol, patient receives standard of care, or death, whichever comes first.  The follow-
up will consist of a phone call between Days 27-30 after the last dose to evaluate adverse events 
that were ongoing and any new events that might be deemed related to the therapy.  
Unacceptable toxicities (i.e., AEs related to the intervention) that have not resolved by Day 30 
post-treatment will be followed via biweekly phone calls until stabilization or resolution. 
5.7 
Criteria for Removal From Study 
Patients will be removed from the MPACT study for one of the following reasons:  
• mutation of interest not detected on pre-treatment biopsy  
• inability to obtain pre-treatment biopsy on study 
• completion of 30-day follow-up period 
• toxicities are unresolved but stabilized 
• patient enrolls on another protocol 
• patient receives standard of care   
• pregnancy 
• death 
 
The reason for study removal and the date the patient was removed must be documented in the 
medical record. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
6.1 
Dose Modifications 
Non-hematologic toxicities should have resolved to ≤ Grade 1 (except electrolyte abnormalities, 
which should resolve to ≤ Grade 2) and hematologic toxicities to ≤ Grade 2 (except 
lymphopenia) prior to starting the next cycle.  Doses of study drugs will not be held or reduced 
for any grade of lymphopenia.  The treatment day count will continue through days when doses 
are held.  A new cycle will not start until the patient starts dosing on the next cycle.  Treatment 
may be delayed for toxicity a maximum of 2 weeks beyond the actual cycle length; in case 
toxicities do not resolve as defined above, the patient will not receive further treatment with that 
regimen and will receive no further therapy on this protocol and will be followed for resolution 
of toxicities.  Patients will be allowed up to 2 dose reductions before being taken off a treatment 
regimen.   
 
For the purposes of dose reduction, the following dose levels will be used:  
 
Drug 
Dose and Schedule 
Dose Level -1 
Dose Level -2 
Veliparib:  
Temozolomide: 
40 mg po BID d1-7 
150 mg/m2 po qd d1-5  
20 mg po BID d1-7 
150 mg/m2 po qd d1-5 
20 mg po BID d1-7 
100 mg/m2 po qd d1-5 
 


CTEP #9149 (01-07-2020) 
 
37 
 
Drug 
Dose and Schedule 
Dose Level -1 
Dose Level -2 
AZD1775: 
Carboplatin: 
225 mg po BID x5 doses 
AUC5 IV d1 
175 mg po BID x5 doses 
AUC 5 IV d1 
175 mg po BID x5 doses 
AUC 4 IV d1 
 
Everolimus: 
10 mg po qd 
5 mg po qd 
 2.5 mg po qd 
 
Trametinib DMSO: 
2 mg qd x28 
1.5 mg qd x28 
1 mg qd x28 
 
Dose modifications will only be made for adverse events that are felt to be related to study drug.  
Non-hematologic toxicities should have resolved to Grade ≤ 1 (except electrolyte abnormalities, 
which should resolve to Grade ≤ 2) and hematologic toxicities should have resolved to grade 2 or 
less prior to starting the next cycle.  Doses will not be held or changed for alopecia, any grade 
lymphopenia, leucopenia in the absence of neutropenia, nausea/vomiting/diarrhea (unless it is 
refractory to palliative treatment), or electrolyte abnormalities.  Patients receiving Veliparib who 
have persistent myelosuppression should be evaluated for the possible development of 
AML/MDS using a bone marrow aspirate with cytogenetics (Section 6.4).   
6.1.1 Grade 2 Drug-Related Toxicity: No changes will be made to the study treatment 
for Grade 2 toxicities. 
6.1.2 Grade 3-4 Drug-Related Non-Hematologic Toxicities: Doses will be held until 
toxicities recover to Grade ≤ 1 (with the exception of electrolyte abnormalities 
which should resolve to grade 2 or less; no dose adjustments will be made for 
electrolyte abnormalities) prior to re-initiating therapy at the next lower dose 
level.   
6.1.3 Grade 3 Drug-Related Hematologic Toxicities: Doses will be held until 
hematologic toxicities (except lymphopenia, leucopenia in the absence of 
neutropenia) have resolved to Grade ≤ 2 or baseline prior to re-starting study 
treatment.  Therapy will be re-initiated at the same dose level.  
6.1.4 Grade 4 Drug-Related Hematologic Toxicities: Doses will be held until 
hematologic toxicities (except lymphopenia, leucopenia in the absence of 
neutropenia) have resolved to ≤ Grade 2 or baseline prior to re-starting study 
treatment.  Therapy will be re-initiated at the next lower dose level.  
 
6.2 
Agent-specific Dose Modifications: Trametinib DMSO 
6.2.1 Ocular toxicities 
Visual changes have been observed in patients receiving trametinib, and can be caused by 
retinal pigment epithelial detachments (RPED) or Retinal Vein Occlusion (RVO).  
Patients are required to have a standard ophthalmic exam performed by an 
ophthalmologist at baseline, at the start of cycle 2, and any time patients report visual 
disturbance.  The exam will include best corrected visual acuity, visual field examination, 
tonometry, slit lamp biomicroscopic examination, and indirect fundoscopy.  Optical 
coherence tomography may be performed at scheduled visits and if retinal abnormalities 


CTEP #9149 (01-07-2020) 
 
38 
 
are suspected.  Other types of ancillary testing including visual field examination, fundus 
photography, and fluorescein angiography may also be indicated as determined by 
clinical exam.  Special attention should be given to retinal (e.g., RPED) or retinal vein 
abnormalities (e.g., RVO).  
 
Guidelines regarding event management and dose reduction for visual changes 
considered to be related to study treatment are provided in the table below. 
 
 


CTEP #9149 (01-07-2020) 
 
39 
 
Management and Trametinib Dose Modification for Visual Changes 
and/or Ophthalmic Examination Findings 
Event 
CTCAE Grade 
Management Guideline 
Dose Modification 
Grade 1* 
 
 
• Consult ophthalmologist 
within 7 days of onset. 
 
• If dilated fundus examination cannot be performed within 7 
days of onset, hold trametinib until RPED and RVO can be 
excluded by retina specialist/ophthalmologist. 
• If RPED and RVO excluded, continue/or restart trametinib at 
same dose level. 
• If RPED suspected/diagnosed:  See RPED dose modification 
table below (following this table); report as SAE. 
• If RVO diagnosed:  Permanently discontinue trametinib 
and report as SAE. 
Grade 2 and 
Grade 3 
 
• Consult ophthalmologist 
immediately. 
 
• Hold trametinib 
• If RPED or RVO excluded, restart trametinib at same dose 
level after visual AE is < grade 1.  If no recovery within 3 
weeks, discontinue trametinib 
• If RPED diagnosed:  See RPED dose modification table 
below; report as SAE. 
• If RVO:  Permanently discontinue trametinib and report 
as SAE. 
Grade 4 
 
• Consult ophthalmologist 
immediately. 
• Report as SAE. 
• Hold Trametinib 
• If RPED/RVO excluded, may restart trametinib at same or 
reduced dose after discussion with the CTEP Medical 
Monitor. 
• If RVO or RPED, permanently discontinue trametinib. 
Abbreviations: RPED = retinal pigment epithelial detachments; RVO = retinal vein occlusion; SAE = serious 
adverse event 
*If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required. 
 
 
Trametinib Dose Modification for RPED 
Event 
CTCAE Grade 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic; 
clinical or diagnostic observations 
only) 
• Continue treatment with retinal evaluation monthly until resolution.  If 
RPED worsens, follow instructions below. 
Grade 2-3 RPED (Symptomatic 
with mild to moderate decrease in 
visual acuity; limiting instrumental 
ADL) 
• Interrupt trametinib. 
• Retinal evaluation monthly. 
• If improved to ≤ Grade 1, restart trametinib with one dose level reduction 
(reduced by 0.5 mg) or discontinue in patients taking trametinib 1 mg 
daily. 
• If no recovery within 4 weeks permanently discontinue trametinib 
 
6.2.2 Rash 
Rash is a frequent AE observed in patients receiving trametinib DMSO (Investigator’s 
Brochure, 2012).  Recommendations for supportive care and guidelines for dose 
modifications for rash are based on experience with other MEK inhibitors and EGFR 
inhibitors [79, 80].  
 
 


CTEP #9149 (01-07-2020) 
 
40 
 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
Prevention/Prophylaxisa 
 
• Avoid unnecessary exposure to sunlight. 
• Apply broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) 
with a skin protection factor (SPF) ≥15 at least twice daily. 
• Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol 
cream) on dry areas of the body at least twice daily. 
• Topical steroids and antibiotics should be applied at least twice daily, starting 
on Day 1 of study treatment, to body areas such as face, chest, and upper back.  
• Use mild-strength topical steroid (hydrocortisone 1% cream) or topical 
antibiotic (e.g., clindamycin) or oral antibiotics (e.g., doxycycline 100 mg 
BID, minocycline 100 mg BID). 
Symptomatic Careb 
 
• Pruritic lesions:  Cool compresses and oral antihistamine therapies. 
• Fissuring lesions:  Monsel’s solution, silver nitrate, or zinc oxide cream. 
• Desquamation:  Thick emollients and mild soap. 
• Paronychia:  Antiseptic bath, local potent corticosteroids in addition to 
antibiotics; if no improvement, consult dermatologist or surgeon. 
• Infected lesions:  Appropriate bacterial/fungal culture-driven systemic or 
topical antibiotics. 
a Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
b Patients who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation 
for symptomatic/supportive care management. 
 
 
Trametinib DMSO Dose Modification Guidelines and Management for Rash 
Rash Severity 
Management Guideline 
Dose Modification 
Grade 1 
 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Continue trametinib. 
• If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce trametinib 
DMSO by one dose level.3 
Grade 2 
 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
 
• Reduce trametinib by one dose level. 
• If rash recovers to ≤ grade 1 within 2 weeks, 
increase dose to previous dose level. 
• If no recovery to ≤ grade 1 within 2 weeks, 
interrupt trametinib until recovery to ≤ grade 1. 
• Restart trametinib at reduced dose level.3 
Grade ≥3 
 
• Use moderate strength topical 
steroids PLUS oral methyl-
prednisolone dose pack.2 
• Consult dermatologist. 
• Interrupt trametinib until rash recovers to ≤ grade 1. 
• Restart with trametinib reduced by one dose 
level.3,4 
• If no recovery to ≤ grade 2 within 4 weeks, 
permanently discontinue trametinib. 
1.  Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
2.  Moderate-strength topical steroids:  Hydrocortisone 2.5% cream or fluticasone priopionate 0.5% cream. 
3.  Approval of CTEP Medical Monitor is required to restart study treatment after >4 weeks of interruption. 
4.  Trametinib may be escalated to previous dose level if no rash is evident 4 weeks after restarting study treatment. 
 
 


CTEP #9149 (01-07-2020) 
 
41 
 
6.2.3 Diarrhea 
Episodes of diarrhea have occurred in patients receiving trametinib DMSO 
(Investigator’s Brochure, 2012).  Other frequent causes may include concomitant 
medications (e.g., stool softeners, laxatives, antacids, etc.), infections by C. difficile or 
other pathogens, or partial bowel obstruction.  Those conditions should be excluded.  
Guidelines regarding management and dose modification for diarrhea considered related 
to trametinib are provided in the table below. 
Management and Trametinib DMSO Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Uncomplicated 
Diarrhea,1 
Grade 1 or 2 
• Diet:  Stop all lactose containing products; eat 
small meals, BRAT-diet (banana, rice, apples, 
toast) recommended. 
• Hydration:  8-10 large glasses of clear liquids 
per day (e.g., Gatorade or broth). 
• Loperamide3:  Initially 4 mg, followed by 2 mg 
every 4 hours or after every unformed stool; 
maximum 16 mg/day.  Continue until diarrhea-
free for 12 hours. 
• Diarrhea >24 hours:  Loperamide 2 mg every 2 
hours; maximum 16 mg/day.  Consider adding 
oral antibiotics. 
• Diarrhea >48 hours:  Loperamide 2 mg every 2 
hours; maximum 16 mg/day.  Add budesonide 
or other second-line therapies (otreotide, or 
tincture of opium) and oral antibiotics. 
• Continue trametinib DMSO. 
• If diarrhea is grade 2 for > 48 h, 
interrupt trametinib until diarrhea 
resolves to grade ≤1. 
• Restart trametinib at the same dose 
level 
• If treatment delay is > 14 days, 
discontinue trametinib. 
Uncomplicated 
Diarrhea,1 
Grade 3 or 4 
 
Any Complicated 
Diarrhea2 
 
• Clinical evaluation mandatory. 
• Loperamide3:  Initially 4 mg, followed by 2 mg 
every 4 hours or after every unformed stool; 
maximum 16 mg/day.  Continue until diarrhea-
free for 12 hours. 
• Oral antibiotics and second-line therapies if 
clinically indicated 
• Hydration:  Intravenous fluids if clinically 
indicated. 
• Antibiotics (oral or intravenous) if clinically 
indicated. 
• Intervention should be continued until the 
subject is diarrhea-free for ≥24 hours. 
• Intervention may require hospitalization for 
subjects at risk of life-threatening 
complications. 
• Interrupt trametinib until diarrhea 
resolves to ≤ grade 1. 
• Restart with trametinib reduced by one 
dose level.4 
• If 3 dose reductions of study treatment 
are clinically indicated, permanently 
discontinue trametinib DMSO. 
• If treatment delay is >21 days, 
discontinue trametinib. 
1.  Uncomplicated diarrhea defined by the absence of symptoms such as cramping, nausea/vomiting, ≥ grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or dehydration requiring 
intravenous fluid substitution. 
2.  Complicated diarrhea defined by the presence of symptoms such as cramping, nausea/vomiting, ≥ grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or dehydration requiring 
intravenous fluid substitution. 
3.  Loperamide should be made available prior to start of study treatment so loperamide administration can begin at 
the first signs of diarrhea. 
4.  Escalation of trametinib to previous dose level is allowed after consultation with the medical monitor and in the 
absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to dose reduction. 


CTEP #9149 (01-07-2020) 
 
42 
 
6.2.4 Liver Chemistry Changes 
 
Trametinib Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and assessment/monitoring 
ALT ≥3x ULN but <5x ULN 
and TB <2x ULN, without 
symptoms considered related 
to liver injury or 
hypersensitivity and who can 
be monitored weekly for 4 
weeks 
 
May continue study drug. 
Report as SAE if CTEP-AERS reporting criteria are met. 
If liver chemistry stopping criteria are met any time, proceed as 
described below. 
 
MONITORING: 
Repeat LFT (ALT, AST, ALK, bilirubin) until they return to 
normal/baseline or stabilise (LFT may be every 2 weeks after 4 weeks 
if ALT <3x ULN and TB <2 ULN). 
Criteria for discontinuing study 
drug:  When any of the liver 
stopping criteria below is met, 
discontinue trametinib  
 
ALT ≥3xULN and bilirubin 
≥2x ULN or >35% direct 
bilirubin 1, 2 
ALT  3xULN and INR >1.5, 
if INR measured2 (INR 
threshold does not apply if 
subject is on anticoagulant) 
ALT ≥5x ULN 
ALT ≥3x ULN persists for 4 
weeks 
ALT ≥3x ULN and cannot be 
monitored weekly for 4 weeks 
ALT ≥3x ULN associated with 
symptoms3 (new or worsening) 
believed to be related to liver 
injury or hypersensitivity 
 
 
Immediately discontinue study treatment. 
Do not restart/rechallenge unless approved by CTEP trametinib medical 
monitor.   
Report as SAE if:  1) CTEP-AERS reporting criteria are met, or 2) 
patients meet criteria 1-2. 
Perform liver event ASSESSMENT AND WORKUP (see below). 
Monitor the subject until liver chemistries resolve, stabilize, or return to 
baseline (see MONITORING below). 
If applicable, provide details on required follow up assessments (e.g., 
follow up for overall survival or disease recurrence or progression).   
 
MONITORING: 
In patients stopping for criteria 1-2 (with abnormal TB and INR, 
indicating potentially more significant liver toxicities): 
Repeat liver chemistries (ALT, AST, ALK, bilirubin) and perform liver 
event follow-up assessments within 24 hours. 
Monitor subjects twice weekly until LFT return to normal/baseline or 
stabilize. 
A specialist or hepatology consultation is recommended. 
In patients stopping for criteria 2-6: 
Repeat LFT and perform liver event follow up assessments within   
24-72 hrs  
Monitor subjects weekly until LFTs return to normal/baseline or 
stabilize. 
 
ASSESSMENT and WORKUP: 
Viral hepatitis serology.4 
If possible, obtain blood sample for PK analysis.5 
Serum CPK and LDH. 
Fractionate bilirubin, if total bilirubin ≥2x ULN. 
CBC with differential to assess eosinophilia. 
Record clinical symptoms of liver injury, or hypersensitivity on AE 
CRF. 
Record concomitant medications (including acetaminophen, herbal 
remedies, other over the counter medications). 
Record alcohol use. 


CTEP #9149 (01-07-2020) 
 
43 
 
Trametinib Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and assessment/monitoring 
Additional work up for patient stopping for criteria 1-2 (with abnormal 
TB and INR, indicating potentially more significant liver toxicities): 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and quantitative total immunoglobulin G 
(IgG or gamma globulins). 
Serum acetaminophen adduct HPLC assay (in subjects with likely 
acetaminophen use in the preceding). 
If there is underlying chronic hepatitis B (e.g. positive hepatitis B 
surface antigen):  quantitative hepatitis B DNA and hepatitis delta 
antibody.6 
Liver imaging (ultrasound, MRI, CT) and /or liver biopsy. 
Footnotes: 
1.  Serum bilirubin fractionation should be performed if testing is available.  If serum bilirubin 
fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, which 
indicates direct bilirubin elevations and suggesting liver injury. 
2.  All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT 3x ULN and 
INR >1.5 (if INR measured) may indicate severe liver injury (possible “Hy’s Law”).  INR measurement 
is not required, and the threshold value stated will not apply to subjects receiving anticoagulants. 
3.  New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such 
as fever, rash, or eosinophilia) 
4.  Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody 
(IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody  
5.  PK sample is desired if feasible.  Record the date/time of the PK blood sample draw and the 
date/time of the last dose of study treatment prior to blood sample draw on the CRF.  If the date or time 
of the last dose is unclear, provide the subject’s best approximation.  If the date/time of the last dose 
cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not 
obtain a PK sample.   
6.  If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D 
RNA virus (where needed) (Le Gal et al., 2005). 
 
6.2.5 Pneumonitis 
Pneumonitis has been observed in patients receiving trametinib DMSO.  To reduce the 
risk of pneumonitis, patients will be monitored closely for symptoms and evaluated with 
imaging and functional tests.  Dose modification and supportive care guidelines for 
pneumonitis are described in the tables below. 
 
 


CTEP #9149 (01-07-2020) 
 
44 
 
Pneumonitis Guidelines for Trametinib Monotherapy 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
CT scan (high-resolution with lung windows) 
recommended. 
Work-up for infection. 
Monitoring of oxygenation via pulse-
oximetry recommended. 
 Consultation with pulmonologist 
recommended. 
Continue trametinib at current dose. 
Grade 2 
CT scan (high-resolution with lung 
windows). 
Work-up for infection. 
Consult pulmonologist. 
Pulmonary function tests:  If < normal, repeat 
every 8 weeks until ≥ normal. 
Bronchoscopy with biopsy and/or BAL 
recommended. 
Symptomatic therapy including 
corticosteroids if clinically indicated. 
Interrupt trametinib until recovery to 
grade ≤1. 
Restart treatment with trametinib 
reduced by one dose level 
Escalation to previous dose level 
after 4 weeks may be considered 
after consultation with medical 
monitor  
If no recovery to grade ≤1 within 4 
weeks, permanently discontinue 
trametinib 
Grade 3 
Same as grade 2 
Interrupt trametinib until recovery to 
grade ≤1. 
After consultation with medical 
monitor, trametinib may be restarted 
reduced by one dose level 
If no recovery to grade ≤1 within 4 
weeks, permanently discontinue 
trametinib 
Grade 4 
Same as grade 2 
Permanently discontinue trametinib. 
Abbreviations:  BAL = bronchoalveolar lavage; CT = computed tomography. 
 
6.2.6 Reduced Left Ventricular Ejection Fraction (LVEF) 
Decreases of LVEF have been observed in patients receiving trametinib DMSO.  
Therefore, ECHOs must be performed in regular intervals outlined in the Study Calendar.  
The same procedure (either ECHO or MUGA, although ECHO is preferred) should be 
performed at baseline, every three cycles, and as clinically indicated.   
 
 


CTEP #9149 (01-07-2020) 
 
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Trametinib Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose 
Modification 
Asymptomatic 
 
Absolute decrease of >10% in 
LVEF compared to baseline 
and ejection fraction below the 
institution’s LLN. 
• Interrupt trametinib and repeat ECHO/MUGA within 2 
weeks.a 
• If the LVEF recovers within 4 weeks (defined as LVEF 
≥LLN and absolute decrease ≤10% compared to baseline): 
− Consult with the CTEP trametinib medical monitor and 
request approval for restart. 
− Restart treatment with trametinib at reduced dose by one 
dose level. 
− Repeat ECHO/MUGA 2, 4, and 12 weeks after re-start; 
continue in intervals of 12 weeks thereafter. 
• If LVEF does not recover within 4 weeks: 
− Consult with cardiologist. 
− Permanently discontinue trametinib. 
− Repeat ECHO/MUGA after 2, 4, 8, 12, and 16 weeks or 
until resolution. 
− Consult with the CTEP trametinib medical monitor.c 
Symptomaticb 
 
• Grade 3:  resting LVEF 39-
20% or >20% absolute 
reduction from baseline 
• Grade 4:  Resting LVEF 
≤20%. 
• Permanently discontinue trametinib. 
• Report as SAE. 
• Consult with cardiologist. 
• Repeat ECHO after 2, 4, 8, 12, and 16 weeks or until 
resolution. 
a If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later. 
b Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks after 
restarting of trametinib.  Approval from the CTEP trametinib medical monitor is required. 
c Symptoms may include:  dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema 
 
6.2.7 QTc Prolongation 
 
Trametinib Withholding and Stopping Criteria for QTc Prolongation 
QTc Prolongationa 
Action and Dose Modification 
• QTcB ≥501 msec, or 
• Uncorrected QT >600 msec, or 
• QTcB >530 msec for subjects with 
bundle branch block 
 
• Interrupt study treatment until QTcB prolongation resolves to grade 1 or 
baseline. 
• Test serum potassium, calcium, phosphorus, and magnesium.  If 
abnormal, correct per routine clinical practice to within normal limits. 
• Review concomitant medication usage for a prolonged QTc. 
• Restart at current dose level.b 
• If the event does not resolve or recurs after restarting, permanently 
discontinue study treatment. 
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using Bazett’s formula 
a Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to 
determine if study treatments should be interrupted or discontinued. 
b if the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the investigator 
and the CTEP trametinib medical monitor agree that the subject will benefit from further treatment. 
 


CTEP #9149 (01-07-2020) 
 
46 
 
6.2.8 Hypertension 
Increases in blood pressure (BP) have been observed in patients receiving trametinib 
DMSO.  Recommendations for BP monitoring and management are provided below. 
 
Monitoring:  All BP assessments should be performed under the following optimal 
conditions: 
• The subject has been seated with back support, ensuring that legs are uncrossed and 
flat on the floor. 
• The subject is relaxed comfortably for at least 5 minutes. 
• Restrictive clothing has been removed from the cuff area, and the right cuff has been 
selected. 
• The subject’s arm is supported so that the middle of the cuff is at heart level. 
• The subject remains quiet during the measurement. 
• In subjects with an initial BP reading within the hypertensive range, a second 
reading should be taken at least 1 minute later, with the two readings averaged to 
obtain a final BP measurement.  The averaged value should be recorded in the eCRF. 
• Persistent hypertension is defined as an increase of systolic blood pressure (SBP) 
>140 mmHg and/or diastolic blood pressure (DBP) >90 mmHg in three consecutive 
visits with blood pressure assessments from two readings as described above.  Visits 
to monitor increased blood pressure can be scheduled independently from the per-
protocol visits outlined in the study calendar.  Ideally, subsequent blood pressure 
assessments should be performed within 1 week. 
 
 


CTEP #9149 (01-07-2020) 
 
47 
 
 
Management and Trametinib Dose Modification for Hypertension 
Event 
Management Guideline 
Dose Modification 
Definitions used in the table: 
− Persistent hypertension:  Hypertension detected in two separate readings during up to three subsequent visits. 
− Well-controlled hypertension:  Blood pressure of SBP ≤140 mmHg and DBP ≤90 mmHg in two separate 
readings during up to three subsequent visits. 
− Symptomatic hypertension:  Hypertension associated with symptoms (e.g., headache, light-headedness, 
vertigo, tinnitus, episodes of fainting or other symptoms indicative of hypertension) that resolve after the blood 
pressure is controlled within the normal range. 
− Asymptomatic hypertension: SBP >140 mmHg and/or DBP >90 mmHg in the absence of the above symptoms. 
(Scenario A) 
• Asymptomatic and persistent SBP 
of ≥140 and <160 mmHg, or DBP 
≥90 and <100 mmHg,  
or 
Clinically significant increase in 
DBP of 20 mmHg (but still below 
100 mmHg). 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP.  If BP is not well-controlled 
within 2 weeks, consider referral to 
a specialist and go to scenario (B). 
Continue trametinib at the current 
dose. 
(Scenario B) 
• Asymptomatic SBP ≥160 mmHg, 
or DBP ≥100 mmHg,  
or 
Failure to achieve well-controlled BP 
within 2 weeks in Scenario A. 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Interrupt trametinib if clinically 
indicated. 
• Once BP is well-controlled, restart 
trametinib reduced by one dose 
level.a 
(Scenario C) 
• Symptomatic hypertension  
or 
Persistent SBP ≥160 mmHg, or DBP 
≥100 mmHg, despite 
antihypertensive medication and 
dose reduction of trametinib 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Referral to a specialist for further 
evaluation and follow-up is 
recommended. 
• Interrupt trametinib. 
• Once BP is well-controlled, restart 
trametinib reduced by one dose 
level.a 
(Scenario D) 
Refractory hypertension 
unresponsive to above interventions 
or hypertensive crisis. 
Continue follow-up per protocol. 
Permanently discontinue 
trametinib. 
a. Escalation of trametinib to previous dose level can be considered if BPs remain well controlled for 4 weeks 
after restarting of trametinib.  Approval from Medical Monitor is required. 
 
6.3 
Agent-specific Dose Modifications: Everolimus 
6.3.1 Hyperglycemia: Grade 2 or higher elevations in blood glucose with the patient 
non-fasting should be confirmed by obtaining fasting values prior to making any 
treatment decisions.  Grade 3 will result in temporary dose reduction, 
management with appropriate therapy, and re-initiation at a lower dose.  


