A Randomized Phase 2/3 Study of Olaparib Plus Temozolomide Versus Investigator's Choice for the Treatment of Patients With Advanced Uterine Leiomyosarcoma After Progression on Prior Chemotherapy
Phase: PHASE2
Conditions: Locally Advanced Uterine Corpus Leiomyosarcoma, Metastatic Uterine Corpus Leiomyosarcoma, Stage III Uterine Corpus Leiomyosarcoma AJCC v8, Stage IV Uterine Corpus Leiomyosarcoma AJCC v8, Unresectable Uterine Corpus Leiomyosarcoma
Sponsor: National Cancer Institute (NCI)

 
 
 
 
1 
Update #05 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
PROTOCOL UPDATE TO ALLIANCE A092104 
 
 
A RANDOMIZED PHASE 2/3 STUDY OF OLAPARIB PLUS TEMOZOLOMIDE VERSUS INVESTIGATOR’S 
CHOICE FOR THE TREATMENT OF PATIENTS WITH ADVANCED UTERINE LEIOMYOSARCOMA AFTER 
PROGRESSION ON PRIOR CHEMOTHERAPY 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
X Editorial/Administrative changes 
 
 
Activation 
 
 
 
 
 
 
Eligibility changes 
 
 
Closure 
 
 
 
 
 
 
Therapy/Dose Modifications/Study Calendar changes 
 
 
Suspension  
 
 
 
 
 
 
Scientific/Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
Correlative Science/BioMS changes 
 
 
 
 
 
 
 
 
X Informed Consent changes  
 
 
 
 
 
 
 
 
X Other: Updated CAEPR for Olaparib  
 
 
 
 
 
The changes included in this update to A092104 have been made in response to the NCI Action Letter 
from Dr. Steve Gore (steve.gore@nih.gov) for Olaparib. This Action Letter is posted on the A092104 
study page on the CTSU website. A revised CAEPR for Olaparib with new risks has been added to the 
protocol. Additionally, Pazopanib risks have been replaced with standard of care risks in the protocol. 
Therefore, the model consent form has been revised to incorporate the new risks, consistent with the 
NCI Model Consent Template instructions. 
 
No recommended level of IRB review is provided by the Alliance as the CIRB is the IRB of record for 
this trial. This amendment must be implemented within 30 days after posting. 
 
A consent form addendum will need to be signed by all patients currently receiving treatment or having 
treatment held with Olaparib or Pazopanib. Please refer to the amendment application and CIRB 
guidelines for further instructions. 
 
UPDATES TO THE PROTOCOL 
 
Cover Page 
• 
Dr. Matthew Ingham has replaced Dr. Brian Van Tine as Study Chair. All contact information has 
been updated accordingly.  
• 
The NRG Oncology Study Chair email contact information has been updated. 

 
 
2  
 
• 
Kayla Kroll has replaced Brandon Bright as the Data Manager and the contact information has 
been updated accordingly.  
• 
The Protocol Coordinator’s contact information has been updated per Alliance protocol template.  
 
Study Resources  
David Chan has replaced Barb Todaro as the Pharmacy Contact. All contact information has been updated 
accordingly.  
 
Section 9.3.1 (Late Phase 2 and Phase 3 Studies) 
The SAE Reporting Table has been updated to the most current CTEP version dated August 30, 2024. 
 
Section 9.3.2 (Expedited AE reporting timelines defined) 
• 
This sub-section has been completely removed as the information no longer pertains to the 
updated SAE Reporting Table in Section 9.3.1.  
• 
The remaining sub-section has been renumbered. 
 
Section 9.4.1 (Comprehensive Adverse Events and Potential Risks list (CAEPR) for Olaparib 
(AZD2281, NSC 747856)) 
This section has been revised to include the updated olaparib CAEPR (Version 2.7 6, June 5, 2023 July 9, 
2025) provided by NCI CTEP. Changes from Version 2.6 to Version 2.7 include the following: 
• 
Added New Risk: 
o Rare but Serious: Blood and lymphatic system disorders - Other (autoimmune hemolytic 
anemia (AIHA)); Blood and lymphatic system disorders - Other (pure red cell aplasia (PRCA)); 
Hepatobiliary disorders - Other (drug-induced liver injury (DILI)) 
• 
Increase in Risk Attribution:  
o Changed to Less Likely from Rare but Serious: Vascular disorders - Other (venous 
thromboembolism) 
o Changed to Rare but Serious from Also Reported on Olaparib Trials But With Insufficient 
Evidence for Attribution: Lymphocyte count decreased 
• 
Decrease in Risk Attribution:  
o Changed to Less Likely from Likely: Abdominal pain; Anorexia; Diarrhea 
o Changed to Also Reported on Olaparib Trials But With Insufficient Evidence for Attribution 
from Less Likely: Abdominal distension; Edema Limbs; Mucositis oral; Muscle cramp; Rash 
maculo-papular; Urinary tract infection 
• 
Deleted Risk:  
o Also Reported on Olaparib Trials But With Insufficient Evidence for Attribution: Bone pain; 
Flushing; Hypermagnesemia; Hypothyroidism; Renal and urinary disorders - Other (decreased 
glomerular filtration rate)  
• 
Provided Further Clarification: 
o Footnote #2 is now added as “Autoimmune hemolytic anemia (AIHA) and Pure red cell aplasia 
(PRCA) have been reported in clinical trials as potential and identified risks when Olaparib is 
used in combination with durvalumab.” 
o Footnote #3 is now added as “Venous thromboembolism includes deep vein thrombosis, 
embolism, pulmonary embolism, thrombosis, vena cava thrombosis and venous thrombosis.” 
o Footnote #4 is now added as “Rash includes exfoliative rash, generalized erythema, rash 
erythematous, rash macular, rash maculo-papular, rash papular and rash pruritic.” 
 

 
 
3  
 
Section 9.4.2 (Comprehensive Adverse Events and Potential Risks list (CAEPR) for Pazopanib 
(GW786034, NSC 737754)) Adverse Event List for Pazopanib 
• 
The title of the section has been updated in accordance with the removal of the Pazopanib 
CAEPR. 
• 
The Pazopanib CAEPR has been completely removed and replaced with Pazopanib AE risk 
tables as per a recent change in CTEP policy, protocols should no longer include the CAEPR for 
Standard of Care agents or regimens being used per FDA label.  
 
10.4 (Pazopanib (GW786034, Votrient, NSC#737754)) 
Subsection ‘Adverse Events’ has been updated to support the removal of the CAEPR in Section 9.4.2 and 
now states, “See CAEPR in Section 9.4.2.”  
 
Section 13.9 (Inclusion of Women and Minorities)  
In both paragraphs, “gender” has been replaced with “sex” in accordance with the January 20, 2025, 
Executive Order 14168, “Defending Women from Gender Ideology Extremism and Restoring Biological 
Truth to the Federal Government.”  
 
 
 
 
UPDATES TO THE MODEL CONSENT FORM: 
In Drug Risks, the table under the ‘Possible Side Effects of Olaparib,’ has been updated and with the 
following risk list changes: 
• 
The Table Version date has been updated from June 5, 2023 to July 9, 2025  
• 
Added New Risk: 
o Rare: Damage to the liver which may cause yellowing of the eyes and skin, swelling 
• 
Increase in Risk Attribution 
o Changed to Occasional from Rare: Blood clot 
• 
Decrease in Risk Attribution:  
o Changed to Occasional from Common: Pain; Diarrhea; Loss of appetite 
o Changed to Rare from Common: Rash  
o Changed to Also Reported on Olaparib Trials But With Insufficient Evidence for Attribution 
from Occasional (i.e. Removed from the Risk Profile): Bloating; Sores in the mouth which may 
cause difficulty swallowing; Swelling of arms, legs; Infection which may cause painful and 
frequent urination 
 
In Drug Risks, the risk tables under the ‘Possible Side Effects of Pazopanib,’ have been completely 
removed and replaced with standard of care, ‘Usual Treatment Risks’ as per a recent change in CTEP 
policy. In the standard of care risks, there is an added new risk:  Non-healing wound. 
 
 INFORMED CONSENT ADDENDUM: 
A new informed consent addendum has been added to reflect the new or additional information for Olaparib 
with this update. This addendum is intended to be signed by all patients currently receiving treatment or 
having treatment held with Olaparib. 
 
A new informed consent addendum has been added to reflect the new or additional information for 
Pazopanib with this update. This addendum is intended to be signed by all patients currently receiving 
treatment or having treatment held with Pazopanib. 
 

 
 
4  
 
A replacement protocol, model consent, and informed consent addendum have been issued.  
 
This study remains closed to new patient accrual. 
 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 

 
Version 11/11/2025 
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Update #05 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
ALLIANCE A092104 
A RANDOMIZED PHASE 2/3 STUDY OF OLAPARIB PLUS TEMOZOLOMIDE VERSUS INVESTIGATOR’S 
CHOICE FOR THE TREATMENT OF PATIENTS WITH ADVANCED UTERINE LEIOMYOSARCOMA AFTER 
PROGRESSION ON PRIOR CHEMOTHERAPY 
NCI-supplied agent: Olaparib (NSC# 747856, IND # 
 IND holder: DCTD, NCI; Commercial 
agents: Temozolomide (NSC# 362856), Trabectedin (NSC# 684766), Pazopanib (NSC# 737754) 
ClinicalTrials.gov Identifier: NCT05432791 
 
Study Chair 
NRG Oncology Study Chair 
Matthew Ingham, MD 
Martee Hensley, MD 
Perlmutter Cancer Center  
NYU Langone Health 
160 E 34th Street, 7th Floor 
New York City, NY 10016 
Tel: 202- 285-4944 
Memorial Sloan-Kettering Cancer Center 
300 E. 66th St, Office 1355 
Tel: 646-888-4222  Fax: 646-888-4268 
hensleym@MSKCC.ORG 
matthew.ingham@nyulangone.org 
 
 
 
Experimental Therapeutics Rare 
Tumors Committee  
Co-Chair 
Experimental Therapeutics Rare 
Tumors Committee Co-Chair and 
Community Oncology Co-Chair 
ECOG-ACRIN  
Study Champion 
Kristen N. Ganjoo, MD 
Pamela Munster, MD 
Pmunster@medicine.ucsf.edu 
 
 
Gary Schwartz, MD 
gks37@case.edu  
 
 
kganjoo@stanford.edu 
 
 
 
Primary Statistician 
Secondary Statistician 
Sumithra Mandrekar, PhD 
Jake Allred, MS 
Tel: 507-266-6724 
Tel: 507-266-2874 
mandrekar.sumithra@mayo.edu 
allred@mayo.edu 
 
 
Protocol Coordinator 
Data Manager 
Beth Smith 
Kayla Kroll 
etrtprotocols@alliancenctn.org 
Tel: 507-293-1767 
 
kroll.kayla@mayo.edu 
 
 
 
 
Participating Organizations  
Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN/ECOG-ACRIN Cancer Research Group, 
NRG/NRG Oncology, SWOG/SWOG 
 
 

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Study Resources: 
Expedited Adverse Event Reporting 
https://ctepcore.nci.nih.gov/ctepaers 
Medidata Rave iMedidata portal 
https://login.imedidata.com 
OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org 
Biospecimen Management System 
http://bioms.allianceforclinicaltrialsinoncology.org 
 
Protocol Contacts: 
A092104 Nursing Contact 
Lisa Kottschade, APRN, MSN, CNP 
kottschade.lisa@mayo.edu 
 
Alliance Biorepository at Washington University 
(WUSTL) 
Washington University as St Louis 
BJC Institute of Health 425 S. Euclid Ave,  
Room 5120 
St. Louis, MO 63110-1005 
Tel: 314-747-4402 
alliance@email.wustl.edu 
A092104 Pharmacy Contact 
David Chan, PharmD, PhD 
dchan@uic.edu 
 
Pharmaceutical Management Branch, 
CTEP/DCTD/NCI 
(240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov 
 
 
 
Protocol-related questions may be directed as follows: 
Questions  
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, and (where 
applicable) Data Manager, (cc Protocol 
Coordinator) 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager 
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
regulatory@alliancenctn.org 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox 
pharmacovigilance@alliancenctn.org 
Questions regarding specimens/specimen 
submissions: 
Alliance Biorepository at Washington University 
(WUSTL) 
Questions regarding drug supply 
PMB 
Questions regarding drug administration 
Pharmacy Contact 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments:  
For data submission:  
Regulatory 
documentation must be 
submitted to the Cancer 
Trials Support Unit 
(CTSU) via the 
Regulatory Submission 
Portal. 
(Sign in at 
https://www.ctsu.org, and 
select the Regulatory > 
Regulatory Submission.) 
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or 
email: 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org 
to receive further instruction 
and support. 
 
Contact 
the 
CTSU 
Regulatory Help Desk at 1-
866-651-CTSU (2878), or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
Refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network 
(OPEN). OPEN is accessed 
at 
https://www.ctsu.org/OPEN_
SYS TEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN related 
questions by phone or email : 
1-888-823-5923, or 
ctsucontact@westat.com. 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the protocol 
for further instructions. 
 
 
The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific page located on the CTSU members’ website 
(https://www.ctsu.org). 
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the Roster Maintenance application and in most cases 
viewable and manageable via the Roster Update Management System (RUMS) on the CTSU members’ 
website. 
Institutions will obtain the following supplies from the CTSU website: PRO CTCAE can be obtained by 
downloading the booklet from the protocol-specific page on the CTSU website.  
For clinical questions (i.e., patient eligibility or treatment-related) see the Protocol Contacts, Page 2 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) 
 
Contact the CTSU Help Desk by phone or email: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 

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A RANDOMIZED PHASE 2/3 STUDY OF OLAPARIB PLUS TEMOZOLOMIDE VERSUS INVESTIGATOR’S 
CHOICE FOR THE TREATMENT OF PATIENTS WITH ADVANCED UTERINE LEIOMYOSARCOMA AFTER 
PROGRESSION ON PRIOR CHEMOTHERAPY 
 
 
 
Schema 
1 Cycle = 21 Days 
Eligibility Criteria (see Section 3.0) 
Histologically confirmed leiomyosarcoma of uterine origin 
Metastatic or locally advanced/unresectable disease 
Measurable disease per RECIST v1.1 (See §11.0) 
Not pregnant and not nursing (See §3.2.3) 
Age ≥18 
ECOG Performance Status ≤ 2  
Prior Treatment: 
- Prior progression on, or intolerance to, at least two prior 
lines of systemic therapy for advanced uLMS, one of 
which 
was 
an 
anthracycline 
(anthracycline 
monotherapy or combination). Adjuvant chemotherapy 
will qualify as a prior line of treatment. Endocrine 
treatment will not qualify as a prior line of treatment. 
- No prior treatment with any PARP inhibitor, 
temozolomide or dacarbazine (IV analogue of 
temozolomide). 
- No prior treatment with at least one of the agents 
included on the investigator’s choice arm: trabectedin, 
pazopanib (or both).  
- Patients must have recovered to baseline or ≤ grade 1 
per CTCAE version 5.0 from toxicity related to any 
prior treatment, unless adverse events are clinically 
nonsignificant and/or stable on supportive therapy, with 
the exception of fatigue (which should be ≤ grade 2), 
alopecia and/or endocrinopathies related to prior 
immunotherapy which are controlled with hormone 
replacement. 
- Patients must have completed all prior anti-cancer 
treatment ≥28 days from registration. 
Prior Surgery: 
- Patients may not have undergone major surgery (related 
or unrelated to their cancer diagnosis) ≥28 days of 
registration. Subjects with clinically relevant ongoing 
complications from prior surgery are not eligible. 
No uncontrolled hypertension, ventricular arrhythmias or 
recent myocardial infarction (See §3.2.9) 
Comorbid conditions (See §3.2.10) 
Concomitant medications (See §3.2.11) 
No use of concurrent strong CYP3A4 inducers/inhibitors 
Must be able to speak and/or read English or Spanish to 
complete PRO-CTCAE surveys.  
Deemed appropriate for treatment with either trabectedin or 
pazopanib per the treating investigator. For all patients, prior 
to randomization and as part of eligibility, the investigator 
must select the agent which the patient would receive if 
assigned to the investigator’s choice arm.   
Required Initial Laboratory Values 
ANC: 
≥ 1500/mm3 
Platelet count: 
≥ 100,000/mm3 
Creatinine1: 
≤ 1.5 x ULN 
Hemoglobin2: 
≥ 9 g/dL 
Total bilirubin3: 
≤ 1.5 x ULN 
AST/ALT: 
≤ 3.0 x ULN 
 
1If creatinine > 1.5* ULN, then CrCl must be > 
50 mL/min, per Cockcroft-Gault method. 
 
2No transfusions ≤ 14 days before C1D1. 
 
3If documented Gilbert’s: ≤ 2.0 x ULN. 
 
 

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RANDOMIZATION 
 
ARM 1 
Olaparib 
+ 
Temozolomide 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Advanced uterine 
LMS with 
progression on 
chemotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ARM 2 
Investigator’s Choice: 
Trabectedin 
or 
Pazopanib 
 
 
 
 
 
 
 
 
 
 
Stratification factors: ECOG PS (0-1 versus 2) and Prior Lines (2 versus 3 or more) 
 
70 patients will be enrolled to the Phase II portion of the trial. Enrollment will be paused at that 
time for treatment evaluation (see Section 13.2.2) 
 
Treatment is to continue until disease progression or unacceptable adverse event(s). Patients 
discontinuing their initial treatment for reasons other than progressive disease will continue following the 
Study Calendar for disease assessments until progressive disease is documented. Upon progression, 
patients will be followed for information on subsequent anti-cancer treatment and survival every 3 months 
for the first 2 years and every 6 months thereafter until 5 years post-randomization or death, whichever 
comes first. Information on the first subsequent anti-cancer treatment and survival status must be 
collected.  
 
Please refer to the full protocol text for a complete description of the eligibility criteria and 
treatment plan. 
 
If the Group credited for enrollment is a non-Alliance Group, then other requirements from the credited 
Group may apply. 
 