CTEP #9149 (01-07-2020) 
 
48 
 
6.3.2 Hyperlipidemia and Hypertriglyceridemia: Grade 3 (measured by cholesterol 
and triglycerides) will result in holding study drug until resolution of toxicity to 
Grade 2 or less, at which point study drug administration will be reinstituted at the 
next lowest dose level.  Grade 4 elevation in either serum cholesterol or 
triglyceride levels will result in study drug discontinuation. 
6.3.3 Skin Toxicity:  For patients with grade 1 toxicity, no specific supportive care is 
usually needed or indicated.  Rash must be reported as an AE.  Patients with grade 
2 or higher toxicity may be treated with the following suggested supportive 
measures at the discretion of the investigator: oral minocycline, topical 
tetracycline, topical clindamycin, topical silver sulfadiazine, diphenhydramine, 
oral prednisolone (short course), topical corticosteroids, or pimecrolimus. 
6.3.4 Angioedema with concomitant use of angiotensin-converting enzyme (ACE) 
inhibitors: Patients taking concomitant ACE inhibitor therapy may be at 
increased risk for angioedema (e.g., swelling of the airways or tongue, with or 
without respiratory impairment). 
Dosing Guidelines for > Grade 3 toxicities associated with Everolimus 
Everolimus will be discontinued for all grade 4 hematologic and non-hematologic 
toxicities.  Patients with reactivated Hepatitis B or C will have everolimus treatment 
discontinued and will be taken off study.   
 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors should be used with caution.  If a patient requires co-administration of 
moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose of everolimus as 
specified in Section 6.0.  If the inhibitor is discontinued, the Everolimus dose should be 
returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor after a 
washout period of 2 to 3 days. 
Dosing guidelines for Grade 3 Everolimus-related non-hematologic toxicities 
AST or ALT elevation Grade 3  
Interrupt Everolimus administration until resolution to ≤ grade 1 
(or ≤ grade 2 if baseline values were within the range of grade 
2).  If resolution occurs ≤ 7 days, Everolimus should be re-
started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, 
hold Everolimus until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce Everolimus at one dose level lower, if 
available. 


CTEP #9149 (01-07-2020) 
 
49 
 
Intolerable grade 2 mucositis, or 
grade 3 AE  
Interrupt Everolimus administration until resolution to ≤ grade 1 
or baseline grade / value. 
If resolution occurs within ≤ 7 days, Everolimus should be re-
started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, 
hold Everolimus until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce Everolimus at one dose level lower, if 
available. 
Drug will be discontinued if patients fail to recover to  grade 1 
or baseline grade / value within 28 days. 
Recurrence of intolerable grade 2 
mucositis or grade 3 event after 
dose reduction 
Reduce dose to the next lower dose level, if available.  If toxicity 
recurs at Grade 3, consider discontinuation 
Grade 3 clinical liver failure 
(asterixis or encephalopathy/coma) 
Discontinue Everolimus 
Any non-hematologic toxicity 
requiring Everolimus interruption 
for > 28 days 
Discontinue Everolimus 
Dosing guidelines for Grade 3 Everolimus-related hematologic toxicities 
Grade 3 thrombocytopenia  
Interrupt Everolimus until resolution to grade 1  
If resolution occurs ≤ 7 days, reintroduce Everolimus at the 
dose level prior to interruption.  If resolution occurs > 7 days, 
or event occurs within 28 days, reintroduce Everolimus at one 
dose level lower, if available. 
Grade 3 neutropenia or anemia  
Interrupt Everolimus until resolution to grade ≤1 or baseline 
value.  If AE resolution occurs ≤ 7 days, reintroduce 
Everolimus at the same dose level.  If AE resolution occurs > 
7 days, or event occurs within 28 days, reintroduce 
Everolimus at one dose level lower, if available. 
Grade 4 neutropenia or anemia 
Interrupt Everolimus until recovery to grade  1 or baseline 
value.  Reintroduce Everolimus at one dose level lower, if 
available* 
Febrile neutropenia 
Interrupt Everolimus until resolution to grade  1 (or baseline 
value) and no fever.  Reintroduce Everolimus at one dose 
level lower, if available* 
Recurrence of grade 3 toxicity after 
dose reduction 
Reduce dose to the next lower dose level, if available.   
Any hematologic toxicity requiring 
Everolimus interruption for > 28 days 
Discontinue Everolimus 
 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of esophageal 
mucosa such as gastroesophageal reflux disease (GERD) and pre-existing stomatitis/mucositis 
must be monitored even more closely.  Patients should be instructed to report the first onset of 
buccal mucosa irritation/reddening to their study physician immediately. 


CTEP #9149 (01-07-2020) 
 
50 
 
 
Management of stomatitis/oral mucositis/mouth ulcers 
Grade 1 (Minimal 
symptoms, normal diet) 
Manage with non-alcoholic or salt water (0.9%) mouth wash several times a 
day. 
Grade 2 (Symptomatic 
but can eat and swallow 
modified diet) 
Temporary dose interruption until recovery to grade ≤1.  Manage with topical 
analgesic mouth treatments (e.g., benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol or phenol) with or without topical corticosteroids (i.e., 
triamcinolone oral paste 0.1%)*.  Re-initiate everolimus at the same dose.  If 
stomatitis recurs at grade 2, interrupt dose until recovery to grade ≤1.  Re-
initiate everolimus at a lower dose. 
Grade 3 (Symptomatic 
and unable to adequately 
eat or hydrate orally) 
Temporary dose interruption until recovery to grade ≤1.  Manage with 
topical analgesic mouth treatments (i.e., benzocaine, butyl aminobenzoate, 
tetracaine hydrochloride, menthol or phenol) with or without topical 
corticosteroids (i.e., triamcinolone oral paste 0.1%)* Re-initiate everolimus 
at lower dose. 
*Do not use agents containing alcohol, hydrogen peroxide, iodine, or thyme derivatives in management of 
stomatitis as they may worsen mouth ulcers. 
 
Non-infectious pneumonitis is a class effect of rapamycin derivatives.  Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking Everolimus. 
 
Management of non-infectious pneumonitis 
Worst grade  Suggested investigations 
Management of pneumonitis 
Grade 1  
CT scans with lung windows. 
No specific therapy is required; initiate 
appropriate monitoring 
Grade 2  
CT scan with lung windows.  Consider 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 saturation 
at rest.  Consider a bronchoscopy with biopsy 
and/or BAL. Monitoring at each visit until 
return to ≤ grade 1.  Return to initial monitoring 
frequency if no recurrence. 
Symptomatic only.  Consider corticosteroids 
and/or other supportive therapy if symptoms 
are troublesome.  Rule out infection and 
consider interruption of Everolimus until 
symptoms improve to Grade ≤ 1.  Re-initiate 
Everolimus at one dose level lower.  
Discontinue Everolimus if failure to recover 
within ≤ 28 days. 
Grade 3  
 
CT scan with lung windows and pulmonary 
function testing includes: spirometry, DLCO, 
and room air O2 saturation at rest.  Monitoring 
at each visit until return to ≤ grade 1.  Return to 
initial monitoring frequency if no recurrence.  
Bronchoscopy with biopsy and/or BAL is 
recommended. 
Consider corticosteroids if infective origin is 
ruled out.  Taper as medically indicated.  
Interrupt Everolimus until symptoms improve 
to Grade ≤ 1.  Consider re-initiating 
Everolimus at one dose level lower.  
Discontinue Everolimus if failure to recover 
within ≤ 28 days.  If toxicity recurs at Grade 3, 
consider discontinuation.   
Grade 4  
CT scan with lung windows and required 
pulmonary function testing, if possible, 
includes: spirometry, DLCO, and room air O2 
saturation at rest.  Monitoring at each visit until 
return to ≤ grade 1.  Return to initial monitoring 
frequency if no recurrence.  Bronchoscopy with 
biopsy and/or BAL is recommended if possible. 
Consider corticosteroids if infective origin is 
ruled out.  Taper as medically indicated.  
Discontinue everolimus.   


CTEP #9149 (01-07-2020) 
 
51 
 
Note: Patients taking concomitant ACE inhibitor therapy may be at increased risk for 
angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). 
6.4 
Agent-specific Dose Modifications: Veliparib 
If a patient taking Veliparib in combination with temozolomide develops bone marrow findings 
consistent with AML/MDS or severe persistent anemia, he or she may be allowed to continue the 
other therapy if they are experiencing clinical benefit and the toxicity is not related to the other 
therapy, based on the opinion of the Principal Investigator.  
 
Hematologic toxicities should have resolved to ≤ Grade 2 (except lymphopenia) prior to starting 
the next cycle.  Doses of study drugs will not be held or reduced for any grade of lymphopenia.  
Treatment may be delayed for toxicity a maximum of 2 weeks beyond the actual cycle length per 
Section 6.1.   
 
Use of hematopoietic agents 
 
Use erythropoietin-stimulating agents per standard of care National Comprehensive Cancer 
Network (NCCN) and/or institutional guidelines, iron supplements, and/or transfusions as 
clinically indicated for management of anemia.   Prescribing information for the erythropoiesis 
stimulating agents (including Aranesp, Epogen and Procrit) highlight that there is a potential risk 
of shortening the time to tumor progression or disease-free survival.   Primary prophylaxis with 
granulocyte colony-stimulating factor (G-CSF) is not recommended.  Aranesp, Epogen and 
Procrit may not alleviate fatigue or increase energy and should not be used in patients with 
uncontrolled hypertension.  The package inserts for these agents should be consulted. 
 
If a patient develops febrile neutropenia, Veliparib should be stopped and appropriate 
management including G-CSF should be given according to local hospital guidelines.   Please 
note that G-CSF should not be used within at least 24 hours of the last dose of veliparib unless 
absolutely necessary.  Platelet transfusions, if indicated, should be done according to local 
hospital guidelines. 
 
Dose modifications for hematologic toxicity 
 
Patients who have veliparib held for hematologic toxicities should have blood counts and 
differentials checked at least weekly until recovery; these data should be recorded in eCRF as 
extra laboratory examinations.   If counts do not improve to CTCAE Grade 2 or better despite 
drug cessation for 2 weeks, patients should be referred to a hematological oncologist for further 
assessment.   A bone marrow analysis should be considered. 
 
Management of anemia 
 
Anemia is a common adverse drug reaction related to Veliparib; management of anemia is in 
accordance with the table below:  
 
CTCAE 
Grade 
Definition 
Dose 
3 
Hb <8 g/dL 
Give appropriate supportive treatment and investigate causality.  
Interrupt veliparib until improved to ≥ Grade 2 or baseline.  Upon 
recovery, therapy will be re-initiated at the same dose level. 


CTEP #9149 (01-07-2020) 
 
52 
 
CTCAE 
Grade 
Definition 
Dose 
4 
 
Hb <8 g/dL 
Give appropriate supportive treatment and investigate causality.  
Interrupt veliparib until improved to ≥ Grade 2 or baseline.  Upon 
recovery, dose reduce veliparib to 20 mg BID. 
BID = twice daily; Hb = hemoglobin 
 
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases, management 
of anemia may require blood transfusions.  Any subsequently required dose interruptions related to 
development of anemia, or coexistent with newly developed neutropenia, and/or 
thrombocytopenia, will require veliparib dose reductions to 20 mg twice daily (BID). 
 
If Hb drops to <8 g/dL despite the dose reduction or more than one blood transfusion is required 
to recover Hb levels with no alternative explanation for the anemia, veliparib should be 
permanently discontinued. 
 
Management of prolonged hematological toxicities while on study treatment 
 
If a patient develops prolonged hematological toxicity such as: 
 
• ≥2-week interruption/delay in veliparib due to CTCAE Grade ≥3 anemia (Hb <8 g/dL) and/or 
development of blood transfusion dependence 
 
• ≥2-week interruption/delay in veliparib due to CTCAE Grade ≥3 neutropenia (ANC <1 x 109/L) 
 
• ≥2-week interruption/delay in veliparib due to CTCAE Grade ≥3 thrombocytopenia and/or 
development of platelet transfusion dependence (Platelets <50 x 109/L) 
 
Check weekly differential blood counts including reticulocytes and peripheral blood smear.   If 
any blood parameters remain clinically abnormal after 2 weeks of dose interruption, the patient 
should be referred to a hematological oncologist for further investigations.   Bone marrow for 
evaluation and cytogenetics should be considered at this stage according to standard 
hematological oncology practice.    
 
Patients who develop MDS/AML on treatment should discontinue veliparib treatment and be 
managed appropriately. 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 


CTEP #9149 (01-07-2020) 
 
53 
 
determine whether the event requires expedited (via CTEP-AERS) in addition to routine 
reporting.   
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
7.1.1 Adverse Event List(s) for Commercial Agents  
Please refer to Sections 8.1 and 8.2 for adverse events related to carboplatin and 
temozolomide.   
7.1.2 CAEPR for Veliparib (NSC 737664)  
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification.  Frequency is provided based on 2310 patients.  Below is the CAEPR for 
ABT-888 (Veliparib). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
Version 2.4, May 13, 2018 
 Adverse Events with Possible  
 Relationship to ABT-888 (Veliparib) 
 (CTCAE 5.0 Term) 
[n= 2310] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
Anemia (Gr 3) 
Febrile neutropenia 
 
Febrile neutropenia (Gr 3) 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
Constipation 
 
Constipation (Gr 2) 
Diarrhea 
 
Diarrhea (Gr 3) 
Nausea 
 
Nausea (Gr 3) 
Vomiting 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Fatigue 
 
Fatigue (Gr 3) 
INVESTIGATIONS 
 
Lymphocyte count decreased  
Lymphocyte count decreased  
(Gr 4) 
Neutrophil count decreased  
Neutrophil count decreased (Gr 4) 
Platelet count decreased 
 
Platelet count decreased (Gr 4) 
Weight loss 
 
Weight loss (Gr 2) 
White blood cell decreased  
White blood cell decreased (Gr 4) 


CTEP #9149 (01-07-2020) 
 
54 
 
 Adverse Events with Possible  
 Relationship to ABT-888 (Veliparib) 
 (CTCAE 5.0 Term) 
[n= 2310] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
Anorexia (Gr 2) 
Dehydration 
 
Dehydration (Gr 3) 
Hypophosphatemia 
 
Hypophosphatemia (Gr 3) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
 
 
Leukemia secondary to 
oncology chemotherapy 
 
 
Myelodysplastic syndrome  
 
Treatment related secondary 
malignancy 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Dysgeusia 
 
Dysgeusia (Gr 2) 
Headache 
 
Headache (Gr 3) 
Seizure 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Rash maculo-papular 
 
 
VASCULAR DISORDERS 
 
Thromboembolic event2 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Thromboembolic events, including deep vein thrombosis and pulmonary embolism, have been observed 
at a higher frequency compared to control arm when administered in combination with temozolomide. 
 
Adverse events reported on ABT-888 (Veliparib) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that ABT-888 (Veliparib) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Blood and 
lymphatic system disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Cardiac disorders - Other (Takotsubo cardiomyopathy); Heart failure; Left 
ventricular systolic dysfunction; Palpitations; Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Colonic obstruction; 
Dental caries; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; Flatulence; 
Gastritis; Gastroesophageal reflux disease; Lower gastrointestinal hemorrhage; Mucositis oral; 
Obstruction gastric; Rectal hemorrhage; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; 
Fever; Flu like symptoms; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (cirrhosis) 


CTEP #9149 (01-07-2020) 
 
55 
 
INFECTIONS AND INFESTATIONS - Appendicitis; Catheter related infection; Infections and 
infestations - Other (peritonsillar abscess); Lung infection; Lymph gland infection; Mucosal infection; 
Sepsis; Shingles; Skin infection; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; 
Radiation recall reaction (dermatologic) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; Cardiac troponin I increased; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypernatremia; 
Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Back 
pain; Bone pain; Generalized muscle weakness; Muscle cramp; Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) -
Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of consciousness; 
Dysarthria; Extrapyramidal disorder; Intracranial hemorrhage; Lethargy; Memory impairment; 
Movements involuntary; Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; 
Presyncope; Reversible posterior leukoencephalopathy syndrome; Stroke; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Psychiatric 
disorders - Other (emotional instability); Psychosis; Restlessness 
RENAL AND URINARY DISORDERS - Dysuria; Hematuria; Proteinuria  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; 
Hypoxia; Nasal congestion; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail 
changes; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Purpura; Rash acneiform 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; Vascular disorders - 
Other (brainstem infarction)  
 
Note: Veliparib (ABT-888) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
7.1.3 CAEPR for AZD1775 (NSC 751084) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform presentation 
of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol 
Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold 
and italicized text.  This subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification.  Frequency is provided based on 299 patients.  Below is the CAEPR for AZD1775 
(MK-1775, NSC 751084).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
NOTE: Many adverse events on this CAEPR are treatment-emergent events that have been observed 
in trials of AZD1775 in combination with chemotherapy including carboplatin, cisplatin, 


CTEP #9149 (01-07-2020) 
 
56 
 
gemcitabine, 5-fluorouracil, paclitaxel, or topotecan.  There are limited adverse event data reported 
with monotherapy of AZD1775 at this time. 
Version 2.4, August 3, 2016 
 Adverse Events with Possible  
 Relationship to AZD1775  
 (CTCAE 4.0 Term) 
[n= 299] 
  Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 Anemia (Gr 3) 
Febrile neutropenia 
 
CARDIAC DISORDERS 
 
Atrial fibrillation 
 
Supraventricular tachycardia  
EAR AND LABYRINTH DISORDERS 
 
Hearing impaired 
 
Tinnitus 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal distension 
 
Abdominal pain 
 Abdominal pain (Gr 2) 
Constipation 
 Constipation (Gr 2) 
Diarrhea 
 Diarrhea (Gr 2) 
Dyspepsia 
 
Flatulence 
 
Mucositis oral 
 Mucositis oral (Gr 2) 
Nausea 
 Nausea (Gr 2) 
Oral pain 
 
Vomiting 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
Edema limbs 
 Edema limbs (Gr 2) 
Fatigue 
 Fatigue (Gr 3) 
Fever 
 Fever (Gr 2) 
Flu like symptoms 
 
Malaise 
 
Non-cardiac chest pain 
 
Pain 
 
HEPATOBILIARY DISORDERS 
 
Hepatobiliary disorders - 
Other (hepatitis) 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
 
INFECTIONS AND INFESTATIONS 
 
Infection (2) 
 Infection[81] (Gr 3) 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
 Alanine aminotransferase 
increased (Gr 2) 
Alkaline phosphatase 
increased 
 
Aspartate aminotransferase 
increased 
 


CTEP #9149 (01-07-2020) 
 
57 
 
 Adverse Events with Possible  
 Relationship to AZD1775  
 (CTCAE 4.0 Term) 
[n= 299] 
  Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Blood bilirubin increased 
 
Creatinine increased 
 
Lymphocyte count decreased 
 
Neutrophil count decreased 
 Neutrophil count decreased (Gr 
4) 
Platelet count decreased 
 Platelet count decreased (Gr 4) 
Weight loss 
 
White blood cell decreased 
 White blood cell decreased (Gr 
4) 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 Anorexia (Gr 2) 
Dehydration 
 
Hyperglycemia 
 
Hypoalbuminemia 
 
Hypocalcemia 
 
Hypokalemia 
 Hypokalemia (Gr 2) 
Hypomagnesemia 
 Hypomagnesemia (Gr 2) 
Hyponatremia 
 
Hypophosphatemia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
Back pain 
 Back pain (Gr 2) 
Musculoskeletal and 
connective tissue disorder - 
Other (muscle spasms) 
 
Myalgia 
 Myalgia (Gr 2) 
Pain in extremity 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 Dizziness (Gr 2) 
Dysgeusia 
 
Headache 
 Headache (Gr 2) 
Intracranial hemorrhage 
 
Paresthesia 
 
PSYCHIATRIC DISORDERS 
 
Insomnia 
 
RENAL AND URINARY DISORDERS 
 
Acute kidney injury (3)  
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 Cough (Gr 2) 
Dyspnea 
 Dyspnea (Gr 2) 
Epistaxis 
 
Hiccups 
 
Hypoxia 
 
Voice alteration 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 


CTEP #9149 (01-07-2020) 
 
58 
 
 Adverse Events with Possible  
 Relationship to AZD1775  
 (CTCAE 4.0 Term) 
[n= 299] 
  Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Hyperhidrosis 
 
Pruritus 
 
Rash (4)  
 Rash[82] (Gr 2) 
VASCULAR DISORDERS 
 
Phlebitis 
 
Thromboembolic event 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3Acute kidney injury includes renal impairment and acute renal insufficiency. 
4Rash may include rash, erythema, eczema, and rash maculo-papular. 
5Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory neuropathy. 
 
Adverse events reported on AZD1775 trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that AZD1775 caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Blood and lymphatic system disorders - Other (thrombocytosis); Leukocytosis 
CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (cardiomegaly); Chest 
pain - cardiac; Myocardial infarction; Palpitations; Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain 
EYE DISORDERS - Blurred vision; Cataract; Conjunctivitis; Eye disorders - Other (eye swelling); Eye 
disorders - Other (visual impairment); Eye pain; Keratitis; Photophobia; Scleral disorder; Watering eyes 
GASTROINTESTINAL DISORDERS - Anal pain; Ascites; Bloating; Cheilitis; Colitis; Dry mouth; 
Duodenal ulcer; Dysphagia; Gastric ulcer; Gastritis; Gastrointestinal disorders - Other (duodenitis); 
Gastrointestinal disorders - Other (eructation); Hemorrhoids; Lower gastrointestinal hemorrhage; Rectal 
pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Gait 
disturbance; General disorders and administration site conditions - Other (catheter site pain); Infusion site 
extravasation 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and 
procedural complications - Other (excoriation); Injury, poisoning and procedural complications - Other 
(ligament sprain) 
INVESTIGATIONS - Electrocardiogram QT corrected interval prolonged; GGT increased; 
Investigations - Other (blood urea increased); Lymphocyte count increased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperkalemia; Hyperuricemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Bone pain; Flank 
pain; Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective tissue 
disorder - Other (groin pain); Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (carcinoid tumor); Tumor 
pain 


CTEP #9149 (01-07-2020) 
 
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NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Dysesthesia; Encephalopathy; Lethargy; 
Nervous system disorders - Other (hemiparesis); Peripheral neuropathy[83]; Presyncope; Somnolence; 
Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression 
RENAL AND URINARY DISORDERS - Hematuria; Urinary frequency; Urinary incontinence; 
Urinary retention; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Female genital tract fistula; Genital 
edema 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Bronchopulmonary hemorrhage; Nasal congestion; Pleural effusion; Pneumonitis; Pulmonary 
hypertension; Respiratory, thoracic and mediastinal disorders - Other (diaphragmalgia); Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin; Pain of skin; 
Palmar-plantar erythrodysesthesia syndrome; Purpura; Rash acneiform; Skin ulceration; Urticaria 
VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypertension; Hypotension 
 
Note: AZD1775 in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
7.1.4 CAEPR for Trametinib DMSO (NSC 763093) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI 
(except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 1111 patients. Below is the CAEPR for Trametinib 
(GSK1120212B). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
   Version 2.6, October 10, 20191 
 
 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
Anemia (Gr 3) 
CARDIAC DISORDERS 
 
Heart failure 
 
Left ventricular systolic 
dysfunction 
 
Sinus bradycardia 
 
EYE DISORDERS 
 
Blurred vision 
 
Dry eye 
 


CTEP #9149 (01-07-2020) 
 
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 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
Eye disorders - Other 
(chorioretinopathy also known as 
retinal pigment epithelial 
detachment) 
 
Eye disorders - Other (retinal vein 
occlusion) 
 
Eye disorders - Other (visual 
disorders)2 
 
 
Papilledema 
 
Periorbital edema 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
Abdominal pain (Gr 2) 
Colitis 
 
Colonic perforation 
 
Constipation 
Constipation (Gr 2) 
Diarrhea 
Diarrhea (Gr 3) 
Dry mouth 
Dry mouth (Gr 2) 
Dyspepsia 
Dyspepsia (Gr 2) 
Mucositis oral 
Mucositis oral (Gr 3) 
Nausea 
Nausea (Gr 3) 
Vomiting 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
Chills (Gr 2) 
Edema face 
 
Fatigue 
Fatigue (Gr 3) 
Fever 
Fever (Gr 2) 
Generalized edema3 
Generalized edema3 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction4 
 
INFECTIONS AND INFESTATIONS 
 
Folliculitis 
Folliculitis (Gr 2) 
Lung infection 
 
Paronychia 
Paronychia (Gr 2) 
Skin infection 
Skin infection (Gr 2) 
INVESTIGATIONS 
 
Alanine aminotransferase increased 
Alanine aminotransferase 
increased (Gr 3) 
Alkaline phosphatase increased 
Alkaline phosphatase increased 
(Gr 2) 
Aspartate aminotransferase 
increased 
Aspartate aminotransferase 
increased (Gr 3) 
CPK increased 
 
Ejection fraction decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
Anorexia (Gr 3) 
Dehydration 
Dehydration (Gr 3) 


CTEP #9149 (01-07-2020) 
 
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 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
Hypoalbuminemia 
 
Hypomagnesemia 
Hypomagnesemia (Gr 2) 
Hyponatremia 
Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
Back pain 
Back pain (Gr 2) 
Pain in extremity 
Pain in extremity (Gr 2) 
Rhabdomyolysis 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
Dizziness (Gr 2) 
Headache 
Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
Cough (Gr 2) 
Dyspnea 
Dyspnea (Gr 3) 
Pneumonitis 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
Alopecia (Gr 2) 
Dry skin 
Dry skin (Gr 2) 
Nail changes 
 
Palmar-plantar erythrodysesthesia 
syndrome 
 
Pruritus 
Pruritus (Gr 2) 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction 
with eosinophilia and systemic 
symptoms [DRESS]) 
 
Skin and subcutaneous tissue 
disorders - Other (rash)5 
 
 
Skin and subcutaneous tissue 
disorders - Other (rash)5 (Gr 3) 
 
Stevens-Johnson syndrome6 
 
VASCULAR DISORDERS 
 
Hypertension 
Hypertension (Gr 3) 
Thromboembolic event (venous) 
 
Vascular disorders - Other 
(hemorrhage)7 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Visual disorders include visual disturbance that can be associated with conjunctival hemorrhage, corneal 
graft rejection, cyclitis, eye nevus, halo vision, iritis, macular edema, retinal hemorrhage, visual acuity 
reduced, visual impairment, and vitreous detachment. 
 
3Generalized edema includes edema, lymphedema, and edema limbs. 
 


CTEP #9149 (01-07-2020) 
 
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4Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased liver function 
tests, and visual disturbances. 
 
5Skin and subcutaneous tissue disorders - Other (rash) may include rash, rosacea, rash acneiform, 
erythematous rash, genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash papular, 
seborrhoeic dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin chapped. 
 
6Stevens-Johnson syndrome has been observed in patients treated with trametinib and dabrafenib 
combination. 
 
7The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a critical 
area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), and fatal intracranial 
hemorrhages have been reported. 
 
 
Adverse events reported on trametinib dimethyl sulfoxide (GSK1120212B) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that trametinib dimethyl 
sulfoxide (GSK1120212B) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular coagulation; Febrile 
neutropenia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Myocardial infarction; Restrictive 
cardiomyopathy; Sinus tachycardia 
EYE DISORDERS - Corneal ulcer; Eyelid function disorder; Flashing lights; Floaters; Glaucoma; 
Photophobia 
GASTROINTESTINAL DISORDERS - Ascites; Duodenal ulcer; Esophageal necrosis; Esophageal ulcer; 
Esophagitis; Gastric hemorrhage7; Gastric ulcer; Gastritis; Gastrointestinal disorders - Other (intestinal 
obstruction); Gastrointestinal disorders - Other (pneumatosis intestinalis); Gastrointestinal fistula; Gingival 
pain; Hemorrhoidal hemorrhage7; Ileus; Obstruction gastric; Pancreatitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; General 
disorders and administration site conditions - Other (axillary pain); Localized edema; Malaise; Non-cardiac 
chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatic pain; Hepatobiliary disorders - 
Other (hepatic encephalopathy) 
INFECTIONS AND INFESTATIONS - Biliary tract infection; Catheter related infection; Device related 
infection; Endocarditis infective; Enterocolitis infectious; Hepatitis viral; Infections and infestations - Other 
(abscess limb); Infections and infestations - Other (necrotizing fasciitis); Infections and infestations - Other 
(oral infection); Pharyngitis; Sepsis; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood bilirubin increased; Blood lactate dehydrogenase increased; Creatinine 
increased; Electrocardiogram QT corrected interval prolonged; GGT increased; Lipase increased; 
Lymphocyte count decreased; Platelet count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; Hyperphosphatemia; 
Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle weakness; 
Muscle cramp; Musculoskeletal and connective tissue disorder - Other (compression fracture); Myalgia; Neck 
pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
hemorrhage7; Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial hemorrhage7; Lethargy; 
Nervous system disorders - Other (diplopia); Seizure; Somnolence; Stroke; Syncope; Transient ischemic 
attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; 
Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Dysuria; Hematuria; 
Proteinuria; Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula; Vaginal hemorrhage7 


CTEP #9149 (01-07-2020) 
 
63 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage7; 
Hypoxia; Laryngeal edema; Oropharyngeal pain; Pleural effusion; Pneumothorax; Productive cough; 
Pulmonary hypertension; Respiratory failure; Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Photosensitivity; Purpura; 
Skin and subcutaneous tissue disorders - Other (erythema nodosum); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension 
 
 
Note: Trametinib (GSK1120212B) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
7.1.5 CAEPR for Everolimus (RAD-001, NSC 733504) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system.  In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text.  This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3033 patients.  Below is the CAEPR for 
Everolimus (RAD-001). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE 
in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and 
has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
Version 2.5, July 3, 2018 
 Adverse Events with Possible  
 Relationship to Everolimus (RAD-001) 
 (CTCAE 5.0 Term) 
[n= 3033] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
 
Anemia (Gr 3) 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
 
Constipation 
 
Diarrhea2 
 
Diarrhea2 (Gr 3)  
Mucositis oral3 
 
Mucositis oral3 (Gr 3) 
Nausea 
 
Nausea (Gr 3) 
Vomiting 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Edema limbs 
 
Edema limbs (Gr 2) 
Fatigue 
 
Fatigue (Gr 3) 
Fever 
 
Fever (Gr 2) 
IMMUNE SYSTEM DISORDERS 
Allergic reaction 
Anaphylaxis 
INFECTIONS AND INFESTATIONS 
Infection4 
 
Infection4 (Gr 3) 


CTEP #9149 (01-07-2020) 
 
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 Adverse Events with Possible  
 Relationship to Everolimus (RAD-001) 
 (CTCAE 5.0 Term) 
[n= 3033] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
Wound complication5 
INVESTIGATIONS 
Alanine aminotransferase 
increased 
 
Alanine aminotransferase increased 
(Gr 2) 
Alkaline phosphatase 
increased 
 
Alkaline phosphatase increased (Gr 2) 
Aspartate aminotransferase 
increased 
 
Aspartate aminotransferase increased 
(Gr 2) 
Cholesterol high 
 
Cholesterol high (Gr 2)  
Creatinine increased 
 
Creatinine increased (Gr 2) 
Lymphocyte count decreased  
Lymphocyte count decreased (Gr 2) 
Neutrophil count decreased  
Neutrophil count decreased (Gr 4) 
Platelet count decreased 
 
Platelet count decreased (Gr 4) 
Weight loss 
 
White blood cell decreased 
 
White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
 
Anorexia (Gr 2) 
Hyperglycemia6 
 
Hyperglycemia6 (Gr 3) 
Hypertriglyceridemia 
 
Hypertriglyceridemia (Gr 4) 
Hypophosphatemia 
 
Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Arthralgia 
 
Back pain 
 
Pain in extremity 
 
NERVOUS SYSTEM DISORDERS 
Dysgeusia 
 
Headache 
 
Headache (Gr 2) 
RENAL AND URINARY DISORDERS 
Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Cough 
 
Cough (Gr 2) 
Dyspnea 
 
Dyspnea (Gr 3) 
Epistaxis 
 
Epistaxis (Gr 2) 
Pneumonitis7 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Dry skin 
 
Pruritus 
 
Rash maculo-papular 
 
Rash maculo-papular (Gr 2) 
Skin and subcutaneous tissue 
disorders - Other 
(angioedema)8  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. 


CTEP #9149 (01-07-2020) 
 
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3Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip 
ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. 
4Infection includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
5Everolimus delays wound healing and increases the occurrence of wound-related complications like 
wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. 
6Hyperglycemia may result in either exacerbation of or development of new onset diabetes mellitus. 
7Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, 
pulmonary toxicity, alveolitis, pulmonary fibrosis, and restrictive pulmonary disease. 
8Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema. 
9Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive 
disorder. 
 
Adverse events reported on everolimus (RAD-001) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that everolimus (RAD-001) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (myocardial abnormality); Chest 
pain - cardiac; Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; Sinus 
bradycardia; Sinus tachycardia; Supraventricular tachycardia  
ENDOCRINE DISORDERS - Endocrine disorders - Other (increased blood follicle stimulating 
hormone [FSH] levels); Endocrine disorders - Other (increased blood luteinizing hormone [LH] levels); 
Hypothyroidism; Testosterone deficiency 
EYE DISORDERS - Blurred vision; Keratitis 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Dry mouth; Dyspepsia; Dysphagia; 
Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (Dieulafoy's lesion); 
Hemorrhoids; Intra-abdominal hemorrhage; Oral pain; Pancreatitis; Periodontal disease; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; 
Edema trunk; Flu like symptoms; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (hepatomegaly) 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bicarbonate decreased; 
Blood bilirubin increased; Blood lactate dehydrogenase increased; CPK increased; GGT increased; INR 
increased; Investigations - Other (low density lipoprotein raised); Investigations - Other 
(thrombocythemia). 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Glucose intolerance; 
Hypercalcemia; Hyperkalemia; Hyperlipidemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Metabolism and nutrition disorders - Other (high ammonia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest wall pain; 
Generalized muscle weakness; Muscle cramp; Muscle weakness lower limb; Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (ovarian cysts) 
NERVOUS SYSTEM DISORDERS - Dizziness; Encephalopathy; Hydrocephalus; Lethargy; 
Paresthesia 
PSYCHIATRIC DISORDERS - Agitation; Anxiety[76]; Delirium; Depression; Insomnia; Irritability; 
Mania 
RENAL AND URINARY DISORDERS - Hematuria; Proteinuria; Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Dysmenorrhea; Genital edema; Irregular 
menstruation; Menorrhagia; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Pharyngolaryngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (rales); Rhinorrhea; Sore throat; Voice alteration 


CTEP #9149 (01-07-2020) 
 
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SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Nail loss; Palmar-plantar erythrodysesthesia 
syndrome; Rash acneiform; Skin and subcutaneous tissue disorders - Other (nail disorder); Skin and 
subcutaneous tissue disorders - Other (skin lesion); Skin ulceration 
VASCULAR DISORDERS - Flushing; Hypertension; Lymphedema; Phlebitis; Thromboembolic event; 
Vascular disorders - Other (acute bowel ischemia); Vascular disorders - Other (hemorrhage) 
 
Note: Everolimus (RAD-001) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.2 
Adverse Event Characteristics  
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized until March 31, 2018 for AE reporting.  CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP Web site (http://ctep.cancer.gov). 
 
• ‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for 
expedited reporting purposes only.  Specific Protocol Exceptions to Expedited Reporting 
(SPEER) appears as bold and italicized text in the CAEPR (Section 7.1). 
 
• Attribution of the AE: Definite – The AE is clearly related to the study treatment; 
Probable – The AE is likely related to the study treatment; Possible – The AE may be 
related to the study treatment; Unlikely – The AE is doubtfully related to the study 
treatment; Unrelated – The AE is clearly NOT related to the study treatment. 
7.3 
Expedited Adverse Event Reporting 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
Event Reporting System), accessed via the CTEP home page 
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented in 
the “CTEP, NCI Guidelines: Adverse Event Reporting Requirements” which can 
be downloaded from the CTEP home page (http://ctep.cancer.gov).  These 
requirements are briefly outlined in the table below (Section 7.3.2). 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification is 
to be made to NCI by telephone at: (301) 897-7497.  An electronic report MUST 
be submitted immediately upon re-establishment of internet connection. 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals: Study Coordinator of the Lead Organization, lead 
organization study research nurses, Principal Investigator, and the local treating 
physician.  CTEP-AERS provides a copy feature for other e-mail recipients. 
7.3.2 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the 
Last Administration of the Investigational agent/Intervention 1,2 


CTEP #9149 (01-07-2020) 
 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
• 
Death 
• 
A life-threatening adverse event  
• 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may 
be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
1) 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
2) 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP 
to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period. 
Effective Date:  May 5, 2011 
 
7.3.3 Protocol-specific expedited AE reporting exclusions. 
Lymphopenia (any grade), alopecia (any grade), anemia (grade 2), electrolytes (grade 2: 
sodium, potassium, phosphorous, and magnesium), albumin (grade 2), hyperuricemia 
(grade 3), INR (grade 2), and PTT (grade 2) will NOT be reported through CTEP-AERS 
but will be reported in the routine data submissions.  
 


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7.3.4 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Neonatal loss”, the Pregnancy Information Form should be completed and faxed along 
with any additional medical information to 301-230-0159.  The potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section of the CTEP-AERS report. 
 
7.3.4.1 Pregnancy 
• Because patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic, DCTD/DCP is requesting that 
pregnancy should 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. 
• The pregnancy outcome for patients on study should be reported via CTEP-AERS 
at the time the outcome becomes known, accompanied by the same Pregnancy 
Report Form used for the initial report 
 
7.3.4.2 Pregnancy loss 
• Pregnancy loss is defined in CTCAE as “Death in utero.” 
• Any pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy 
loss” under the Pregnancy, puerperium and perinatal conditions SOC. 
• A pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS 
recognizes this event as a patient death. 
 
7.3.4.3 Death Neonatal 
• Neonatal death, defined in CTCAE as “A disorder characterized by cessation of 
life occurring during the first 28 days of life” that is felt by the investigator to be 
at least possibly due to the investigational agent/intervention, should be reported 
expeditiously. 
• A neonatal death should be reported expeditiously as Grade 4 “Death neonatal” 
under the General disorders and administration SOC. 
• Neonatal death should NOT be reported as Grade 5 “Death neonatal” under the 
General disorders and administration SOC.  If reported as such, the CTEP-AERS 
interprets this as a death of the patient being treated. 
 
7.4 
Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
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.  AEs are reported in a routine manner at scheduled times 


CTEP #9149 (01-07-2020) 
 
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during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
7.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS.  Three options are available to describe the event:  
 
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.  
7.6 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified. 
 
8. PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with these agents can be found in 
Section 7.1. 
8.1 
Temozolomide (NSC 362856) 
Availability: Please refer to the FDA-approved package insert for complete product information.  
Commercial supplies of temozolomide will be purchased by the DCTD, NCI and distributed by 
the Pharmaceutical Management Branch, CTEP.  
 
Toxicities: The most common adverse events across the cumulative temozolomide experience 
were alopecia, nausea, vomiting, anorexia, headache, and constipation.  Forty-nine percent 
(49%) of patients treated with temozolomide reported one or more severe or life-threatening 
events, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia 
(5%).  Myelosuppression (neutropenia and thrombocytopenia), which is a known DLT for most 
cytotoxic agents, was observed, as were Grade 3 or Grade 4 neutrophil abnormalities including 
neutropenic events, and Grade 3 or Grade 4 platelet abnormalities, including thrombocytopenic 
events. 
 
Chemical Name: 3,4-dihydro-3-11 methyl-4-oxoimidazo(5,1-d)-as-tetrazine-8-carboxamide. 
 
Other Names: Temodar®, Temodal, Temcad 


CTEP #9149 (01-07-2020) 
 
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CAS Registry Number: 85622-93-1 
 
Molecular Formula: C6H6N6O2  
 
M.W.:  194.15 
 
Mode of Action:  Temozolomide is not directly active but undergoes rapid nonenzymatic 
conversion at physiologic pH to the reactive compound MTIC.  The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA.  Alkylation (methylation) occurs mainly at the 
O6 and N7 positions of guanine. 
 
How Supplied:  PMB, CTEP, DCTD distributes commercially labeled Temozolomide as 5 mg, 
20 mg, 100 mg and 250 mg capsules for oral administration.  Each bottle contains 5 capsules.  
The dose of temozolomide is to be rounded to the nearest 5 mg.  The manufacturer of the NCI-
purchased supplies may vary throughout the course of the trial.  Temozolomide capsules contain 
the following inactive ingredients: lactose anhydrous, colloidal silicon dioxide, sodium starch 
glycolate, tartaric acid, and stearic acid in varying quantities per capsule strength.  Refer to the 
approved package insert for complete product information and physical description of the 
supplied product. 
 
Storage:  Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). 
 
Stability:  Refer to the package label for shelf life. 
 
Route of Administration:  Oral.   
 
Method of Administration:  Take each day’s dose of capsules at one time, with a full glass of 
water.  They should be swallowed whole and never chewed.  If capsules are vomited do not take 
a second dose.  New capsules should not be taken until the next planned dose.  The incidence of 
nausea and vomiting is decreased when temozolomide is taken on an empty stomach. 
8.2 
Carboplatin (NSC 241240) 
Availability: Please refer to the FDA-approved package insert for complete product information. 
Commercial supplies of Carboplatin will be purchased by the DCTD, NCI and distributed by the 
Pharmaceutical Management Branch, CTEP. 
 
How supplied: PMB, CTEP, DCTD distributes commercially-labeled supplies of Carboplatin 
aqueous solution Injection as 450 mg/45 mL (10 mg/mL in Water for Injection) multi-dose vials.  
The manufacturer of the NCI-purchased supplies may vary throughout the course of the trial.  
Refer to the approved package insert for complete product information and description of the 
supplied product. 
 
Preparation: Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 
mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. 
 


CTEP #9149 (01-07-2020) 
 
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Storage and Stability: Unopened vials of Carboplatin aqueous solution are stable to the date 
indicated on the package when stored at 25°C (77°F); excursions permitted from 15°-30°C (59°-
86°F) [see USP Controlled Room Temperature]. Protect from light. 
Carboplatin aqueous solution multi-dose vials maintain microbial, chemical, and physical 
stability for up to 14 days at 25°C following initial vial entry. When prepared as directed, 
carboplatin solutions for infusion are stable for 8 hours at room temperature (25°C). Prepared 
solutions for infusion are to be discarded 8 hours after preparation. 
 
NOTE: Aluminum reacts with carboplatin, causing precipitate formation and loss of potency. 
Therefore, needles or intravenous sets containing aluminum parts that may come in contact with 
the drug must not be used for the preparation or administration of carboplatin.  
 
Dosing and Administration: Carboplatin will be administered concomitantly with AZD1775 as 
an i.v. infusion over 30-70 minutes.  The dose will be calculated based on the patient’s actual 
body weight at each treatment visit and the AUC (area under curve) dosing according to the 
formula provided below.   
 
The calculated GFR for the carboplatin dose will be based on the calculated creatinine clearance 
using the Cockroff-Gault formula.  
Calvert Formula for carboplatin dose: AUC Dose = 5.0 x (GFR + 25) 
Where GFR (Cockroff-Gault):  
GFR = (140 – pt. age in years) (weight in Kg) x 0.85 (females) or 1.0 (males)  
 
 
 
serum creatinine x 72 
 
The GFR (calculated by Cockcroft-Gault or any other means using creatinine) used in the 
Calvert formula to calculate AUC-based dosing should not exceed 125 mL/min under any 
circumstance.  By definition, this results in the following upper limits on the dose to be 
administered, by AUC target: 
 
AUC target 
(mg•min/mL) 
Maximum carboplatin dose 
(mg) 
4 
600 
5 
750 
 
 
Questions about this calculation should be directed at the study investigator. 
 
Toxicities: Some of the expected adverse events from carboplatin are listed below.  For further 
description of adverse events, see Package Insert.  
 
Hematologic: Myelosuppression 
Gastrointestinal: Nausea, vomiting, diarrhea, weight loss, constipation, gastrointestinal pain 
Metabolic: Electrolyte imbalances, hypomagnesemia, hypocalcemia, hyponatremia, 
hyperuremia, hypokalemia 
Hepatic:Elevated alkaline phosphatase, AST, and total bilirubin 


CTEP #9149 (01-07-2020) 
 
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CNS: Peripheral neuropathies (mild paresthesias, clinical ototoxicity and other sensory 
abnormalities are rare) 
Genitourinary: Renal tubular damage, renal insufficiency, impotence, sterility, amenorrhea, 
gynecomastia 
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, pruritis, and rarely 
hypotension or bronchospasm 
Other: Alopecia, pain, asthenia, and mucosal side effects 
Patient Care Implications: Patients taking carboplatin should avoid the use of live vaccines and 
close contact with those who have received live vaccines.  Examples of live vaccines include 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and 
TY21a typhoid vaccines. 
8.3 
Everolimus (NSC 733504) 
Chemical Name: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-
dihydroxy-12-{(1R)-2-((1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl)-1-
methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-
azatricyclo(30.3.1.04,9)hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone 
 
Other Names: RAD001, Afinitor 
 
Classification: mTOR inhibitor 
 
CAS Registry Number: 159351-69-6 
 
Molecular Formula:  C53H83NO14  
M.W.: 958.2 
 
Mode of Action: Everolimus is an inhibitor of selective mammalian target of rapamycin 
(mTOR), the effects of which specifically target the mTOR-raptor signal transduction complex 1 
(mTORC1).  Inhibition of mTORC1, an essential regulator of global protein synthesis 
downstream on the PI3K/AKT/mTOR pathway, reduces tumor cell proliferation, glycolysis, and 
angiogenesis.  The PI3K/AKT/mTOR pathway is dysregulated in the majority of human cancers 
and is the object of many targeted agents. 
 
Description: White to faintly yellow powder 
 
How Supplied: Novartis supplies and PMB, CTEP, DCTD distributes commercially labeled 
Everolimus as 2.5 mg, 5 mg, and 10 mg tablets for oral administration.  Each box of 28 tablets 
contains 4 blistercards of 7 tablets each.  The white to slightly yellow, elongated tablets are 
distinguished as follows: 
 
• 2.5 mg tablet is engraved with “LCL” on one site and “NVR” on the other 
• 5 mg tablet is engraved with “5” on one side and “NVR” on the other 
• 10 mg tablet is engraved with “UHE” on one side and “NVR” on the other 
 


CTEP #9149 (01-07-2020) 
 
73 
 
Tablet excipients include drug substance, 0.2% butylated hydroxytoluene (BHT), magnesium 
stearate, lactose anhydrous/anhydrous lactose, lactose monohydrate, 
hypromellose/hydroxypropyl methylcellulose, and crospovidone. 
 
Storage: Store at 25°C (77°F) [excursions permitted between 15 to 30°C (59 to 85°F].  
 
Stability: Refer to the package label for shelf life.  Store tablets in the original container and 
protect from light and moisture. 
 
Route and Method of Administration: Oral administration.  Tablets should be swallowed whole 
with a glass of water.  They can be taken with or without food but should be taken consistently the 
same time every day.  If a dose is missed, it can still be taken up to 6 hours after the usual time of 
administration.  Missed doses more than 6 hours late should be skipped for that day. 
 
Potential Drug Interactions: Everolimus is a substrate of CYP3A4 and P-glycoprotein (PgP).  
Concomitant treatment with strong inhibitors or inducers of CYP3A4 or PgP should be avoided.  
Use caution when everolimus is given concomitantly with moderate inhibitors or inducers of 
CYP3A4 and PgP.  Consult the protocol document or study investigator prior to making any 
dose adjustments related to potential drug-drug interactions. 
 
In vitro, everolimus is a competitive inhibitor of CYP3A4, a mixed inhibitor of CYP2D6, an 
inhibitor of transport proteins, OATP1B1 and OATP1B3 and a moderate inhibitor of P-gp.  
Exercise caution when everolimus is taken in combination with orally administered substrates of 
these enzymes and transporters, in particular, CYP3A4 substrates with a narrow therapeutic 
index. 
 
Co-administration with angiotensin-converting enzyme (ACE) inhibitors may increase the risk 
for angioedema based on results of a pooled analysis of randomized, double blind studies. 
 
Patient Care Implications: Patients taking everolimus should avoid the use of live vaccines and 
close contact with those who have received live vaccines.  Examples of live vaccines include 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and 
TY21a typhoid vaccines. 
8.4 
Veliparib (NSC 737664) 
Chemical Name: 1H-Benzimidazole-7-carboxamide, 2-[(2R)-2-methyl-2-pyrrolidinyl]- 
Other Names:ABT-888, A-861695.0 
Classification: Poly (ADP-ribosome) polymerase (PARP) Inhibitor 
CAS Registry Number: 912444-00-9 
Molecular Formula: C13H16N4O  
M.W.:  244.29 
Approximate Solubility: Freely soluble at pH < 6.9, soluble at pH 6.9 to 7.1, and slightly soluble 
at pH > 7.1. 
Mode of Action: Veliparib inhibits the formation of poly (ADP-ribose) (PAR) polymers in vitro 
and in vivo.  It inhibits the repair of DNA when the DNA is damaged by cytotoxic agents.  


CTEP #9149 (01-07-2020) 
 
74 
 
Veliparib increases antitumor efficacy when added to DNA-damaging therapies such as 
temozolomide. 
Description: White to light yellow solid.   
How Supplied: Veliparib capsules are available in 10 mg, 20 mg, 40 mg, and 50 mg immediate 
release capsules.  The inactive ingredients are microcrystalline cellulose, colloidal silicon dioxide, 
magnesium stearate, gelatin, sodium lauryl sulfate, FD&C yellow #5, and titanium dioxide.  The 
capsules are packaged in HDPE bottles, and each HDPE bottle contains 16 capsules or 64 capsules. 
 
Veliparib capsules may be repackaged from the supplied HDPE bottles into amber (or other low-
actinic) child resistant pharmacy dispensing bottles.  Expiration will be 30 days from the 
repackaging date (or the original retest date, whichever is earlier) when stored at 15°C to 25°C 
(59°F to 77°F).  
 
Storage:  Store the original bottle at 15º to 25º C (59º to 77º F).  
Stability:  Shelf-life stability studies for Veliparib capsules are ongoing.  
Route(s) of Administration:  Oral 
Method of Administration:  Administer Veliparib orally without regards to meals.  
Potential Drug Interactions: Clinical studies evaluating the metabolism of Veliparib have not been 
conducted.  However, results from the in vitro analysis reveal that this agent is metabolized by 
multiple isoenzymes – CYP1A1, 2D6, 2C19, and 3A4.  Veliparib is neither a potent inhibitor nor a 
potent inducer of the CYP-450 isoenzymes.  Use caution when concomitantly administering with 
drugs that are substrate, inhibitor, or inducers of CYP1A1, 2D6, 2C19 and 3A4.  Veliparib clears 
primarily in the urine as intact parent drug along with metabolites suggesting that renal function 
plays an important role in the drug clearance and its metabolites.   
Patient Care Implications: Patients may feel fatigue or tiredness.  Loss of appetite and losing 
weight are common.  Provide appropriate supportive care for diarrhea.  Avoid long-sun exposure as 
it might exacerbate skin rash. 
Availability: Veliparib is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI.  Veliparib is provided to the NCI under a 
Collaborative Agreement between the Pharmaceutical Collaborator and the DCTD, NCI. 
8.5 
AZD1775 (NSC 751084) 
Chemical Name: 2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[4-(4-methylpiperazin-
1-yl)anilino] pyrazolo[3,4-d]pyrimidin-3-one hemihydrate 
 
Classification: Inhibitor of Wee1-kinase 
 
CAS: 277170-60-1 
 
Molecular Formula:  C27H32N8O2·0.5H2O  
M.W.: 518.623 
 
Approximate Solubility: Aqueous solubility is 0.02 mg/mL.   
 


CTEP #9149 (01-07-2020) 
 
75 
 
Mode of Action: AZD1775 is an inhibitor of the Wee1-kinase.  Wee1 is a tyrosine kinase 
upstream of CDC2 thereby involved in regulation of cell cycle checkpoints, particularly the G2 
checkpoint.  As the majority of human cancers harbor abnormalities in the p53 pathway, they 
become more dependent on S- and G2-phase checkpoints.  In preclinical models, AZD1775 
selectively enhanced chemotherapy-induced death of cells deficient in p53 signaling.  
 
Description: AZD1775 is a crystalline, non-hygroscopic, monohydrate of the neutral drug.  It 
dehydrates upon heating leading to formation of a crystalline anhydrate. 
 
How Supplied: AZD1775 is supplied by AstraZeneca and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI as capsules available in 25 mg (yellow color, size 2 gelatin 
capsule) and 100 mg (orange color, size 2 gelatin capsule) strengths.  Due to no further 
manufacturing, the 200 mg (light brown color, size 0 gelatin capsule) strength is available only as 
inventory allows until the shelf life is reached.  The capsules consist of a roller compacted granule 
of agent, lactose, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.  Each 
high-density polyethylene (HDPE) bottle contains 20 capsules. 
 
Storage: Store bottles at controlled room temperature, not to exceed 30° C. 
 
Stability:  Shelf life studies of AZD1775 are on-going. 
 
Route of Administration: Oral administration.  Take AZD1775 at least two hours before or two 
hours after a meal. 
 
Potential Drug Interactions: AZD1775 is primarily metabolized by CYP3A4 and is a weak, 
time-dependent inhibitor of CYP3A4.  Avoid concomitant CYP3A4 moderate or strong 
inhibitors/inducers, and sensitive substrates with a narrow therapeutic index.  AZD1775 is also a 
weak inhibitor of CYP2C19.  Caution should be exercised with concomitant administration of 
sensitive substrates or substrates with a narrow therapeutic index. 
 
In vitro transporter studies have shown that AZD1775 was an inhibitor of OATP1B1, OATP1B3, 
MATE1, MATE2K, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), and a 
substrate for P-gp and BCRP.  The PK parameters of AZD1775 could be altered if AZD1775 is 
co-administered with P-gp and BCRP inhibitors/inducers, and there is potential for drug-drug 
interactions when co-administered with OATP1B1, OATP1B3, MATE1, MATE2K, P-gp and 
BCRP substrates.  This finding is particularly relevant for drugs administered orally where 
exposure is normally limited by BCRP-mediated efflux, in particular some statins.  Modelling 
has predicted a substantial increase in the exposure of atorvastatin when co-administered with 
AZD1775 and the use of atorvastatin is therefore prohibited. 
 
Contraindications: Treatment with AZD1775 is contraindicated in subjects with 
hypersensitivity to any component of the drug.  Developmental and reproductive toxicity studies 
of AZD1775 have not been performed.  AZD1775 is not to be given to women who are pregnant 
or breast feeding.  
 


CTEP #9149 (01-07-2020) 
 
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Availability AZD1775 is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI.  AZD1775 is provided to the NCI under a 
Collaborative Agreement between the Pharmaceutical Collaborator and DCTD, NCI. 
8.6 
Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) 
Chemical Name (IUPAC): equimolecular combination of acetamide, N-[3-[3-cyclopropyl-5-[(2-
fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro6,8-dimethyl- 2,4,7-trioxopyrido[4,3-d]pyrimidin-
1(2H)-yl]phenyl] with 1,1’-sulfinylbis[methane] 
 
Other Names: trametinib, GSK1120212, JTP-74057, JTP-78296, JTP-75303, Mekinist 
 
CAS Registry Number: 1187431-43-1 
 
Classification: MEK inhibitor 
 
Molecular Formula:  C26H23FIN5O4 •  C2H6OS M.W.: 693.53  
 
Approximate Solubility: Trametinib dimethyl sulfoxide is almost insoluble in water (<0.0001 
mg/mL at 25° C) 
 
Mode of Action: Trametinib dimethyl sulfoxide is a reversible, highly selective, allosteric 
inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2.  
Tumor cells commonly have hyperactivated extracellular signal-related kinase (ERK) pathways 
in which MEK is a critical component.  Trametinib dimethyl sulfoxide inhibits activation of 
MEK by RAF kinases and MEK kinases. 
 