 
 

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Table of Contents 
1.0 
Background ..................................................................................................................................... 8 
2.0 
Objectives ....................................................................................................................................... 14 
2.1 
Primary objective ........................................................................................................................ 14 
2.2 
Secondary objectives .................................................................................................................. 15 
2.3 
Exploratory Objective ................................................................................................................. 15 
3.0 
Patient Selection ............................................................................................................................ 15 
3.1 
On-Study Guidelines ................................................................................................................... 15 
3.2 
Eligibility Criteria ....................................................................................................................... 15 
4.0 
Patient Registration ...................................................................................................................... 19 
4.1 
Investigator and Research Associate Registration with CTEP ................................................... 19 
4.2 
Cancer Trials Support Unit Registration Procedures .................................................................. 20 
4.3 
Patient Registration Requirements .............................................................................................. 22 
4.4 
Patient Enrollment ...................................................................................................................... 22 
4.5 
Stratification Factors and Treatment Assignments ..................................................................... 23 
5.0 
Study Calendar .............................................................................................................................. 24 
6.0 
Data and Specimen Submission ................................................................................................... 30 
6.1 
Data Collection and Submission ................................................................................................. 30 
6.2 
Specimen collection and submission .......................................................................................... 32 
6.3 
Submission of Patient Completed Measures ............................................................................... 32 
7.0 
Treatment Plan/Intervention ....................................................................................................... 34 
7.1 
Arm 1 (Olaparib + Temozolomide) ............................................................................................ 34 
7.2 
Arm 2 (Investigator’s Choice: Trabectedin or Pazopanib) ......................................................... 37 
8.0 
Dose and Treatment Modifications ............................................................................................. 39 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care ......................................... 39 
8.2 
Dose Modifications ..................................................................................................................... 42 
9.0 
Adverse Events .............................................................................................................................. 52 
9.1 
Routine Adverse Event Reporting .............................................................................................. 53 
9.2 
CTCAE Routine Reporting Requirements .................................................................................. 54 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) .................................................................. 55 
9.4 
CAEPRs ...................................................................................................................................... 58 
10.0 
Drug Information .......................................................................................................................... 67 
10.1 
General Considerations: .............................................................................................................. 67 
10.2 
CTEP agent ordering, accountability and inventory records, IB availability, and contacts ........ 67 
10.3 
Olaparib (AZD2281), IND #
 IND Holder: NCI DCTD, NSC#747856 ......................... 68 

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10.4 
Pazopanib (GW786034, Votrient, NSC#737754) ....................................................................... 71 
10.5 
Temozolomide (Temodar, NSC362856) ..................................................................................... 73 
10.6 
Trabectedin (Yondelis, NSC#737754) ........................................................................................ 75 
11.0 
Measurement of Effect.................................................................................................................. 76 
11.1 
Schedule for Assessment of Disease ........................................................................................... 76 
11.2 
Definitions of Measurable and Non-Measurable Disease ........................................................... 76 
11.3 
Guidelines for Evaluation of Measurable Disease ...................................................................... 77 
11.4 
Measurement of Effect ................................................................................................................ 78 
12.0 
End of Treatment .......................................................................................................................... 82 
12.1 
Duration of Protocol Treatment .................................................................................................. 82 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention ............................................... 82 
12.3 
Follow-up .................................................................................................................................... 82 
12.4 
Extraordinary Medical Circumstances ........................................................................................ 83 
12.5 
Managing ineligible patients and registered patients who never receive protocol intervention . 83 
13.0 
Statistical Considerations ............................................................................................................. 84 
13.1 
Study Design ............................................................................................................................... 84 
13.2 
Statistical Design and Analysis for the Phase 2 Portion ............................................................. 85 
13.3 
Statistical Design and Analysis for the Phase 3 Portion ............................................................. 86 
13.4 
Sample Size, Accrual Time, and Study Duration ....................................................................... 87 
13.5 
Secondary Endpoint Analysis Plans ........................................................................................... 87 
13.6 
Exploratory Objective Analysis Plan .......................................................................................... 88 
13.7 
Adverse Event Stopping Rule ..................................................................................................... 89 
13.8 
Study Reporting .......................................................................................................................... 89 
13.9 
Inclusion of Women and Minorities ........................................................................................... 90 
14.0 
BIOBANKING FOR FUTURE Correlative SCIENCE ............................................................ 91 
15.0 
Monitoring Plan ............................................................................................................................ 91 
15.1 
IRB terminations ......................................................................................................................... 91 
16.0 
References ...................................................................................................................................... 92 
Appendix I:  CRADA ................................................................................................................................ 95 
Appendix II:  Patient Clinical Trial Wallet Card .................................................................................. 97 
Appendix III:  A092104 Olaparib Medication Diary ............................................................................ 98 
Appendix IV:  A092104 Temozolomide Medication Diary ................................................................. 100 
Appendix V:  A092104 Pazopanib Medication Diary .......................................................................... 102 
Appendix VI:  ECOG Performance Status Scale ................................................................................. 104 
Appendix VII:  New York Heart Association (NYHA) Functional Classification ............................ 105 

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months (95% CI 5.4 months – NE) (Figure 1). Median PFS for T + O among patients treated in the 
third-line setting was 11.0 months (n = 5). An objective reduction in the size of target tumor lesions 
was observed in 60% of patients (Figure 2). Among the 6 patients achieving partial response, the 
median duration of response was 12.0 months (9.5 months – NE). Responses occurred early in 
treatment, 3 of 6 patients achieving partial response remain on active therapy and a number of patients 
achieved prolonged stable disease (Figure 3). 
 
 
Figure 1: Kaplan-Meir PFS Plot for NCI Protocol 10250 
 
 
Figure 2: Waterfall Plot/Best Overall Response per RECIST 
 

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Paired tissue biopsies were obtained from all patients participating on NCI 10250. Tissue is being 
evaluated with several assays intended to measure HR deficiency. These include (a) whole exome 
sequencing (WES) for genomic alterations in HR pathway genes (b) RAD51 foci formation, a 
functional biomarker for HR pathway status and (c) SLFN11 expression. In addition, tumors are 
being evaluated for MGMT expression, because MGMT deficiency is a known predictive biomarker 
for response to T in other cancer types. 
Results of WES are available for a subset of patients (n = 16) with adequate DNA extracted from 
tumor biopsies. In this analysis, 3 patients who ended treatment for toxicity and did not undergo 
study-specified restaging imaging (and for whom efficacy cannot therefore be assessed) were 
excluded. In this analysis, we found one homozygous deletion in RAD51B, one homozygous deletion 
in PALB2, one deleterious mutation in ATR and two deleterious mutations in ATRX (Figure 4). The 
patients with homozygous deletions of RAD51B and PALB2 were the patients with the longest PFS 
on study among patients with available WES data (Figure 4). However, patients with no detectable 
genomic alterations in the defined panel of HR pathway genes also experienced objective responses 
and prolonged PFS. The study team is attempting additional DNA extractions on the remaining 
patients for whom WES could not be performed during the first analysis. 
We also analyzed pre-treatment samples using a RAD51 foci formation assay developed by Shapiro 
et. al. The RAD51 assay is a functional assessment of HR pathway status. RAD51 assay results are 
available for 16 patients (for 4 patients, no tissue was available, and for 2 patients, the assay yielded 
an indeterminate result). We found that, overall, 52% of tumors were HR deficient by the RAD51 
assay. Patients with HR deficient tumors by this assay had increased clinical benefit from study 
treatment. Unfortunately, there were limited samples available from patients with best response of 
PD or PR.  6 of 12 patients with available pre-treatment samples yielded an HR-deficient result. There 
appeared to be enrichment of HR-deficiency as measured by this assay among patients with 
prolonged PFS; however, some patients with objective responses and prolonged PFS were still 
classified as HR-proficient (Figure 4). Of patients with PFS ≥ 6 months who had results available 
from the assay, 7/8 (87%) had HR deficient tumors. Of patients with PFS < 6 months, only 2/8 (25%) 
were HR deficient. In addition, the median PFS for patients with HR deficient tumors and HR 
proficient tumors was 342 days versus 56 days, respectively (log rank p = 0.0024). 
In an exploratory analysis, we determined HRD scores using WES data from pre-treatment samples 
and the scarHD algorithm. The HRD score is the sum of telomeric allelic imbalance, loss of 
heterozygosity and large-scale state transitions and may represent a genomic “scar” reflecting an HR 
deficient phenotype. HRD scores determined using WES data have been shown to correlate well with 
traditional SNP-based assays[22]. HRD scores have shown some predictive potential for response to 
PARPi in ovarian cancer and other contexts. The HRD scores in our uLMS cohort appear elevated 
(Figure 4). Among the 13 patients with HRD score assessed on a pre-treatment biopsy, the median 
HRD score was 51 (range 36-66) and 10/13 had a score ≥ 42.  In a TCGA analysis of 33 tumor types, 
the median HRD score was approximately 20[23]. In studies in ovarian cancer, HRD cutoff scores 
above 42 were associated with greater likelihood of benefit from PARPi. These findings are 
suggestive of HR deficiency even in cases without a discernable mutation in an HR pathway gene or 
a deficient result from the  RAD51 foci formation assay. These findings could reflect the high levels 
of genomic and replicative stress present in uLMS, which could itself impart sensitivity to PARPi in 
the absence of alterations in HR genes based on emerging research.  

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      Figure 4: Whole-exome sequencing results in HR-gene panel annotated by clinical outcome 
We also evaluated SLFN11 and MGMT expression by RNAseq. We did not observe a correlation 
between SLFN11 or MGMT expression in either the pre-treatment or on-treatment biopsies and 
clinical outcomes (ORR, PFS) (Figure 5). COSMIC signature 3, although present in some samples, 
also did not appear to predict for clinical benefit.  
In summary, a subset of patients deriving greater benefit from olaparib and temozolomide could be 
identified by WES for HR gene defects and the RAD51 foci formation assay. The RAD51 assay 
appears particularly promising for selecting patients for treatment with this approach, but limitations 
include the need for a tissue biopsy prior to treatment and the fact this assay is not currently CLIA 
certified. Some patients who derived clinical benefit could not be identified by the biomarker analysis 
used in this study. Overall, results from NCI 10250 are supportive of further development of this 
treatment approach in a biomarker-unselected population at this time.  

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Figure 5: SLFN11 and MGMT expression by RNAseq 
Therefore, on the basis of emerging evidence that uLMS may represent an HR-deficient cancer with 
high levels of replicative stress, supportive preclinical data and the results of a completed single-arm 
phase 2 study, we propose to further evaluate temozolomide and olaparib versus investigator’s choice 
for the treatment of patients with advanced uLMS who have progressed on prior chemotherapy. 
2.0 
OBJECTIVES 
2.1 
Primary objective 
2.1.1 
Phase 2 primary objective 
To compare the progression free survival (PFS) of olaparib plus temozolomide (Arm 1) as 
compared to investigator’s choice (trabectedin or pazopanib) (Arm 2) for the treatment of 
patients with advanced uLMS who have received two or more prior lines of therapy as 
determined by investigator (local site) assessment. 
2.1.2 
Phase 3 primary objective 
To compare the overall survival (OS) of olaparib plus temozolomide (Arm 1) as compared 
to investigator’s choice (trabectedin or pazopanib) (Arm 2) for the treatment of patients 
with advanced uLMS who have received two or more prior lines of therapy. 

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___ 
3.2.1 
Documentation of Disease: 
- 
Histologically confirmed leiomyosarcoma of uterine origin, as established by the site 
institutional practice for pathology confirmation for research studies when enrolling 
the patient on study. Central pathology review will not occur. 
- 
Metastatic or locally advanced and surgically unresectable disease, in the opinion of 
the treating investigator. 
___ 
3.2.2 
Measurable Disease per RECIST v1.1 (see Section 11.0): Patients must have at 
least one lesion that is measurable per RECIST v1.1 criteria to be eligible for the study. 
___ 
3.2.3 
Not Pregnant and Not Nursing, because this study involves agents that have 
known genotoxic, mutagenic and teratogenic effects. 
Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 
days prior to registration is required. 
___ 
3.2.4 
Age ≥ 18 years 
___ 
3.2.5 
ECOG Performance Status ≤ 2 (See Appendix VI) 
___ 
3.2.6 
Prior Treatment 
- 
Patients must have had prior progression on, or intolerance to, at least two prior lines 
of systemic therapy for advanced uLMS, one of which was an anthracycline 
(anthracycline monotherapy or combination). Adjuvant chemotherapy will qualify as 
a prior line of treatment. Endocrine treatment will not qualify as a prior line of 
treatment. 
- 
Patients may not have received prior treatment with any PARP inhibitor, temozolomide 
or dacarbazine (IV analogue of temozolomide). 
- 
Patients may not have had prior treatment with BOTH of the agents included on the 
investigator’s choice arm: trabectedin AND pazopanib. If the patient has had prior 
treatment with one of these agents, they are eligible; however, they must be assigned 
to the other agent for investigator’s choice. That is, patients who have received prior 
pazopanib must be assigned to trabectedin, and patients who have received prior 
trabectedin must be assigned to pazopanib.  
- 
Patients must have recovered to baseline or ≤ grade 1 per CTCAE version 5.0 from 
toxicity related to any prior treatment, unless adverse events are clinically 
nonsignificant and/or stable on supportive therapy, with the exception of fatigue 
(which must be ≤ grade 2), alopecia and/or endocrinopathies related to prior 
immunotherapy which are controlled with hormone replacement. 
- 
Patients must have completed all prior anti-cancer treatment, including radiation,  ≥ 28 
days prior to registration. 
___ 
3.2.7 
Prior Surgery 
- 
Patients may have undergone major surgery (related or unrelated to their cancer 
diagnosis) ≥ 28 days of registration. Subjects with clinically relevant ongoing 
complications from prior surgery are not eligible. 

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___ 
3.2.8 
Required Initial Laboratory Values: 
Absolute Neutrophil Count (ANC) 
≥ 1500/mm3 
Platelet count 
≥ 100,000/mm3 
Creatinine1 
≤ 1.5 * ULN 
Hemoglobin2 
≥ 9 g/dL 
Total bilirubin3 
≤ 1.5 x ULN 
AST/ALT 
≤ 3 x ULN 
1 If creatinine > 1.5 * ULN, CrCl must be > 50 mL/min per Cockcroft-Gault method.  
2 No transfusions ≤ 14 days before C1D1 
3 If documented Gilbert’s: ≤ 2.0 x ULN 
All criteria are specified with reference to the institution’s normal ranges.  
___ 
3.2.9 
Comorbidities – Cardiovascular Conditions 
- 
Patients may not have uncontrolled hypertension defined as a BP > 150/90 on two 
consecutive assessments during the screening period. If a patient is found to have a BP 
> 150/90 on two consecutive assessments during the screening period, the patient may 
be started on an anti-hypertensive regimen, and will be considered eligible if two 
subsequent measurements are performed and the BP is ≤ 150/90. If BP is in range on 
the first measurement, no further measurements are needed.  
- 
Patients must demonstrate a QTcF (Fredericia formula) ≤ 470 msec on an EKG 
performed during screening. This criterion applies only to patients who will receive 
pazopanib if randomized to Arm 2 (see Section 3.2.13). Repeat EKG testing during the 
screening period is allowed. 
- 
Patients may not have an uncontrolled ventricular arrhythmia or recent (within 3 
months) myocardial infarction 
- 
In addition to the above, patients with known history or current symptoms of cardiac 
disease, or history of treatment with cardiotoxic agents, should have a clinical risk 
assessment of cardiac function using the New York Heart Association Functional 
Classification (see Appendix VII). To be eligible, patients should be class 2B or better.  
___ 
3.2.10 Comorbid Comorbidities – Other Conditions 
- 
Patients may not have a history of active or unresolved: perforation, abscess or 
fistula within 28 days prior to registration (either clinically or radiographically). 
- 
MDS/AML: Patients must not have myelodysplastic syndrome (MDS)/acute myeloid 
leukemia (AML) or a history of bone marrow biopsy findings at any time consistent 
with MDS and/or AML. 
- 
Hepatitis B: For patients with evidence of chronic hepatitis B (HBV) infection, the 
HBV viral load must be undetectable on suppressive therapy, if indicated. 
- 
Hepatitis C: Patients with a history of hepatitis C virus (HCV) infection must have 
been treated and cured. For patients with HCV infection who are currently on 
treatment, they are eligible if they have an undetectable HCV viral load.  
- 
HIV/Immunosuppressive Conditions: HIV-infected patients on effective anti-
retroviral therapy with undetectable viral load within 6 months are eligible for this trial. 

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- 
Other Malignancies: Patients with a prior or concurrent malignancy whose natural 
history or treatment does not have the potential to interfere with the safety or efficacy 
assessment of the investigational regimen are eligible for this trial.  
- 
CNS/Leptomeningeal Disease: Patients with CNS/leptomeningeal disease must have 
undergone definitive treatment, have no evidence of CNS progression on follow-up 
imaging performed at least 4 weeks after the CNS-directed therapy is completed, and 
be off all steroids, in order to be eligible..  
- 
Other Medical Conditions: Patients must not have an uncontrolled intercurrent 
illness including, but not limited to, ongoing or active infection, uncontrolled major 
seizure disorder, unstable spinal cord compression, superior vena cava syndrome, 
extensive interstitial bilateral lung disease on high resolution computed tomography 
(HRCT) scan or any other condition that would limit compliance with study 
requirements. 
- 
Patients must be able to swallow oral medications. 
___ 
3.2.11 Concomitant medications 
- 
Patients may not require concomitant use of known strong CYP3A inhibitors (e.g., 
itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir 
or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, 
verapamil). The required washout period prior to starting study treatment is 2 weeks. 
See Section 8.1.10 for more information.  
- 
Patients may not require concomitant use of known strong (e.g., phenobarbital, 
enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine 
and St John’s Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, 
modafinil). The required washout period prior to starting study treatment is 5 weeks 
for enzalutamide or phenobarbital and 3 weeks for other agents. See Section 8.1.11 for 
more information.  
___ 
3.2.12 Language 
In order to complete the mandatory patient-completed measure, participants must be able 
to read English or Spanish. Non-English or non-Spanish readers may still participate in the 
study but are not required to complete the PRO-CTCAE side effect surveys. 
___ 
3.2.13 Investigator’s Choice Arm Assignment and Eligibility 
For all patients, prior to randomization and as part of eligibility, the investigator must select 
the agent which the patient would receive if assigned to the investigator’s choice arm, prior 
to randomization. The patient must meet all eligibility criteria for that agent during 
screening and prior to randomization.  
Patients without central venous access must be willing to undergo placement of central 
venous access (i.e. port or PICC line, per institutional practice). if assigned to the 
investigator’s choice arm and if the investigator intends to treat the patient with trabectedin. 
The site must be able to place central venous access within 10 days of 
registration/randomization. 
OPTIONAL: This signature line is provided for use by institutions wishing to use the eligibility 
checklist as source documentation. 
Alliance Patient Number ______________________  

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In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting or treating investigator in OPEN, or as the CI on the DTL must be rostered 
at the enrolling site with a participating organization. 
Refer to the NCI RCR page on the CTEP website for additional information. For questions, 
please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
4.2 
Cancer Trials Support Unit Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on the person and site roster assignment housed in the Roster Maintenance application 
and in most cases viewable and manageable via the Roster Update Management System 
(RUMS) on the Cancer Trials Support Unit (CTSU) members’ website. 
This study is supported by the NCI CTSU. 
IRB Approval 
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB) in order to participate in Cancer Therapy Evaluation Program 
(CTEP) and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases. 
In addition, U.S.-based sites must accept the NCI CIRB review to activate new studies at the 
site after March 1, 2019. Local IRB review will continue to be accepted for studies that are not 
reviewed by the CIRB, or if the study was previously open at the site under the local IRB. 
International sites should continue to submit Research Ethics Board (REB) approval to the 
CTSU Regulatory Office following country-specific regulations. 
Sites participating through the NCI CIRB must submit the Study Specific Worksheet (SSW) for 
Local Context to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email (CTSURegPref@ctsu.coccg.org) or by calling 1-888-651-CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the IRB/REB 
approval) must meet the following criteria for the site to be able to have an Approved status 
following processing of the IRB/REB approval record: 
• 
Have an active CTEP status; 
• 
Have an active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) on at least one participating organization’s roster; 
• 
If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• 
Include the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; 
• 
List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• 
Have the appropriate CTEP registration type for the protocol. 
4.2.1 
Additional Site Registration Requirements 
Additional site requirements to obtain an approved site registration status include: 