Description:  Trametinib dimethyl sulfoxide is a white to almost white powder. 
 
How Supplied: Novartis supplies and CTEP, NCI, DCTD distributes 0.5 mg and 2 mg (as free 
base) tablets.  Each commercially-labeled bottle contains 30 tablets with a desiccant. 
 
The tablet core contains mannitol, microcrystalline cellulose, hypromellose, croscarmellose 
sodium, magnesium stearate (non-animal), colloidal silicon dioxide, and sodium lauryl sulfate.  
 
• 0.5 mg tablets are yellow, modified oval, biconvex and film-coated with ‘GS’ debossed on one 
face and ‘TFC’ on the opposing face.  Aqueous film coating consists of hypromellose, titanium 
dioxide, polyethylene glycol, iron oxide yellow. 
• 2 mg tablets are pink, round, biconvex and film-coated with ‘GS’ debossed on one face and 
‘HMJ’ on the opposing face.  Aqueous film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, polysorbate 80, iron oxide red. 
 
Storage: Store tablets at 2°C -8°C in the original bottle.  Do not repackage tablets or remove 
desiccant.  Bottles should be protected from light and moisture. 
 
If a storage temperature excursion is identified, promptly return trametinib to 2°C -8°C and 
quarantine the supplies.  Provide a detailed report of the excursion (including documentation of 


CTEP #9149 (01-07-2020) 
 
77 
 
temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability. 
 
Stability: Refer to the package label for expiration. 
 
Route of Administration: Oral.  Take by mouth on an empty stomach, either 1 hour before or 2 
hours after a meal.  If a dose of trametinib is missed, the dose can be taken if it is more than 12 
hours until the next scheduled dose. 
 
Potential Drug Interactions: In vitro studies suggest that trametinib dimethyl sulfoxide is not a 
substrate of CYP enzymes or of human BCRP, MRP2, OATP1B1, OATP1B3, OATP2B1, OCT1, 
or MATE1 transporters.  Trametinib elimination by deacetylation to metabolite M5 is dependent 
on carboxylesterases (CES1b, CES1c, and CES2).  M5 is eliminated by CYP3A4 and other 
pathways, presenting the clinically relevant, albeit low, potential for drug-drug interaction.  
Trametinib is a substrate for P-gp and BSEP, but this is not expected to be clinically relevant due 
to trametinib’s high permeability. 
 
Trametinib dimethyl sulfoxide is an in vitro inhibitor of CYP 2C8 and is anticipated to have 
overall low potential for drug interactions as a perpetrator.  It is also a weak CYP3A4 inducer 
and expected to have little clinical effect on sensitive substrates.  Trametinib is not an inhibitor 
of CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 3A4 and not an inhibitor of P-gp, BCRP, 
OATP1B1, OATP1B3, OAT1, OAT3, OCT2 MRP2 and MATE1.  
 
Patient Care Implications: Advise women study participants of reproductive potential to use 
effective contraception while receiving study treatment and for 4 months after the last dose of 
trametinib.  Refer to the protocol document for specific guidance. 
8.7 
Agent Ordering 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned to the 
treatment arm prior to submitting the clinical drug request to PMB. 
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. 
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, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management.   


CTEP #9149 (01-07-2020) 
 
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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 Everolimus, Veliparib, AZD1775, and Trametinib dimethyl 
sulfoxide will be accessible to site investigators and research staff through the PMB OAOP 
application.  Access to OAOP requires the establishment of a CTEP IAM account and the 
maintenance of an “active” account status, a “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  
• IB Coordinator:  IBCoordinator@mail.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) 
 
9. GENETIC ANALYSIS 
9.1 
Tumor Biopsies 
A mandatory pre-treatment tumor biopsy (2 cores) will be obtained from all patients after signing 
the consent and enrolling on the study to determine whether the tumor has a mutation in one of 
the pathways of interest, unless an FFPE block that meets Eligibility Criterion 3.1.2 is provided 
or a CLIA genetic testing report from a MATCH-designated lab is available and indicates an 
actionable mutation of interest.  Patients entered on trial based on outside reports from MATCH-
designated labs will be biopsied during their first week on study for confirmatory screening with 
the Oncominev3 (MATCHv3) assay.  Biopsy samples will be fixed in formalin and shipped as 
described in Section 9.3.   
 
Additionally, an optional tumor biopsy (2-5 cores) may be taken at or near the time of disease 
progression to assess for new acquired mutations. 
 
There is increasing awareness that biopsies lacking tumor of sufficient quantity or quality for 
analysis are a barrier to clinical research in both trials for which genetic sequencing establishes 
eligibility and in trials where paired pre- and post-treatment biopsies are collected to quantify 


CTEP #9149 (01-07-2020) 
 
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target modulation.  In a retrospective analysis, we found that only 70% of the 18-gauge needle 
biopsies collected met pharmacodynamic assay quality control criteria due to necrosis, fibrosis, 
no or insufficient tumor content, and/or poor morphology; the success rate is only 50% when 
both pre- and post- treatment (paired) biopsies are required (Ferry-Galow et al., manuscript in 
preparation).  The NCI is currently promoting efforts and providing resources to improve 
research biopsy quality given that insufficient tumor tissue samples compromise the scientific 
value of the study, the patients’ contribution to research, and the staff resources devoted to 
clinical trials.   
 
Based on our experience, immediate and significant improvements in biopsy quality can be 
achieved simply from better communication with the interventional radiologists performing the 
biopsy procedures.  We therefore recommend that participating site PIs invite their site’s 
radiologists to join the research team and to review and discuss this protocol and the biopsy and 
specimen handling requirements.   We recognize that these individuals are not always 
compensated for the additional time required to participate nor recognized for their effort, but at 
a minimum, communicating that research biopsies present requirements beyond those of biopsies 
collected for diagnostic purposes is of considerable value.  Collecting multiple cores from each 
patient during each biopsy procedure increases the probability of obtaining sufficient samples for 
analysis, and the radiologist is best placed to determine how many cores are safe and feasible and 
evaluate patient willingness to continue donation.  In the absence of a reliable and rapid method 
for “real-time” tumor content evaluation and given the need to preserve the tissue rapidly to 
ensure optimal sample quality, the interventional radiologist’s judgment and experience are 
critical to procuring and preserving quality material.    
 
An adequate tumor biopsy sample will contain at least 50% tumor cells with minimal necrosis 
and stromal tissue; samples with less than 50% tumor cells will undergo tumor enrichment using 
a standardized macrodissection protocol.  In case of samples with insufficient tumor content or 
DNA yield for analysis, the patient will be given the option to undergo a repeat tumor biopsy to 
obtain more tissue.  Patients from whom sufficient tumor DNA material cannot be obtained for 
targeted analysis will be taken off-study.  
9.1.1 Biopsy Procedure 
No more than three serial tumor biopsies will be obtained through Interventional 
Radiology by a percutaneous approach: one mandatory at screening baseline; one 
optional repeat biopsy if sufficient tumor DNA cannot be isolated at baseline; and one 
optional biopsy at time of disease progression (this biopsy may instead be collected on 
day 1 (± 2 days) of the cycle following any restaging at which a 10-19% increase in 
tumor volume is observed, per RECIST criteria, if the patient has been on study for at 
least 4 cycles).   
 
For eligibility determination, it is preferred that up to three core biopsies18-gauge in 
diameter and at least 1 cm in length are obtained.  Only percutaneous biopsies will be 
performed on patients with solid tumors.  However, excisional biopsy is allowed if 
indicated and can be used for analysis.  Biopsies will be sent for analyses as defined in 
the protocol.  It is estimated that there will be between 2-5 million cells from each biopsy.  
If a site is deemed appropriate for biopsy with minimal risk to the participant by 


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agreement between the investigators and Interventional Radiology, an attempt at biopsy 
will be made.   
 
The biopsy procedure to be used in this protocol is described below; local anesthesia will 
be administered.  Such biopsies can be safely performed as evidenced by literature 
reports [93] as well as our experience at the Clinical Center.  Risks of the procedure 
include, but are not limited to, bleeding, infection, pain, and scarring.  Each site will 
follow local Interventional Radiology SOPs for coagulant panel and platelets. 
 
• All biopsies will be by percutaneous approach unless excisional biopsy is 
indicated. 
• No biopsy by an invasive (endoscopic, laparoscopic, or surgical) procedure will 
be performed. 
 
The use of imaging to facilitate biopsies will be decided by members of the Interventional 
Radiology team and may include ultrasound, CT scan, or MRI.  Should CT scan be 
needed for biopsy, the number of scans for each procedure will be limited to the 
minimum number needed to safely obtain a biopsy.  Tumor biopsies and local anesthesia 
will be administered only if they are considered to be of low risk to the participant as 
determined by the investigators and Interventional Radiology.  
 
If an initial attempt at percutaneous biopsy is unsuccessful, the patient will be given an 
option to proceed with a repeated attempt at percutaneous biopsy.  If a pre-treatment 
biopsy sample is unable to be obtained for a given patient, or the patient chooses not to 
undergo the pre-treatment tumor biopsy, he/she must be taken off study because the 
genetic data from the tumor biopsy are essential to the primary objective of the trial. 
9.2 
Screening Eligibility Sample Collection and Processing 
At the NCI, the research nurse will contact the NCI Phase I/II PK/PD Support Group in NIH 
Building 10 at least 24 hours prior to sample collection (E-mail: NCIPK-
PDsupportgroup@mail.nih.gov; Pager: 102-12798; Phone: 301-451-1169; Fax: 301-480-5871).  
The lab staff will be paged for sample pick-up.  At the NCI only, 2-3 additional cores may be 
collected and snap frozen (see NCI Supplementary Appendix).   
 
Other participating sites should follow the sample collection instructions in Appendix E.  
 
Formalin jars (prefilled 30 mL) pre-labeled with the participant ID, biopsy date, protocol 
number, and site of tissue biopsy will be used for biopsy collection.  Surgical tumor tissue and 
needle core biopsies (collected by 16-18-gauge needles) collected in neutral buffered formalin 
(one core per jar) will be shipped via overnight courier at ambient temperature on the day of 
biopsy collection to Dr. Mickey Williams’ laboratory (MoCha) at the Frederick National 
Laboratory for Cancer Research (FNLCR) as defined in Appendix E.   


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9.3 
Shipping for Genetic Analysis 
9.3.1 Tumor Samples 
For all patients, formalin-fixed tumor tissue or suitable FFPE block will be submitted for 
the genetic analyses described below.  Genetic analysis will be done by the MoCha 
Laboratory.  Samples labeled with unique patient IDs only will be sent directly to Dr. 
Mickey Williams’ laboratory.  Do NOT include patient identifiers (e.g., medical 
record number, patient name, or initials) with the samples.   
 
Please e-mail NCI-FrederickMPACTCLIA@mail.nih.gov if you have any questions 
about sample shipping.  A sample shipping manifest is included in Appendix E. 
 
Following processing and paraffin embedding, one tissue section will be stained with 
H&E for histopathological examination by a designated pathologist.  Tumor cellular 
content must be at least 50% and estimated tumor content will be recorded.  The 
remaining biopsy will be extracted for nucleic acids using the Qiagen FFPET All-Prep 
procedure.  DNA will be assessed for quantity and quality by spectroscopy (OD 260/280) 
and a PCR-based amplification quality assessment test.  All specimens that meet 
necessary quantity and quality will be sequenced using a targeted sequencing assay.  This 
assay will identify those mutations that are used for treatment assignment.   
 
If sufficient DNA is available from the tumor biopsy, whole-exome sequencing will be 
performed retrospectively for research purposes on samples unlinked from patient 
identifiers.   
9.3.2 Blood Samples for Genetic Analysis 
Whole blood samples will be collected to obtain plasma and mononuclear cells.  All 
sequencing analysis from the plasma and mononuclear cells will be performed only after 
the samples are unlinked and stripped of the patient identifiers for retrospective research 
sequencing.  The nucleic acid extracted from the unlinked patient’s mononuclear cells 
will be sequenced to compare somatic mutational status to the tumor biopsy specimen.  
Plasma collected in this process will be delinked and used in exploratory research 
protocol to study (but not limited to), circulating tumor DNA.   
 
Two 10-mL cell-free DNA BCT (Streck) tubes should be collected on the same day as 
the screening eligibility biopsy (collection time can be either pre- or post-biopsy) and 
shipped at ambient temperature as described in Appendix E.  The samples should be 
labeled with only the unique patient ID.  Do NOT include patient identifiers (e.g., 
medical record number, patient name, or initials) with the samples.    
 
Please e-mail NCI-FrederickMPACTCLIA@mail.nih.gov if you have any questions 
about sample shipping.  A sample shipping manifest is included in Appendix E.   
 
Upon receipt at the service laboratory, genomic DNA will be extracted for clinical 
targeted sequencing. 


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9.4 
Sample Handling and Unlinking Procedures 
Biospecimens will be collected and processed using locked SOPs that will ensure both specimen 
quality and patient confidentiality pursuant to informed consent provisions. 
 
Using a computerized inventory system, all specimen collection and processing steps will be 
documented and the specific location of each specimen will be tracked.  Each new specimen 
collected will be assigned a unique barcode identifier that can be linked to the original specimen 
collected and other relevant information within the inventory system.  To ensure patient 
confidentiality, only containers used for the initial specimen collections will be labeled with 
patient identifiers.  Only the barcode identifier will be applied to all subsequent specimen 
containers.  When specimens are processed and aliquoted, no patient information will be 
included on the new containers.  Original specimen containers will be discarded.  Only barcode-
labeled specimens without patient identifiers will be shipped for analysis and/or storage.  
Specimen labels will indicate: CTEP protocol number 9149, unique patient accession number, 3-
digit sample number (see list below), collection time, and total volume collected, as appropriate.  
Samples from sets of at least three patients will be grouped for scientific analysis.   
 
Standardized 3-digit sample collection numbers: 
300 series: blood for pharmacodynamics  
500 series: tumor biopsies 
800 series: blood for research (Streck tubes)  
 
The inventory process contains other security provisions sufficient to safeguard patient privacy 
and confidentiality.  Access to the inventory system and associated documents will be restricted 
to appropriate individuals.  Requests to use specimens stored in the repository must be approved.  
The only patient information available in the inventory system will be the patient sex, diagnosis, 
and level of informed consent given.  SOPs ensure that any changes in informed consent made 
by a patient and relayed to the PI will be reflected in the inventory system to ensure that 
specimens are destroyed as appropriate.  All laboratory personnel will be trained to adhere to 
SOPs and will be monitored for high-quality performance. 
 
Any new use of these samples will require prospective IRB review and approval.  Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material. 
 
 
 
If at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request.  Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB.  Samples which are unlinked cannot be traced to the individual patients, and the patient’s 
request cannot be met.  Any samples lost (in transit or by a researcher) or destroyed due to 
unknown sample integrity (e.g., broken freezer allows for extensive sample thawing, etc.) will be 
reported as such to the IRB. 
 
 
 


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9.4.1 Sample Unlinking 
Clinical information linked to the unique patient IDs will be stored in a bioinformatics 
database along with the targeted sequencing panel.  Once patient has completed treatment 
on study and has been taken off study, the unique patient ID will be deleted and a new 
random ID generated (arbitrary or random alphanumeric code) in the database by the 
bioinformatics team, thereby delinking the patient identifier from the information in the 
database.  Patient consent to allow research use of his/her samples will be confirmed at 
this time.  The Bioinformatics team will inform Dr. Mickey Williams’ laboratory of the 
new random ID, all samples from a given patient will be transferred to the new ID, and 
Dr. Williams’ lab will also break the link to the unique patient ID.  The unique patient 
IDs will be discarded so there is no possibility of linking the samples to the sources.  
Dr. Williams’ lab will proceed with (but not limited to) whole exome sequencing on de-
identified samples for research purposes only.  Data reports sent to the clinical site will be 
summary reports with no identifiable patient IDs whatsoever.   
 
When the study was re-opened with a new non-randomized design, a singular patient 
continued to receive randomized first-line study treatment.  As of Amendment Y 
(January 7, 2020), sample unlinking (as described above) may occur while this patient 
remains on study treatment, if the patient consents to this change, in order to enable 
research-use analysis of samples in parallel with the other results from the randomized 
phase of the study. 
 
10. STUDY CALENDAR:  
Baseline evaluations are to be conducted within 8 days prior to start of protocol therapy.  If the 
patient’s condition deteriorates prior to initiation of treatment, evaluations should be repeated 
within 48 hours prior to initiating treatment.  Scans and x-rays must be done within 28 days prior 
to the start of therapy.  The start of the next cycle may be delayed for up to 1 week to 
accommodate scheduling conflicts.  Treatments within a cycle may be delayed up to +/- 1 day to 
accommodate scheduling conflicts.  Cycles may be continued until a patient meets one of the 
criteria in Section 5.6.  Additional evaluations will be conducted as clinically indicated at the 
investigator’s discretion.  


CTEP #9149 (01-07-2020) 
 
84 
 
 
Pre-
Study 
Cycle 1 
Week 1 
Cycle 1 
Week 2 
Cycle 1 
Week 3 
Cycle 1 
Week 4 
Cycle 2 
onwards 
Week 1 
 
Informed consent 
 
X 
 
 
 
 
 
Tumor biopsy and blood 
sample for genetic analysis 
X 
 
 
 
 
 
Study Druga 
 
Xa 
Xa 
Xa 
Xa 
Xa 
 
Demographics 
 
X 
 
 
 
 
 
 
Medical historyb 
 
X 
X 
 
 
 
 
Concurrent meds 
X 
        X………………...………...………………...……...X 
 
Physical examb 
 
X 
X 
 
 
 
X 
 
Vital signsb 
 
X 
X 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
Weightb 
 
X 
X 
 
 
 
X 
 
Performance status 
 
X 
X 
 
 
 
X 
 
CBC w/diff, pltsc 
 
X 
X 
X 
X 
X 
X 
 
Serum chemistryc 
 
X 
X 
X 
X 
X 
X 
 
EKGi 
 
X 
 
 
 
 
X 
Adverse event evaluation 
X 
        X……………..……………………..………………X 
Radiologic evaluation 
X 
Tumor measurements are repeated every 2 cycles*  
Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
 
-HCGd 
 
X 
 
 
 
 
 
X 
Ophthalmologic exame 
X 
 
 
 
 
X 
ECHO/MUGAf 
X 
 
 
 
 
 
Lipid monitoringg 
X 
Lipid monitoring every 2 cycles 
Urinary Proteinh 
X 
 
 
 
 
X 
a:  Patients will be assigned to receive one of the following study drugs or drug combinations at 
the assigned dose (cycles +/- 1 day for scheduling):  
• Veliparib: 40 mg orally BID qd days 1-7 plus temozolomide 150 mg/m2 orally qd days 1-
5 (no food restrictions) in 28-day cycles.  Patients who receive temozolomide will have an 
evaluation of their LFTs at the time of coming off-treatment. 
• Everolimus: 10 mg orally each day (no food restrictions) in 28-day cycles. 
• Trametinib DMSO:  2 mg orally each day either one hour before or two hours after a 
meal in 28-day cycles. 
• AZD1775:  225 mg orally BID x 5 doses either at least two hours before or two hours after 
a meal plus carboplatin (AUC 5) IV on day 1 of every 21-day cycle. 
b:  History and physical, including vital signs and weight at the start of each cycle (up to 3 days 
before start of new cycle). 


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c:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, creatinine, 
glucose, phosphorus, potassium, SGOT[AST], SGPT[ALT], sodium, magnesium prior to 
treatment (up to 8 days prior) and as indicated.  CBC w/diff, platelets and serum chemistries 
should be performed prior to cycle 1 treatment (up to 8 days prior), weekly throughout 
cycle 1, and at the start of each subsequent cycle (up to 3 days before start of new cycle).  
CBC with differential will be performed more frequently in patients with grade 4 neutropenia 
or thrombocytopenia until resolution to ≤ grade 3. 
d:   Urine or serum pregnancy test (women of childbearing potential) pre-study.  Repeat 
pregnancy test at the start of each subsequent cycle (up to 3 days before start of new cycle) for 
patients on AZD1775 only. 
e:   Complete ophthalmologic examination at baseline for patients on MEK inhibitors only 
(within 6 months prior to start of therapy), and at the start of the second cycle.  Additional 
ophthalmologic exams may be performed as clinically indicated.    
f:  Repeat echocardiograms for patients on trametinib DMSO or everolimus only, every 3 cycles.  
Additional echocardiograms may be performed as clinically indicated.  The same modality 
(either ECHO or MUGA) should be used at baseline and at follow-up. 
g: Repeat lipid monitoring for patients on everolimus only (within 1 week prior to enrollment), 
and every 2 cycles. 
h: Repeat urinary protein at baseline for patients on everolimus only (within 1 week prior to 
enrollment), and at the start of each subsequent cycle (up to 3 days before start of new cycle). 
i:  Repeat EKGs at the start of each subsequent cycle (up to 3 days before start of new cycle) for 
patients on AZD1775 only. 
* CT scans can be performed every 4 cycles (for both the 21-day and 28-day cycles) for patients 
on study more than one year; it the patient changes therapy, CT scans will be performed once 
every 2 cycles for 1 year. 
Baseline evaluations are to be conducted within 8 days prior to start of protocol therapy.  If the 
patient’s condition deteriorates prior to initiation of treatment, evaluations should be repeated 
within 48 hours prior to initiating treatment.  Scans and x-rays must be done within 28 days prior 
to the start of therapy.  The start of the next cycle may be delayed for up to 1 week to 
accommodate scheduling conflicts.  Treatments within a cycle may be delayed up to +/- 1 day to 
accommodate scheduling conflicts.  Cycles may be continued until a patient meets one of the 
criteria in Section 5.4.  
 
 


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86 
 
11. MEASUREMENT OF EFFECT 
11.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated every 2 cycles (every 4 cycles for 
patients on study more than one year).  Response and progression will be evaluated in this study 
using the new international criteria proposed by the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1) [94].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria.   
11.1.1 Definitions 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their 
first treatment with study drug. 
 
Evaluable for objective response:  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters 
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. 
 
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 recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short 
axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 


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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. 
 
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 which 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. 
 
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.  
11.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
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. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  


CTEP #9149 (01-07-2020) 
 
88 
 
 
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.  
 
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).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
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.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
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 


CTEP #9149 (01-07-2020) 
 
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in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [95-
97].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression 
criteria which are to be integrated with objective tumor assessment for use in first-line 
trials in ovarian cancer [98]. 
 
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). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
11.1.4 Response Criteria 
11.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): 
 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or 


CTEP #9149 (01-07-2020) 
 
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non-target) must have reduction in short axis to 
<10 mm. 
 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference 
the baseline sum of 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). 
 
Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking 
as reference the smallest sum of diameters while 
on study 
11.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 
mm short axis) 
 
  
 
 
 
 
 
 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD:  
 
 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 


CTEP #9149 (01-07-2020) 
 
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progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
11.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
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 
> 4 wks.  Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
> 4 wks.  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 > 4 wks.  
from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
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 
 


CTEP #9149 (01-07-2020) 
 
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11.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
Study Oversight 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
Safety Monitoring Committee 
Because this is a multi-institutional protocol for which the NCI DTC is the coordinating center, it 
will be monitored by the DTC Safety Monitoring Committee (SMC).  
12.1 
Data Reporting 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Rave Read-Only, Rave CRA (Lab Admin), Rave SLA, or 
Rave Investigator) on either the LPO or participating organization roster at the enrolling site. To 
hold the Rave CRA role or Rave CRA (Lab Admin) role, the user must hold a minimum of an 
AP registration type.  To hold the Rave Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in Rave.   


CTEP #9149 (01-07-2020) 
 
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Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account.  Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
12.1.1 Method 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted three times annually (one annual site visit and two data 
audits).  For CTMS monitored studies, after users have activated their accounts, please 
contact the Theradex Help Desk at (609) 619-7862 or by e-mail at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
12.1.2 Responsibility for Data Submission 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For Institutional Performance Monitoring, data will be 
considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS are reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 


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regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)   
and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials), and a 
description of any dose-limiting toxicities (DLTs).  CTMS will utilize a core set of 
eCRFs that are Cancer Data Standards Registry and Repository (caDSR) compliant 
(http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate 
to meet unique study requirements.  The PI is encouraged to review the eCRFs, working 
closely with CTMS to ensure prospectively that all required items are appropriately 
captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs with 
built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
12.2 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
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/industry) 
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. 
 


CTEP #9149 (01-07-2020) 
 
95 
 
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 to Collaborator(s), the NCI, and the FDA, as appropriate and 
unless additional disclosure is required by law or court order as described in the IP Option 
to Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used, and 
disclosed consistent with all applicable federal statutes and regulations for the protection 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is 
a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication.  Collaborator(s) will have 30 days from the date of receipt for 
review.  Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days 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 


CTEP #9149 (01-07-2020) 
 
96 
 
manuscript, abstract and/or press release/ media presentation should be sent to: E-mail: 
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. 
 
12.3 
Publication Policy 
Recognizing the need to make clinical trial outcomes rapidly available to the cancer clinical trials 
community [99], publication of the results from this study will be a priority following 
completion of accrual, follow up, and data analyses.   
 
Authorship of this group-wide study will include the Coordinating Center PI, the study 
statistician, and one representative from each participating institution listed on the cover page of 
the protocol that contributed more than 10% of the eligible, evaluable cases.  The first author, 
last author, corresponding author(s), and study statistician, will all be NCI investigators.  The 
CTEP medical monitor will also be listed as an author.  Lead investigators from laboratories 
involved in conducting correlative studies will be listed as authors if data from their laboratories 
are included in the clinical results manuscript.  
 
If several investigators were responsible for a participating institution’s accrual, the designated 
representative from that institution ordinarily will be the PI.  When an individual other than the 
PI is largely responsible for a participating institution’s accrual, the PI is expected to substitute 
that individual as an author in place of himself/herself.  The intent is to offer recognition to the 
individuals who have been most directly involved in the study.  Because the Coordinating Center 
PI will often be unaware of the relative contributions of investigators at each institution, the PIs 
at participating institutions accruing more than 10% of cases will be solicited routinely to 
determine whether another individual should be substituted for them in authorship.  There will be 
only one author from each of the participating institutions listed on the cover page of the 
protocol.  If the PI is already an author, based on scientific contribution to the study, a second 
person from that PI’s institution will not automatically be accepted for authorship based on 
institutional accrual.   
 
This protocol includes several correlative studies that may be published with the group-wide 
clinical results paper or as separate, stand-alone scientific papers.  The decision to publish 
correlative study papers separately will be made by the Coordinating Center PI and relevant 
correlative study investigators, and will be subject to the Collaborative Agreement for study 
publications described in Section 12.3.  Authorship of the correlative results paper will include 
the Coordinating Center PI, the correlative study lead investigators, and researchers from the 
correlative studies laboratories nominated by the correlative study lead investigators.  Correlative 
study lead investigators may also nominate authors who have contributed to the feasibility of the 
study and/or the development of assays and procedures that supported evaluation of study 
samples.  The final decision on the authorship of any manuscripts related to this trial will be 
made by the Coordinating Center PI. 
 


CTEP #9149 (01-07-2020) 
 
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13. STATISTICAL CONSIDERATIONS 
This is a multi-histology pilot trial with patients enrolled into multiple cohorts. Up to 30 patients 
will be treated within each of the targeted agent cohorts.  
 
All eligible patients who have initiated treatment will be included in the OR and PFS analyses 
within each agent cohort in which objective response rate and PFS (as a secondary endpoint) will 
be assessed against the historical standards of 5% response rate and 25% 4-month PFS.  We will 
allow patients to be entered on trial and begin treatment based on CLIA genetic testing reports 
from MATCH-designated labs indicating actionable mutations of interest in study DNA damage 
repair genes.  On-study biopsies will be collected from these patients for study confirmatory 
screening with the Oncominev3 (MATCHv3) assay.  Those whose aMOIs cannot be confirmed 
can choose to remain on study and receive study drugs but will not be counted as eligible or 
included in the primary efficacy analysis or the futility analysis. 
 
1. Within each agent cohort, up to 30 eligible patients will be accrued, to discriminate between 
tumor response rates of 20% vs. 5%.  If at least 4 objective responses (at least 13%) are 
observed among the 30 patients, this agent will be considered promising for this mutation 
category.  If no objective responses are observed among the initial 12 eligible patients, 
beginning, for the veliparib plus temozolomide arm, with Amendment U), the cohort will be 
terminated early.  Accrual to the cohort will be paused after accrual of the initial 12 eligible 
patients until at least 1 objective response is observed.  This design yields at least 88% power 
to detect a true objective response rate of at least 20%.  It yields at least .94 probability of a 
negative result if the true objective response rate is no more than 5%.  As a secondary 
endpoint, 4-month PFS will be evaluated.  If at least 12 instances of 4-month PFS (at least 
40%) are observed among the 30 patients, 4-month PFS will be considered promising.  This 
will occur with 90% likelihood if the true 4-month PFS rate is 50% (median PFS of 
4 months) and with 5% likelihood if the true 4-month PFS rate is 25% (median PFS of 
2 months). 
 
13.1 
Sample Size/Accrual Rate 
Given the relative frequencies of mutations it is anticipated that we will need to enroll up to 100 
patients until we have 30 evaluable patients on each open agent cohort.  Once all sites are open, 
we hope to accrue 150-200 patients a year.  It is anticipated that accrual will require at least 1.5 - 
3 years. 
 
13.2 
Analysis of Additional Endpoints 
All molecular and other secondary evaluations will be considered for exploratory analyses.  In 
general, it is anticipated that non-parametric analyses will be used for these evaluations.  In view 
of the exploratory nature of these analyses, any p-values reported will not be adjusted for 
multiple comparisons, and any such analyses will be stated carefully as being hypothesis-
generating.  All eligible patients who have initiated treatment will be included in the toxicity 
assessments. 
 


CTEP #9149 (01-07-2020) 
 
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14. HUMAN SUBJECTS PROTECTIONS 
14.1 
Rationale for Subject Selection 
This study will be open to all individuals regardless of gender, ethnicity, or race provided that the 
aforementioned inclusion and exclusion criteria are met.  For safety reasons, pregnant women 
and children are excluded from this study.  Patients for this study will be recruited through 
internal referral, our physician referral base, and through various cancer information hotlines 
(i.e., Clinical Studies Support Center, 1-800-4Cancer).  Participants should realize that there is 
no guarantee of benefit to them from participation in this trial.  The results of this trial may 
benefit future cancer patients.  To date, there is no information that suggests that differences in 
drug metabolism or effect on tumor would be expected in one ethnic group compared to another.  
Efforts will be made to extend accrual to each representative population, but a balance must be 
struck between participant safety considerations and limitations on the number of individuals 
exposed to potentially ineffective treatments on the one hand and the need to explore 
racial/ethnic aspects of clinical research on the other hand.  If differences in outcome that 
correlate to ethnic identity are noted, a follow-up study may be written to investigate those 
differences more fully. 
14.1.1 Inclusion of Women and Minorities 
This study will be open to all individuals regardless of gender, ethnicity, or race provided 
that the aforementioned inclusion and exclusion criteria are met. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
 18 
 
18 
 
36 
Not Hispanic or Latino 
72 
 
 72 
 
144 
Ethnic Category: Total of all subjects 
 
 90  (A1) 
+ 
90 (B1) 
= 
180 (C1) 
Racial Category 
 
American Indian or Alaskan Native 
 1 
 
1 
 
2 
Asian 
 8 
 
 8 
 
16 
Black or African American 
 8 
 
 8 
 
16 
Native Hawaiian or other Pacific Islander 
1 
 
1 
 
2 
White 
 72 
 
72 
 
144 
Racial Category: Total of all subjects 
90 (A2) 
+ 
90 (B2) 
= 
 180 (C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
Accrual Rate: 
2-3 
pts/month 
Total Expected Accrual: 
45 
Min 
700 
Max 
Projected Start Date of study:
10/20/12 
 
 
 
 
 
 


CTEP #9149 (01-07-2020) 
 
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14.2 
Justification for Exclusions 
Because the effects of study investigational agents on the developing human fetus are unknown, 
pregnant women will be excluded from this trial.  Nursing women are also excluded, as there is 
an unknown but potential risk for adverse events in nursing infants secondary to treatment of the 
mother with study medications.  
 
Participants with unstable or serious medical conditions (ongoing or active infection, 
symptomatic congestive heart failure [AHA Class II or worse], unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements) are excluded due to the possibility that the underlying condition may obscure the 
attribution of effect and adverse events with respect to study drugs and may limit study 
compliance.   
14.2.1 Participation of Children   
Because no dosing or adverse event data are currently available on the use of many of 
these investigational agents in patients <18 years of age, children are excluded from this 
study, but may be eligible for future pediatric Phase I/II trials. 
14.3 
Evaluation of Benefits and Risks/Discomforts 
There may or may not be any clinical benefit to a patient from participation in this trial.  Their 
participation will benefit future cancer patients.  Potential risks include the possible occurrence 
of any of a range of side effects that are listed in the consent document, as well as the risks 
associated with the acquisition and disclosure of information about germline variants relevant to 
a patient’s hereditary risk of disease. 
 
The procedure for protecting against or minimizing risks will be to medically evaluate patients as 
described in the Study Calendar (Section 10).  To minimize the risk of disclosing information 
about potential nonambiguous germline variants from whole exome sequencing, samples will be 
de-identified once the patient has completed treatment and is taken off study.  No genetic data 
will be shared with the patient other than the data from the targeted sequencing panel.  A 
Certificate of Confidentiality has been obtained for this study.  
 
The research component of this study (2 CT tumor biopsies, with the possibility of a third 
optional biopsy should a baseline tumor biopsy sample contain insufficient DNA) confers 
radiation exposure at an effective dose of 1.6 rem at the NIH Clinical Center.  This dose is below 
NIH RSC guidelines for adults of 5.0 rem per year and represents a slightly greater than minimal 
risk to patients.  
14.4 
Consent and Assent Process and Documentation 
This protocol includes separate informed consent forms for tumor biopsy collection and 
treatment. An associate or principal investigator on the trial will inform patients of the purpose, 
alternatives, drug administration plan, research objectives, and follow-up of this trial.  The 
patient will be provided IRB-approved consent(s) for review and signature and his/her questions 
will be answered.  After a decision is made to enroll into the study, a signature will be obtained 


CTEP #9149 (01-07-2020) 
 
100 
 
from the patient.  The original signed consent(s) go to Medical Records; a copy is placed in the 
research record. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 
14.5 
Procedure for Protecting Against or Minimizing Any Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity.  This study may involve risks to patients, which are currently unforeseeable.  All 
patients will be monitored for side effects from taking study medication and from undergoing 
blood sampling procedures.  If patients suffer any physical injury as a result of the participation 
in this study at the NCI, immediate medical treatment is available at the Clinical Center, National 
Cancer Institute, Bethesda, Maryland.  Although no compensation is available, any injury will be 
evaluated and treated in keeping with the benefits or care to which patients are entitled under 
applicable regulations.   


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Ding, J., et al., Emerging cancer therapeutic opportunities target DNA-repair systems. Trends 
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Pallis, A.G. and M.V. Karamouzis, DNA repair pathways and their implication in cancer 
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6. 
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7. 
Memisoglu, A. and L. Samson, Base excision repair in yeast and mammals. Mutat Res, 2000. 
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Ruscetti, T., et al., Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) 
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Fernet, M., et al., Poly(ADP-ribose) polymerase, a major determinant of early cell response to 
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Shall, S. and G. de Murcia, Poly(ADP-ribose) polymerase-1: what have we learned from the 
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Masutani, M., et al., The response of Parp knockout mice against DNA damaging agents. Mutat 
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Sulkowski, P.L., et al., 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses 
homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med, 2017. 
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APPENDIX A: Performance Status Criteria 
 
 
 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on normal activity or to 
do active work. 
60 
Requires occasional assistance, but is able to care for 
most of his/her needs. 
50 
Requires considerable assistance and frequent medical 
care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not 
imminent. 
20 
Very sick, hospitalization indicated.  Death not 
imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B: Potential Drug Interactions and Drug Information Handouts  
 
CYP2C19 Inhibitors 
Amiodarone 
Amitriptyline 
Amprenavir 
Aprepitant 
Azelastine 
Bortezomib 
Buprenorphine 
Cholecalciferol/Vitamin D3 
Cimetidine 
Citalopram 
Clotrimazole 
Clozapine 
Delavirdine 
Diazepam 
Dimethyl sulfoxide 
Drospirenone 
Efavirenz 
Entacapone 
Ethinyl estradiol 
Ethotoin 
Felbamate 
Fenofibrate 
Fluconazole 
Fluoxetine 
Fluvoxamine 
Fosamprenavir 
Gefitinib 
Gemfibrozil 
Imipramine 
Indinavir 
Indomethacin 
Isoniazid 
Ketoconazole 
Lansoprazole 
Letrozole 
Loratadine 
Losartan 
Mephobarbital 
Mestranol 
Methimazole 
Methoxsalen 
Methsuximide 
Miconazole 
Moclobemide 
Modafinil 
Nelfinavir 
Nicardipine 
Nilutamide 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxcarbazepine 
Paroxetine 
Pentamidine 
Pimozide 
Pioglitazone 
Probenecid 
Progesterone 
Propofol 
Rabeprazole 
Ritonavir 
Rosiglitazone 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sulconazole 
Telmisartan 
Ticlopidine 
Tioconazole 
Topiramate 
Torsemide 
Tranylcypromine 
Valdecoxib 
Valproic acid 
Voriconazole 
Warfarin 
Zafirlukast 
 
CYP2C19 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Phenytoin 
Rifampin 
 
St. John’s wort  
 
CYP2C19 Substrates 
Carisoprodol 
Cilostazol 
Citalopram 
Clobazam 
Clomipramine 
Desogestrel 
Diazepam 
Escitalopram  
Esomeprazole  
Fosphenytoin 
Imipramine 
Lansoprazole 
Mephenytoin 
Mephobarbital 
Methsuximide 
Moclobemide  
Nelfinavir  
Nilutamide 
Omeprazole 
Pantoprazole 
Pentamidine 
Phenobarbital 
Phenytoin 
Progesterone  
Rabeprazole 
Sertraline 
Trimipramine 
Voriconazole 
 
CYP3A4 Inhibitors 
Acetaminophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cyclosporine 
Danazol 
Dasatinib  
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Glyburide 
Grapefruit juice  
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan  
Lovastatin 
Mefloquine 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 


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Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol  
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort  
 
CYP3A4 Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazapine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Delavirdine 
Diazepam 
Digitoxin 
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fosamprenavir 
Fulvestrant 
Gefitinib 
Halofantrine 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide dinitrate 
Isosorbide mononitrate 
Ketoconazole 
Lansoprazole 
Letrozole 
Levomethadyl acetate 
hydrochloride 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Quetiapine 
Quinidine 
Rabeprazole 
Repaglinide 
Rifabutin 
Rifampin 
Ritonavir 
Saquinavir 
Sertraline 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Terbinafine 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 


CTEP #9149 (01-07-2020) 
 
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Dihydroergotamine 
Diltiazem 
Disopyramide 
Isradipine 
Itraconazole 
Ketamine 
Pioglitazone 
Primaquine 
Progesterone 
Zonisamide 
Zopiclone 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers.  In: Lacy CF, 
Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; 
LexiComp Inc. 2007: 1899-1912.   
 
Only major substrates and effective inducers are listed.  Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated medical reference. 
 
 
PgP substrates, inducers, and inhibitors  
Substrates: colchicine, digoxin, fexofenadine, indinavir, paclitaxel, talinolol, topotecan, 
vincristine, everolimus 
Inducers: rifampin, St John’s wort 
PgP Inhibitors and PgP/CYP3A Dual Inhibitors: amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, erythromycin, 
felodipine, fexofenadine, fluvoxamine, ginkgo (ginkgo biloba), indinavir, itraconazole, 
lopinavir, mibefradil, milk thistle (silybum marianum), nelfinavir, nifedipine, nitrendipine, 
paroxetine, quercetin, quinidine, ranolazine, rifampin, ritonavir, saquinavir, Schisandra 
chinensis, St John’s wort, talinolol, Telaprevir, telmisartan, ticagrelor, tipranavir, tolvaptan, 
valspodar, verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated 29-Oct-
2012 which summarizes DDI data from three sources including the FDA’s “Guidance for 
Industry, Drug Interaction Studies”, the University of Washington’s Drug Interaction Database, 
and Indiana University School of Medicine's Drug Interaction Table. 
 
 
 


CTEP #9149 (01-07-2020) 
 
110 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Veliparib and Other Drugs and Herbal Supplements  
 
The patient ______________________________________ is enrolled on a clinical trial using 
the experimental study drug Veliparib.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others 
who care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
Veliparib interacts with certain specific enzymes in the liver. 
• The enzymes in question are CYP1A1, CYP2D6, CYP2C19, and CYP3A4.  Veliparib is 
metabolized by these enzymes and may be affected by other drugs that inhibit or induce 
these enzymes. 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Veliparib may interact with other drugs which can cause side effects.  For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part 
in a clinical trial.  
 
These are the things that you and they need to know:  
 
Veliparib must be used very carefully with other medicines that need certain liver enzymes to be 
effective or to be cleared from your system.  Before you enroll onto the clinical trial, your 
study doctor will work with your regular health care providers to review any medicines and 
herbal supplements that are considered “strong inducers/inhibitors of CYP 1A1, CYP2D6, 
CYP2C19, and CYP3A4.” 
 
•  Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
•  Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.   
Your study doctor’s name is ______________________________________________  
and he or she can be contacted at _____________________________________.           


CTEP #9149 (01-07-2020) 
 
111 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Information Wallet Card  
You are enrolled on a clinical trial using the experimental 
study drug Veliparib.  This clinical trial is sponsored by 
the NCI.  Veliparib may interact with drugs that are 
processed by your liver.  Because of this, it is very 
important to: 
➢ Tell your doctors if you stop taking any medicines or if 
you start taking any new medicines 
➢ Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or 
pharmacists) that you are taking part in a clinical trial 
➢ Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplements such as St. John’s Wort 
➢ Avoid grapefruit, grapefruit juice, Seville oranges, and 
starfruit while taking this drug 
Veliparib interacts with CYP 1A1, 2D6, 2C19, and 3A4, 
and must be used very carefully with other medicines that 
interact with these enzymes and proteins. 
• Before you enroll onto the clinical trial, your study doctor 
will work with your regular health care providers to 
review any medicines and herbal supplements that are 
considered “strong inducers/inhibitors of CYP 1A1, 
CYP2D6, CYP2C19, and CYP3A4” 
• Before prescribing new medicines, your regular 
prescribers should go to a frequently-updated medical 
reference for a list of drugs to avoid, or contact your 
study doctor.   
• Your study doctor’s name is:  
and can be contacted at: 


CTEP #9149 (01-07-2020) 
 
112 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with AZD1775 and Other Drugs and Herbal Supplements  
 
The patient _____________________________________ is enrolled on a clinical trial using the 
experimental study drug AZD1775.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others 
who care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
AZD1775 interacts with certain specific enzymes in the liver and certain transport proteins that 
help move drugs in and out of cells. 
 
• The enzyme in question is CYP 3A4.  AZD1775 is metabolized by CYP3A4 and may be 
affected by other drugs that inhibit or induce this enzyme.  AZD1775 is an inhibitor of 
CYP 3A4 and may affect the metabolism of other drugs. 
 
• The proteins in question are OATP1B1, OATP1B3, MATE1, MATE2K, P-gp, and BCRP.  
AZD1775 is a substrate of P-gp and BCRP and may be affected by other drugs that inhibit 
or induce these transporters.  AZD1775is an inhibitor of OATP1B1, OATP1B3, MATE1, 
MATE2K, P-gp, and BCRP and may affect transport of other drugs in and out of cells. 
 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
AZD1775 may interact with other drugs which can cause side effects.  For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part 
in a clinical trial.  
 
These are the things that you and they need to know:  
 
AZD1775 must be used very carefully with other medicines that need certain liver enzymes or 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto 
the clinical trial, your study doctor will work with your regular health care providers to review 
any medicines and herbal supplements that are considered “strong inducers/inhibitors or 
substrates of CYP 3A4, OATP1B1, OATP1B3, MATE1, MATE2K, P-gp, and BCRP.” 
 
 


CTEP #9149 (01-07-2020) 
 
113 
 
•  Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
•  Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.   
Your study doctor’s name is ________________________________________________  
 
and he or she can be contacted at_____________________________________                                 
                                                 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Information Wallet Card  
You are enrolled on a clinical trial using the experimental 
study drug AZD1775.  This clinical trial is sponsored by 
the NCI.  AZD1775 may interact with drugs that are 
processed by your liver, or use certain transport 
proteins in your body.  Because of this, it is very 
important to: 
➢ Tell your doctors if you stop taking any medicines or if 
you start taking any new medicines 
➢ Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or 
pharmacists) that you are taking part in a clinical trial 
➢ Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplements such as St. John’s Wort 
➢ Avoid grapefruit, grapefruit juice, Seville oranges, and 
starfruit while taking this drug 
AZD1775 interacts with CYP 3A4, OATP1B1, OATP1B3, 
MATE1, MATE2K, P-gp, and BCRP, and must be used 
very carefully with other medicines that interact with these 
enzymes and proteins. 
• Before you enroll onto the clinical trial, your study doctor 
will work with your regular health care providers to review 
any medicines and herbal supplements that are 
considered “strong inducers/inhibitors of CYP 3A4, 
PgP and BCRP, and sensitive substrates of 
OATP1B1, OATP1B3, MATE1 and MATE2K" 
• Before prescribing new medicines, your regular 
prescribers should go to a frequently-updated medical 
reference for a list of drugs to avoid, or contact your 
study doctor.   
• Your study doctor’s name is:  
and can be contacted at:  


CTEP #9149 (01-07-2020) 
 
114 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Everolimus and Other Drugs and Herbal Supplements  
 
The patient ______________________________________ is enrolled on a clinical trial using 
the experimental study drug Everolimus.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others 
who care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
Everolimus interacts with certain specific enzymes in the liver. 
• The enzyme in question is CYP3A4.  Everolimus is metabolized by this enzyme and may 
be affected by other drugs that inhibit or induce this enzyme. 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Everolimus may interact with other drugs which can cause side effects.  For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part 
in a clinical trial.  
 
These are the things that you and they need to know:  
 
Everolimus must be used very carefully with other medicines that need certain liver enzymes to 
be effective or to be cleared from your system.  Before you enroll onto the clinical trial, your 
study doctor will work with your regular health care providers to review any medicines and 
herbal supplements that are considered “strong inducers/inhibitors of CYP3A4.” 
 
•  Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
•  Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.   
Your study doctor’s name is ______________________________________________  
and he or she can be contacted at _____________________________________.                                          
 
 


CTEP #9149 (01-07-2020) 
 
115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Information Wallet Card  
You are enrolled on a clinical trial using the experimental 
study drug Everolimus.  This clinical trial is sponsored by 
the NCI.  Everolimus may interact with drugs that are 
processed by your liver.  Because of this, it is very 
important to: 
➢ Tell your doctors if you stop taking any medicines or if 
you start taking any new medicines 
➢ Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or 
pharmacists) that you are taking part in a clinical trial 
➢ Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplements such as St. John’s Wort 
➢ Avoid grapefruit, grapefruit juice, Seville oranges, and 
starfruit while taking this drug
Everolimus interacts with CYP3A4, and must be used 
very carefully with other medicines that interact with these 
enzymes and proteins. 
• Before you enroll onto the clinical trial, your study doctor 
will work with your regular health care providers to 
review any medicines and herbal supplements that are 
considered “strong inducers/inhibitors of CYP3A4” 
• Before prescribing new medicines, your regular 
prescribers should go to a frequently-updated medical 
reference for a list of drugs to avoid, or contact your 
study doctor.   
• Your study doctor’s name is:  
and can be contacted at: 


CTEP #9149 (01-07-2020) 
 
116 
 
APPENDIX C: Medications That May Cause QTc Prolongation 
 
The following table presents a list of drugs that prolong, may prolong, or are unlikely to prolong the 
QTc.  Please note that this list is frequently updated.  For the most current list of medications, users 
should be directed to the following website: http://crediblemeds.org/ 
 
Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes 
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de Pointes 
Drugs that, in some reports, have been 
weakly associated with Torsades de 
Pointes and/or QTc prolongation but that 
are unlikely to be a risk for Torsades de 
Pointes when used in usual recommended 
dosages and in subjects without other risk 
factors (e.g., concomitant QTc prolonging 
drugs, bradycardia, electrolyte 
disturbances, congenital long QTc 
syndrome, concomitant drugs that inhibit 
metabolism) 
  
  
  
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Amiodarone /Cordarone® 
Alfuzosin /Uroxatral® 
Amitriptyline /Elavil® 
Amiodarone /Pacerone® 
Amantadine /Symmetrel® 
Ciprofloxacin /Cipro® 
Arsenic trioxide /Trisenox® 
Atazanavir /Reyataz® 
Citalopram /Celexa® 
Astemizole /Hismanal® 
Azithromycin /Zithromax® 
Clomipramine /Anafranil® 
Bepridil /Vascor® 
Chloral hydrate /Noctec® 
Desipramine /Pertofrane® 
Chloroquine /Aralen® 
Clozapine /Clozaril® 
Diphenhydramine /Benadryl® 
Chlorpromazine /Thorazine® 
Dolasetron /Anzemet® 
Diphenhydramine /Nytol® 
Cisapride /Propulsid® 
Dronedarone /Multaq® 
Doxepin /Sinequan® 
Clarithromycin /Biaxin® 
Felbamate /Felbatrol® 
Fluconazole /Diflucan® 
Disopyramide /Norpace® 
Flecainide /Tambocor® 
Fluoxetine /Sarafem® 
Dofetilide /Tikosyn® 
Foscarnet /Foscavir® 
Fluoxetine /Prozac® 
Domperidone /Motilium® 
Fosphenytoin /Cerebyx® 
Galantamine /Reminyl® 
Droperidol /Inapsine® 
Gatifloxacin /Tequin® 
Imipramine /Norfranil® 
Erythromycin /Erythrocin® 
Gemifloxacin /Factive® 
Itraconazole /Sporanox® 
Erythromycin /E.E.S.® 
Granisetron /Kytril® 
Ketoconazole /Nizoral® 
Halofantrine /Halfan® 
Indapamide /Lozol® 
Mexiletine /Mexitil® 
Haloperidol /Haldol® 
Isradipine /Dynacirc® 
Nortriptyline /Pamelor® 
Ibutilide /Corvert® 
Lapatinib /Tykerb® 
Paroxetine /Paxil® 
Levomethadyl /Orlaam® 
Lapatinib /Tyverb® 
Protriptyline /Vivactil® 
Mesoridazine /Serentil® 
Levofloxacin /Levaquin® 
Sertraline /Zoloft® 


CTEP #9149 (01-07-2020) 
 
117 
 
 
Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes 
 
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de Pointes 
 
Drugs that, in some reports, have been 
weakly associated with Torsades de 
Pointes and/or QTc prolongation but that 
are unlikely to be a risk for Torsades de 
Pointes when used in usual recommended 
dosages and in subjects without other risk 
factors (e.g., concomitant QTc prolonging 
drugs, bradycardia, electrolyte 
disturbances, congenital long QTc 
syndrome, concomitant drugs that inhibit 
metabolism) 
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Methadone /Dolophine® 
Lithium /Lithobid® 
Solifenacin /VESIcare® 
Methadone /Methadose® 
Lithium /Eskalith® 
Trimethoprim-Sulfa /Sulfa® 
Pentamidine /Pentam® 
Moexipril/HCTZ /Uniretic® 
Trimethoprim-Sulfa /Bactrim® 
Pentamidine /NebuPent® 
Moxifloxacin /Avelox® 
Trimipramine /Surmontil® 
Pimozide /Orap® 
Nicardipine /Cardene® 
  
Probucol /Lorelco® 
Nilotinib /Tasigna® 
  
Procainamide /Pronestyl® 
Octreotide /Sandostatin® 
  
Procainamide /Procan® 
Ofloxacin /Floxin® 
  
Quinidine /Cardioquin® 
Ondansetron /Zofran® 
  
Quinidine /Quinaglute® 
Oxytocin /Pitocin® 
  
Sotalol /Betapace® 
Paliperidone /Invega® 
  
Sparfloxacin /Zagam® 
Perflutren lipid microspheres 
/Definity® 
  
Terfenadine /Seldane® 
Quetiapine /Seroquel® 
  
Thioridazine /Mellaril® 
Ranolazine /Ranexa® 
  
  
Risperidone /Risperdal® 
  
  
Roxithromycin* /Rulide® 
  
  
Sertindole /Serlect® 
  
  
Sertindole /Serdolect® 
  
  
Sunitinib /Sutent® 
  
  
Tacrolimus /Prograf® 
  
  
Tamoxifen /Nolvadex® 
  
  
Telithromycin /Ketek® 
  
  
Tizanidine /Zanaflex® 
  
  
Vardenafil /Levitra® 
  
  
Venlafaxine /Effexor® 
  
  
Voriconazole /VFend® 
  
  
Ziprasidone /Geodon® 
  
References: 
Physician’s Desk Reference 2002 
Facts and Comparisons (update to June 2005) 
The Pharmacological Basis of Therapeutics 9th Edition, 1996 
 


CTEP #9149 (01-07-2020) 
 
118 
 
APPENDIX D: Patient Study Diaries 
 
Study Name: Molecular Profiling-based Assignment of Cancer Therapy for Patients With 
Advanced Solid Tumors 
 
CTEP Study ID: 9149 
 
 
Patient Name:  _________________________________________________________ 
 
Instructions to the patient:  
Please complete this form and return to the research nurse or doctor every cycle (28 days) 
 
You will take:         Veliparib and Temozolomide  
Medication dose:   Take Veliparib capsules twice each day (morning and evening) on  
days 1 to 7 and take temozolomide capsules once each day on days 1 to 5 
Take temozolomide capsules one at a time with a full glass of water.  
Temozolomide capsules should not be opened, crushed, or chewed.  
Temozolomide capsules should be swallowed whole and never chewed.  If 
you vomit the capsules, do not take a second dose.  Capsules can be taken 
with or without food, but please try and take them at the same time every 
day, and if possible, always with or always without food.  Avoid grapefruit, 
grapefruit juice, Seville oranges, starfruit, and the herbal supplement St. 
John’s Wort while taking this drug.  
 
Do not open, crush, or chew Veliparib capsules. 
 