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• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); 
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• 
Compliance with all applicable protocol-specific requirements (PSRs). 
4.2.2 
Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted to institutions and their associated investigators and staff on a 
participating roster. To view/download site registration forms: 
• 
Log in to the CTSU members’ website (https://www.ctsu.org); 
• 
Click on Protocols in the upper left of the screen: 
o 
Enter the protocol number in the search field at the top of the protocol tree; or 
o 
Click on the By Lead Organization folder to expand, then select Alliance, and 
protocol number A092104. 
• 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.) 
4.2.3 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website. 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-
CTSU (2878), or CTSURegPref@ctsu.coccg.org to receive further instruction and support. 
4.2.4 
Checking Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website. 
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go: 
o 
Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks 
4.2.5 
Delegation of Task Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL 
application which is accessible via the Delegation Log link on the CTSU members’ website 

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or directly at https://dtl.ctsu.org. The Clinical Investigator (CI) is required to review and 
electronically sign the DTL prior to the site receiving an approved site registration status 
and enrolling patients to the study. To maintain an approved site registration status the CI 
must re- sign the DTL at least annually and when a new version of the DTL is released; and 
to activate new task assignments requiring CI sign-off. Any individual at the enrolling site 
on a participating roster may initiate the site DTL. Once the DTL is submitted for CI 
approval, only the designated DTL Administrators or the CI may update the DTL. 
Instructions on completing the DTL are available in the Help Topics button in the DTL 
application and describe DTL task assignments, CI signature, and CTEP registration 
requirements, as well as include a Master Task List. 
4.3 
Patient Registration Requirements 
4.3.1 
Informed consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current human 
protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
Patients with impaired decision making capacity may be enrolled on this study, where 
institutional policy and IRB of record allow.  
4.3.2 
Patient-reported outcomes 
This study includes the use of the mandatory patient completed measures, PRO-CTCAE. 
The measures are available in English and Spanish. Patients who are able to speak, 
understand, and read English or Spanish will be required to participate in completing the 
PRO-CTCAE. For eligible patients that are non-English or non-Spanish readers, they may 
still participate in this study, but will not complete the PRO-CTCAE surveys. 
Patient-reported outcomes for this study will be assessed using paper booklets. 
Patient questionnaire booklets 
Patient questionnaire booklets are to be downloaded prior to the registration of any patients. 
The current version of the patient-completed booklets can be downloaded from the CIRB 
Approved Documents tab of the A092104 page of the CTSU website. Booklets will be 
provided in English and Spanish (see Section 6.3).   
4.3.3 
Selecting Study Agent 
The investigator must select the agent which the patient will receive if assigned to the 
investigator’s choice arm prior to randomization See Section 4.5.  
4.4 
Patient Enrollment 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs’ 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access: 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems; 

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• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, or receiving investigator for a patient transfer in OPEN, the IVR or 
NPIVR must list the Institutional Review Board (IRB) number used on the site’s IRB approval 
on their Form Food and Drug Administration (FDA) 1572 in the Registration and Credential 
Repository (RCR). If a DTL is required for the study, the IVR or NPIVR must be assigned the 
appropriate OPEN- related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and 
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.5 
Stratification Factors and Treatment Assignments 
4.5.1 
Stratification Factors 
1) ECOG PS: 0 or 1 vs. 2 
2) Prior lines of treatment: 2 vs. 3 or more 
4.5.2 
Treatment Assignments  
The factors defined in Section 4.5.1 will be used as stratification factors. 
After the patient has been registered into the study, the values of the stratification factors 
will be recorded, and the patient will be assigned to one of the following treatment groups 
using the Pocock and Simon dynamic allocation procedure [19] which balances the 
marginal distributions of the stratification factors between the treatment groups. 
The treating physician must determine whether the patient will be treated with either 
trabectedin or pazopanib (should the patient be assigned to investigator’s choice) 
prior to randomization and this information will be collected prior to randomization. 
If the patient is assigned to Arm 2, the patient will then initiate treatment with that 
agent. The drug to which the patient is assigned will be recorded in the eCRFs. The treating 
investigator will discuss the outcome of the randomization and the treatment assignment 
with the patient. 
1) Arm 1: Olaparib + Temozolomide 
2) Arm 2: Investigator’s Choice: Trabectedin or Pazopanib 
 

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5.0 
STUDY CALENDAR 
Pre-study Testing Intervals 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial. 
When calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test were done on a Monday, the Monday one week later would be considered 
Day 7. 
Study Calendar Key: 
“*”, “**”, “†”, etc., are used for additional information relating to the column headers. 
“(1)”, “(2)”, “(3)”, are added to the X’s for further explanation.  
“X”’s are replaced with “A” “B” “C”, for tests that vary from the schedule named in the column header. 
 
Study Calendar Arm 1: Olaparib + Temozolomide 
 
Prior to 
Registration* 
Day 1 of Every 
Cycle** 
Post-treatment 
follow-up  
(short-term 
follow-up)*** 
Long-term 
follow-up**** 
Tests & Observations 
 
 
 
 
H&P, weight, ECOG PS 
X(1) 
X(1) 
X(1) 
 
Height 
X 
 
 
 
Vital signs 
X 
X 
X 
 
Adverse Event Assessment -
CTCAE 
X(2) 
X(2) 
X(2) 
 
Adverse Event Assessment- 
PRO-CTCAE 
X(2) 
X(2) 
 
 
Patient medication diary 
 
X(3) 
 
 
Survival Follow-up 
 
 
 
X 
Laboratory Studies 
 
 
 
 
Complete blood count with 
differential7 
X 
X 
X 
 
Complete chemistry8 
X 
X 
X 
 
Serum or urine HCG 
X(4) 
 
 
 
Staging 
 
 
 
 
Genomic sequencing results 
X(5) 
 
 
 
Imaging (CT or MRI) 
X(6) 
X(6) 
X(6) 
 
Correlative Studies: For Patients who consent to participate 
A092104 Biobanking 
Blood and tissue samples will be collected; see Sections 6.2 and 14.0 

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* 
All screening assessments must be completed ≤ 28 days prior to registration, except for the 
pregnancy test, which must be completed ≤ 7 days prior to registration. Patients must begin 
treatment within 14 days after registration/randomization. 
** 
Labs completed prior to registration may be used for C1D1 if obtained ≤ 7 days prior to treatment. 
For subsequent cycles, all assessments may be obtained within 72 hours (3 days) prior to day of 
treatment. If there is a change in the patient’s clinical status, the assessments should be repeated 
prior to beginning treatment for that respective cycle. After C1D1, a new treatment cycle may 
begin ± 3 days from the planned date. 
*** 
Physical examination, adverse event assessment, and medication diary are required 4 weeks (± 7 
days) after the end of treatment (defined as the day the investigator determines the patient will not 
continue study treatment). Patients will then enter long-term follow-up as described below. 
Patients discontinuing treatment for reasons other than progressive disease will continue 
following the Study Calendar for disease assessments (i.e. imaging) until progressive disease is 
documented, and will then enter long-term follow-up. 
**** Upon progression, patients will be followed every 3 months (±7 days) for the first 2 years, then 
every 6 months (±14 days) thereafter until 5 years post-randomization or death, whichever comes 
first. Information must be collected on (a) the first subsequent anticancer treatment received and 
(b) survival status. Information may be collected by telephone call or clinical visits conducted as 
standard of care, per investigator’s discretion. 
1 
A complete physical exam is performed at screening and the post treatment follow-up visit. A 
limited, symptom based, physical exam is performed at other timepoints. 
2 
CTCAE must be completed during screening but prior to C1D1, on Day 1 of every cycle, and at 
the post-treatment follow-up visit. PRO-CTCAE must be completed during screening but prior to 
C1D1 and on Day 1 of every cycle through cycle 11. Collection of PRO-CTCAE is discontinued 
after cycle 11. PRO-CTCAE is required only for English and Spanish readers. 
3 
If the sample medication diary in Appendix III and IV is used, it should begin the day the patient 
starts taking the medication and should be completed and returned to the treating institution on 
Day 1 of every cycle beginning with Cycle 2. Compliance must be documented by any member 
of the care team.. 
4 
For women of childbearing potential (see Section 3.2.3). Must be done ≤ 7 days prior to 
registration. 
5 
Results from genomic sequencing assays will be collected when known to the treating investigator 
and previously performed as part of the patient’s clinical care. Results from any genomic testing 
performed on tumor tissue should be reported, including next generation sequencing (extended or 
targeted panels), whole exome and/or whole genome sequencing. Results will be abstracted and 
entered into a study-specific form in Medidata by site staff. Copies of deidentified reports from 
the assay(s) will also be uploaded. Sites must provide this information when available within 60 
days of registration. 
6 
CT scan with IV and oral contrast is recommended to assess disease status. MRI and/or bone scans 
may be used as clinically indicated per the treating physician’s discretion. Imaging is performed 
every 2 cycles (6 weeks) as measured from C1D1 until disease progression. A window of ±7 days 
is permitted. Imaging should be performed before a new cycle starts whenever possible. 
7 
Include white blood cells, absolute neutrophils, hemoglobin, hematocrit and platelets 
8 
Include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, total 
bilirubin, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase.  
 
 

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Study Calendar Arm 2: Trabectedin 
 
Prior to 
Registration* 
Day 1 of Every 
Cycle** 
Post-treatment 
follow-up  
(short-term 
follow-up)*** 
Long-term 
follow-up**** 
Tests & Observations 
 
 
 
 
H&P, weight, ECOG PS  
X(1) 
X(1) 
X(1) 
 
Height 
X 
 
 
 
Vital signs 
X 
X 
X 
 
Adverse Event Assessment -
CTCAE 
X(2) 
X(2) 
X(2) 
 
Adverse Event Assessment- 
PRO-CTCAE 
X(2) 
X(2) 
 
 
Survival follow-up 
 
 
 
X 
Laboratory Studies 
 
 
 
 
Complete blood count with 
differential7 
X 
X 
X 
 
Complete chemistry8 
X 
X 
X 
 
CPK9 
 
X 
X 
 
Serum or urine HCG 
X(3) 
 
 
 
Echocardiogram/MUGA 
 
X(A) 
 
 
Staging 
 
 
 
 
Genomic sequencing results  
X(5) 
 
 
 
Imaging (CT or MRI) 
X(6) 
X(6) 
X(6) 
 
Correlative Studies: For Patients who consent to participate 
A092104 Biobanking 
Blood and tissue samples will be collected; see Sections 6.2 and 14.0 
* 
All screening assessments must be completed ≤ 28 days prior to registration, except for the 
pregnancy test, which must be completed ≤ 7 days prior to registration, and the baseline MUGA can 
be obtained up to  ≤ 28 days prior to registration. Patients must begin treatment within 14 days after 
registration/randomization. 
** Labs completed prior to registration may be used for C1D1 if obtained ≤ 7 days prior to treatment. 
For subsequent cycles, all assessments may be obtained within 72 prior to day of treatment. If there 
is a change in the patient’s clinical status, the assessments should be repeated prior to beginning 
treatment for that respective cycle. After C1D1, a new treatment cycle may begin ± 3 days from the 
planned date. 
*** Physical examination, adverse event assessment, and medication diary are required 4 weeks (± 7 
days) after the end of treatment (defined as the day the investigator determines the patient will not 
be continuing study treatment). Patients will then enter long-term follow-up as described below. 
Patients discontinuing their treatment for reasons other than progressive disease will continue 
following the Study Calendar for disease assessments (i.e. imaging) until progressive disease is 
documented, after which these patients will also enter long-term follow-up. 
**** Upon progression, patients will be followed every 3 months (±7 days) for the first 2 years, then 
every 6 months (±14 days) thereafter until 5 years post-randomization or death, whichever comes 

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first. Information must be collected on (a) the first subsequent anticancer treatment received and (b) 
survival status. Information may be collected by telephone call or clinical visits conducted as 
standard of care, per investigator’s discretion.  
1 
A complete physical exam is performed at screening and the post-treatment follow-up visit. A 
limited, symptom based, physical exam is performed at other timepoints. 
2 
CTCAE must be completed during screening but prior to C1D1, on Day 1 of every cycle, and at the 
post-treatment follow-up visit. PRO-CTCAE must be completed during screening but prior to C1D1 
and on Day 1 of every cycle through cycle 11. Collection of PRO-CTCAE is discontinued after 
cycle 11. PRO-CTCAE is required only for English and Spanish readers. 
 
3 
For women of childbearing potential (see Section 3.2.3). Must be done ≤ 7 days prior to registration. 
4 
Results from genomic sequencing assays will be collected when known to the treating investigator 
and previously performed as part of the patient’s clinical care. Results from any genomic testing 
performed on tumor tissue should be reported, including next generation sequencing (extended or 
targeted panels), whole exome and/or whole genome sequencing. Results will be abstracted and 
entered into a study-specific form in Medidata by site staff. Copies of deidentified reports from the 
assay(s) will also be uploaded. Sites must provide this information when available within 60 days 
of registration. 
5 
CT scan with IV and oral contrast is recommended to assess disease status. MRI and/or bone scans 
may be used as clinically indicated per the treating physician’s discretion. Imaging is performed 
every 2 cycles (6 weeks) as measured from C1D1 until disease progression. A window of ±7 days 
is permitted. Imaging should be performed before a new cycle starts whenever possible. 
6 
Include white blood cells, absolute neutrophils, hemoglobin, hematocrit and platelets. 
7 
Include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, total 
bilirubin, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase. 
8 
CPK must be performed and resulted, on day 1 of every cycle prior to treatment with trabectedin.  
A 
Perform transthoracic echocardiography (TTE) or MUGA at baseline (before C1D1 treatment), and 
while on treatment with trabectedin, as clinically indicated. 
 
 

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Study Calendar Arm 2: Pazopanib 
 
Prior to 
Registration* 
Day 1 of Every 
Cycle** 
Post-treatment 
follow-up  
(short-term 
follow-up)*** 
Long-term 
follow-up**** 
Tests & Observations 
 
 
 
 
H&P, weight, ECOG PS  
X(1) 
X(1) 
X(1) 
 
Height 
X 
 
 
 
Vital signs 
X 
X 
X 
 
Adverse Event Assessment -
CTCAE 
X(2) 
X(2) 
X(2) 
 
Adverse Event Assessment- 
PRO-CTCAE 
X(2) 
X(2) 
 
 
Patient medication diary 
 
X(3) 
 
 
Assess for dose escalation 
 
X(4) 
 
 
Survival follow-up 
 
 
 
X 
Laboratory Studies 
 
 
 
 
Complete blood count with 
differential12 
X 
X 
X 
 
Complete chemistry13 
X 
X 
X 
 
TSH 
 
X(5) 
 
 
Urine spot protein : creatinine 
ratio (UPC) 
 
X(6) 
 
 
Serum or urine HCG 
X(7) 
 
 
 
EKG 
X(8) 
 
 
 
Echocardiogram/MUGA 
 
X(A) 
 
 
Staging 
 
 
 
 
Genomic sequencing results 
X(10) 
 
 
 
Imaging (CT or MRI) 
X(11) 
X(11) 
X(11) 
 
Correlative Studies: For Patients who consent to participate 
A092104 Biobanking 
Blood and tissue. Samples will be collected; see Sections 6.2 and 14.0 
* 
All screening assessments must be completed ≤ 28 days prior to registration, except for the pregnancy 
test, which must be completed ≤ 7 days prior to registration. The MUGA can be obtained up to  ≤ 28 
days 
prior 
to 
registration. 
Patients 
must 
begin 
treatment 
within 
14 
days 
after 
registration/randomization. 
** 
Labs completed prior to registration may be used for C1D1 if obtained ≤ 7 days prior to treatment. 
For subsequent cycles, all assessments may be obtained within 72 prior to day of treatment. If there 
is a change in the patient’s clinical status, the assessments should be repeated prior to beginning 
treatment for that respective cycle. 
*** Physical examination, adverse event assessment, and medication diary are required 4 weeks (± 7 
days) after the end of treatment (defined as the day the investigator determines the patient will not be 
continuing study treatment). Patients will then enter long-term follow-up as described below. Patients 

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discontinuing their treatment for reasons other than progressive disease will continue following the 
Study Calendar for disease assessments (i.e. imaging) until progressive disease is documented, after 
which these patients will also enter long-term follow-up.  
****  Upon progression, patients will be followed every 3 months (±7 days) for the first 2 years, then every 
6 months (±14 days) thereafter until 5 years post-randomization or death, whichever comes first. 
Information must be collected on (a) the first subsequent anticancer treatment received and (b) 
survival status. Information may be collected by telephone call or clinical visits conducted as standard 
of care, per investigator’s discretion.  
1 
A complete physical exam is performed at screening and the post-treatment follow-up visit. A limited, 
symptom based, physical exam is performed at other timepoints. 
2 
CTCAE must be completed during screening but prior to C1D1, on Day 1 of every cycle, and at the 
post-treatment follow-up visit. PRO-CTCAE must be completed during screening but prior to C1D1 
and on Day 1 of every cycle through cycle 11. Collection of PRO-CTCAE is discontinued after cycle 
11. PRO-CTCAE is required only for English and Spanish readers. 
3 
If the sample medication diary in Appendix V is used, it should begin the day the patient starts taking 
the medication and should be completed and returned to the treating institution on Day 1 of every 
cycle beginning with Cycle 2. Compliance must be documented by any member of the care team.. 
4 
Pazopanib will be initiated at 400 or 600 mg per day per the treating investigator’s discretion. 
Pazopanib can be dose escalated in 200 mg increments to a maximum dose of 800 mg per day at day 
1 visits, or earlier intervals, per usual clinical practice. Pazopanib can be dose de-escalated. 
5 
TSH should be measured as clinically indicated during treatment with pazopanib.  
Testing should be performed after registration and once every other cycle (i.e. screening, C2D1, 
C4D1, …) or more frequently as clinically indicated. 
6. 
UPC should be measured as clinically indicated during treatment with pazopanib. See Section 8 for 
management of abnormal UPC occurring while on treatment. 
7 
For women of childbearing potential (see Section 3.2.3). Must be done ≤ 7 days prior to registration.  
8 
For patients randomized to Arm 2 and treated with pazopanib an EKG should be performed after 
registration and prior to treatment start if they have a history of or signs/symptoms of dysrhythmias 
or prolonged QT syndrome or relevant preexisting cardiac disease, and/or on medication for 
dysrhythmias, and/or electrolyte imbalances that could promote dysrhythmias or to prolong the QT 
interval. During treatment EKG monitoring, including serum electrolytes (e.g., calcium, magnesium) 
is per clinical discretion as clinically indicated. 
9 
Results from genomic sequencing assays will be collected when known to the treating investigator 
and previously performed as part of the patient’s clinical care. Results from any genomic testing 
performed on tumor tissue should be reported, including next generation sequencing (extended or 
targeted panels), whole exome and/or whole genome sequencing. Results will be abstracted and 
entered into a study-specific form in Medidata by site staff. Copies of deidentified reports from the 
assay(s) will also be uploaded. Sites must provide this information when available within 60 days of 
registration. 
10 
CT scan with IV and oral contrast is recommended to assess disease status. MRI and/or bone scans 
may be used as clinically indicated per the treating physician’s discretion. Imaging is performed every 
2 cycles (6 weeks) as measured from C1D1 until disease progression. A window of ±7 days is 
permitted. Imaging should be performed before a new cycle starts whenever possible. 
11 
Include white blood cells, absolute neutrophils, hemoglobin, hematocrit and platelets. 
12 
Include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, total 
bilirubin, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase. 
A 
Perform transthoracic echocardiography (TTE) or MUGA at baseline (before C1D1 treatment),  and 
while on treatment with pazopanib, as clinically indicated.  
 