Cycle number:      _________ 
Start date:  
_________ 
 
 
Patient Signature:  _____________________________________ 
 
 
 
 
 


CTEP #9149 (01-07-2020) 
 
119 
 
DATE 
DAY 
Time taken 
Veliparib  
Time taken 
Temozolomide 
COMMENTS: 
Side effects/missed dose 
AM 
PM 
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
No drug taken today 
 
 
7 
 
 
No drug taken today 
 
 
8 
No drug taken today 
No drug taken today 
 
 
9 
No drug taken today 
No drug taken today 
 
 
10 
No drug taken today 
No drug taken today 
 
 
11 
No drug taken today 
No drug taken today 
 
 
12 
No drug taken today 
No drug taken today 
 
 
13 
No drug taken today 
No drug taken today 
 
 
14 
No drug taken today 
No drug taken today 
 
 
15 
No drug taken today 
No drug taken today 
 


CTEP #9149 (01-07-2020) 
 
120 
 
 
16 
No drug taken today 
No drug taken today 
 
 
17 
No drug taken today 
No drug taken today 
 
 
18 
No drug taken today 
No drug taken today 
 
 
19 
No drug taken today 
No drug taken today 
 
 
20 
No drug taken today 
No drug taken today 
 
 
21 
No drug taken today 
No drug taken today 
 
 
22 
No drug taken today 
No drug taken today 
 
 
23 
No drug taken today 
No drug taken today 
 
 
24 
No drug taken today 
No drug taken today 
 
 
25 
No drug taken today 
No drug taken today 
 
 
26 
No drug taken today 
No drug taken today 
 
 
27 
No drug taken today 
No drug taken today 
 
 
28 
No drug taken today 
No drug taken today 
 
 
 
 


CTEP #9149 (01-07-2020) 
 
121 
 
Patient Study Diary 
 
Study Name: Molecular Profiling-based Assignment of Cancer Therapy for Patients With 
Advanced Solid Tumors 
 
CTEP Study ID: 9149 
 
 
Patient Name:  ______________________________________________________ 
 
Instructions to the patient: Please complete this form and return to the research nurse or doctor 
every cycle (21 days) 
 
You will take:       AZD1775 and carboplatin 
Medication dose:   Take AZD1775 capsules twice each day on days 1 and 2 (morning and 
evening) and once on day 3 (either in the morning or evening) at least two 
hours before or two hours after a meal.  Do not open, crush, or chew the 
capsules.  Avoid grapefruit, grapefruit juice, Seville oranges, starfruit, and the 
herbal supplement St. John’s Wort while taking this drug.   
Carboplatin will be given by intravenous administration at the day hospital on 
day 1 only of each 21-day cycle.  
 
Cycle number:      _________ 
Start date:  
_________ 
 
Patient Signature:  _____________________________________ 
 
 
 
 


CTEP #9149 (01-07-2020) 
 
122 
 
DATE 
DAY 
Time taken 
AZD1775  
COMMENTS: 
Side effects/missed dose 
 
1 
AZD1775 and carboplatin 
will be given in clinic today.  
Take one dose of AZD1775 
in the evening 
Time evening: ________ 
 
 
2 
Take 2 doses of AZD1775 
today.  Take one dose of 
AZD1775in the morning 
and one in the evening. 
Time morning: ________ 
Time evening: ________ 
 
 
3 
Take only one dose of 
AZD1775 today 
Time: _________ 
 
 
4 
No drug taken today 
 
 
5 
No drug taken today 
 
 
6 
No drug taken today 
 
 
7 
No drug taken today 
 
 
8 
No drug taken today 
 
 
9 
No drug taken today 
 
 
10 
No drug taken today 
 


CTEP #9149 (01-07-2020) 
 
123 
 
DATE 
DAY 
Time taken 
AZD1775  
COMMENTS: 
Side effects/missed dose 
 
11 
No drug taken today 
 
 
12 
No drug taken today 
 
 
13 
No drug taken today 
 
 
14 
No drug taken today 
 
 
15 
No drug taken today 
 
 
16 
No drug taken today 
 
 
17 
No drug taken today 
 
 
18 
No drug taken today 
 
 
19 
No drug taken today 
 
 
20 
No drug taken today 
 
 
21 
No drug taken today 
 
 
 


CTEP #9149 (01-07-2020) 
 
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Patient Study Diary 
 
 
Study Name: Molecular Profiling-based Assignment of Cancer Therapy for Patients With 
Advanced Solid Tumors 
 
CTEP Study ID: 9149 
 
 
Patient Name:  ____________________________________________________________ 
 
Instructions to the patient: Please complete this form and return to the research nurse or doctor 
every cycle (28 days) 
 
You will take:       Everolimus        
Medication dose:  Take everolimus tablets once a day every day for 28 days.  Tablets should not   
be crushed or chewed, and should be swallowed whole with a glass of water.  
Tablets can be taken with or without food, but please try and take them at the 
same time every day, and if possible, always with or always without food.  If 
you vomit the tablet, do not take another tablet that day.  Avoid grapefruit, 
grapefruit juice, Seville oranges, starfruit, and the herbal supplement  
St. John’s Wort while taking this drug.  Caregivers should wash their hands 
with soap and water after touching the tablets.   
 
Cycle number:      _________ 
Start date:  
_________ 
 
Patient Signature:  _____________________________________ 
 
 
 
 
 


CTEP #9149 (01-07-2020) 
 
125 
 
DATE 
DAY 
Time taken 
Everolimus 
COMMENTS: 
Side effects/missed dose 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 


CTEP #9149 (01-07-2020) 
 
126 
 
DATE 
DAY 
Time taken 
Everolimus 
COMMENTS: 
Side effects/missed dose 
 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 
 


CTEP #9149 (01-07-2020) 
 
127 
 
Patient Study Diary 
 
 
Study Name: Molecular Profiling-based Assignment of Cancer Therapy for Patients With 
Advanced Solid Tumors 
 
CTEP Study ID: 9149 
 
 
Patient Name:  _____________________________________________________________ 
 
Instructions to the patient: Please complete the form on the next page and return it to the 
research nurse or doctor every cycle (28 days).  Store trametinib DMSO tablets in the 
refrigerator.  Keep the tablets in the bottle they come in and do not move to a pill holder.  Do not 
take out the anti-moisture cube or packet. 
 
You will take:      Trametinib DMSO 
Medication dose:  Take Trametinib DMSO tablets once a day for 28 days with a full glass of 
water either 1 hour before or 2 hours after a meal.  If you vomit the tablets, do 
not take an additional dose.  If you miss a dose, take it as soon as you 
remember.  If it is less than 12 hours until your next dose, skip the dose. 
 
Cycle number:      _________ 
Start date:  
_________ 
 
Patient Signature:  _____________________________________ 
 
 
 


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DATE 
DAY 
Time taken 
Trametinib DMSO 
COMMENTS: 
Side effects/missed dose 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 


CTEP #9149 (01-07-2020) 
 
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DATE 
DAY 
Time taken 
Trametinib DMSO 
COMMENTS: 
Side effects/missed dose 
 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 
 
 


CTEP #9149 (01-07-2020) 
 
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Study Chart: 
 
Treatment cycles will be repeated as long as you are tolerating the study drug and your cancer is 
either stable or getting better.  Each cycle is numbered in consecutive order.  The chart below 
shows what will happen during Cycle 1 and future cycles.  The left-hand column shows the day 
in the cycle, and the right-hand column tells you what will happen on that day.  This schedule 
shows what will happen to you after you sign the consent and start the study.  
 
Day 
What to do and what will happen to you 
Before 
starting 
study 
drugs 
• Check in at the Outpatient Clinic 
• Get routine blood tests 
• EKG  
• Eye exam (depending on the study treatment) 
• Pregnancy test 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• CT scan will be done 
Day 1 
• Check in at the Outpatient Clinic 
• Based on analysis of gene variations in your tumor, you may be given one of 
the following drugs: Trametinib DMSO, or everolimus, or Veliparib and 
temozolomide, or AZD1775 and carboplatin 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• Get routine blood tests  
• During the first week, have a tumor biopsy to confirm your genetic testing 
report (no biopsy if you already had one for screening on this study) 
Day 8 
• Continue taking your study drug by mouth each day (if taking everolimus or 
Trametinib DMSO) according to the instructions in your study medication 
diary  
• Get routine blood tests (Cycle 1 only) 
Cycle 2  
Day 1 
• For patients getting AZD1775 plus carboplatin only, check in at the Outpatient 
Clinic (first day of every cycle only).  
• Continue taking your study drug by mouth each day  
• Eye exam (depending on the study treatment) 
Cycle 3 
onwards 
• CT scans to determine how your tumor is responding to the treatment will be 
done every 2 cycles (less often if you have been on study for more than one 
year. 
• Echocardiogram (depending on the study treatment) to check for possible 
damage to your heart may be done every 3 cycles  
 
On the days that you will be taking the study drug you will be asked to fill in a diary to show 
when you took the study drug and how many tablets or capsules you took, and report any side 
effects that you may have had.   
 
 
 


CTEP #9149 (01-07-2020) 
 
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APPENDIX E: MPACT (9149) Sample Shipping Instructions and Manifest 
 
This protocol collects formalin-fixed tumor samples (2 cores) from the initial screening biopsy procedure.  Please consult with the study PI 
for more information and discuss the handling requirements for each core sample collected with the interventional radiologist.   
 
 
Sample collection and shipping items to be purchased by each participating site: 
Biopsy collection*:  
• Pre-filled 10% neutral-buffered formalin specimen jar, 30 mL (e.g., Leica 3800770), one jar per core sample 
 
Blood collection: 
• 2 cell-free DNA BCT tubes, 10 mL (e.g., Streck 218961)  
 
Shipping supplies:  
• Specimen bags (zip-lock)  
• Absorbent paper for packing  
• Controlled room temperature (CRT) gel packs (e.g., STT-521-500 Saf-T-Temp CRT PCM Paks) 
• Small thermo-shipper boxes (e.g., Thermo-safe 14100-434)  
 
Notes:  
Follow manufacturer’s instructions for specimen collection and handling.   
Put shipping manifest in a plastic zip-lock bag in case of sample leakage.  Include the Clinical Center number, study number (9149), patient 
ID, site of biopsy, patient diagnosis, biopsy/blood collection date, and fixation time (i.e., initial/date/time placed into 10% NBF) on the 
manifest.  Do not include patient identifiers. 
 
Please do not collect samples on Fridays for overnight delivery as FNLCR cannot accept weekend courier delivery.  If Friday collection is 
unavoidable, ship the samples via overnight delivery but contact NCI-FrederickMPACTCLIA@mail.nih.gov and include two CRT gel 
packs in the shipper boxes.  The samples will be stable until Monday delivery.  
 
*Archival FFPE tumor blocks may be acceptable if collected within 6 months of registration and if the patient has not received targeted or 
investigational therapy since collection; check with study investigator for details  
 


CTEP #9149 (01-07-2020) 
 
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GENETIC SAMPLE SHIPPING MANIFEST 
Protocol 9149 
Shipping date:  
Carrier:  
SHIP FROM: 
Ordering 
Physician/PI: 
 
SHIP TO: 
MoCha Histology Laboratory (K. Benauer) 
   Address: 
 
   Address: 
    
Leidos Biomedical Research Inc. (FNLCR) 
 
1050 Boyles St. Bldg 321, Room #107 
 
Frederick, MD 21702 
  Contact Name: 
 
 
   Telephone: 
 
Telephone: 
301-846-6083/301-846-1535 
   Email: 
 
Email: 
NCI-FrederickMPACTCLIA@mail.nih.gov 
Item 
Unique GeneMed ID* 
(Sample ID) 
Biopsy Site 
Diagnosis 
Date 
Collected 
No. Containers/Tubes 
Fixation Time 
Biopsy 
Blood 
FFPE block 
Into 10%NBF-Site 
(Initial/Date/Time) 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
TOTAL No. ITEMS 
 
 
 
 
COMMENTS: 
*DO NOT include patient identifiers 
 
 
 
 
 
 


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APPENDIX F: Biopsy Sequencing Results and Analysis Form 
 
Form begins on the next page. 


 
 
134 
 
 
Molecular Characterization Laboratory   
Frederick National Laboratory for Cancer Research   
(Leidos Biomedical Research, Inc.)    
459 Miller Drive, Frederick, MD 21702   
301.846.7689 
CLIA Laboratory ID 21D2097127 
 
CTEP-9149 TUMOR SPECIMEN REPORT 
Patient ID:   
Report Date:   
 
Patient ID: 
 
MoCha ID: 
HIS- 
Principal Investigator: 
Alice Chen, MD 
Diagnosis: 
 
 
Biopsy Site: 
 
Date 
Collected: 
 
DNA/cDNA 
Block Source: 
 
Tumor Content 
(%)1: 
 
 
This report identifies only actionable MOIs (aMOIs) relevant to the genes currently validated for clinical application.  
aMOIs not detected are not otherwise identified. 
 
DNA Repair :   None identified (delete this text if variants are reported) 
aMOIs Detected 
Gene 
Chr. 
Position 
REF (hg19) 
ALT (Tumor) 
Transcript 
ID 
Amino Acid 
Change 
VAF 
Variant ID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Preanalytical preparation was performed by the MoCha Histology Laboratory, 321 Ware Drive, Frederick, MD 21702 [CLIA ID 21D2137521].  Reported 
assay characteristics cannot be guaranteed for specimens that present a tumor content below 20%. 
KEY: NA=Not Applicable; Chr=Chromosome;  REF (HG19)=Reference base, Human Reference Genome hg19); ALT (Tumor)=Variant base 
  Comments:   
   
SIGNATURE APPROVAL:   
The signature below attests that the signee has reviewed the data and results reported and concurs with the stated conclusions. 
 
 
 
DISCLAIMER:  This assay is considered a Laboratory Developed Test (LDT).  Its performance characteristics have been determined through extensive 
testing although it has not been cleared by the US Food and Drug Administration and such approval is not required for clinical implementation. Furthermore, 
any Comments included in this report are strictly interpretive and the opinion of the reviewer. This laboratory is certified under the Clinical Laboratory 
Improvement Amendments (CLIA) for the performance of high-complexity molecular testing for clinical purposes. 
 


 
 
135 
 
 
Molecular Characterization Laboratory   
Frederick National Laboratory for Cancer Research   
(Leidos Biomedical Research, Inc.)    
459 Miller Drive, Frederick, MD 21702   
301.846.7689 
CLIA Laboratory ID 21D2097127 
 
Methodology, Scope, and Application:  The sequencing test utilizes the Thermo Fisher Scientific Oncomine® Comprehensive Assay v3.0 (OCAv3), a next-
generation sequencing (NGS) assay that utilizes a multiplex polymerase chain reaction (PCR) with DNA extracted from formalin-fixed tissue for sequencing 
on the Ion S5 XL platform. The OCv3 NGS Assay can reliably identify the presence or absence of known (reported in COSMIC or ClinVar databases) aMOIs in 
15 DNA repair genes, with results compared to Human Reference Genome hg19. The table below lists these genes with the aMOIs t hat can be identified. The 
remainder of the genes included in the Oncomine panel include no relevant hotspots.  Novel deleterious calls and truncating mutations (frameshift indels 
and/or nonsense mutations) will also be considered actionable.  The OCAV3 NGS Assay is a laboratory developed test designed to find gene mutations 
within tumors (somatic mutations). It was not designed to find hereditary mutations.  
Analytical Sensitivity and Specificity:  The OCAV3 NGS Assay has been determined to be suitably analytically sensitive and specific for the various types of 
abnormalities within its reportable range, demonstrating 97.18% sensitivity compared with orthogonal assay results and 100% s pecificity for the mutation types 
reported.  99.99% or greater reproducibility has been demonstrated. All quality measures for this assay were within defined assay parameters. 
 
Gene 
Pathway 
Identifiable aMOIs (defined as Coding Sequence Change) 
Functionality 
ATM 
DNA repair 
c.1009C>T, c.1009C>A, c.1010G>C, c.1010G>A, c.5558A>T, c.6490G>C, c.6490G>A, c.7325A>C, 
c.7325A>G, c.7327C>G, c.7328G>A, c.8083G>T, c.8083G>A, c.8084G>C, c.8494C>T, c.8494C>A, 
c.8624A>G, c.8624A>C, c.8625T>A, c.8668C>G, c.8669T>G, c.8860T>A, c.8861A>G, c.9022C>A, 
c.9022C>T, c.9023G>T, c.9023G>A 
Loss 
NBN 
DNA repair 
Novel loss of function frameshift or nonsense mutation 
Loss 
RAD51 
DNA repair 
Novel loss of function frameshift or nonsense mutation 
Loss 
RAD51B 
DNA repair 
Novel loss of function frameshift or nonsense mutation 
Loss 
RAD51C 
DNA repair 
Novel loss of function frameshift or nonsense mutation 
Loss 
RAD51D 
DNA repair 
Novel loss of function frameshift or nonsense mutation 
Loss 
PALB2 
DNA repair 
Novel loss of function frameshift or nonsense mutation 
Loss 
BRCA1 
DNA repair 
c.5363G>T, c.5277+1G>A, c.441+2T>G, c.5468-40T>A, c.5467G>A, c.5359T>A, c.5332+1G>A, 
c.5331_5332+1delinsCAACAT, c.5324T>G, c.5324T>A, c.5297T>G, c.5291T>C, c.5278-2del, c.5212G>A, 
c.5194-12G>A, c.5153-1G>C, c.5152+3A>C, c.5152+1G>T, c.5143A>C, c.5123C>A, 
c.5117G>A, c.5095C>T, c.5074+1G>A, c.5074G>A, c.5074G>C, c.5074G>T, c.5054C>T, c.5053A>G, 
c.4987-1G>A, c.4986+6T>C, c.4986+6T>G, c.4986+4A>G, c.4986+4A>C, c.4986+4A>T, c.4675+3A>T, 
c.4675+1G>A, c.4675G>A, c.4675G>C, c.4484G>T, c.4357+1G>A, c.4185G>A, c.4097-1G>A, 
c.547+2T>A, c.302-1G>C, c.302-3C>G, c.213-3C>G, c.213-11T>G, c.213-12A>G, c.212+3A>G, 
c.212G>A, c.211A>G, c.191G>A, c.181T>G, c.131G>A, c.130T>A, c.122A>G, c.115T>C, c.110C>A, 
c.65T>C, c.3G>T, c.2T>C, c.2T>G, c.1A>G, c.5513T>A 
Loss 
BRCA2 
DNA repair 
c.2T>G, c.3G>T, c.475G>A, c.475+1G>A, c.476-2A>G, c.631G>C, c.631G>A, c.682-2A>G, c.7007G>C 
c.7007G>T, c.7008-2A>T, c.7617+1G>A, c.7618-1G>A, c.7878G>C, c.7879A>T, c.7976G>C, c.7988A>T, 
c.8009C>T, c.8165C>G, c.8167G>C, c.8168A>G, c.8243G>A, c.8487+1G>A, c.8953+1G>T,  
c.8954- 3C>G, c.9154C>T 
Loss 
CHEK1 
DNA repair 
Novel loss of function frameshift or nonsense mutation 
Loss 
CHEK2 
DNA repair 
c.1556G>A, c.1169A>G, c.1141A>G 
Loss 
FANCA 
DNA repair 
Novel loss of function frameshift or nonsense mutation 
Loss 
MRE11A 
DNA repair 
Novel loss of function frameshift or nonsense mutation 
Loss 
IDH1 
DNA repair 
c.394C>A, c.395_396GT>AC, c.394_395CG>GT, c.394_395CG>TC, c.395G>A, c.395G>T, c.394C>G, 
c.394C>T 
Altered 
IDH2 
DNA repair 
c.515_516GG>AT, c.516G>C, c.516G>T, c.515G>A, c.515G>C, c.515G>T, c.514A>T, 
c.514A>G, c.419G>A, c.419G>T, c.418C>G, c.418C>T 
Altered 
aMOI COSMIC ID may be found at: Catalog of Somatic Mutations in Cancer, https://cancer.sanger.ac.uk/cosmic  
 
 
 
 


CTEP #9149 (01-07-2020) 
 
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APPENDIX G: Molecular Tumor Board Members 
 
The Molecular Tumor Board is a multidisciplinary group with expertise in molecular and clinical 
genetics, gene analysis, pharmacogenomics, pharmacodynamics, statistics, and bioinformatics 
assembled to review and select the genetic variants being assessed on this study.  The Board will 
meet on an ad hoc basis to review and discuss findings and results but will not influence initial 
treatment assignments.   
 
Name 
Affiliation 
Specialty 
Alice Chen, MD 
CTEP/DCTD/NCI 
Clinical oncology 
James H. Doroshow, MD 
DCTD/NCI 
Molecular and clinical oncology 
Jeff Hildesheim, PhD 
CCBB/NCI 
Molecular oncology 
Robert Kinders, PhD 
Leidos Biomed., FNLCR Molecular oncology and pharmacodynamics 
Chris Karlovich, PhD 
Leidos Biomed., FNLCR Molecular oncology and genetic analysis 
Paul Meltzer, MD, PhD 
GB/CCR/NCI 
Molecular oncology and genetic analysis 
Eric Polley, PhD 
Mayo 
Statistics 
Yves Pommier, MD, PhD 
LMP/CCR/NCI 
Molecular oncology 
Larry Rubinstein, PhD 
DCTD/NCI 
Statistics 
Jim Tricoli, PhD 
Leidos Biomed., FNLCR Molecular oncology and genetic analysis 
Mickey Williams, PhD 
Leidos Biomed., FNLCR Molecular oncology and genetic analysis 
 
 
 
 
 


CTEP #9149 (01-07-2020) 
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APPENDIX H: Example Tumor Variant Patient Report   


CTEP #9149 (01-07-2020) 
 
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APPENDIX I: Veliparib plus Temozolomide (Proprietary Information) 
 
Veliparib is an orally available, small molecule inhibitor of PARP.  Preclinical and clinical data 
show that inhibition of PARP potentiates the effects of DNA-damaging chemotherapeutic drugs 
such as the alkylating agent temozolomide [67].  In this study, Veliparib and temozolomide will be 
administered to patients with defects in DNA repair pathways.   
 
Nonclinical Studies 
One of the most studied alkylating agents in combination with PARP inhibition is temozolomide, 
which is used in the treatment of CNS tumors and melanoma.  In vitro, potentiation of 
temozolomide-induced cytotoxicity was observed in the MMR-deficient HCT-116 cell line.  In 
nonclinical models of murine melanoma, dose-dependent potentiation of temozolomide was 
demonstrated with 12.5 mg/kg BID of orally administered Veliparib that was identified as the 
maximally efficacious dose (AUC, 3 µg•hr/mL) [100].  Preliminary human pharmacokinetic (PK) 
results indicate that an oral dose of 40 mg Veliparib BID achieves the exposure (AUC) that was 
maximally effective in murine efficacy models.  The predicted efficacious exposures are below 
Veliparib concentrations that resulted in a NOAEL in repeated-dose toxicity studies in rats and 
dogs. 
 
The PK profile of Veliparib was evaluated in tumor-bearing rats by measuring drug in plasma as 
well as in brain and tumor tissues.  After multiple doses of Veliparib (50 mg/kg/day), the 
concentration of the compound 2 hours after dosing (near Cmax) was 1.36 ± 0.16 μg/mL in 
plasma, 0.72 ± 0.12 μg/g in brain, and 3.00 ± 0.16 μg/g in tumor tissue.  Co-administration with 
temozolomide did not alter the plasma pharmacokinetic profile of Veliparib. 
 
Ataxia, tremors, seizures/convulsions, and other behaviors consistent with CNS effects were 
observed after repeated oral doses in dogs during multiple studies.  In the aggregate of studies in 
which convulsions were observed in dogs, the lowest plasma concentration of Veliparib measured 
at time of convulsion was 1.16 µg/mL, and the lowest calculated AUC0-24 corresponding to 
convulsion was 16.7 µg•hr/mL.  The lowest observed exposure values correspond to an exposure 
of approximately 5.5-fold above the predicted clinical maximum plasma concentration (Cmax) of 
0.210 µg /mL, and approximately 6-fold above the predicted clinical AUC0-24 of 3 µg•hr/mL.  
Convulsions were either self-resolving or resolved after treatment with diazepam.  There was no 
evidence of abnormal cortical activity or seizures occurring at a dose of 20 mg/kg BID in an EEG 
study in the conscious dog.  There is no proposed pathophysiologic mechanism for the observed 
seizures.  No seizures have been reported in clinical trials with Veliparib to date. 
 
In a separate study in rats in which Veliparib was combined with temozolomide, observed 
toxicities were consistent with exacerbation of known temozolomide toxicity.  Co-administration 
of temozolomide at 16 mg/kg/day and Veliparib at doses of 12.5 and 25 mg/kg/day (divided BID) 
resulted in increased toxicity over that observed with temozolomide administration alone, 
effecting bone marrow, lymphoid tissues, testes, and ovaries.  Most toxicological findings 
resolved at the end of a 22-day recovery period, with the exception of the testes.  In this study, the 
combination of Veliparib (50 mg/kg/day) in combination with temozolomide significantly reduced 
tumor volume by 63%, which was more effective than temozolomide alone (44%) [100].   
 


CTEP #9149 (01-07-2020) 
 
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The reversible and nonlethal exacerbation of temozolomide hematologic toxicity in the rat 
occurred at doses of Veliparib that, in previous studies, resulted in exposures that were similar to 
or greater than anticipated clinically efficacious exposure (AUC).   
 
Veliparib can produce fetal toxicities, including decreased fetal weights, increased post-
implantation loss, fetal malformation and variations (external, visceral, and skeletal), and delayed 
skeletal ossification.  The rat is the most sensitive species for fetal toxicity, with the Cmax at the 
NOEL for rat and rabbit of 0.02 and 2.4 µg/mL, respectively.  There are no data regarding the 
effects of Veliparib on pregnancy in humans. 
 
Clinical Studies 
Pharmacokinetic results from a Phase I study of Veliparib in combination with temozolomide 
(Study M06-862) were consistent with those seen in the Phase 0 study [100].  Similar to results 
from CTEP Study 7675 (A06-161), Veliparib absorption and elimination were relatively rapid 
after administration of Veliparib alone on Day 7.  Across Study M06-862 subjects, the time to the 
maximum concentration (Tmax) averaged 1.2 hours and the predose concentration averaged 27% 
of the maximum concentration (Cmax).  The coefficients of variation in dose-normalized Cmax and 
area under the curve (AUC) over a dosing interval (AUC0-12) on Day 7 were 40% and 50%, 
respectively.  Veliparib 40 mg twice daily (BID) produced an average steady-state AUC0-24 of 
4.81 µg•hr/mL, assuming equivalent AUCs following the morning and evening doses.  This 
clinical regimen exposure is comparable to that associated with the maximally effective Veliparib 
regimens in murine efficacy models (3.0 µg•hr/mL).  Across the dose range studied, Veliparib 
Cmax and AUC were approximately dose-proportional with minimal accumulation of plasma 
Veliparib concentrations following BID dosing.  Additionally in Study M06-862, the potential 
pharmacokinetic interaction between Veliparib and temozolomide is being assessed by 
determination of the pharmacokinetics of temozolomide and Veliparib when administered alone 
on Days 1 and 7, respectively, and when co-administered on Day 3.  At the dose levels studied to 
date, there is no indication of a significant pharmacokinetic interaction between Veliparib and 
temozolomide.  Preliminary Veliparib pharmacokinetics in another Phase 1 Study M10-128 show 
trends of approximately dose-proportional pharmacokinetics and absence of a significant food 
effect. 
 
Preliminary safety and/or efficacy results are available from 5 Phase 1, 1 Phase 1/2, and 4 Phase 2 
Abbott-sponsored studies of Veliparib in combination with a DNA-damaging agent [100].  In the 
Phase 1 Study M06-862, doses in the dose-escalation portion of the study ranged from 10 mg 
Veliparib BID/150 mg/m2 temozolomide once daily (QD) to 80 mg Veliparib BID/200 mg/m2 
temozolomide QD.  No DLTs were reported for the first 3 dose-escalation cohorts (10, 20, and 40 
mg Veliparib BID).  In cohorts receiving 60 and 80 mg BID, events of grade 4 neutropenia or 
thrombocytopenia were reported.  The MTD combination dose was defined as 40 mg Veliparib 
BID/200 mg/m2 temozolomide QD.  In addition to defining the MTD, a second dose, lower than 
the MTD but also predicted to be biologically active, was defined as 20 mg Veliparib BID/200 
mg/m2 temozolomide QD. 
 