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6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data Collection and Submission 
6.1.1 
Data submission schedule 
A Data Submission Schedule (DSS) is available on the Alliance study webpage, within the 
Case Report Forms section. The Data Submission Schedule is also available on the CTSU 
site within the study-specific Case Report Forms folder. 
6.1.2 
Medidata Rave 
Medidata Rave is the clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and 
role assignments. 
Requirements to access Rave via iMedidata: 
• 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• 
Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• 
Rave Read Only or Rave SLA role must have at a minimum an Associate (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required.  
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access 
to Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in the Regulatory application, all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
email from iMedidata. No action will be required; each study invitation will be 
automatically accepted and study access in Rave will be automatically granted. Site staff 
will not be able to access the study in Rave until all required Medidata and study-specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings) 
and can be accessed by clicking on the eLearning link in the Tasks pane located in the 
upper right corner of the iMedidata screen. If an eLearning is required for a study and has 
not yet been taken, the link to the eLearning will appear under the study name in the Studies 
pane located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC 
link will replace the eLearning link under the study name. 
No action will be required by site staff (to activate their account) who have not previously 
activated their iMedidata/Rave account at the time of initial site registration approval for 
the study in the Regulatory application. Pending study invitations (previously sent but not 
accepted or declined by a site user) will be automatically accepted and study access in Rave 
will be automatically granted for the site user. Account activation instructions are located 

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on the CTSU website in the Data Management section under the Data Management Help 
Topics > Rave resource materials (Medidata Account Activation and Study Invitation). 
Additional information on iMedidata/Rave is available on the CTSU members’ website in 
the Data Management > Rave section or by contacting the CTSU Help Desk at 1-888-823-
5923 or by email at ctsucontact@westat.com. 
6.1.3 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics. 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports 
modules are available to access details and reports of unanswered queries, delinquent 
forms, forms with current status, and timeliness reports. Site staff should review the DQP 
modules on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to the CTSU 
website. Staff who have Rave study access can access the Rave study data via direct links 
available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a month. 
These notifications serve as alerts that queries and/or delinquent forms require site review, 
providing a summary count of queries and delinquent forms for each Rave study that a site 
is participating in. Additional site staff can subscribe and unsubscribe to these notifications 
using the CTSU Report and Information Subscription Portal on the CTSU members’ 
website. 
To learn more about DQP use and access, click on the Help Topics button displayed on the 
Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports 
modules. 
6.1.4 
Supporting documentation to be submitted to the Alliance 
This study requires supporting documentation for screening, on study, response and 
progression. Supporting documentation will include radiology reports, pathology reports 
and clinical notes. These must be submitted at the following time points: 
Screening: Pathology report 
On-Study: Clinic note, radiology report of the screening/baseline scan, pathology report 
and tumor genomics (see immediately below).  
This study will collect results of genomic testing conducted on tumor tissue which was 
previously performed as part of the patient’s clinical care and for which results are known 
to the treating investigator at the time of registration.  Relevant information includes tumor 
genomics obtain using next generating sequencing (targeted or extended panels), whole 
exome and/or whole genome sequencing from in-house platforms or commercial entities 
(i.e. Foundation Medicine, Caris). Only testing on tumor tissue will be collected. Results 
from testing on peripheral blood or other sources will not be collected. Relevant data will 
be abstracted and entered into a study-specific form. Sites will also upload deidentified 
result reports from the assays. This information must be provided within 60 days of 
registration. 
Partial or Complete Response – Radiology report. 

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Progression: Radiology report and clinic note for patients deemed to have progression 
based on clinical deterioration. 
Supporting documentation is to be submitted via Rave. 
6.1.5 
Rave-CTEP-AERS integration 
See Section 9.1.1 for information regarding submission of adverse event information 
utilizing the Rave-CTEP-AERS integration. 
6.2 
Specimen collection and submission 
The Alliance A092104 Correlative Science Manual (CSM) contains instructions for specimen 
collection, processing and shipping. The manual can be found on the BioMS and CTSU 
websites. Questions regarding the CSM should be addressed to the contacts specified in the 
manual. 
For patients consenting to A092104 Biobanking: All participating institutions must ask 
patients for their consent to participate in biobanking for future research, although patient 
participation is optional. For patients who consent to participate, tissue and blood will be 
collected at the following time points for biobanking. Please also see the study CSM for more 
instructions regarding specimen collection and submission. 
6.2.1 
Overview of Specimen Requirements 
 
Within 60 
days of 
registration 
Prior to C1D1 
C2D1 
(Prior to 
treatment) 
C5D1 
(Prior to 
treatment) 
Progression/ 
End of 
Treatment 
 
For patients registered to A092104 biobanking, submit the following: 
Archival FFPE 
tumor tissue  
X 
 
 
 
 
Plasma and buffy 
coat from whole 
blood in EDTA 
tubes1  
 
2 x 10 mL 
2 x 10 mL 
2 x 10 mL 
2 x 10 mL 
1. Buffy coat is required only at one timepoint; preferred at Prior to C1D1, but any later timepoint is acceptable. 
6.3 
Submission of Patient Completed Measures 
Patient completed measures will be performed using paper questionnaire booklets. 
Patient-completed questionnaire booklets for this study are to be downloaded prior to the 
registration of any patients (see Section 4.3.2, Patient-reported outcomes). Booklets must be 
given to patients to complete and patients should be instructed to return the booklets/responses 
to site staff in person, by mail, or by phone) and site staff will enter patient responses into 
Medidata Rave. The method of administration (in person, by mail, etc.) should be documented 
in the source documents. At visits in which booklets are to be completed, the booklet should be 
given to the patient before any discussion of the patient’s health status or test results. The method 
of collection should be documented in Rave. 
Please note that PRO-CTCAE is required for all patients if they are English and Spanish readers 
per the study calendar. 

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Verbal administration of the measures for visually impaired patients is permitted if the measure 
and verbal administration of the measure is conducted in a language understandable to the 
patients. 
6.3.1 
Patient Language Considerations 
The PRO-CTCAE are available in English and Spanish and are required only for English 
and Spanish readers. Participation in Alliance A092104 is not restricted to patients who are 
able to read and understand these languages. The translated measures are available on the 
A092104 CTSU and Alliance study pages. Ad-hoc translation of patient-completed 
measures is not permitted. 
 

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7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin within 14 days from the date of study of registration. 
For questions regarding treatment, please see the study contacts page. 
Please see the study calendar for allowable windows in which treatment cycles must begin. In 
addition, patients are permitted to have a new cycle of treatment delayed for up to 7 days for major 
life events (e.g., serious illness in a family member, major holiday, vacation that cannot be 
rescheduled) without this delay being considered a protocol violation. Documentation to justify this 
delay should be provided. 
70 patients will be enrolled to the Phase II portion of the trial. Enrollment will be paused at 
that time for treatment evaluation (see Section 13.2.2) 
7.1 
Arm 1 (Olaparib + Temozolomide) 
Patients assigned to Arm 1 will receive treatment with olaparib plus temozolomide. 
Temozolomide (TMZ) is administered at 75 mg/m2 orally once daily in combination with 
olaparib (tablets) 200 mg orally twice daily on days 1-7 of a 21-day cycle. 
Please see below for additional instructions on how to administer this regimen. 
Regimen Description 
Agent 
Premedications 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Olaparib 
Do not consume 
grapefruit juice. 
Take concurrently 
with TMZ. 
See Section 8. 
200 mg  
PO twice daily Days 1-7 
21 days  
(3 weeks) 
 
 
 
Temozolomide  Ondansetron 8 mg 
PO once prior to 
TMZ (required 
during cycle #1, 
optional thereafter). 
TMZ can be taken 
with or without food 
but it may be better 
tolerated if taken on 
an empty stomach.  
Take TMZ with a 
full glass of water 
with the AM dose of 
olaparib; or if 
nausea is a 
difficulty, take TMZ 
with or without food 
with the PM dose of 
olaparib 
75 mg/m2 
 
See below 
for dose 
table. 
PO once daily 
Days 1-7 

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Regimen Description 
Agent 
Premedications 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Recommend 
consistency daily 
regarding with or 
without food and 
regarding AM or 
PM dosing 
 
See Section 8. 
The dose and schedule for temozolomide and olaparib reflect the recommended phase 2 dose 
(RP2D) from a phase 1 study with this combination in small cell lung cancer. The same RP2D 
was also determined in a phase 1 clinical trial of this combination in Ewing sarcoma 
(NCT01858168; unpublished, study team’s communication with study PI) and is currently being 
used in an ongoing phase II study in neuroendocrine tumors (NCT04394858). 
Furthermore, this dose and schedule were used in our completed phase 2 study. Hematologic 
toxicity was the most commonly reported adverse event and included grade 3/4 neutropenia 
(59%, 18%), thrombocytopenia (15%, 18%) and anemia (32%, 0%). Protocol-mandated dose 
reductions for temozolomide were made in 54% of patients. Clinically significant complications 
of myelosuppression, including febrile neutropenia or thrombocytopenia with bleeding, were 
not observed. 
Temozolomide: 
Patients will be administered TMZ once daily (QD). The TMZ capsules should be swallowed 
whole with a glass of water and not opened, crushed, chewed, or dissolved. TMZ can be taken 
with or without food, but if there are issues with nausea, fasting is recommended (should be 
taken on an empty stomach [i.e. in the fasted state, either 1 hour before, or 2 hours after, a meal]).                           
Patients should take ondansetron 8 mg PO once concurrently or up to 30 minutes before the 
TMZ dose during cycle 1. If vomiting occurs, do not repeat dose, patients should wait until next 
scheduled dose. 
If patients have a medical contraindication to ondansetron, another anti-emetic may be 
substituted. The use of ondansetron beyond cycle 1 is at the discretion of the principal 
investigator. 
TMZ is rapidly and completely absorbed after oral administration with a peak plasma 
concentration achieved in a median of 1 hour. Food reduces the extent of TMZ absorption. 
Should any patient enrolled on the study miss a scheduled dose of temozolomide for any reason 
(e.g., as a result of forgetting to take the tablets or vomiting), the patient should not repeat dose 
if vomiting occurs after dose is administered; and should wait until the next scheduled dose.  
Temozolomide doses are calculated based on body surface area (BSA). Temozolomide doses 
should be adjusted if a patient’s weight changes >10% or more from the baseline (screening) 
weight. The total daily dose of temozolomide (75 mg/m2) based on patient BSA and the 
recommended combination of temozolomide capsule strengths to achieve this dose is provided 
in the tables below. In the event the patient’s dose of temozolomide is modified while on the 

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study, re-calculate the total daily dose, and round off the resulting dose to the nearest 5 mg 
increment. 
 
Total Daily Dose of TMZ (75 
mg/m2) Based on BSA 
BSA 
(m2) 
75 mg/m2 
(mg daily) 
1.0 
75 
1.1 
82.5 
1.2 
90 
1.3 
97.5 
1.4 
105 
1.5 
112.5 
1.6 
120 
1.7 
127.5 
1.8 
135 
1.9 
142.5 
2.0 
150 
2.1 
157.5 
2.2 
165 
2.3 
172.5 
2.4 
180 
2.5 
187.5 
 
Number of Daily Capsules by Strength (mg) to Achieve Daily Dose 
Total Daily 
Dose (mg) 
180 mg 
140 mg 
100 mg 
20 mg 
5 mg 
75 
0 
0 
0 
3 
3 
82.5 
0 
0 
0 
4 
0 
90 
0 
0 
0 
4 
2 
97.5 
0 
0 
1 
0 
0 
105 
0 
0 
1 
0 
1 
112.5 
0 
0 
1 
0 
2 
120 
0 
0 
1 
1 
0 

Alliance A092104 
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 Update #05 
127.5 
0 
0 
1 
1 
1 
135 
0 
0 
1 
1 
3 
142.5 
0 
1 
0 
0 
0 
150 
0 
1 
0 
0 
2 
157.5 
0 
1 
0 
1 
0 
165 
0 
1 
0 
1 
1 
172.5 
0 
1 
0 
1 
2 
180 
1 
0 
0 
0 
0 
187.5 
1 
0 
0 
0 
1 
 
Olaparib: 
Patients will be administered olaparib twice daily (BID). Olaparib tablets should be taken at the 
same time each day approximately 12 hours apart with one glass of water. The first olaparib 
dose of the day should be taken concomitantly with TMZ. The olaparib tablets should be 
swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets can be taken 
with or without food; however, since the morning dose is taken with TMZ, both agents should 
be taken together on an empty stomach for the morning dose. If taken with or without food, it 
should consistently be taken in that manner. It is prohibited to consume grapefruit, grapefruit 
juice, or Seville oranges while on olaparib therapy. 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted. Should any patient enrolled on the 
study miss a scheduled dose of olaparib for any reason (e.g., as a result of forgetting to take the 
tablets or vomiting the tablets), the patient will be allowed to take the scheduled dose of olaparib 
up to a maximum of 2 hours after the scheduled dose time. If greater than 2 hours after the 
scheduled dose time, the missed dose of olaparib is not to be taken and the patient should take 
the next dose at the next scheduled time. 
7.2 
Arm 2 (Investigator’s Choice: Trabectedin or Pazopanib) 
Patients randomized to Arm 2 may be treated with investigator’s choice of either trabectedin or 
pazopanib. If the patient is randomized to Arm 2, the treating investigator will decide 
whether the patient will receive treatment with trabectedin or pazopanib. The patient 
must have previously met all eligibility criteria for the drug to which they are assigned. 
Crossover from trabectedin or pazopanib to olaparib and temozolomide is not permitted. 
Trabectedin 
Trabectedin will be administered at the FDA-approved dose and schedule: 1.5 mg/m2 
continuous intravenous infusion through a central venous line over 24 hours. Trabectedin must 
be administered through a central line and cannot be infused peripherally. Dexamethasone 20 
mg IV is administered approximately 30 minutes prior to beginning the trabectedin infusion. In 
subsequent cycles after cycle 1, the dexamethasone dose can be lowered at the investigator’s 
discretion per institutional guidelines/practice. 
Trabectedin doses are calculated based on body surface area (BSA). Institutional practice may 
be followed in determining the trabectedin dose for a given patient. Trabectedin doses should 
be adjusted if a patient’s weight changes >10% or more from the baseline (screening) weight. 

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Growth factor must be administered with trabectedin. Institutional practice can be followed 
with regard to the type of growth factor administered. A recommended approach is to use the 
pegfilgrastim delivery kit which may be applied when the patient returns to disconnect the 
trabectedin infusion. 
Regimen Description 
Agent 
Premedications 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Trabectedin 
Dexamethasone 
20 mg IV 
approximately 
30 minutes prior 
to infusion. 
Appropriate 
antiemetics (for 
moderate 
emetogenic 
potential) per 
institutional 
practice.  
Administer 
growth factor 
(GCSF or 
GMCSF) 
following the 
trabectedin 
infusion (see 
Section 8.1.7) 
1.5 mg/m2  
Continuous IV 
infusion over 24 
hours on Day 1 
through a central 
venous line 
(peripheral 
administration is 
not permitted). 
Day 1 
21 days  
(3 weeks) 
 
Pazopanib 
Pazopanib will be administered orally once every day. The FDA approved dose and schedule of 
pazopanib is 800 mg once daily continuously. However, 800 mg daily is not tolerable for many 
patients, and most sarcoma medical oncologists initiate treatment with pazopanib at a lower 
dose and escalate to 800 mg if tolerated. 
The most recent randomized clinical trial employing pazopanib (Alliance A091304: a 
randomized phase 2 trial of MLN0128 versus pazopanib) was interrupted and amended to 
change the starting dose of pazopanib from 800 mg to 400 mg because of intolerable toxicity on 
the pazopanib arm where the drug was administered at 800 mg daily to all patients. In the 
amended version of A091304, investigators were allowed to escalate the dose of pazopanib from 
the starting dose of 400 mg in 200 mg increments (separated by a minimum of two-week 
intervals) to a maximum of 800 mg if the drug was well tolerated and at the discretion of the 
treating investigator. 
We will use a similar approach in this study. Patients may start pazopanib at either 400 mg 
or 600 mg daily per the treating investigator’s discretion. Patients will be assessed at the day 
1 visit of every cycle and may escalate in 200 mg intervals to a maximum of 800 mg daily at 
the discretion of the treating investigator. Patients may be assessed at an earlier timepoint, and 

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the dose escalated an earlier timepoint, at the investigator’s discretion, per usual standard of 
care. Dose de-escalation is also allowed per the treating investigator’s discretion. 
Patients should take pazopanib on an empty stomach either 1 hour before or 2 hours after food. 
The tablets should be swallowed whole and cannot be crushed or broken. If a dose is missed, it 
should not be taken if it is less than 12 hours until the next dose. 
 
Regimen Description 
Agent 
Premedications 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Pazopanib None 
See Section 8 
Initiate at 400-600 mg 
daily; may increase in 
200 mg increments to 
maximum of 800 mg 
(see above). 
Orally 
Daily, 
continuously 
21 days  
(3 weeks) 
 
8.0 
DOSE AND TREATMENT MODIFICATIONS 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other treatment which would be considered treatment for 
leiomyosarcoma or impact the primary endpoint. This includes any surgical intervention, 
non-palliative radiotherapy, any radiotherapy to target lesions, or other local intervention 
directed at the primary neoplasm or sites of metastatic disease. 
8.1.2 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent 
medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study treatment 
administration until 30 days after the final dose will be recorded in the medical records. 
8.1.3 
Treatment with hormones or other chemotherapeutic agents may not be administered 
except for steroids given for adrenal failure; hormones administered for non-disease-
related conditions (e.g., insulin for diabetes); and intermittent use of dexamethasone as an 
antiemetic. 
8.1.4 
Antiemetics may be used at the discretion of the treating investigator, to manage treatment 
or disease-related nausea and vomiting. Specific anti-emetics will be administered prior to 
temozolomide and trabectedin, as described in Section 7.0. 
8.1.5 
Diarrhea management is per the discretion of the treating investigator. Diarrhea is a 
common side effect of olaparib and pazopanib. Diarrhea can be managed conservatively 
with medications such as loperamide. Patients with severe diarrhea should be assessed for 
intravenous hydration and correction of electrolyte imbalances. If infection is suspected, 
the appropriate testing should be performed. 
8.1.6 
Care of patients with a history of HIV, Hepatitis C, and Hepatitis B 
For eligible patients with a history of chronic HBV infection (whether on suppressive 
therapy or not) or HCV infection (either treated and cured or on treatment), new or 
progressive elevation in ALT levels while on study treatment should prompt measurement 
of HBV or HCV RNA levels. If the patient is found with detectable HBV or HCV RNA, 

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the patient should be referred to a hepatologist and managed per standard of care for the 
hepatitis infection. If a change in medical therapy for HBV or HCV is indicated and would 
result in the use of a prohibited medication as otherwise defined in this section, then the 
patient should be removed from the study.  
For eligible patients with HIV infection, clinical parameters related to the HIV infection, 
including lymphocyte subset counts and HIV RNA levels, should be monitored by the 
patient’s infectious disease physician per standard of care. Should unfavorable changes 
occur and a change in medical therapy is indicated which would result in the use of a 
prohibited medication as otherwise defined in this section, then the patient should be 
removed from the study.  
8.1.7 
Palliative radiation therapy may not be administered to patients enrolled on this study. 
8.1.8 
Alliance Policy Concerning the Use of Growth Factors 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. 
Epoetin (EPO): Use of epoetin in this protocol is permitted at the discretion of the treating 
investigator. The treating investigator should carefully consider the risk/benefit ratio before 
initiating such treatment. 
Filgrastim (G-CSF) tbo-filgrastim, and sargramostim (GM-CSF) are permitted at the 
discretion of the treating investigator. Use of growth factor support is required for patients 
receiving trabectedin. Their use must be documented and reported. 
8.1.9 
Hypersensitivity/infusion reactions 
Treat hypersensitivity and infusion reactions per institutional standards. 
8.1.10 CYP3A4 Inhibitors 
Chronic concomitant treatment with strong or moderate inhibitors of CYP3A4 is not 
allowed on this trial. The following drugs are EXAMPLES of strong or moderate inhibitors 
of CYP3A4 and are not allowed during treatment on any of the study arms 
(temozolomide/olaparib, trabectedin and pazopanib). 
• 
Indinavir 
• 
Clarithromycin 
• 
Ketoconazole 
Because lists of these agents are constantly changing, please consult and review any drugs 
for their potential to inhibit CYP3A4. Examples of resources that may be utilized include 
the product information for the individual concomitant drug in question, medical reference 
texts such as the Physicians’ Desk Reference, the FDA website, or your local institution’s 
pharmacist. 
8.1.11 CYP3A4 Inducers 
Chronic concomitant treatment with strong or moderate inducers of CYP3A4 is not 
allowed on this trial. The following drugs are EXAMPLES of strong or moderate inducers 
of CYP3A4 and are not allowed during treatment on any of the study arms 
(temozolomide/olaparib, trabectedin and pazopanib) 
• 
Rifampin 
• 
Carbamazepine 

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Because lists of these agents are constantly changing, please consult and review any drugs 
for their potential to induce CYP3A4. Examples of resources that may be utilized include 
the product information for the individual concomitant drug in question, medical reference 
texts such as the Physicians’ Desk Reference, the FDA website, or your local institution’s 
pharmacist. 
8.1.12 P-gp Inhibitors 
It is possible that co-administration of P-gp inhibitors (e.g., amiodarone, azithromycin) 
may increase exposure to olaparib. Caution should therefore be exercised when using these 
agents for patients assigned to temozolomide/olaparib. 
8.1.13 Other Drug-Drug Interactions 
Olaparib 
Medication/Class of Drug 
Precautions/Notes 
• CYP3A4 substrates: hormonal 
contraceptives, simvastatin, 
cisapride, cyclosporine, fentanyl, 
pimozide, sirolimus, tacrolimus and 
quetiapine 
• CYP2B6 substrates: buproprion, 
efavirinez 
• OATP1B1 substrates: bosentan, 
glibenclamide, repaglinide, statins 
and valsartan 
• OCT1, MATE1 and MATE2K 
substrates: metformin 
• OCT2 substrates: serum creatinine 
• OCT3 substrates: furosemide, 
methotrexate 
Based on limited in vitro data, olaparib 
may increase the exposure to substrates 
of CYP3A4, OATP1B1, OCT1, OCT2, 
OCT3, MATE1 and MATE2K.  
Based on limited in vitro data, olaparib 
may reduce the exposure to substrates of 
CYP2B6.  
Caution should be used if substates of 
these isoenzymes or transporter proteins 
are co-administered.  
Anticoagulant therapy  
Patients who are taking warfarin may 
participate in this trial; however, it is 
recommended that the international 
normalized ratio (INR) be monitored 
carefully at least once per week for the 
first month, then monthly if the INR is 
stable. Subcutaneous heparin and low 
molecular weight heparin are permitted.  
 
Pazopanib 
Concomitant use of pazopanib with other agents with narrow therapeutic windows that are 
metabolized by CYP26 or CYP2C8 is not recommended. Concomitant use of pazopanib 
and simvastatin increases the risk of ALT elevations and should be undertaken with caution 
and close monitoring. Simvastatin, and other statins, should be discontinued prior to 
starting pazopanib whenever possible. 

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8.1.14 Dietary Restrictions and Over-the-Counter/Self-Medication 
It is prohibited to consume grapefruit, grapefruit juice, Seville oranges, or Seville orange 
juice while on olaparib therapy. The use of any natural/herbal products or other traditional 
remedies should be discouraged for all patients. 
8.2 
Dose Modifications 
8.2.1 
Dose Modifications for Olaparib and Temozolomide 
The following general guidelines apply to dose reductions and delays: 
Dosing for a given cycle will be based on adverse events observed during the prior cycle. 
When multiple adverse events occur, the modification that would require the patient to 
receive the lowest dose combination should be used. 
When toxicity requires a new treatment cycle to be delayed, both olaparib and 
temozolomide should be held until the toxicity resolves and then both drugs resumed 
simultaneously. 
If toxicity requires olaparib or temozolomide to be held during the dosing phase (days 1-
7) of a cycle, then, in general, both agents should be interrupted, and, in general, treatment 
should resume at the time of the next scheduled cycle (i.e. the missed doses should not be 
made up). Deviations from this approach can be discussed with the study chair. When an 
adverse event results in a study agent(s) being interrupted during a cycle, all planned 
assessments for that cycle will occur as scheduled. When treatment is interrupted during a 
dosing cycle due to toxicity, the agent to which toxicity is attributed should be dose-
reduced by one level at the time treatment is resumed. 
A subject may incur up to 2 dose reductions of both olaparib and temozolomide prior to 
discontinuation of that agent. Temozolomide may not be dose reduced below 25 mg/m2 
daily and olaparib may not be dose reduced below 100 mg BID; in the event reduction 
below these dose levels is indicated, that study agent should be discontinued. However, 
after discontinuation of one study agent, the other study agent may be continued at the 
discretion of the treating investigator. 
For adverse events that have not resolved at the scheduled start of a cycle per “Criteria to 
Begin a New Cycle” immediately below, treatment may be delayed for up to 3 weeks. If, 
after a 3-week delay, the adverse events have still not resolved, the patient should be 
removed from the study. 
AERS reporting may be required for some adverse events (See Section 9.0 ). 
PRO-CTCAE data should not be used for determining dose delays or dose modifications 
or any other protocol-directed action. 
Criteria to Begin a New Cycle  
A new cycle of therapy may begin only if each of the following criteria are met: 
Parameter 
Value 
ANC 
≥ 1,500/μL 
Hemoglobin 
≥ 8 g/dL 
Platelets 
≥ 100,000/μL 
Total bilirubin 
≤ 2* ULN 

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AST and ALT 
≤ 3* ULN 
Non-hematologic toxicity 
Grade ≥ 2 non-hematologic adverse 
events (except for alopecia) have 
resolved to grade ≤ 1, acceptable grade 
2 (in the opinion of the treating 
investigator), or baseline. 
Dose Levels 
The following dose levels apply to olaparib and temozolomide. 
Note: Olaparib and temozolomide may be dose modified independently. 
Dose Level 
Olaparib 
TWICE A DAY  
x 7 days q21days 
Temozolomide 
DAILY x 7 days 
q21days 
Initial Dose 
200 mg PO BID 
75 mg/m2 PO daily 
Dose reduction 1 
150 mg PO BID 
50 mg/m2 PO daily 
Dose reduction 2 
100 mg PO BID 
25 mg/m2 PO daily 

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Management of Hematologic Toxicity 
Observed Toxicity 
Recommended Management 
for Agent to Which Toxicity is 
Attributed  
See also instructions below this table 
ANC < 1000/μL 
 
Platelets < 50,000/μL 
 
Grade 3 or 4 neutropenic fever 
 
Grade 3 thrombocytopenia with bleeding 
 
Hemoglobin < 7 g/dL 
 
Other hematologic adverse events ≥ grade 
3 deemed clinically significant by the 
treating investigator. 
Delay cycle. Monitor complete 
blood count at least weekly. 
When criteria for new cycle are 
met, resume at one dose level 
lower for the agent to which 
toxicity is assessed. 
ANC 1000-1499/μL 
 
Platelets 50,000/mcL - 99,999/mcL 
 
Hemoglobin < 8 g/dL 
Delay cycle. Monitor complete 
blood count at least weekly. 
When criteria for new cycle are 
met, resume treatment at same 
dose level.  
If a treatment delay of more 
than 7 days is required, then, 
when criteria for the new cycle 
are met, resume at one dose 
level lower for the agent to 
which toxicity is assessed. 
 
Both temozolomide and olaparib are associated with myelosuppression. In the event of 
hematologic toxicity requiring dose modification, the investigator should modify the 
dose of the agent to which the toxicity is attributed. In general, dose modification of 
temozolomide is appropriate for initial events of neutropenia, thrombocytopenia and 
anemia. If the investigator is uncertain to which agent toxicity is attributable and 
recurrent events occur, a stepwise alternating approach in which temozolomide is 
modified first, followed by olaparib, and so on, can be used. If guidance is needed, the 
treating investigator should contact the Study Chair. 
Should any subject develop evidence of severe and prolonged hematologic toxicity, 
including but not limited to ≥2 week interruption/delay in study drug administration due to 
any of the following, additional monitoring is indicated: 
• 
grade 3 anemia (Hgb <8 g/dL) 
• 
grade 3 neutropenia (ANC <1000/mcL) 
• 
grade 3 thrombocytopenia (platelets <50/mcL) and/or  
• 
development of transfusion dependence for red blood cells or platelets 

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In any of these cases, weekly blood counts including reticulocytes and peripheral smear, 
should be monitored. If toxicity has not resolved to ≤ grade 1 within 3 weeks of study drug 
treatment being held, the patient should be referred to a hematologist for further evaluation 
and the patient should be removed from the study. Bone marrow biopsy should be 
considered for evaluation including cytogenetics. Patients who develop MDS or AML 
while on study treatment should discontinue study participation and be managed 
appropriately by a hematologist. 
Management of Non-Hematologic Toxicity Attributed to Olaparib 
Diarrhea Related to 
Olaparib 
Recommended Management 
Grade 1 
Continue treatment. 
Grade 2 
Continue treatment. Evaluate for infectious 
etiology if clinically indicated. Institute anti-
diarrheal therapy with loperamide. If diarrhea 
persists ≥ grade 2 for > 5 days despite supportive 
care, interrupt olaparib or delay cycle (as 
appropriate) and manage supportively. 
Reinstitute at same dose when symptoms 
improve to ≤ grade 1. 
 
Recurrent grade 2 diarrhea: Interrupt olaparib or 
delay cycle (as appropriate). Evaluate for 
infectious etiology. Manage supportively. Upon 
resolution to ≤ grade 1, resume at one dose level 
lower for olaparib. 
Grade 3, and/or 
treatment interrupted 
due to adverse event. 
Interrupt olaparib or delay cycle (as appropriate) 
until ≤ grade 1. Evaluate for infectious etiology if 
clinically indicated. Institute anti-diarrheal 
therapy. Resume at one dose level lower for 
olaparib when symptoms improve to ≤ grade 1. 
Grade 4 
Discontinue olaparib permanently. 
 
Other Non-
Hematologic Toxicity 
Attributed to Olaparib 
Recommended Management 
Grade 1 or 2 
No change in dose. Continue treatment at the 
investigator’s discretion, or interrupt treatment 
for clinically significant toxicity. For second and 
subsequent clinically significant grade 2 non-
hematologic adverse events attributed to 
olaparib, dose-reduce olaparib by one dose level.  

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Other Non-
Hematologic Toxicity 
Attributed to Olaparib 
Recommended Management 
Grade 3 non-
hematologic toxicity 
deemed clinically 
significant by the 
treating investigator, 
and/or treatment 
interrupted due to 
adverse event, and not 
attributable to TMZ or 
underlying disease 
Interrupt olaparib or delay cycle (as appropriate) 
until event resolved to grade ≤ 1, acceptable 
grade 2 (in the opinion of the treating 
investigator), or baseline. Then resume at one 
dose level lower for olaparib. 
Grade 4 non-
hematologic toxicity not 
attributable to TMZ or 
underlying disease 
(except for grade 4 
alopecia, fatigue, nausea 
and vomiting not 
maximally managed 
with supportive care) 
Discontinue olaparib permanently. 
Management of Non-Hematologic Toxicity Attributed to Temozolomide 
Non-Hematologic 
Toxicity Attributed to 
TMZ 
Recommended Management 
Intolerable grade 2 
toxicity 
Interrupt TMZ or delay cycle (as appropriate) 
until resolved to grade 1, or deemed tolerable with 
supportive care, then resume at the same dose 
level. 
 
Grade 3/4 fatigue, 
nausea, constipation 
and/or diarrhea which 
persist > 3 days despite 
optimal supportive care 
 
Other grade 3 adverse 
event deemed clinically 
significant by the treating 
investigator, and/or 
treatment interrupted due 
to adverse event. 
Interrupt TMZ or delay cycle (as appropriate) 
until event resolved to grade 1, acceptable grade 2 
(in the opinion of the treating investigator), or 
baseline. Then resume at one lower dose level for 
TMZ. 
Grade 4 (except for grade 
4 alopecia, fatigue, 
Discontinue TMZ permanently. 

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nausea and vomiting not 
maximally managed with 
supportive care) 
8.2.2 
Dose Modifications for Trabectedin 
The following general guidelines apply to dose reductions and delays for trabectedin: 
Dosing for a given cycle will be based on adverse events observed during the prior cycle. 
When multiple adverse events occur, the modification that would require the patient to 
receive the lowest dose of trabectedin is used. 
A subject may incur up to 2 dose reductions of trabectedin; in the event that dose reduction 
below 1 mg/m2 is indicated, trabectedin should be discontinued.  
For adverse events that have not resolved at the scheduled start of a cycle per “Criteria to 
Begin a New Cycle” immediately below, treatment may be delayed for up to 3 weeks. If, 
after a 3 week delay, the adverse events have still not resolved, the patient should be 
removed from the study. 
Management guidelines for dose modification of trabectedin are consistent with guidelines 
from the FDA label where available. Investigators may also consult the FDA label/package 
insert prescribing information for trabectedin. 
Patients may not undergo dose re-escalation of trabectedin after dose reduction, consistent 
with the package insert. 
AERS reporting may be required for some adverse events (See Section 9.0). 
PRO-CTCAE data should not be used for determining dose delays or dose modifications 
or any other protocol-directed action. 
Criteria to Begin a New Cycle 
A new cycle of therapy may begin only if each of the following criteria are met: 
Parameter 
Value 
ANC 
≥ 1,500/μL 
Hemoglobin 
≥ 8 g/dL 
Platelets 
≥ 100,000/μL 
Total bilirubin 
≤ 1.5 x ULN 
AST and ALT 
≤ 2.5 x ULN 
CPK 
≤ 2.5 x ULN 
Non-hematologic toxicity 
Grade ≥ 3 non-hematologic adverse events 
(except for alopecia) have resolved to grade ≤ 
1, or acceptable grade 2 (in the opinion of the 
treating investigator), or baseline. 
Dose Levels 
Dose Level 
Trabectedin 
Initial Dose 
1.5 mg/m2 

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Dose reduction 1 
1.2 mg/m2 
Dose reduction 2 
1 mg/m2 
Management of Hematologic Toxicity 
Observed Toxicity 
Recommended Management 
ANC < 500/μL for > 5 days 
 
Platelets < 25,000/μL 
 
Grade 3 or 4 neutropenic fever 
 
Grade 3 thrombocytopenia 
with bleeding 
 
Hemoglobin < 7 g/dL 
 
Other hematologic adverse 
events ≥ grade 3 deemed 
clinically significant by the 
treating investigator. 
Delay cycle. Monitor complete blood 
count at least weekly. When criteria for 
new cycle are met, resume at one dose 
level lower for trabectedin. 
ANC < 500/μL for ≤ 5 days 
 
ANC 500-1499/μL 
 
Platelets 25,000/mcL - 
99,999/mcL 
 
Hemoglobin < 8 g/dL 
Delay cycle. Monitor complete blood 
count at least weekly. When criteria for 
new cycle are met, resume treatment at 
same dose level. 

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Management of Non-Hematologic Toxicity 
Observed Toxicity 
Recommended Management 
Total bilirubin > 2 * ULN and AST or 
ALT > 3 * ULN 
 
Clinical rhabdomyolysis 
Permanently discontinue 
trabectedin. 
Total bilirubin > 1.5 * ULN 
 
AST/ALT > 5 * ULN 
 
Alkaline phosphatase > 2.5 * ULN 
 
CPK > 5 * ULN without clinical 
symptoms of rhabdomyolysis 
Delay cycle. Monitor labs at least 
weekly. When criteria for new 
cycle are met, resume at one dose 
level lower. 
AST/ALT > 2.5 * ULN 
but ≤ 5 * ULN 
 
CPK > 2.5 * ULN 
but ≤ 5 * ULN 
Delay cycle. Monitor labs at least 
weekly. When criteria for new 
cycle are met, resume treatment at 
same dose level. 
Absolute decrease in left ventricular 
ejection fraction of 10% or more from 
baseline (screening echocardiogram or 
MUGA) and less than lower limit of 
normal, or clinical evidence of 
cardiomyopathy or heart failure. 
Delay cycle. Refer to cardiology. 
If clinical symptoms resolve and 
left ventricular ejection fraction 
improves to within the normal 
range, resume treatment at one 
dose level lower at the 
investigator’s discretion. 
Grade 3 toxicity not otherwise 
specified 
Delay cycle. When improved to 
baseline, grade 1 or tolerable grade 
2, resume treatment at one dose 
level lower, except for grade 3 
fatigue, nausea or vomiting lasting 
< 5 days with supportive care, in 
which case patient may resume at 
the same dose level. 
Grade 4 (except for grade 4 alopecia, 
fatigue, nausea and vomiting not 
maximally managed with supportive 
care) 
Discontinue trabectedin 
permanently. 
8.2.3 
Dose Modifications for Pazopanib 
The following general guidelines apply to dose reductions and delays for pazopanib: 
Pazopanib will be initiated at 400 or 600 mg per day per the treating investigator’s 
discretion. Pazopanib can be dose escalated in 200 mg increments to a maximum dose of 
800 mg per day at day 1 visits, or earlier intervals, per usual clinical practice. Pazopanib 
can be dose de-escalated in 200 mg increments to a minimum dose of 200 mg per day. If 
dose reduction below 200 mg daily is needed, the drug should be permanently 

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discontinued. Patients may undergo dose re-escalation after prior dose de-escalation at the 
investigator’s discretion per usual clinical practice. 
Management guidelines for dose modification of pazopanib are consistent with guidelines 
from the FDA label, where available. Investigators may also consult the FDA 
label/package insert prescribing information for pazopanib. 
AERS reporting may be required for some adverse events (See Section 9.0). 
PRO-CTCAE data should not be used for determining dose delays or dose modifications 
or any other protocol-directed action. 
Dose Levels 
Dose Level 
Pazopanib 
Dose Level 1 
200 mg daily 
Dose Level 2 
400 mg daily 
Dose Level 3 
600 mg daily 
Dose Level 4 
800 mg daily 
Dose level 2 or 3 may be used as the 
starting dose per the treating 
investigator’s discretion. See Section 7.2. 
Management of Hematologic Toxicity 
Observed Toxicity 
Recommended Management 
ANC < 1000/μL 
 
Platelets < 50,000/μL 
 
Grade 3 or 4 neutropenic fever 
 
Grade 3 thrombocytopenia with bleeding 
 
Other hematologic adverse events ≥ grade 
3 deemed clinically significant by the 
treating investigator. 
Interrupt pazopanib.  
Monitor complete blood count 
at least weekly.  
When ANC and platelets 
improved to grade ≤ 2 (and any 
infection or bleeding event is 
resolved), resume at one dose 
level lower for pazopanib. 
 