Although no DLTs were reported in Study M06-862 subjects in the 40 mg Veliparib BID 200 
mg/m2 temozolomide QD dose-escalation cohort, 2 subjects enrolled at the same dose in the 
expanded MTD safety cohort experienced serious adverse events of grade 4 neutropenia and/or 
thrombocytopenia, and 8 of all 12 subjects receiving 40 mg Veliparib BID 200 mg/m2 experienced 


CTEP #9149 (01-07-2020) 
 
140 
 
grade 3 or 4 adverse events of neutropenia and/or thrombocytopenia.  In general, subjects with 
these events recovered after dose reduction of Veliparib and/or temozolomide, and all subjects 
remained on study. 
 
To minimize these hematologic toxicities, Study M06-862 protocol was modified to treat new 
subjects with 40 mg Veliparib BID in combination with 150 mg/m2 temozolomide QD in the first 
cycle.  If a subject did not experience grade 3 or 4 neutropenia or thrombocytopenia or other 
clinically significant NCI CTCAE greater than grade 3, the temozolomide dose was escalated to 
200 mg/m2 QD.  In addition to neutropenia and thrombocytopenia, the other most commonly 
reported adverse events in Study M06-862 occurring in ≥ 30% of subjects were nausea, fatigue, 
vomiting, constipation, decreased appetite, and headache.  All of the most commonly reported 
adverse events have previously been reported in subjects receiving temozolomide.   
 
For Study M06-862, preliminary data on tumor assessment was available for 42 subjects. 
Two of 42 subjects (4.76%) experienced an objective partial response.  Of these, one subject, a 
BRCA-deficient ovarian cancer patient, experienced an objective partial response in Cycle 6 and 
this partial response was confirmed in Cycles 8 and 10.  The other, a subject with hepatocellular 
carcinoma (HCC), experienced a partial response in Cycle 4 that was confirmed in Cycles 6, 8, 
10, and the Final Visit. 
 
In the Phase 1/2 Study M10-190, Veliparib was administered in combination with radiation 
therapy with concurrent and adjuvant temozolomide (75 mg/m2 for 6 weeks). 
Preliminary safety data were available for 18 subjects.  The most commonly reported adverse 
events occurring in ≥ 30% of subjects were nausea, fatigue, headache, insomnia, and 
thrombocytopenia.  Study M10-440 is a Phase 2 randomized, double blind, placebo-controlled 
study of Veliparib (20 or 40 mg BID) in combination with temozolomide (150 mg/m2/day with 
possible escalation to 200 mg/m2).  This study is fully enrolled and ongoing.  Preliminary blinded 
safety data are available for 344 subjects.  The most common AEs (reported in ≥ 30% of subjects 
receiving Veliparib plus temozolomide) were nausea, fatigue, constipation, thrombocytopenia, and 
vomiting. 
 
In the Phase 2 Study M10-757, preliminary safety data are available for 165 subjects.  The most 
common treatment-emergent AEs (reported for ≥ 30% of subjects receiving Veliparib plus 
temozolomide at any point) reported in subjects with recurrent high-grade serous ovarian cancer 
treated with Veliparib plus with temozolomide versus PLD alone, were nausea, fatigue, 
thrombocytopenia, vomiting, constipation, neutropenia, and decreased appetite.  Preliminary 
efficacy data are not yet available.  Preliminary safety data are available for 26 subjects.  The most 
common treatment-emergent AEs (≥ 30% of all subjects) reported in Study M11-070, a trial 
evaluating subjects with metastatic castration-resistant prostate cancer treated with Veliparib plus 
temozolomide, were fatigue, nausea, and platelet count decreased.  Preliminary data on maximum 
percentage reduction from baseline in PSA values are available for 25 subjects.  Confirmed PSA 
responses have been observed in 2 subjects.  The mean (SD) for the largest observed decrease 
from baseline in PSA values was 11.7% (48.3%).  In an extension study of Study M11-846, 
preliminary safety data available are for 23 subjects.  The most common treatment-emergent AEs 
(≥ 30% of all subjects) reported in Study M12-273, a trial evaluating subjects with solid tumors 
treated with Veliparib plus temozolomide, were nausea, fatigue, vomiting, abdominal pain, 
decreased appetite, and thrombocytopenia.  No preliminary efficacy data are available.   


CTEP #9149 (01-07-2020) 
 
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APPENDIX J: AZD1775 (Proprietary Information) 
 
AZD1775 with Carboplatin (Investigators Brochure) 
AZD1775 is a selective, adenosine-triphosphate (ATP) competitive, small molecule inhibitor of 
Wee1 kinase (IC50 = 5.18 nM), that directly inhibits phosphorylation of CDC2 at Tyr15.  The 
antitumor effect of AZD1775 in combination with carboplatin was investigated in the HeLa-luc 
(human cervical adenocarcinoma) nude rat xenograft model.  AZD1775 was administered orally 
to the animals 24 hr after carboplatin (50 mg/kg: MTD) at doses of 10, 20 and 30 mg/kg; single 
IV bolus treatments of carboplatin showed significant antitumor efficacy with %T/C = 70%.  
Tumor growth was not inhibited by AZD1775 monotherapy at a dose of 30 mg/kg, with %T/C = 
96%.  AZD1775 dose-dependently enhanced the anti-tumor effect of carboplatin in HeLa-luc 
tumors with %T/C = 85, 39 and 28% at doses of 10, 20 and 30 mg/kg, respectively.  AZD1775 did 
not cause significant enhancement of carboplatin-induced reduction of WBC (38 - 45% control) 
and platelets (15 - 26% control), and these parameters returned to normal by Day 20 and 10 in the 
combination arms.  AZD1775 alone did not show severe blood cell toxicity.  No severe body 
weight loss (-2 to -5% delta change vs. control), abnormal physical signs or mortality were 
observed in any treatment group.  These results suggest that the combination of AZD1775 with 
carboplatin has anti-tumor efficacy and is well tolerated. 
 
An additional tolerability study was conducted in non-tumor bearing nude rats dosed with 
carboplatin alone or in combination with AZD1775 over multiple cycles.  Doses of carboplatin 
(50 mg/kg IV), alone and in combination with AZD1775 (20 mg/kg orally, 24 hrs after 
carboplatin dosing), were administered once during a 28-day cycle for 3 consecutive cycles.  
Body weight and blood cell counts were monitored during the study period.  There were no 
significant changes in toxicity parameters between the carboplatin alone and the carboplatin + 
AZD1775 treatment arms.  Thus, AZD1775 did not significantly enhance the toxicity parameters 
of carboplatin when used in the multi-cycle dosing schedule. 
 
Non-clinical Toxicology 
The toxicology profile of AZD1775 in rats involved the lymphoid and hematopoietic organs and 
gastrointestinal tract, and included decreased food consumption, body weight loss, hematologic 
and serum chemistry changes, decreased urine volume and soft feces.  AZD1775 had no effect on 
CNS function in mice.  The cardiovascular effects of AZD1775 were examined in 5 isoflurane-
anesthetized and mechanically vented dogs.  At doses of 3 and 10 mg/kg, QTc was marginally 
prolonged by an average of 5% and 7%, respectively.  No QTc changes were observed in the 
intact dog studies or human studies.  Evidence of reversibility of all toxicity changes was 
generally demonstrated by the end of the 2-week recovery period.  In a single dose oral toxicity 
study, severe irreversible toxicity (mortality) was seen in 1 female out of 10 female rats after a 
single dose at 300 mg/kg (1800 mg/m2).  
 
Based on the preliminary safety data available, the most frequent AEs observed were blood and 
lymphatic disorders (thrombocytopenia, neutropenia, anemia, febrile neutropenia), gastrointestinal 
disorders (diarrhea, vomiting, nausea, abdominal pain, constipation), and investigation findings 
(hematology and serum chemistry).  The single-dose TD for both the gemcitabine and cisplatin 
combination therapies was 200 mg of AZD1775.  DLTs tended to be hematological in nature in 
the gemcitabine group and constitutional in the cisplatin group.  The single-dose MTD for the 


CTEP #9149 (01-07-2020) 
 
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combination with carboplatin was 325 mg of AZD1775.  DLTs in this group were related to 
serum chemistry. 
 
Clinical Studies 
AZD1775 has been administered to patients in 12 AstraZeneca-sponsored or Merck-sponsored 
clinical studies, 6 of which are ongoing.  
Completed or terminated early:  
• PN001 (NCT00648648): a first-time-in-patients (FTIP), Phase I, dose-escalation study 
evaluating AZD1775 both as monotherapy and combination therapy with gemcitabine, 
cisplatin, or carboplatin in adult patients with advanced solid tumours   
• PN004 (NCT01357161): a Phase II study evaluating AZD1775 combined with carboplatin 
and paclitaxel in patients with platinum-sensitive p53-mutant ovarian cancer  
• PN005 (NCT01047007): a Phase I, dose-escalation study evaluating AZD1775 as 
monotherapy (Part 1), combination therapy with 5-FU (Part 2), and combination therapy 
with 5-FU plus cisplatin (Part 3) in adult Japanese patients with advanced solid tumours 
was terminated early due to portfolio prioritisation in oncology at Merck after 3 patients 
had been enrolled in Part 1 and 8 patients had been enrolled in Part 2. Part 3 was not 
initiated.  
• PN008 (NCT01076400): a Phase I/IIa, dose-escalation study evaluating AZD1775 in 
combination with topotecan plus cisplatin in adult patients with cervical cancer was 
terminated early due to portfolio prioritisation in oncology at Merck after 7 patients had 
been enrolled in the dose-escalation part of the study. The Phase IIa part was not initiated.  
• D6011C00001 (NCT02087176; SCRI LUN 262): a lead-in Phase II multicentre, 
randomised, double-blind study comparing AZD1775 plus docetaxel with placebo plus 
docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC)  
• D6011C00002 (NCT02087241; SCRI LUN 261): a Phase II study of AZD1775 plus 
pemetrexed and carboplatin followed by a randomised comparison of pemetrexed and 
carboplatin with or without AZD1775 in patients with previously untreated stage IV non-
squamous NSCLC.  
Ongoing:  
• D6010C00004 (NCT02272790; SCRI GYN 49): multicentre Phase II study of AZD1775 
plus either paclitaxel, gemcitabine, carboplatin, or pegylated liposomal doxorubicin in 
patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal 
cancer  
• D6010C00005 (NCT02511795; SCRI REFMAL 384): Phase I study evaluating AZD1775 
in combination with olaparib in refractory solid tumours.  
• D6011C00003 (NCT02341456): Phase Ib dose-finding study evaluating AZD1775 as 
monotherapy and in combination with carboplatin and paclitaxel in adult Asian patients 
with advanced solid tumours  
• D6015C00001 (NCT02482311; SCRI REFMAL 383): Phase I, dose escalation, safety and 
pharmacokinetic study of AZD1775 monotherapy (Schedule 1) in patients with advanced 
or metastatic solid tumours  
• D6015C00002 (NCT02617277; SCRI REFMAL 412): Phase I study assessing the safety, 
tolerability, and pharmacokinetics of AZD1775 in combination with MEDI4736 in 
patients with advanced solid tumours  
• D6015C00003 (NCT02610075; SCRI REFMAL 398): Phase Ib study to determine the 


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maximum-tolerated dose (MTD) of AZD1775 monotherapy (Schedule 2) in patients with 
locally advanced or metastatic solid tumours.  
• In addition, Phase I and II studies are being conducted and sponsored by the National 
Cancer Institute’s (NCI) Cancer Therapy Evaluation Program, and by several other 
institutions as investigator-sponsored studies.  
 
As of 11 November 2016, a total of approximately 551 patients have been exposed to AZD1775 
in AstraZeneca-sponsored or Merck-sponsored clinical studies. Of these 551 patients, 103 
received AZD1775 monotherapy, 407 patients received AZD1775 in combination with cytotoxic 
chemotherapy agents and the remaining 41 patients received AZD1775 in combination with 
targeted therapies MEDI4736 or olaparib.  In addition, approximately 350 patients have also 
received AZD1775 as part of externally-sponsored scientific research.  These patients have 
received single doses per cycle as high as 1300 mg of AZD1775 as monotherapy, 325 mg of 
AZD1775 in a single-dose in combination with chemotherapy, and 325 mg twice a day (BID) in a 
multiple-dose regimen in combination with chemotherapy. 
 
The PK data of AZD1775 following a single oral administration showed a moderate rate of  
absorption with a Tmax occurring at 3 to 4 hours.  Post-peak plasma concentrations declined  
essentially in a mono-exponential manner with a t1/2 in the region of 10 hours.  Exposure as  
measured by maximum plasma drug concentration observed (Cmax) and AUC0-∞ increased in a 
dose-proportional manner over the dose range of 325 to 1300 mg.  Following single (100 to 325 
mg) and multiple dose administrations of AZD1775 (25 to 325 mg BID and 100 to 200 mg once 
daily [QD]) with carboplatin, cisplatin, and gemcitabine, plasma exposure of AZD1775 was 
consistent with predictions based on the single-dose regime.  Preliminary investigation of drug-
drug interactions in Study PN001 suggest a 40% to 60% increase in the exposure of AZD1775 in 
the presence of aprepitant (moderate CYP3A4 inhibitor), but no effect with the concomitant 
administration of various different corticosteroids (moderate CYP3A4 inducers). Preliminary 
studies also suggested that the PMF of AZD1775 was similar to that of the FFP formulation. 
 
Based on the safety data from the 3 completed AZD1775 clinical studies and preliminary data 
from ongoing studies, the most frequent adverse events (AEs) observed were blood and lymphatic 
disorders (leukopenia, lymphopenia, neutropenia, thrombocytopenia, anaemia, febrile 
neutropenia, pancytopenia), gastrointestinal disorders (diarrhoea, vomiting, nausea, abdominal 
pain, constipation), general disorders and administration site conditions (fatigue, fever, chills), and 
investigation findings (haematology and serum chemistry). Cardiac disorders (tachycardia, 
palpitations, QTc prolongation) were not observed frequently, but are considered to be important 
identified risks. Gastrointestinal haemorrhage is considered an important potential risk to be 
monitored closely as the programme progresses. 
 
Based on the safety data from the completed AZD1775 clinical studies and preliminary data from 
ongoing studies adverse drug reactions to AZD1775 monotherapy include: anaemia, neutropenia, 
thrombocytopenia, QTc prolongation, gastrointestinal events such as dyspepsia, diarrhoea, nausea 
and vomiting (with or without dehydration or serum electrolyte decreases), as well as decreased 
appetite. In addition, the following events are also considered expected during treatment with 
AZD1775 in combination with cytotoxic chemotherapy: febrile neutropenia, leukopenia, 
stomatitis, asthenia, fatigue, mucosal inflammation and myalgia. 
 


CTEP #9149 (01-07-2020) 
 
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Based on information emerging during the clinical development programme of AZD1775, 
potential risks with AZD1775 monotherapy include asthenia/fatigue, febrile neutropenia, 
gastrointestinal haemorrhage, lymphopenia/lymphocyte count decreased, leukopenia/WBC count 
decreased, myalgia, stomatitis, sepsis and transaminases elevation. 
 
In addition, the following events are also considered potential risks for AZD1775 in combination 
with cytotoxic chemotherapy: tachycardia and pancytopenia.  Refer to the IB for AZD1775 for 
information on the potential benefits and assessment of potential and known risks. 
 
In Study PN001, of 176 evaluable patients who received AZD1775 (either single or multiple  
doses) as monotherapy or in combination with gemcitabine, cisplatin, or carboplatin, a partial 
response (PR) (confirmed and unconfirmed) was observed in 17 (9.7%) patients, and stable 
disease (SD) was observed in 94 (53.4%) patients.  No complete responses (CRs) or PRs were 
observed in either of Studies PN005 or PN008 at the time that they were terminated.  
In Study PN004, all patients were treated at the 225 mg AZD1775 BID 2.5 day dose level in  
combination with paclitaxel and carboplatin.  Of the 14 evaluable patients by RECIST v1.1 in  
Part 1, there were 11 PRs (6 confirmed and 5 unconfirmed), and 3 SDs; 7 patients were  
evaluable by CA-125 with 3 CRs and 4 PRs.  Final data for Part 2 was not available as of the  
cut-off date for this brochure.  
In Study D6011C00001, 32 patients with NSCLC were treated with 225 mg AZD1775 BID  
over 2.5 days in combination with docetaxel (75 mg/m2 IV) administered on Day 1 followed  
by pegfilgrastim on Day 4 of each 21-day cycle.  The 3 patients (9.4%) that achieved PR by  
RECIST v1.1 had TP53 mutations.  Twenty-one patients (65.6%) had SD and 10 (47.6%) of  
these patients had TP53 mutations.  The planned Interim Analysis of 32 patients in the single 
cohort lead-in (Part A) suggested that toxicities associated with AZD1775 given in  
combination with docetaxel were greater in frequency and severity than with docetaxel alone.  
Additionally, the analysis revealed that it was very unlikely the target response rate would be 
reached in this study and a decision was made to terminate enrolment.  
 
In Study D6011C00002, 14 patients with NSCLC were treated with 225 mg AZD1775 BID  
over 2.5 days in combination with pemetrexed 500 mg/m2 IV and carboplatin AUC 6 IV, both 
administered on Day 1 of each 21-day cycle.  Enrolment was stopped because of the  
introduction of new therapies for the treatment of first-line NSCLC, such as immunotherapy,  
which resulted in challenges in patient recruitment.  In addition, the planned Interim Analysis  
of Study D6011C00001 revealed that it was very unlikely that the target response rate would  
be reached, and increased gastrointestinal and hematologic toxicities associated with  
AZD1775 were observed. 
 
Clinical Pharmacokinetics 
 
The major metabolic pathway of AZD1775 in human liver preparations is oxidative metabolism.  
Oxidative metabolism of AZD1775 is mediated predominantly by cytochrome P450 (CYP) 3A4 
and FMO3.  AZD1775 is also a weak reversible inhibitor of CYP2C8, CYP2C9, CYP2C19 and 
CYP3A4.  In addition, AZD1775 is a time-dependent inhibitor of CYP3A4 in in vitro human liver 
microsomes.  
 
 
 


CTEP #9149 (01-07-2020) 
 
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APPENDIX K: Trametinib DMSO (Proprietary Information) 
 
Trametinib DMSO is a reversible, highly selective allosteric inhibitor of MEK1/MEK2 activation 
and kinase activity.  The safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and 
activity of trametinib DMSO are currently being evaluated in 13 ongoing monotherapy and 
combination therapy clinical trials involving subjects with a variety of cancers. 
 
In May 2013, the FDA approved trametinib DMSO for the treatment of patients with unresectable 
or metastatic melanoma with BRAFV600E or BRAFV600K mutations.  In January 2014, the FDA also 
granted accelerated approval to the combination of trametinib DMSO and dabrafenib to treat 
patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. 
 
Nonclinical Pharmacology 
MEK proteins are critical components of the extracellular signal-related kinase (ERK) pathway 
which is commonly hyperactivated in tumor cells.  Oncogenic mutations in both B-RAF and RAS 
signal through MEK1 and MEK2.  Trametinib DMSO is non-competitive towards ATP and 
inhibits activation of MEK by RAF kinases as well as MEK kinase activity.  The specificity of 
trametinib DMSO to MEK1 and MEK2 was confirmed against a panel of 183 kinases, including 
MEK5, the closest kinase homolog to MEK1 and MEK2, and no significant inhibitory activity 
was measured [101].  In vitro, 80% of cell lines carrying activating mutations of B-Raf and 72% 
of Ras mutant cancer cell lines were sensitive to trametinib DMSO in cell proliferation assays, 
and a majority (83%) of hematopoietic cancers from acute or chronic myeloid leukemia (AML or 
CML, respectively) origins were also very sensitive. 
 
Antitumor Activity in vitro 
Cancer cells expressing high constitutive levels of activated ERK (pERK) tended to be more 
sensitive to trametinib DMSO than those with lower levels of pERK, suggesting that tumors with 
B-RAF or RAS mutations and/or high levels of pERK may respond to trametinib DMSO 
treatment.  In all cell lines, pERK was strongly inhibited following treatment with trametinib 
DMSO and was independent of their proliferative response, suggesting that pERK inhibition is 
necessary but not sufficient to inhibit cell proliferation.  In cell lines that were sensitive to the 
anti-proliferative activity of the agent, the response was associated with arrest in G1 phase of the 
cell cycle, accumulation of p27, reduction of cyclin D1 and phospho-retinoblastoma protein.  
Induction of apoptosis was demonstrated in some cell lines.  Inhibition of pERK and inhibition of 
cancer cell proliferation were fully reversible following compound removal, suggesting that 
sustained exposure to trametinib DMSO, or potential combination with other drugs, may be 
required for full activity. 
 
When trametinib DMSO was combined with standard of care drugs against human cancer cell 
lines in vitro, an additive effect was observed for pancreatic cancer with gemcitabine or erlotinib 
and for colon cancer with 5-FU or irinotecan.  The combination of trametinib DMSO with 
rapamycin, ara-C, bexarotene or sorafanib produced an additive effect against most AML cell 
lines tested.  In addition, combination of agent with an investigational phosphoinositide 3-kinase 
(PI3K) inhibitor, as well as with a Centromer Protein-E (CENP-E) inhibitor, was synergistic on 
inhibition of cell growth in various cancer (pancreas, colon, lung) cells.  Additionally, the 
combination of trametinib DMSO and a CENP-E inhibitor increased caspase activity, indicating 
enhanced apoptosis in colon cancer cell lines. 


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146 
 
 
While many proliferating human cells are sensitive to trametinib DMSO in vitro, the agent did not 
affect non-dividing normal cells and did not completely inhibit bone marrow progenitor cells at 
concentrations demonstrating anti-proliferative activity on very sensitive cancer cell lines.  
 
Antitumor Activity in vivo 
Trametinib DMSO was orally bioavailable in mice, and doses as low as 1 mg/kg reached blood 
concentrations that caused sustained reductions of pERK, an accumulation of p27, and a decrease 
of Ki67 in tumor xenografts; brain exposure levels were ~10% of those in blood, and no 
significant pERK inhibition was measured in brain tissue.  In mice, exposure to trametinib DMSO 
produced dose- and schedule-dependent anti-tumor responses correlating with blood levels.  
Typically, B-RAF--mutant xenografts responded with tumor regression while K-RAS-mutant 
xenografts responded with tumor growth inhibition.  In vivo combination studies testing 
trametinib DMSO together with various other anticancer drugs showed good potential for 
synergistic effects. 
 
Safety Pharmacology 
In a rat neurobehavioral screen, following a single oral dose of trametinib DMSO at 650 mg/m2 to 
male rats, diarrhea, prone position, blepharoptosis, piloerection, reduced spontaneous locomotion 
and mydriasis were observed between 2 and 24 hours post dose.  In a respiratory safety 
pharmacology study in rats, an oral dose of 1 mg/m2 produced a mild, transient decrease in body 
temperature (up to 0.8°C) at 1 hour post dose.  There were no other effects on ventilatory 
function, airway resistance or body temperature.  Trametinib DMSO inhibited hERG channel 
repolarization in HEK293 with an IC50 of 1.54 μM (950 ng/mL).  In a rabbit left ventricular 
wedge assay, trametinib DMSO had no significant effect on QT interval at concentrations up to 30 
μM (18450 ng/mL; limit of solubility).  However, significant decreases in isometric contractile 
force occurred at concentrations of 10 (6150 ng/mL) and 30 μM.  Trametinib DMSO also 
decreased the Tp-e interval at a concentration of 30 μM.  A single intravenous infusion of drug in 
dogs at 20 mg/m2 over 10 minutes (Cmax of 2.5 μM or 1500 ng/mL) produced no changes in 
electrocardiogram (ECG) parameters, blood pressure, or heart rate during the 30 minute 
measurement period.  In addition, single oral doses up to 1.5 mg/m2 in dogs produced no changes 
in arterial blood pressure, heart rate, body temperature, or ECG intervals, including QTc.  While 
trametinib DMSO affected cardiac electrophysiology in vitro, no effects were observed in vivo at 
doses that were maximally tolerated in dogs.  This difference in responses is likely related to the 
very low Cmax (~10 ng/mL total drug) at tolerated doses in dogs and the high protein binding 
(97% in dogs) of agent.  The concentrations at which effects were seen in these in vitro studies are 
significantly higher than the free fraction observed in nonclinical toxicology studies or the clinical 
dose (2 mg).  These results suggest a low risk for cardiovascular effects in the clinic. 
 
Pharmacokinetics and Product Metabolism in Animals 
Trametinib DMSO exhibited low plasma clearance among nonclinical species (mouse, rat, dog 
and monkey) with varied but generally long half-lives.  Oral bioavailability ranged between 42% 
and 100%.  Since trametinib DMSO is a low solubility, high permeability molecule, its absorption 
is likely limited by solubility and dissolution.  Plasma protein binding was high in nonclinical 
species and human (>95%) and blood cell association was low.  Consistent with high 
permeability, trametinib DMSO had moderate to high volume of distribution among the 
nonclinical species studied and DRM was widely distributed into rat tissues.  The low 


CTEP #9149 (01-07-2020) 
 
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concentration of DRM observed in the brain up to 8 hours post dose was observed.  Although 
studies showed protracted elimination of DRM (consistent with high volume and long half-life), 
DRM in tissues was not detectable by 35 days post dose.  In rats and dogs after repeat oral dosing 
up to 13 weeks, systemic exposure increased approximately dose-proportionally at higher doses or 
when steady state was reached at Week 3.  Upon repeat dosing, increases in systemic exposure 
after Day 1 were observed up to Week 3; however, between Weeks 4 and 13, there was no marked 
increase in systemic exposure for either pre-clinical species.  A tendency for higher exposure in 
females than in males was observed in some studies in both rats and dogs. 
 
No apparent human-specific metabolite was observed in the in vitro cross-species [14C] 
trametinib DMSO metabolism study.  [14C] trametinib DMSO was also found to metabolize 
predominantly via a non-cytochrome P450 (CYP) mediated deacetylation with secondary 
oxidation or glucuronidation biotransformation pathways.  CYP3A4 was implicated in the in-vitro 
formation of M7, a metabolite mediated by both non-CYP and CYP pathways.  The relative 
contribution of CYP3A4 to the total metabolic clearance of trametinib DMSO in human in vivo is 
not currently understood and, therefore, the possibility of a metabolic drug interaction cannot be 
eliminated.  Elimination of DRM in rat and dog after oral administration occurred predominantly 
via the feces (>60% of dose), with urinary excretion (<7% of dose) representing a minor route. 
 
Trametinib DMSO is metabolized predominantly via deacetylation (non-cytochrome P450 
[CYP450]-mediated) with secondary oxidation or in combination with glucuronidation 
biotransformation pathways (Investigator’s Brochure, 2012).  Deacetylation is likely mediated by 
hydrolytic esterases, such as carboxylesterases, or amidases.  Based on in vitro studies, trametinib 
is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4.  Trametinib DMSO 
has an overall low potential for drug-drug interactions.  There was no evidence of time-dependent 
inhibition with any of the CYP enzymes investigated.  
 