Management of Non-Hematologic Toxicity 
Hepatic Toxicity 
Observed Toxicity 
Recommended Management 
AST or ALT < 5 * ULN or 
Bilirubin ≤ 3 
 
Continue pazopanib at the investigator’s 
discretion with weekly monitoring until 
improved to ≤ grade 1 or baseline. 

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AST or ALT ≥ 5 * ULN or 
Bilirubin > 3 * ULN 
 
Interrupt pazopanib with weekly monitoring 
until improved to ≤ grade 1 or baseline. 
 
Resume pazopanib at one dose level lower 
(and no higher than 400 mg, whichever is 
lower), and monitor hepatic function weekly 
for at least 8 weeks. 
 
If recurrent AST/ALT ≥ 5 * ULN, 
permanently discontinue pazopanib. 
AST or ALT > 3 * ULN and 
bilirubin > 1.5 * ULN 
Permanently discontinue pazopanib and 
monitor hepatic function weekly until 
resolution. 
 
In patients with known Gilbert’s syndrome 
and mild, indirect hyperbilirubinemia, 
manage per recommendations for isolated 
ALT elevations. 
Cardiovascular Toxicity 
Absolute decrease in left 
ventricular ejection fraction 
of 10% or more from baseline 
and less than lower limit of 
normal, or clinical evidence 
of cardiomyopathy or heart 
failure. 
Interrupt pazopanib. Refer to cardiology. If 
clinical symptoms resolve and left 
ventricular ejection fraction improves to 
within the normal range, resume treatment 
at one dose level lower at the investigator’s 
discretion.  
Grade 3 hypertension 
Interrupt pazopanib. Consult a cardiologist 
or nephrologist if indicated. Begin anti-
hypertensive regimen or modify the existing 
regimen. Resume pazopanib at one dose 
level lower when blood pressure has 
improved to ≤ grade 2. 
Grade 4 hypertension, 
hypertensive emergency, 
malignant hypertension 
Permanently discontinue pazopanib. 
Grade 2 or 3 venous 
thrombosis requiring 
anticoagulation 
 
Interrupt pazopanib. If the planned duration 
of full dose anticoagulation is ≤ 2 weeks, 
omit pazopanib until anticoagulation is 
completed, then resume pazopanib at same 
dose. If the planned duration of full dose 
anticoagulation is > 2 weeks, resume 
pazopanib at the same dose during 
anticoagulation if the patient is on a stable 
dose of anticoagulation and is without 
increased risk of bleeding in the opinion of 
the treating investigator.  

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Recurrent venous 
thromboembolic events or 
grade 4 thromboembolic 
event. 
Permanently discontinue pazopanib. 
Arterial thromboembolic 
event of any grade 
Permanently discontinue pazopanib. 
Proteinuria 
Proteinuria with spot urine 
protein creatinine (UPC) ratio 
≥ 2.0 but < 3.0; or urine 
protein ≥ 2.0 g/24 hours but < 
3.0. 
Interrupt pazopanib until proteinuria 
resolves to UPC < 2.0 or urine protein < 2.0 
g/24 hours, then resume pazopanib at same 
dose level. 
Proteinuria with UPC ratio ≥ 
3.0 and < 4.0 or urine protein 
≥ 3.0 g/24 hours and < 4.0 
g/24 hours.  
Interrupt pazopanib until proteinuria 
resolves to UPC < 2.0 or urine protein < 2.0 
g/24 hours. Once resolved, resumed 
pazopanib at one dose level lower. 
Proteinuria with UPC ratio ≥ 
4, or urine protein ≥ 4.0 g/24 
hours, or clinical  nephrotic 
syndrome. 
Permanently discontinue pazopanib. 
Other Toxicity 
Any perforation, fistulization, 
leak or wound dehiscence 
attributed to pazopanib.  
Permanently discontinue pazopanib. 
Grade 3 or 4 hypothyroidism 
or hyperthyroidism 
Permanently discontinue pazopanib. 
Grade 3 or 4 toxicity not 
otherwise specified. 
 
Interrupt. When improved to baseline, grade 
1 or tolerable grade 2, resume treatment at 
one dose level lower, except for grade 3 
fatigue, nausea or vomiting lasting < 5 days 
with optimization of supportive care, in 
which case treatment may resume at the 
same dose level. 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 

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ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Attribution 
to 
protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details 
on AE reporting procedures. 
Clinician graded CTCAE is the AE safety standard. PRO-CTCAE items are to complement CTCAE 
reporting. Patients will respond to PRO-CTCAE items but no protocol directed action will be taken. 
The specific PRO-CTCAE items for this protocol can be found in Appendix VI. PRO-CTCAE is not 
intended for expedited reporting, real time review, or safety reporting. 
9.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. 
9.1.1 
Rave CTEP-AERS integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) Integration enables evaluation of Adverse Events (AE) entered in Rave to 
determine whether they require expedited reporting and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting. Sites must initiate all AEs for this study in 
Medidata Rave. 
Treatment-emergent AEs: All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each treatment 
course or reporting period and is used to collect AEs that start during the period or persist 
from the previous reporting period. AEs that occur 30 days after the last administration of 
the investigational study agent/intervention are collected using the Late Adverse Event 
form. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is query-free. 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form (i.e., checking the box 
Send All AEs for Evaluation and save the form). Both NCI and protocol-specific reporting 
rules evaluate the AEs submitted for expedited reporting. A report is initiated in CTEP-
AERS using information entered in Medidata Rave for AEs that meet reporting 
requirements. The CRA completes the report by accessing CTEP-AERS via a direct link 
on the Medidata Rave Expedited Reporting Evaluation form. Contact the CTSU Help Desk 
at 1-888-823-5923 or by email at ctsucontact@westat.com if you have any issues 
submitting an expedited report in CTEP- AERS. 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to be made 
to CTEP by telephone at 301-897-7497. Once internet connectivity is restored, the 24-hour 
notification that was phoned in must be entered immediately into CTEP-AERS using the 
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Additional information about the CTEP-AERS integration is available on the CTSU 
members’ website: 
• 
Study specific documents: Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting; and 
• 
Additional resources: Resources > CTSU Operations Information> User Guides 
& Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website: 
• 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available 
at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
e lines.pdf. 
9.1.2 
Solicited adverse events 
The following adverse events are considered "expected" and their presence/absence should 
be solicited, and severity graded, at baseline and for each cycle of treatment. 
CTCAE v5.0 Term 
CTCAE v5.0 System Organ 
Class (SOC) 
PRO-CTCAE Term 
Fatigue 
General disorders and 
administrative site conditions  
Fatigue 
Nausea 
Gastrointestinal disorders 
Nausea 
Diarrhea 
Gastrointestinal disorders* 
Diarrhea 
Anemia 
Blood and lymphatic system 
disorders 
 
White blood cell 
decreased 
Investigations 
 
Neutrophil count 
decreased 
Investigations 
 
Platelet count 
decreased 
Investigations 
 
Alanine 
aminotransferase 
increased 
Investigations 
 
Aspartate 
aminotransferase 
increased 
Investigations 
 
* At baseline, the number of stools per day will be collected. 
Symptomatic adverse events reported by patients through PRO-CTCAE are not safety 
reporting and may be presented with other routine Adverse Event data. 
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 

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Alliance Statistics and Data Center. Questions about routine reporting should be directed to the 
Data Manager. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs). 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) Adverse Events CRF - Applies to AEs occurring between registration and within 30 days 
of the patient’s last treatment date. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date, or as part of the Clinical Follow-up Phase or Survival Follow-
up Phase. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. The descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5 will be utilized for AE reporting. The CTCAE 
is 
identified 
and 
located 
on 
the 
CTEP 
website 
at: 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
appropriate 
treatment areas should have access to a copy of the CTCAE.  
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI. 
Note: All deaths on study require both routine and expedited reporting regardless of causality. 
Attribution to treatment or other cause should be provided. 
9.3.1 
Late Phase 2 and Phase 3 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/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY SAEs, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64). 
An AE is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening AE 
3) 
An AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
 

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Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours. 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
Pregnancy loss and death neonatal 
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. 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
New Malignancies 
All new malignancies must be reported via CTEP-AERS whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be 
reported, i.e. solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. 
Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, 
any associated risk factors or evidence regarding how long the new malignancy may have 
been present, when and how the new malignancy was detected, molecular characterization 
or cytogenetics of the original tumor (if available) and of any new tumor, and new 
malignancy treatment and outcome, if available. 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via Rave. 

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

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SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Pruritus; 
Rash4 
VASCULAR DISORDERS - Arterial thromboembolism; Hot flashes; Hypertension; Hypotension; 
Peripheral ischemia; Thromboembolic event 
Note: Olaparib (AZD2281) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
9.4.2 
Adverse Event List for Pazopanib  
Adverse Event 
All Grades 
Grade 3/4 
Fatigue 
65% 
14% 
Diarrhea 
59% 
5% 
Nausea 
56% 
3% 
Weight decreased 
48% 
4% 
Hypertension 
42% 
7% 
Appetite decreased 
40% 
6% 
Hair color changes 
39% 
0% 
Vomiting 
33% 
3% 
Tumor pain 
29% 
8% 
Dysgeusia 
28% 
0% 
Headache 
23% 
1% 
Musculoskeletal pain 
23% 
2% 
Myalgia 
23% 
2% 
Gastrointestinal pain 
23% 
3% 
Dyspnea 
20% 
5% 
Exfoliative rash 
18% 
< 1% 
Cough 
17% 
< 1% 
Peripheral edema 
14% 
2% 
Mucositis 
12% 
2% 
Alopecia 
12% 
0% 
Dizziness 
11% 
1% 
Skin disorder* 
11% 
2% 
Skin hypopigmentation 
11% 
0% 
Stomatitis 
11% 
< 1% 
Chest Pain 
10% 
2% 

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Other adverse reactions observed more commonly in patients 
treated with pazopanib that occurred in ≥ 5% of patients and 
at an incidence of more than 2% difference from placebo 
included insomnia (9% versus 6%), hypothyroidism (8% 
versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 
2%), left ventricular dysfunction (8% versus 4%), dyspepsia 
(7% versus 2%), dry skin (6% versus < 1%), chills (5% 
versus 1%), vision blurred (5% versus 2%), and nail disorder 
(5% versus 0%). 
* 27 of the 28 cases of skin disorder were palmar-plantar 
erythrodysesthesia 
Data are from the phase 3 study of pazopanib vs placebo in 
soft tissue sarcoma (n=363) administered as 800 mg once 
daily or placebo. While these data reflect a large study of 
pazopanib monotherapy, they may not be fully generalizable 
to a sarcoma population and when the drug is used in 
combination with another agent. 
 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 9.2): 
 
CTCAE SOC 
Adverse Event 
Grade 
≥24h Hospitalizationa 
Alkaline phosphatase increased ALK increased 
3 
No 
Alanine aminotransferase 
increased 
ALT increased 
3 
No 
Aspartate aminotransferase 
increased 
AST increased 
3 
No 
Anorexia 
Decreased appetite 
3 
No 
Cough 
Cough 
2 
No 
Constipation 
Constipation 
3 
No 
Diarrhea 
Diarrhea 
3 
No 
Fatigue 
Fatigue 
3 
No 
Headache 
Headache 
3 
No 

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CTCAE SOC 
Adverse Event 
Grade 
≥24h Hospitalizationa 
Nausea 
Nausea 
3 
No 
Neutrophil count decreased 
Neutropenia 
3 
No 
Platelet count decreased 
Thrombocytopenia 
3 
No 
Hyponatremia 
Sodium decreased 
3 
No 
Vomiting 
Vomiting 
3 
No 
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient. All such events must be reported via CTEP-AERS. 
 
9.4.3 
Adverse Event List for Temozolomide 
Adverse Event 
All Grades 
Grade 3/4 
Nausea 
53% 
10% 
Vomiting 
42% 
6% 
Headache 
41% 
6% 
Fatigue 
34% 
4% 
Constipation 
33% 
1% 
Convulsions 
23% 
5% 
Hemiparesis 
18% 
6% 
Diarrhea 
16% 
2% 
Asthenia 
13% 
6% 
Fever 
13% 
2% 
Dizziness 
12% 
1% 
Coordination, abnormal 
11% 
1% 
Peripheral edema 
11% 
1% 
Data are from the phase 3 study of temozolomide in 
anaplastic astrocytoma (n=158) administered as 150 mg/m2 
days 1-5 of a 28 day-cycle. While these data reflect the 
largest study of TMZ monotherapy, they may not be fully 
generalizable to a sarcoma population and when the drug is 
used in combination with another agent.  
 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 

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For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 9.2): 
 
CTCAE SOC 
Adverse Event 
Grade 
≥24h Hospitalizationa 
Anemia 
Anemia 
3 
No 
Anorexia 
Decreased appetite 
3 
No 
Cough 
Cough 
2 
No 
Constipation 
Constipation 
3 
No 
Diarrhea 
Diarrhea 
3 
No 
Fatigue 
Fatigue 
3 
No 
Headache 
Headache 
3 
No 
Nausea 
Nausea 
3 
No 
Neutrophil count decreased 
Neutropenia 
3 
No 
Platelet count decreased 
Thrombocytopenia 
3 
No 
Vomiting 
Vomiting 
3 
No 
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient. All such events must be reported via CTEP-AERS. 
 
9.4.4 
Adverse Event List for Trabectedin 
Adverse Event 
All Grades 
Grade 3 
Grade 4 
Nausea 
73% 
5% 
 
Fatigue 
67% 
6% 
 
Neutropenia 
49% 
21% 
16% 
ALT increased 
45% 
25% 
1% 
Vomiting 
44% 
5% 
 
Anemia 
39% 
14% 
 
Constipation 
36% 
1% 
 

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AST increased 
35% 
12% 
1% 
Decreased appetite 
34% 
2% 
 
Diarrhea 
34% 
2% 
 
Thrombocytopenia 
30% 
8% 
9% 
Dyspnea 
25% 
4% 
<1% 
Peripheral edema 
24% 
1% 
 
Headache 
23% 
<1% 
 
ALK increased 
20% 
1% 
 
Cough 
18% 
<1% 
 
Arthralgia 
15% 
 
 
Insomnia 
15% 
<1% 
 
Myalgia 
12% 
 
 
Rare (<10%): Decreased left ventricular ejection fraction, hypoesthesia, 
paresthesia, peripheral neuropathy, pulmonary embolus, rhabdomyolysis.  
Adverse event data from Demetri et. al. (n= 340) and FDA label[24] 
 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
For this protocol only, the AEs/grades listed below do not require expedited reporting via CTEP-AERS.  
However, they still must be reported through the routine reporting mechanism (Section 9.2): 
 
CTCAE SOC 
Adverse Event 
Grade 
≥24h Hospitalizationa 
Anemia 
Anemia 
3 
No 
Alkaline phosphatase increased 
ALK increased 
3 
No 
Alanine aminotransferase increased 
ALT increased 
3 
No 
Aspartate aminotransferase increased 
AST increased 
3 
No 
Anorexia 
Decreased appetite 
3 
No 
Cough 
Cough 
2 
No 
Constipation 
Constipation 
3 
No 
Creatinine phosphokinase increased 
CPK increased 
3 
No 
Diarrhea 
Diarrhea 
3 
No 
Fatigue 
Fatigue 
3 
No 
Headache 
Headache 
3 
No 

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CTCAE SOC 
Adverse Event 
Grade 
≥24h Hospitalizationa 
Nausea 
Nausea 
3 
No 
Neutrophil count decreased 
Neutropenia 
3 
No 
Platelet count decreased 
Thrombocytopenia 
3 
No 
Vomiting 
Vomiting 
3 
No 
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient. All such events must be reported via CTEP-AERS. 
 
10.0 DRUG INFORMATION 
10.1 
General Considerations: 
The total administered dose of chemotherapy may be rounded up or down within a range of 10% 
of the actual calculated dose.  
It is not necessary to change the doses of temozolomide or trabectedin due to changes in weight 
unless the calculated dose changes by >10%. 
All study agents are to be administered at the registering institution. 
If the Group credited for enrollment is a non-Alliance Group, then other requirements from the 
credited Group may apply. 
10.2 
CTEP agent ordering, accountability and inventory records, IB availability, and contacts 
10.2.1 Ordering NCI-Supplied Agents 
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. 
Sites may order supplies once a patient has been enrolled to the trial. 
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. 
10.2.2 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 

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(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. 
10.2.3 Investigator Brochure Availability 
The current versions of the IBs for the agents 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. 
10.2.4 Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Registration: RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
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) 
10.3 
Olaparib (AZD2281), IND #
, IND Holder: NCI DCTD, NSC#747856 
Description 
Chemical Name: 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
Other Names: AZD2281; KU-0059436; CO-CE 42, Lynparza 
Classification: PARP inhibitor 
CAS Registry Number: 763113-22-0 
Molecular Formula: 
 C24H23FN4O3 
 
M.W.: 434.46 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
Mode of Action: Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5’ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3). In tumors that are deficient in 
the homologous recombination DNA repair pathway (example, BRCA mutants), inhibition of 
PARP by olaparib causes accumulation of DNA double-strand breaks and genomic instability. 
Olaparib may also enhance the effects of DNA damage caused by ionizing radiation and 
chemotherapy. 
Description: crystalline solid 

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Formulation 
AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, film-coated tablets in 
100 mg and 150 mg strengths. 
• 
100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 
150 mg are 14.5 mm x 7.25 mm oval-shaped 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with child-
resistant closures. Each bottle contains 32 tablets with desiccant. 
Tablet core components include active drug substance, copovidone, colloidal silicon dioxide, 
mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl methylcellulose 
(hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, iron oxide yellow 
and iron oxide black. 
Storage 
Store in a secure location below 30° C (86° F). 
If a storage temperature excursion is identified, promptly return olaparib (AZD2281) to room 
temperature and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation 
of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability 
Shelf-life studies are ongoing. Sites are not permitted to re-package tablets. Once the bottle is 
opened, olaparib tablets must be used within 3 months of the opening date; unused tablets should 
be discarded. Instruct patients not to open a bottle until they are ready to use it. 
Route and Method of Administration 
Oral. Take tablets without regard to meals. 
Potential Drug Interactions 
In vivo data indicate that CYP3A4/5 is important for olaparib metabolism and clearance in 
humans. For this reason, avoid concomitant administration of strong and moderate CYP 3A4/5 
inducers and inhibitors. Consult the protocol document or study investigator prior to making 
any dose adjustments related to potential drug-drug interactions. 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for organic anion-
transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 (OCT1), 
multi-drug resistance protein 2 (MRP-2) efflux transporter or breast cancer resistance protein 
(BCRP). Administration of strong P-gp inhibitors and inducers should be avoided with 
concurrent olaparib. 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and induces 
CYP 1A2, 2B6, and 3A4. Therefore, avoid concomitant administration of sensitive substrates, 
particularly those with narrow therapeutic ranges. 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an inhibitor 
of OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase exposure of 
substrates of these transport systems, although the clinical relevance is not clear. The 
manufacturer recommends that statins, in particular, should be administered with caution when 
given concomitantly with olaparib. 

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Patient Care Implications 
Pre-clinical data indicate that olaparib adversely affects embryofetal survival and development. 
Therefore, women of child-bearing potential and their partners should agree to use contraception 
according to what is specified in the protocol document.  It is not known whether olaparib is 
found in seminal fluid, so as a precaution, male study participants must use a condom according 
to what is specified in the protocol document. The study investigator should discuss the most 
appropriate forms of highly effective contraceptive methods for each patient.  
Lactation is a protocol exclusion criterion and not advised since there is potential for 
serious adverse reactions in breastfed infants. Advise lactating women to not breastfeed 
during study treatment and for one (1) month after receiving the last dose of olaparib. 
Adverse Events 
See CAEPR in Section 9.4.1. 
Nursing Guidelines 
• 
Olaparib may be administered with or without food. Patients must be instructed to swallow 
pills whole.  
• 
Patients should be instructed to avoid grapefruit or grapefruit juice while taking olaparib. 
• 
Assess patient’s medication list including OTC and herbal products while patients are taking 
olaparib as there are many drug to drug interactions. 
• 
Instruct patients to report any edema. Rarely patients may experience venous thrombosis.  
• 
Patients may experience headache, dizziness while on olaparib. Instruct patients to use 
caution when doing tasks that require attention, until they can ascertain their tolerability to 
olaparib. 
• 
Gastrointestinal side effects are common, including nausea, vomiting, diarrhea, etc. Treat 
symptomatically and monitor for effectiveness. 
• 
Monitor CBC w/diff as cytopenias are common. Instruct patients to report any unusual 
bruising or bleeding and/or signs symptoms of infection to the study team. 
• 
Monitor renal function and assess for any urinary symptoms. Patients may experience 
urinary tract infection and/or increased creatinine. 
• 
Patients may experience rhinitis, respiratory tract infection, cough, etc. Treat 
symptomatically and monitor for effectiveness of intervention. 

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10.4 
Pazopanib (GW786034, Votrient, NSC#737754) 
Description 
Chemical Name: 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2 
methylbenzene sulfonamide monohydrochloride 
Other Names: Pazopanib HCl, GW786034B (the suffix B denotes the monohydrochloride salt), 
Votrient. 
Classification: VEGFR tyrosine kinase inhibitor 
Molecular Formula: 
C21H23N7O2S-HCl 
 
M.W.: 474.0 (monohydrochloride salt)  
437.5 (free base) 
Approximate Solubility: The monohydrochloride salt is very slightly soluble in 0.1 M HCl (0.65 
mg/mL), and is practically insoluble in pH 7.0 phosphate buffer (0.00005 mg/mL), and in pH 11 
piperidine buffer (0.0002 mg/mL). 
Mechanism of Action: Pazopanib is a highly potent inhibitor of vascular endothelial growth 
factor (VEGF) receptor tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3), platelet derived 
growth factor receptor (PDGFR alpha and beta) and C-Kit. Vascular endothelial growth factor 
receptor inhibition may block VEGF driven angiogenesis and, as a consequence, constrain tumor 
growth. 
Agent ordering and agent accountability 
Institutional pharmacy shall obtain supplies from normal commercial supply chain or 
wholesaler. 
Formulation 
Pazopanib is available as a 200 mg tablet. Pazopanib is commercially available and not provided 
by the study. 
Storage 
Store tablets at room temperature (20° C to 25° C or 68° F to 77° F); excursions permitted to 
15° C to 30° C (59 F° to 86° F) [USP controlled room temperature]. 
Route and Method of Administration 
Oral. Take on an empty stomach either 1 hour before or 2 hours after food. The tablets should 
be swallowed whole and cannot be crushed or broken. If a dose is missed, it should not be taken 
if it is less than 12 hours until the next dose. 
Potential Drug Interactions 
In vitro data indicate that pazopanib is primarily metabolized by CYP3A4 isoenzyme with minor 
contributions from CYP 1A2 and 2C8. Potent CYP3A4 inducers and inhibitors are prohibited 
on pazopanib trials. Pazopanib is also a substrate for p-glycoprotein and breast cancer resistance 
protein (BCRP) transporters and concomitant administration of inhibitors such as lapatinib will 
result in increased plasma pazopanib concentrations. 
Clinical studies indicate that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 
and not an inhibitor of CYP 2C9, 2C19 or 1A2. Use caution when combining pazopanib with 
CYP3A4, CYP2C8, and CYP2D6 substrates known to have a narrow therapeutic window. 
In vitro studies also showed that pazopanib is a potent inhibitor of UGT1A1 and OATP1B1. 
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Avoid co-administration of pazopanib with medicines that increase gastric pH. If the 
concomitant use of a proton pump inhibitor (PPI) is medically necessary, pazopanib should be 
taken without food once daily in the evening with the PPI. If the concomitant administration of 
an H2-receptor antagonist is medically necessary, pazopanib should be taken without food at 
least 2 hours before or at least 10 hours after a dose of an H2-receptor antagonist. Administer 
pazopanib at least 1 hour before or 2 hours after administration of short-acting antacids. 
Avoid co-administration of pazopanib with simvastatin. Concomitant use of pazopanib and 
simvastatin increases the risk of ALT elevation. Data are not sufficient to assess the risk of 
concomitant administration of other statins and pazopanib. 
Precautions: Pazopanib should be used with caution in patients with a history of QT interval 
prolongation, in patients taking antiarrhythmics or other medications that may prolong QT 
interval, and those with relevant pre-existing cardiac disease. Monitor ECGs and serum 
electrolytes (e.g., calcium, magnesium, potassium) at baseline and periodically and maintain 
within the normal range. 
For patients who develop hepatic impairment, refer to the protocol document for appropriate 
dose modification or dose delay. 
Advise women study participants of reproductive potential to use effective contraception 
methods while receiving study treatment and for 2 weeks after the last dose of pazopanib. Men 
receiving study treatment should be advised to use condoms during sexual intercourse and for 
at least 2 weeks after the last dose of pazopanib to avoid potential drug exposure to pregnant 
partners and women partners of reproductive potential. Refer to the protocol document for 
specific guidance. 
Refer to package insert for drug-drug interactions 
Adverse Events 
See Section 9.4.2. 
Pharmacokinetics  
Metabolism: Hepatic; primarily via CYP3A4, minor metabolism via CYP1A2 and CYP2C8 
Excretion: Feces (primarily); urine (<4%) 
Time to peak: Plasma: 2 to 4 hours 
Half-life elimination: ~31 hours 
Protein binding: >99% 
Bioavailability: The AUC and Cmax are increased by ~2-fold with a meal (high-fat or low-fat). 
If tablets are crushed, the AUC is increased by 46%, the Cmax is increased by 2-fold, and the 
Tmax is decreased by ~2 hours (do not crush tablets). 
Nursing Guidelines 
• 
Pazopanib should be taken without food (1 hour before or 2 hours after a meal). Should be 
taken whole with water and not broken or crushed. If a dose is missed, do not take if it is 
less than 12 hours until the next dose. 
• 
There are numerous drug to drug interactions between pazopanib and other agents 
metabolized through the P450 system. Assess patient’s concomitant medications, including 
OTC and herbal products.  
• 
Hypertension is a commonly reported side effect. Monitor blood pressure closely per study 
guidelines. Administer anti-hypertensives as ordered by MD. 

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• 
Inform patient of possible changes in hair color. 
• 
Gastrointestinal side effects are common (diarrhea, nausea, vomiting, loss of appetite). Treat 
symptomatically and assess for effectiveness. 
• 
Due to the similarity in nature of this agent to other VEGF inhibitors (bevacizumab, VEGF-
trap, etc.) monitor for signs of bleeding, thrombosis and PE. Instruct patient to report any 
calf tenderness, shortness of breath, chest pain or bleeding immediately. 
• 
Cytopenias are common. Monitor CBC w/diff and instruct patient to report any unusual 
bruising or bleeding and/or signs of infection to study team. 
• 
Monitor LFT’s. Patients who have AST/ALT levels > 3x ULN and concurrent bilirubin >2X 
ULN should permanently discontinue pazopanib. Patients with AST/ALT levels as above 
and mild hyperbilirubinemia (with suspected or known Gilbert’s syndrome) should be 
monitored weekly while continuing pazopanib. 
• 
Cardiac side effects (CHF, MI, chest pain, etc.) while rare can be serious and life 
threatening. Instruct patient to report any cardiac symptoms to study team immediately. 
• 
RPLS, CVA, and TIA are uncommon, but are life threatening. Instruct patient to report any 
neurological symptoms to the study team immediately. 
10.5 
Temozolomide (Temodar, NSC362856) 
Agent ordering and agent accountability 
Institutional pharmacy shall obtain supplies from normal commercial supply chain or 
wholesaler. 
Formulation 
Temozolomide is available as 5 mg, 20 mg, 100 mg, 140 mg, 180 mg and 250 mg capsules 
Storage 
Store capsules at room temperature. 
Administration 
Swallow capsules whole with a full glass of water; do not open or chew. Administer consistently 
with respect to food (either consistently fasting or non-fasting). Administer on an empty stomach 
in the am. Do not repeat dose if vomiting occurs after dose is administered; wait until the next 
scheduled dose. If capsules are accidently opened or damaged, avoid inhalation or contact with 
skin or mucous membranes. 
Drug Interactions 
Refer to package insert for drug-drug interactions. 
Pharmacokinetics (from Facts and Comparisons) 
Absorption 
Oral: Rapid and complete (100% bioavailable) 
Distribution 
Vd: Parent drug: 0.4 L/kg. Temozolomide penetrates blood-brain barrier; cerebrospinal fluid 
levels are ~35% to 39% of plasma levels  
Metabolism 

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Prodrug, hydrolyzed to the active form, MTIC; MTIC is eventually eliminated as CO2 and 5-
aminoimidazole-4-carboxamide (AIC), a natural constituent in urine; CYP isoenzymes play 
only a minor role in metabolism (of temozolomide and MTIC) 
Excretion 
Urine (~38%; parent drug 6%; AIC 12%); feces <1%. 
Clearance: 5.5 L/hour/m2; pediatric subjects 3 to 17 years have similar temozolomide clearance 
as adults. 
Time to peak 
Oral: Median: 1 hour; with food (high-fat meal): 2.25 hours. 
Half-life elimination 
Mean: Parent drug: Children: 1.7 hours; Adults: 1.8 hours 
Protein binding 
15% 
Adverse Events 
Consult the package insert for the most current and complete information. 
See Section 9.4.3. 
Nursing Guidelines 
• 
Myelosuppression has been found to be the dose-limiting toxicity. Gr 3 thrombocytopenia 
occurred in 6% of patients and Gr 4 in 1%. Gr 3 and Gr 4 lymphopenia occurred in 55% of 
patients. Leukopenia, lymphopenia, thrombocytopenia and anemia usually occur 2-8 weeks 
after initiation of treatment. Monitor CBC carefully and report any significant changes to MD. 
Instruct patient to report signs/symptoms of infection, unusual bruising and bleeding to health 
care team. 
• 
In previous studies, patients have developed pneumocystis carinii pneumonia (PCP) when 
taking concomitant temozolomide and steroids. Instruct patient to report any fever, cough, 
chest pain, of other signs of infection to the health care team. Counsel patients on the 
importance of taking PCP prophylaxis as prescribed if ordered. 
• 
Advise patient that a mild-moderate rash may be experienced. 
• 
Fatigue may be experienced. Work with patient in energy conserving lifestyle. 
• 
Remind patient that drug needs to be taken on an empty stomach with a full glass of water. 
Drug should not be crushed, chewed, opened, or dissolved. 
• 
Nausea and vomiting are common. Teach patient to self-medicate with anti-emetics one hour 
prior to dose. Assess for effectiveness. If vomiting occurs, do not repeat dose. Wait until next 
scheduled dose. 
• 
Temozolomide may interact with valproic acid by reducing the clearance of temozolomide by 
5%. Assess concomitant medication use. 
• 
Constipation is common. Encourage patient to increase fluid intake. Administer stool softeners 
or laxatives as ordered and monitor for their effectiveness. 
• 
Monitor for cytopenias (i.e. CBC w/differential). Instruct patient to report any fever, signs or 
symptoms of infection, or any unusual bruising or bleeding to the study team. 

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• 
Headache may be seen. Assess for more serious condition (i.e. cerebral bleed, disease 
progression) first and then treat symptomatically and monitor for effectiveness. 
10.6 
Trabectedin (Yondelis, NSC#737754) 
Agent ordering and agent accountability 
Institutional pharmacy shall obtain supplies from normal commercial supply chain or 
wholesaler. 
Formulation 
Trabectedin available in 1 mg vial 
Storage 
Store intact vials at 2-8° C (36-46° F) 
Stability 
Solutions diluted for infusion should be used within 30 hrs of reconstitution. Infusion should be 
completed within that 30 hours. 
Preparation 
Reconstitute the 1 mg vial with 20 mL sterile water for injection resulting in a reconstituted 
concentration of 0.05 mg/mL. Shake until completely dissolved. Immediately after 
reconstitution, further dilute for infusion in 500 mL sodium chloride 0.9% or dextrose 5% in 
water. Diluted solution is compatible in type I glass, polyvinyl chloride (PVC) and polyethylene 
(PE) bags and tubing, PE and polypropylene (PP) mixture bags, polyethersulfone (PES) inline 
filters, titanium, platinum, or plastic ports, silicone and polyurethane catheters, and pumps with 
PVC, PE, or PE/PP contact surfaces. Do not mix with other medications. 
Administration 
Administer trabectedin over 24 hours via a central line. 
Infuse through a central line with a 0.2 micron polyethersulfone filter. Infusion must be 
completed within 30 hours of reconstitution. 
Drug Interactions 
Trabectedin is a major substrate of CPY3A4. Refer to package insert for drug-drug interactions. 
Pharmacokinetics (from Facts and Comparisons) 
Distribution: Vdss: >5,000 L 
Metabolism: Extensively hepatic; via CYP3A4 
Excretion: Feces (58%; only negligible amounts as unchanged drug); urine (6%; only negligible 
amounts as unchanged drug) 
Half-life elimination: ~175 hours 
Protein binding: ~97%; to plasma protein 
Adverse Events 
Consult the package insert for the most current and complete information. 
See Section 9.4.3.  

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Nursing Guidelines 
• 
GI side effects are commonly seen, including nausea, vomiting, diarrhea, constipation and 
decreased appetite. Treat symptomatically and monitor for effectiveness. 
• 
Monitor CBC with differential as cytopenias can be seen and can be severe. 
• 
Elevated liver function tests are common. Monitor liver function per protocol and inform 
treating provider of any changes. 
• 
Patients may experience arthralgia and myalgias. Instruct patient to report these to the study 
team. 
• 
Monitor renal function and encourage patient to stay adequately hydrated. 
11.0 MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using Response Evaluation Criteria in Solid 
Tumors (RECIST version 1.134). Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the short axis measurements in the case of lymph nodes are used in the RECIST 
guideline. 
11.1 
Schedule for Assessment of Disease 
• 
Baseline imaging should include a CT or MRI of the chest/abdomen/pelvis for all 
patients to adequately evaluate for distant metastatic disease. CT scans should be done 
with IV and oral contrast (if clinically indicated) unless allergy prevents administration. 
If MRI is chosen as imaging modality for following target/non-target lesions then MRI 
should be used for evaluation of response during the study. 
• 
Repeat imaging to evaluate disease status will be performed every 2 cycles (6 weeks). 
A window of ±7 days is permitted. Imaging should be performed before a new cycle 
starts whenever possible. 
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.2.1   Measurable Disease 
• 
A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT 
component of a PET/CT, or MRI.  
• 
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in 
diameter as assessed using calipers (e.g. skin nodules) or imaging.  In the case of 
skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended. 
• 
A malignant lymph node is considered measurable if its short axis is >1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm).   
• 
Tumor lesions in a previously irradiated area are considered measurable disease 
under the following conditions:  
o If there is a soft tissue component that has grown since completion of 
radiation. 
o Bone metastases with a soft tissue component are considered measurable.  
 

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11.2.2 Non-Measurable Disease 
All other lesions (or sites of disease) are considered non-measurable disease, including 
pathological nodes (those with a short axis ≥1.0 to <1.5 cm).  Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
Note:  ‘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.  In addition, lymph nodes that have a short axis <1.0 cm are considered non-
pathological (i.e., normal) and should not be recorded or followed. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.3.1 Measurement Methods:   
• 
All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
For patients having only lesions measuring at least 1 cm to less than 2 cm must use 
CT imaging for both pre- and post-treatment tumor assessments.   
• 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used at the same evaluation to assess the antitumor effect 
of a treatment.  
11.3.2 Acceptable Modalities for Measurable Disease:       
• 
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.     
o 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.  The lesions should be measured on the same pulse 
sequence.  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:  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.   
• 
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 scans are 
preferable. 
• 
Physical Examination:  For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. In the case of skin 

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lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is recommended. 
• 
FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease.  A 
‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid with an 
update greater than twice that of the surrounding tissue on the attenuation corrected 
image; otherwise, an FDG-PET scanned lesion is considered ‘negative.’  New 
lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm: 
o Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a sign 
of PD based on a new lesion. 
o 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 at the same evaluation, additional follow-up CT scans 
(i.e., additional follow-up scans at least 4 weeks later) are needed to 
determine if there is truly progression occurring at that site. In this 
situation, the date of PD will be the date of the initial abnormal PDG-
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, it is not classified as PD. 
11.3.3 Measurement at Follow-up Evaluation:   
• 
In the case of stable disease (SD), follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of [6 weeks, not less 
than 6-8] weeks (see Section 11.4.3). 
• 
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. 
• 
Cytologic and histologic techniques can be used to differentiate between PR and 
CR in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, 
where known residual benign tumors can remain.) 
11.4 
Measurement of Effect 
11.4.1 Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 11.2.1) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” and 
recorded and measured at baseline.  These lesions can be non-nodal or nodal (as 
defined in 11.21), where no more than 2 lesions are from the same organ and no 
more than 2 malignant nodal lesions are selected.  
• 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there 
often will be), there is no reason to perform additional studies beyond those 
specified in the protocol to discover new lesions.   