Toxicology 
Systemic toxicity of trametinib DMSO has been evaluated following oral dosing in rats and dogs 
for up to 13 weeks.  In the most sensitive nonclinical species, rat, the principal adverse effects 
seen in oral toxicity studies of up to 13 weeks with daily dosing were skin and stomach erosions, 
skin ulcerations, which were secondary to reduced proliferation, altered phosphate homeostasis 
that resulted in soft tissue mineralization, hepatocellular necrosis, bone marrow 
degeneration/necrosis and ovarian perturbations.  The skin and stomach findings and 
phosphatemia demonstrated reversibility with 4 weeks of recovery.  MTD in rats in the definitive 
13 week study with daily dosing was 0.25 mg/m2/day (AUC0-t of 126 ng.h/mL, end of study).  
Reversible acute effects (diarrhea, decreased body weight gain, prone position, blepharoptosis, 
piloerection, reduced spontaneous locomotion and mydriasis) were observed following a single 
high dose of 650 mg/m2 to rats.  In dogs, the principal dose-limiting toxicities seen oral toxicity 
studies of up to 13 weeks with daily dosing were related to gastrointestinal and hematopoietic 
perturbations.  Inflammatory responses to gastrointestinal erosions were observed in dogs and 
were reversible following a recovery period.  In the definitive 13 week daily oral dosing study in 
dogs, the NOAEL was 0.45 mg/m2/day (AUC0-t of 139 ng.h/mL, end of study).  Principal adverse 
effects were consistent with inhibition of cell proliferation and were monitorable and generally 
reversible.  Trametinib DMSO was negative in both in vitro and in vivo genotoxicity assays. 
 
 


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Effects in Humans 
The effect of Trametinib DMSO in subjects with a variety of refractory cancers is currently under 
evaluation in 14 clinical studies.  As of 14 April 2011, 657 subjects with cancer have received at 
least one dose of trametinib DMSO in the ongoing Phase I/II/III clinical studies.  There are no 
completed clinical trials to date.  Preliminary trametinib DMSO pharmacokinetics were 
determined after single- and repeat dose oral administration of tablets in subjects with solid 
tumors.  Trametinib DMSO is absorbed rapidly with median Tmax generally occurring within 1-3 
hours after oral administration under fasting conditions.  Following repeat-dosing the mean area 
under the curve (AUC0-τ) and maximum concentrations (Cmax) increased in an approximately 
dose proportional manner.  Trametinib DMSO accumulates with repeat dosing with a mean 
effective half-life of approximately 5 days.  The MTD was established at 3.0 mg once daily (QD), 
and the recommended Phase II dose was identified as 2.0 mg QD. 
 
Phase 
 Study # 
Treatment Regimen  
Study Population  
Monotherapy Studies  
I  
MEK111054  
Single agent (First-time-in-human)  
Solid tumors and BRAF-
mutant melanoma  
I/II  
MEK111759  
Single Agent  
Leukemia 
II  
MEK113583  
Single agent  
BRAF-mutant Melanoma  
III  
MEK114267 
Randomized comparison GSK1120212 vs. 
chemotherapy (dacarbazine, or paclitaxel)  
BRAF-mutant melanoma  
MEK113708  
Phase I ADME study  
Solid tumors  
MEK113709  
Phase I Food-Effect study  
 
Combination Therapy Studies  
IB/II  
MEK112110  Combination with everolimus (mTOR-
inhibitor)  
Solid tumors  
I/IB  
MEK112111  Combination with gemcitabine  
Solid tumors and pancreatic 
cancer  
I/IB 
MEK113486  
Multi-arm combination with docetaxel, 
pemetrexed, pemetrexed/carboplatin, nab-
paclitaxel, or erlotinib  
Solid tumors  
I  
MEK114784  Single agent and combination with 
gemcitabine  
Japanese subjects with solid 
tumors  
I/II  
BRF113220  
Combination with GSK2118436 (BRAF-
inhibitor)  
BRAF-mutant melanoma  
I  
TAC113886  
Combination with GSK214795 (AKT-
inhibitor)  
Solid tumors  
I  
P3K113794  
Combination with GSK2126458 (PI3 
Kinase-inhibitor)  
Advanced solid tumors  
II  
MEK113487  Randomized combination GSK1120212 with 
gemcitabine vs. gemcitabine  
Pancreatic cancer  
 
 
 


CTEP #9149 (01-07-2020) 
 
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Safety/Tolerability Profile 
The maximum tolerated dose was established at 3 mg daily.  The safety profile at doses greater 
than 2 mg QD was not as favorable with a larger percent of subjects with Grade 2 rash, rash 
leading to dose reduction, peripheral edema, and cardiac failure.  A dose of 2 mg QD was selected 
to minimize need for dose reduction and allow subjects to receive the highest dose that is well 
tolerated. 
 
The most common AEs experienced following 2 mg daily are diarrhea, rash, nausea, fatigue, 
vomiting, anemia, peripheral edema, abdominal pain, constipation, dermatitis acneiform, decreased 
appetite, pruritus, dyspnea, pyrexia, pneumonia, febrile neutropenia, AST increased, ALT 
increased, and dry skin.  
 
Other clinically important adverse reactions observed in ≤10% of patients (n=329) treated with 
trametinib were: nervous system disorders (dizziness, dysgeusia), ocular disorders (blurred vision, 
dry eye), infections and infestations (folliculitis, rash pustular, cellulitis), cardiac disorders 
(bradycardia), gastrointestinal disorders (xerostomia), and musculoskeletal and connective tissue 
disorders (rhabdomyolysis).   
 
 
 


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APPENDIX L: NCI Correlative Imaging Studies 
 
Patients at the NCI will be asked to sign a separate consent to allow collection and use of the 
standard-of-care images (CT or MRI) that qualified the patient for inclusion in this trial, along with 
the images taken during image-guided biopsy and any follow up imaging studies showing 
progression, to allow research into correlation of the image phenotypic features with genomic 
analyses.  Research analysis of these images will only be done once the images have been de-
identified; no research data generated from any image will be reported back to the patient, and no 
clinical decisions will be made based on research data generated from any image collected under 
this protocol.   
 
To accomplish delinking, the NCI’s secure GeneMed bioinformatics database will assign an 
imaging ID that, initially, will be coupled with the MPACT protocol ID in the GeneMed database.  
When a patient is off-study, GeneMed will provide the limited clinical information from that 
patient to the Cancer Imaging Archive (TCIA), linked through the imaging ID (not the patient 
protocol ID).  GeneMed will assign a new ID that will trigger permanent recoding of the physical 
tissue, which will undergo whole exome sequencing.  Following recoding, all samples and images 
will be completely unlinked from the clinical database.  
 
Patient images will be de-identified of PHI at the CCR Molecular Imaging Program before leaving 
the NIH Clinical Center site and stored in an NIH policy compliant internet-accessible collection, 
The Cancer Imaging Archive (TCIA), with controlled access.   
 
Images for TCIA are processed at the clinical site through a program developed by the 
Radiological Society of North America and NCI called the Clinical Trials Processor (CTP) 
[102].  Images are directly sent to the TCIA where they are sequestered pending, as needed, further 
QC/QA and appropriate sponsor access approvals. 
 
The individual responsible for this process is Justin Kirby (kirbyju@mail.nih.gov).  
 
The CTP is the primary means for uploading images into TCIA.  CTP is a client-server software 
package with the server installed on a special intake system at TCIA.  The CTP client, containing 
de-identification scripts customized for the trial site and specific trial data collection, will be 
installed in the Molecular Imaging Program in CCR.   
 
The Digital Imaging and Communications in Medicine (DICOM) image is sequestered in TCIA 
pending review, QC/QA, and sponsor permission to link to genomic and limited clinical data after 
it has been delinked from the patient identifiable data. 
 
The de-identification process follows the DICOM WG18 Supplement 142 standard.  The following 
are examples of the changes made: 
• Patient Names – Real patient names and initials are removed.  
• Patient IDs - Institutionally created patient identifiers that can be traced back to individual 
patients are replaced with another unique identifier that cannot be traced back to the patient.  
• Patient Demographics – Although patient date of birth is removed, patient age and gender 
are retained. 


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151 
 
• Dates related to the examination – For a given collection/site, dates are offset by a fixed 
number of days, preserving time intervals between exams for each subject.  
• Exam Identifiers – Codes assigned to exams and images are altered to prohibit the 
possibility of tracing an exam back to an institution and individual patient. 
 
As part of the QC/QA process TCIA will also review submitted images for vendor specific 
DICOM tags.  Vendor DICOM Conformance Statements are reviewed to learn which tags might 
contain PHI.  These tags are reviewed and PHI removed if found.   
 
 


CTEP #9149 (01-07-2020) 
 
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APPENDIX M: Treatment Assignment Flow Chart  
 
 

ICF_001.pdf: 
 
i 
 
To: 
CTEP Protocol and Information Office 
From: 
, MD, DTC, NCI 
Date: 
January 7, 2020 
Re: 
Amendment to Protocol 9149: Molecular Profiling-based Assignment of Cancer Therapy for 
Patients With Advanced Solid Tumors (MPACT) 
With this amendment, we would like to update the Treatment consent form to allow the sole patient who 
continues to receive randomized Trametinib DMSO treatment (22+ cycles) to consent to having her mutational 
status and arm assignment (i.e., experimental or control) disclosed to herself and/or her treating physician now, 
rather than wait until disease progression, given the new non-randomized study design and statistical analysis 
plan.  We would also like to allow this patient to consent to sample unlinking while she remains on study, in 
order to enable research-use analysis of the sample in parallel with the other results from the randomized phase 
of the study.  Thank you for your consideration. 
 
# 
Section 
Comments 
1. 
Header 
Updated the protocol version date. 
2. 
How long will I be in 
this study? 
 
My choices if I joined 
the study before 2019 
Given the new non-randomized study design and statistical 
analysis plan, we would like to revise and update the protocol 
to allow the sole patient who continues to receive randomized 
Trametinib DMSO treatment (22+ cycles to consent to having 
her mutational status and arm assignment (i.e., experimental or 
control) disclosed to herself and/or her treating physician now, 
rather than wait until disease progression to find out per the 
original study plan.  The patient, in discussion with the treating 
physician, will have the same on-study treatment options at 
progression as before, but because she is unblinded we think 
she will have better information sooner about her future 
treatment options.   
3. 
My choices if I joined 
the study before 2019 
Revised document to allow the sole remaining randomized 
patient to give her consent for sample unlinking to occur while 
the patient remains on study, in order to enable research 
analysis of the sample in parallel with the other results from the 
randomized phase of the study. 


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Consent Form 
 
Study Title for Study Participants: MPACT study to compare effects of targeted drugs on 
tumor gene variations  
 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: P9149, 
Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced Solid 
Tumors (MPACT)  
 
What is the usual approach to my cancer? 
You are being asked to take part in this research study because standard medical treatments such as 
chemotherapy, surgery, and/or radiotherapy have not been very effective for the type of advanced cancer that 
you have.  
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices.  For example: 
• your doctor will discuss possible treatment options for your cancer  
• you may choose to take part in a different research study, if one is available 
• or you may choose not to be treated for cancer, but you may want to receive comfort care to relieve 
symptoms. 
 
Why is this study being done? 
Blood, tissue, and tumor cells contain genes which are made up of DNA and which serve as the “instruction 
book” for each cell in the body.  We know that variations in some tumor genes play an important role in how 
cancers grow.  Identifying these tumor variations and selecting drugs that work against them is one way 
scientists are trying to treat cancer.  However, we do not know whether patients treated with a drug designed to 
target their tumor variation actually get benefit from the treatment (that is, show tumor shrinkage or tumor 
stability over time).  In this research study, we are studying four different investigational treatments:  
• AZD1775 with carboplatin  
• Trametinib DMSO  
• Everolimus  
• Veliparib with temozolomide   
The study drugs on this trial are all investigational and are not approved by the Food and Drug Administration 
(FDA) for your type of cancer.  Some of these drugs are approved by the FDA to treat other types of cancer.  
Please ask your study doctor for more information about this.   
 
To do this research study, we first needed to find out if your tumor had one of the gene variations we are 
studying.  Our results show that you do have one of these variations.  Up to 100 patients will participate in this 
research study at several cancer research centers in North America. 


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What are the study groups? 
The design of this study has changed since we first opened it in 2014.  At that time, patients were randomized 
(like flipping a coin) to receive either a study drug thought to work on their tumor gene variation (group 1), or 
a study drug thought not to work on their tumor gene variation (group 2).  The study drugs were one of the four 
treatments on the previous page.  We have since completed enrolling patients on 3 of the 4 treatment groups.  
Some patients are still receiving these study treatments.  We learned that these 3 treatments did not work better 
in patients who had that tumor variation than in patients who did not.  We have not yet learned if the 4th 
treatment, veliparib with temozolomide, works better in patients with your tumor variation.  New patients who 
agree to take part in this study will be given the study drugs veliparib and temozolomide.  After the first 12 
patients have taken part, we will stop adding new patients if the drugs are not working.  Please feel free to ask 
your study team for more information about this.   
 
If your cancer gets worse, we may ask you for a tumor biopsy to find out if your tumor gene variations have 
changed since you began taking study drugs.  This biopsy is optional and for research.   
 
All of the study drugs are taken by mouth except for carboplatin, which is administered by IV (through a vein in 
your arm).  Your study doctor will explain how often you will take the drugs and when you will need to come to 
the Clinical Center for study tests and procedures.  The treatment is given over cycles, which are either 3 or 4 
weeks long depending on which drug you are given.  The drugs used in this study have known side effects that 
we will discuss with you before you sign this consent form. 
 
How long will I be in this study? 
You will receive study drugs for as long as you are tolerating them and your cancer is either stable or getting 
better.  After you finish this research study, we would like to look in more detail at your tumor to find out if it 
had other gene variations.  We will only do this once you have finished taking study drugs and we have deleted 
all your personally identifiable information (such as your name and medical record number) from each sample 
so that we cannot “link” your personal information with the genetic results.  
Your doctor will continue to watch you for side effects and follow your condition for 30 days after you finish 
the study, or until any drug-related side effects you may have had have stabilized or resolved.   
If you joined the study before 2019, you were randomized to treatment group 1 or treatment group 2.  You and 
your doctor were not told which group you were placed in.  Now that we are done comparing the two groups, 
we would like to ask you if you would like to know now which group you are in.  The original plan was to wait 
until your cancer got worse before telling you.  You will still be able to switch to a different study treatment that 
is thought to work on your tumor gene variation if you are not currently being treated with that drug.  Please ask 
your study doctor for more information about this. 
 
 
What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of the usual approach for your cancer.  
However, there are some extra tests and procedures that you may need to have if you take part in this study that 
are not part of the usual approach for your type of cancer.   
 
Before you begin the study: 
 


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You will need to have the following extra tests and procedures to find out if you can be in the study: 
• a pregnancy test, if you are a woman capable of becoming pregnant.  If you are pregnant you will not be 
eligible to take part in this research study.  
• an eye exam for patients taking certain study drugs.  This will be explained by your study doctor.   
• an echocardiogram (depending on the study treatment)  
 
If the extra tests and procedures show that you can take part in the study, and you choose to take part, then you 
will have the following extra tests and procedures during the study:  
• an optional tumor biopsy, if your cancer gets worse on treatment (we will ask you to sign a separate 
consent document for this procedure) 
• an echocardiogram (depending on the study treatment) may be done every 3 cycles 
 
We will give you a study chart so that you can see when you need to come in to the Clinic to have these tests 
and procedures done.   
 
What possible risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s office than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
• There is a risk someone could get access to the personal information in your medical records or other 
information researchers have kept about you.  Someone might be able to trace this information back to 
you.  The researchers believe the chance that someone will identify you is very small, but the risk may 
change in the future as people come up with new ways of tracing information.  In some cases, this 
information could be used to make it harder for you to get or keep a job.  There are laws against misuse of 
genetic information, but they may not give full protection.  The researchers believe the chance these 
things will happen is very small, but cannot promise that they will not occur. 
• The study drugs may not be better, and could possibly be worse, than the usual approach for your cancer. 
• There can also be a risk in finding out new genetic information about you.  New health information about 
inherited traits that might affect you or your blood relatives could be found during the study. 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National Institutes of 
Health.  With this Certificate, the researchers cannot be forced to disclose information that may identify you, 
even by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings.  The researchers will use the Certificate to resist any demands for information that would identify 
you, except that the Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects or for information that 
must be disclosed in order to meet the requirements of the US Food and Drug Administration (FDA).  Please 
understand that a Certificate of Confidentiality does not prevent you, the researchers, or a member of your 
family from voluntarily releasing information about yourself or your participation in this research.  If an insurer, 
employer, or other person obtains your written consent to receive research information, then the researchers 
may not use the Certificate to withhold that information.  There also may be other privacy risks that we have 
not foreseen. 
 
The drugs used in this study may affect how different parts of your body work such as your liver, kidneys, 
heart, and blood.  The study doctor will be testing your blood and will let you know if changes occur that may 
affect your health.  Here are important points about side effects: 


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• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are having a side 
effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
Inform your physician and study healthcare team about current medications including over the counter drugs, 
herbals, or natural medicines.  We do not know if taking any of the study drugs will cause other drugs you may 
be taking to work differently.  It is very important that you talk to a member of the research team before 
beginning any new drugs, over-the-counter medications, vitamins, or alternative therapies. 
 
The tables on the next pages show the most common and the most serious side effects that researchers know 
about.  There might be other side effects that researchers do not yet know about.  If important new side effects 
are found, the study doctor will discuss these with you. 
Let your study doctor know of any questions you have about possible side effects.  You can ask your 
study doctor questions about side effects at any time. 
 
 




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Possible side effects of Carboplatin: 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin, more than 20 and up to 100 may have: 
• Hair loss 
• Vomiting, nausea 
• Infection, especially when white blood cell count is low 
• Anemia which may cause tiredness, or may require blood transfusions 
• Bruising, bleeding 
• Belly pain 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin, from 4 to 20 may have: 
• Diarrhea, Constipation 
• Numbness and tingling in fingers and toes 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of 
the face or throat 
 
RARE, AND SERIOUS 
In 100 people receiving Carboplatin, 3 or fewer may have: 
• Changes in vision 
• Changes in taste 
• Damage to organs which may cause hearing and balance problems 
 
 
Recommendations when taking this drug:  
The use of live vaccines and close contact with those who have received live vaccines should be avoided during 
treatment with carboplatin. 
 
 
 
 
 


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Possible side effects of Everolimus: 
 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving everolimus, more than 20 and up to 100 may have: 
• 
Anemia, which may require blood transfusion 
• 
Diarrhea 
• 
Sores in the mouth which may cause difficulty swallowing 
• 
Tiredness 
• 
Rash 
 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving everolimus, from 4 to 20 may have: 
• Pain 
• Constipation, nausea, vomiting 
• Swelling of arms, legs 
• Fever 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Weight loss, loss of appetite 
• Changes in taste 
• Headache 
• Cough, shortness of breath 
• Nose bleed 
• Damage to the lungs which may cause shortness of breath 
• Dry skin 
• Itching  
 
 
RARE, AND SERIOUS 
In 100 people receiving everolimus, 3 or fewer may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat  
• Non-healing surgical site 
• Kidney damage which may require dialysis 
 
 
 
Recommendations when taking this drug: 
 
The use of live vaccines and close contact with those who have received live vaccines should be avoided 
during treatment with everolimus. 
 
 
Taking this drug?  Yes/No 


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Possible side effects of Temozolomide 
 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Temozolomide, more than 20 and up to 100 may have: 
• Headache, seizure 
• Constipation, nausea, vomiting, diarrhea 
• Trouble with memory 
• Difficulty sleeping 
• Muscle weakness, paralysis, difficulty walking 
• Dizziness 
• Tiredness 
• Hair loss 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Temozolomide, from 4 to 20 may have: 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Anemia which may cause tiredness, or may require transfusions 
• Severe skin rash with blisters and can involve inside of mouth and other parts of the body 
• Rash 
 
RARE, AND SERIOUS 
In 100 people receiving Temozolomide, 3 or fewer may have: 
• Cough, damage to the lungs which may cause shortness of breath 
• Damage to the bone marrow (irreversible) which may cause infection, bleeding, may require blood 
transfusions 
• Liver damage which may cause yellowing of eyes and skin, swelling 
• A new cancer including leukemia resulting from treatment of a prior cancer 
 
 
 
Possible side effects of Veliparib: 
  
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving veliparib, more than 20 and up to 100 may have: 
 Nausea 
 Tiredness 
 Bruising, bleeding 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving veliparib, from 4 to 20 may have: 
Taking these drugs?  Yes/No 


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Anemia which may require blood transfusion 
Infection, especially when white blood cell count is low 
Belly pain 
Constipation, diarrhea, vomiting 
Weight loss, loss of appetite 
Dehydration 
 
Dizziness, headache 
Changes in taste 
Rash 
 
RARE, AND SERIOUS 
In 100 people receiving veliparib, 3 or fewer may have: 
Cancer of bone marrow caused by chemotherapy 
Damage to the bone marrow (irreversible) which may cause infection, bleeding, may require transfusions 
A new cancer resulting from treatment of earlier cancer 
Seizure 
Blood clot which may cause swelling, pain, shortness of breath 
 
 
Recommendations when taking this drug: 
 
We recommend that you avoid being in the sun as much as possible because this can make any skin rash 
you might get from Veliparib worse.  You should also use a sun screen. 


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Possible side effects of Trametinib DMSO: 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving trametinib (GSK1120212B), more than 20 and up to 100 may have: 
• 
Diarrhea, nausea 
• 
Tiredness 
• 
Swelling of the body 
• 
Skin changes including rash, acne 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving trametinib (GSK1120212B), from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Abnormal heartbeat 
• Blurred vision or other visual disturbances 
• Dry eye, mouth, skin 
• Swelling of the eye 
• Pain 
• Constipation, heartburn, vomiting 
• Sores in the mouth which may cause difficulty swallowing 
• Chills, fever 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
• Infection 
• Change in heart function 
• Loss of appetite, dehydration 
• Dizziness, headache 
• Cough, shortness of breath 
• Hair loss, itching 
• Change in or loss of some or all of the finger or toenails 
• High blood pressure which may cause headaches, dizziness, blurred vision 
• Bleeding 
 
RARE, AND SERIOUS 
In 100 people receiving trametinib (GSK1120212B), 3 or fewer may have: 


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• Heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
• Changes in the eyes (blood clot or retinal detachment) which may cause blindness  
• Blood clot which may cause swelling, pain, shortness of breath 
• A tear or hole in the bowels that may require surgery 
• Damage to muscle which may cause muscle pain, dark red urine 
• Damage to the lungs which may cause shortness of breath 
• Redness, pain or peeling of palms and soles 
• Skin rash developing 1-8 weeks after a drug is given which may be accompanied by fever, lymph 
node swelling and organ failure 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of the body 
 
Recommendations when taking this drug: 
Tell your doctor about any changes in your vision; your doctor will send you for eye exam and treatment may 
need to be interrupted.  It is important that you do not drive a car or work with machinery if you are 
experiencing any visual changes. 
 


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You should not get pregnant or breastfeed while on this study or for 3 months after you finish study treatment.  
The drugs used in this study could be very damaging to an unborn baby or nursing child.  It is important that 
you use a combination of any two of the following (a+b or a+c or b+c): 
a.      Use of oral, injected, implanted, or other hormonal methods of contraception 
b.      Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c.      Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/vaginal suppository 
 
As a male participant in the study, you must agree to use a condom during intercourse and not father a child 
during the study and for the period of 3 months following stopping of study treatment.  In addition, it is advised 
that your female partner uses a highly effective form of birth control method (contraception) if she is sexually 
active and may become pregnant.  
 
 
What possible benefits can I expect from taking part in this study? 
We do not know if you will receive personal, medical benefit from taking part in this study.  The knowledge 
gained from this study may help others in the future who have cancer.   
 
 
Can I stop taking part in this study? 
Yes.  You can decide to stop at any time.  If you decide to stop for any reason, it is important to let the study 
doctor know as soon as possible so you can stop taking study drugs safely.  If you stop, you can decide whether 
or not to let the study doctor continue to provide your medical information to the organization running the 
study. 
 
The study doctor will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
The study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow the study rules 
• If you become pregnant 
• If the study is stopped by the sponsor, the IRB (people who review the research to protect the people 
taking part in the study), or FDA. 
 
What are my rights in this study? 
Taking part in this study is your choice.  No matter what decision you make, and even if your decision changes, 
there will be no penalty to you.  You will not lose medical care or any legal rights. 
 
For questions about your rights while in this study, call the ________________________ (insert name of 
center) Patient Representatives __________________ (insert telephone number)  
 
 


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What are the costs of taking part in this study? 
Veliparib, trametinib DMSO, AZD1775, everolimus, temozolomide, and carboplatin will be supplied at no 
charge while you take part in this study.  The cost of getting the study agent ready and giving it to you is not 
paid by the study sponsor, so you or your insurance company will have to pay for this.  It is possible that the 
study agents may not continue to be supplied while you are on the study.  Although not likely, if this occurs, 
your study doctor will talk to you about your options.   
 
You and/or your health plan/insurance company will need to pay for all of the other costs of caring for your 
cancer while in this study, including the cost of tests, procedures, or medicines to manage any side effects, 
unless you are told that certain tests are supplied at no charge.  Before you decide to be in the study, you should 
check with your health plan or insurance company to find out exactly what they will pay for. 
 
You will not be paid for taking part in this study. 
 
 
What happens if I am injured or hurt because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, please tell your 
study doctor.  The study sponsors and pharmaceutical collaborators will not offer to pay for medical treatment 
for injury.  Your insurance company may not be willing to pay for study-related injury.  If you have no 
insurance, you would be responsible for any costs. 
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive payment for this 
even though you are in a study. 
 
 
Who will see my medical information? 
Your privacy is very important to us and the researchers will make every effort to protect it.  Your information 
may be given out if required by law.  For example, certain states require doctors to report to health boards if 
they find a disease like tuberculosis.  However, the researchers will do their best to make sure that any 
information that is released will not identify you.  Some of your health information, and/or information about 
your specimen, from this study will be kept in a secure central database for research.  Your name or contact 
information will not be put in the database. 
 
There are organizations that may inspect your records.  These organizations are required to make sure your 
information is kept private, unless required by law to provide information.  Some of these organizations are: 
• The study sponsor, drug companies, and pharmaceutical collaborators supporting the study  
• The IRB (Institutional Review Board), a group of people who review the research with the goal of 
protecting the people who take part in the study. 
• The Food and Drug Administration (FDA) and the National Cancer Institute (NCI) in the U.S., and 
similar ones if other countries are involved in the study. 
 
 
 


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Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general information 
about cancer.  You may also call the NCI Cancer Information Service to get the same information at: 1-800-4-
CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  
This Web site will not include information that can identify you.  At most, the Web site will include a summary 
of the results.  You can search this Web site at any time. 
 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to report side 
effects or injuries.  Contact the study doctor __________________________________ (insert name of study 
doctor[s]) at _________________________ (insert telephone number). 
 
My choices if I joined the study before 2019 
Please read each sentence below and think about your choice.  After reading each sentence, circle and initial the 
answer that is right for you.  No matter what you decide to do, it will not affect your care.  Circle your choice of 
“yes” or “no” for the following:  
 
1. My doctor can be told the results of my tumor gene variations and my treatment group assignment now, 
instead of waiting until my cancer gets worse. 
Yes              No                
 
2. If my doctor is told the results of my tumor gene variations and my treatment group assignment before my 
cancer gets worse, I can be told the results at that time too. 
Yes              No                
 
3. My tumor samples that were collected during the screening part of this study can be separated from my 
personally identifiable information and used for research now, instead of when I finish taking study drugs. 
Yes              No                
 
 
 
My Signature Agreeing to Take Part in the Main Study 
 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and my questions 
have been answered.  I will be given a signed copy of this form.  I agree to take part in the main research study.   
 
Participant’s signature______________________________________ 
 
Print name: ________________________________________    
 
Date of signature_____________________