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• 
Target lesions and target lymph nodes should be selected on the basis of their size, 
be representative of all involved sites of disease, but in addition should be those 
that lend themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion (or malignant lymph node) does not lend itself 
to reproducible measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be selected.   
• 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the baseline sum of dimensions (BSD).  The BSD will 
be used as reference to further characterize any objective tumor response in the 
measurable dimension of the disease.   
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the post-baseline sum of dimensions (PBSD).  If the 
radiologist is able to provide an actual measure for the target lesion (or target 
lymph node), that should be recorded, even if it is below 0.5 cm.  If the target lesion 
(or target lymph node) is believed to be present and is faintly seen but too small to 
measure, a default value of 0.5 cm should be assigned.  If it is the opinion of the 
radiologist that the target lesion or target lymph node has likely disappeared, the 
measurement should be recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
11.4.2 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.2.2) are classified as non- target lesions or 
non-target lymph nodes and should also be recorded at  baseline.  These lesions and lymph 
nodes should be followed in accord with  Section 11.4.3. 
11.4.3 Response Criteria Target Lesions 
• 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest X-
ray/physical examination must be measured on re-evaluation at evaluation times 
specified in Section 11.1.  Specifically, a change in objective status to either a PR 
or CR cannot be done without re-measuring target lesions and target lymph nodes.  
• 
Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response.  In 
selected circumstances, certain non-target organs may be evaluated less frequently.  
For example, bone scans may need to be repeated only when complete response is 
identified in target disease or when progression in bone is suspected. 
• 
Evaluation of Target Lesions: Complete Response (CR): All of the following 
must be true: 
o Disappearance of all target lesions. 
o Each target lymph node must have reduction in short axis to <1.0 cm. 
• 
Partial Response (PR):  At least a 30% decrease in PBSD (sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target lymph 
nodes at current evaluation) taking as reference the BSD (see Section 11.4.1). 
• 
Progression (PD):  At least one of the following must be true: 

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o At least one new malignant lesion, which also includes any lymph node that 
was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short 
axis during follow-up.  
o At least a 20% increase in PBSD (sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes at current 
evaluation) taking as reference the MSD (Section 11.4.1).  In addition, the 
PBSD must also demonstrate an absolute increase of at least 0.5 cm from the 
MSD.  
o See Section 11.3.2 for details in regards to the requirements for PD via FDG-
PET imaging. 
• 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD taking as reference the MSD. 
o At least one new malignant lesion, which also includes any lymph 
node that was normal at baseline (< 1.0 cm short axis) and increased 
to ≥ 1.0 cm short axis during follow-up.  
o At least a 20% increase in PBSD (sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph 
nodes at current evaluation) taking as reference the MSD (Section 
11.4.1).  In addition, the PBSD must also demonstrate an absolute 
increase of at least 0.5 cm from the MSD.  
o See Section 11.3.2 for details in regards to the requirements for PD via 
FDG-PET imaging. 
• 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD taking as reference the MSD. 
11.4.4 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
• 
Complete Response (CR):  All of the following must be true: 
o Disappearance of all non-target lesions.  
o Each non-target lymph node must have a reduction in short axis to 
<1.0 cm. 
• 
Non-CR/Non-PD:  Persistence of one or more non-target lesions or non-target 
lymph nodes. 
• 
Progression (PD):  At least one of the following must be true: 
o At least one new malignant  lesion, which also includes any lymph 
node that was normal at baseline (< 1.0 cm short axis) and increased 
to ≥ 1.0 cm short axis during follow-up.   
o Unequivocal progression of existing non-target lesions and non-target 
lymph nodes.  (NOTE:  Unequivocal progression should not normally 
trump target lesion and target lymph node status.  It must be 
representative of overall disease status change.)  
o See Section 11.3.2 for details in regards to the requirements for PD via 
FDG-PET imaging. 
11.4.5 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the patient’s 
status on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, 
and new disease as defined in the following tables:  

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12.3.2 Follow-up for Patients who Stop Study Treatment Early 
Follow-up for patients who stop due to toxicity 
Patients should complete the end-of-treatment visit/short-term follow-up as described in 
the Study Calendar. All AEs considered at least possibly-related to study treatment will be 
followed until resolution, stabilization, return to baseline, or until deemed irreversible. The 
frequency of follow-up and any associated investigations will be determined by the treating 
investigator as clinically appropriate.  
Patients should continue to undergo imaging to evaluate disease status (imaging) as per the 
Study Calendar until progression of disease occurs or a new non-protocol therapy is 
initiated. Thereafter, patients should be followed per Section 12.3.1 above. 
Follow-up for patients who receive non-protocol therapy 
Patients should be followed per Section 12.3.1 above. 
12.4 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
12.5 
Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patient 
A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible. 
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, study chair, and executive officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), the follow-up requirements are specified below. 
Baseline, off treatment, and post-treatment follow up (i.e., progression, and survival) data 
submission required. See the Data Submission Schedule accompanying the All Forms Packet. 

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13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
This Phase II/III trial is designed to test the efficacy of olaparib plus temozolomide (Arm 1) vs. 
investigator’s choice (identified prior to randomization) (Arm 2) of either trabectedin or 
pazopanib in patients with advanced uterine leiomyosarcoma after progression on 2 or more 
lines of prior chemotherapy. The primary objective for the phase 2 portion will be measured by 
comparing progression-free survival (PFS) between Arms 1 and 2. The primary objective for 
the phase 3 portion will be measured by comparing overall survival (OS) between Arms 1 and 
2. 
The assumptions for the median PFS and OS for trabectedin and pazopanib are based on 
published subset analyses from the phase 3 registration-directed clinical trials conducted with 
these agents. 
A randomized, controlled, multi-center, phase 3 study assigned 518 patients with 
leiomyosarcoma and liposarcoma to treatment with trabectedin or dacarbazine and was the basis 
for FDA approval for trabectedin in sarcoma [16]. Hensley, et. al. conducted a subset analysis 
of that study to evaluate outcomes among the 232 patients with uLMS with at least 2 prior lines 
of therapy and reported a median PFS of 4.0 months for trabectedin versus 1.5 months for 
dacarbazine. The median OS was 13.4 months for trabectedin and 12.9 months for dacarbazine 
[4]. 
A randomized, controlled, multi-center phase 3 study assigned 372 patients with soft tissue 
sarcoma to pazopanib or placebo and led to the approval of pazopanib in soft tissue sarcoma 
[17]. Benson, et. al. conducted a subset analysis evaluating the outcome of patients with uterine 
sarcoma assigned to pazopanib on this phase 3 study and also on the preceding phase 2 study. 
In that analysis, 89% of patients with uterine sarcoma had uLMS, and this study represents the 
most informative benchmark for pazopanib’s activity in uLMS [5]. The median PFS and OS 
associated with pazopanib were 3.0 months and 11.0 months, respectively [5]. In a prospective 
randomized study of gemcitabine plus pazopanib versus pazopanib alone in patients with pre-
treated soft tissue sarcomas, patients with LMS demonstrated a PFS of 3.0 months on pazopanib 
[31]. In another randomized study of pazopanib versus doxorubicin as first-line treatment in 
sarcoma patients older than 60 (approximately 30% of whom had uLMS), pazopanib provided 
a PFS of 4.4 months [32]. In a retrospective observational study of outcomes of soft tissue 
sarcoma patients treated with pazopanib in the Kaiser group, the median PFS for 40 LMS 
patients on pazopanib was 3.0 months [33]. In a prospective randomized study of gemcitabine 
plus pazopanib versus pazopanib alone in patients with pre-treated soft tissue sarcomas, patients 
with LMS demonstrated a PFS of 3.0 months on pazopanib [31]. In another randomized study 
of pazopanib versus doxorubicin as first-line treatment in sarcoma patients older than 60 
(approximately 30% of whom had uLMS), pazopanib provided a PFS of 4.4 months [32]. In a 
retrospective observational study of outcomes of soft tissue sarcoma patients treated with 
pazopanib in the Kaiser group, the median PFS for 40 LMS patients on pazopanib was 3.0 
months [33]. 
 
Based on the above, we hypothesize that the median PFS and OS in the control arm for patients 
who have received 2 or more prior lines of treatment would be 4 and 13 months respectively. 
Median PFS from the phase II study of olaparib and temozolomide in uLMS conducted by our 
group and described above was 6.9 months. Five patients in this phase II study had received 2 
prior lines of treatment and demonstrated a median PFS of approximately 11.0 months, and 1-
year OS rate of 100% (median OS not reached). Given this promising data but acknowledging 

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the limitations of a small single-arm trial, we hypothesize that the median PFS and OS in the 
experimental arm will be 8 months and 23 months respectively. 
Overall Plan for Analysis 
All randomized patients will be considered evaluable for primary endpoints of OS and PFS 
based on the intent-to-treat principle and regardless of whether or not they initiate treatment. 
We will tabulate the number (percent) of patients who withdraw consent prior to treatment to 
monitor the feasibility of the trial design. If the withdraw of consent rate prior to treatment in 
Arm 2 is  ≥ 5% than the withdraw of consent rate prior to treatment in Arm 1, feasibility will be 
further evaluated by the study team, CTEP, and Alliance DSMB. Summary statistics for patient 
and tumor characteristics, eligibility rates, length of follow-up, and treatment acceptance rates 
will be calculated by assigned treatment arms. 
Summary statistics for patient and tumor characteristics, eligibility rates, length of follow-up, 
and treatment acceptance rates will be calculated by assigned treatment arms. 
OS and PFS will be estimated using the Kaplan-Meier method [20], where the stratified log-
rank test will be used to compare the distributions across the treatment arms. PFS and OS rates 
at 1 year, 2 years, and 5 years will also be reported, along with 95% confidence intervals. 
Univariable and multivariable Cox models stratified by the stratification factors used in the 
randomization will be assessed as well. 
13.2 
Statistical Design and Analysis for the Phase 2 Portion 
13.2.1 Definition 
PFS is defined as the time between the date of randomization and the earliest of disease 
progression (PD) or death. Patients alive without PD, lost to follow-up, or who withdraw 
consent prior to PD will be censored at the date of their most recent disease assessment for 
PFS. Patients who start a non-protocol therapy without PD will also be censored at the time 
of their last disease assessment for PFS. Intention to treat principles will be used. RECIST 
v1.1 [15] will be used to assess disease status and clinical or symptomatic deterioration 
will be allowed for the determination of PD. 
13.2.2 Statistical Design and Analysis Plan 
Assuming a median PFS of 4 months for control arm (Ho), the investigational treatment 
(olaparib plus temozolomide) will be considered promising if median PFS is increased to 
8.0 months (Ha), corresponding to an observed hazard ratio (HR) of 0.5 favoring olaparib 
plus temozolomide. In addition, the following conditions were assumed for the study 
design and used in EAST v6.5 software to develop the design: Target power of 90% and 
1-sided alpha 0.10. 
1. Testing for superiority (1-sided alpha). 
2. Accrual of 3 patients/month. 
3. Interim analysis for futility at 50% of information utilizing Rho Family spending 
function (rho=1.675) boundaries [18]. 
4. Intention to treat principles for analyses. 
To test these hypotheses, we will enroll a total of 70 evaluable patients using a 1:1 
randomization and with the following stratification factors: ECOG PS (0 or 1 vs. 2) and 
prior lines of treatment (2 vs. 3 or more). The randomization algorithm will be the dynamic 
allocation method of Pocock and Simon [20]. Disease assessments will be required every 
2 cycles. A minimum of 6 months follow-up for disease status and survival will be required.  

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Olaparib plus temozolomide will be considered superior if the p-value associated with the 
stratified LogRank test statistic is ≤ 0.10 at the time we have observed 58 events (i.e. the 
phase 2 portion of the study has completed and analyzed, with 90% power). 
Note that accrual will be halted between the phase 2 and 3 portions of the trial in order to 
fully assess the phase 2 primary endpoint. 
13.2.3 Interim Analysis 
There will be one planned interim look for futility at 50% information. If, after the 29th 
PFS event, the HR comparing Olaparib + temozolomide to trabectedin or pazopanib is 
greater than 1.0 (p-value > 0.50) then the study will be stopped for futility. Using 
simulations, the probability of stopping early (i.e. after one of the interim analyses) under 
the alternative hypothesis is estimated at 8%. These boundaries were created using the Rho 
Family spending function (rho=1.675) in EAST v6.5 [18]. 
13.3 
Statistical Design and Analysis for the Phase 3 Portion 
13.3.1 Definition 
OS is defined as the time between the date of randomization and the date of death from any 
cause. Patients alive at the time of last follow-up, lost to follow-up, or who withdraw 
consent will be censored at the date of their most recent follow-up for OS. 
13.3.2 Statistical Design and Analysis Plan 
If the results of the phase 2 design are positive, then accrual to the phase 3 portion will 
begin. The phase 3 portion is seeking to improve OS from a median of 13 months to 23 
months. The following conditions were assumed for the study design and EAST v6.5 
software was used to develop the design: 
1. Target power of 90% and 1-sided alpha 0.025 
2. Testing for superiority (1-sided alpha). 
3. Accrual of 3 patients/month. 
4. Interim analysis for futility at 50% of information utilizing Rho Family spending 
function (rho=3.23) boundaries [18]. 
5. Intention to treat principles for analyses. 
A total of N=165 patients with 130 OS events are required for the phase 3 portion of the 
trial. All evaluable patients from the phase 2 portion will be utilized; therefore, 
approximately, 95 additional patients will be needed. Olaparib plus temozolomide will be 
considered superior in terms of OS if the p-value associated with the stratified LogRank 
test statistic is ≤ 0.025 at the time we have observed 130 events (i.e. the phase 3 portion of 
the study has passed efficacy, with 90% power). 
13.3.3 Interim Analysis 
There will be one planned interim look for futility at 50% information. If, after the 65th 
OS event, the HR comparing Olaparib + temozolomide to trabectedin or pazopanib is 
greater than 1.0 (p-value > 0.50) then the study will be stopped for futility. These 
boundaries were created using the Rho Family spending function (rho=3.23) in EAST v6.5. 

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13.4 
Sample Size, Accrual Time, and Study Duration 
13.4.1 Sample Size 
Up to 165 evaluable patients will be accrued in the event that both phases of the trial fully 
accrue (i.e. the study successfully passes (1) the phase 2 interim analysis, (2) the final phase 
2 analysis, and (3) the phase 3 interim analysis). In addition to these 165 patients, we will 
plan to enroll another 25 patients to the trial to account for dropouts, considering that the 
trial does not allow for crossover. Thus, the maximum overall accrual will be 190 patients. 
Note that phase 2 patients’ data will be used in the phase 3 portion of the trial. 
13.4.2 Accrual Rate and Study Duration 
It is expected that accrual will occur at approximately 3 patients per month. Assuming this 
trial meets full accrual, it will require approximately 87 months (27 months to accrue to 
the phase 2 portion plus 6 months to acquire follow up data for phase 2 when the trial will 
be temporarily suspended for accrual plus 37 months to accrue additional phase 3 patients 
plus 17 months for data follow up. On the other hand, the phase 2 interim analysis is 
expected to occur after ~50 patients have been enrolled (i.e. the 29th progression is 
expected after 50 patients have been enrolled). This corresponds to approximately 17 
months after study activation. Accounting for these 2 extremes (i.e. failure at the phase 2 
interim analysis (17 months) and full accrual (87 months)) the total study time should be 
between 17 months (failure at phase 2 interim analysis) and 87 months (full accrual). 
If accrual is slower than expected, the study team and Alliance Experimental Therapeutics 
and Rare Tumors (ETRT) leadership will meet to review reasons to identify barriers to 
accrual and discuss with CTEP. In this situation, we will consider modifying eligibility 
criteria to allow enrollment of patients with RECIST evaluable disease only, if this change 
is felt to increase the accrual rate of the study based on discussion with the site investigators 
for the study and with CTEP. 
13.5 
Secondary Endpoint Analysis Plans 
13.5.1 Overall Response Rate (ORR) 
The ORR will be estimated by dividing the number of evaluable patients that achieve a 
confirmed response (PR or better) by the total number of evaluable patients. This estimate 
will be calculated by arm and will also include a 95% confidence interval using the 
properties of the binomial distribution, and compared between the arms using a chi-square 
test. 
13.5.2 Duration of Response (DOR) 
This analysis is restricted to those patients that achieved a confirmed response (PR or 
better). For these patients, the duration of response is defined as the time from first evidence 
of response until disease progression (or death). Patients that go off of study treatment prior 
to progression will have their DOR time censored at that time. 
13.5.3 Disease Control Rate (DCR) 
DCR will be estimated by dividing the number of patients that achieve complete response, 
partial response, or stable disease at the 6 week assessment divided by all evaluable 
patients. This estimate will be calculated by arm and will also include a 95% confidence 
interval using the properties of the binomial distribution, and compared between the arms 
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13.7 
Adverse Event Stopping Rule 
This study will be monitored by the Alliance DSMB on a bi-annual basis.  In addition, the study 
chair and study statistician will review the accrual and safety data periodically and in 
conjunction with the Alliance Group Meeting reports to identify any feasibility problems 
associated with accrual rates and adverse events.  
The stopping rule specified below is based on the knowledge available at study development. 
We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) the 
study re-opening to accrual after any temporary suspension or (2) at any time during the conduct 
of the trial and in consideration of newly acquired information regarding the adverse event 
profile of the treatment(s) under investigation. The study team may also suspend accrual because 
of unexpected safety signals/adverse event profiles that have not crossed the specified rule 
below. 
Accrual will be temporarily suspended to this study if at any time we observe adverse events 
that satisfy any of the following criteria, where AEs regardless of attribution will be considered: 
• 
If at any time up to 15 patients per arm (30 total) that are evaluable for AEs, the number 
of patients who experience a grade 4 or grade 5 non-hematologic adverse event in one 
arm exceeds the other by at least 5 patients. 
• 
After 15 total patients are evaluable for AEs in each arm, the number of patients who 
experience a grade 4 or grade 5 non-hematologic adverse event in one arm exceeds 
another by at least 5 patients AND at least a 10% difference in AE rates. 
• 
If 4 or more patients in the first 20 patients, and at least 20% after the first 20 patients  
across both arms experience a grade 3 or 4 febrile neutropenia event that is deemed at 
least possibly related to study treatment. 
13.8 
Study Reporting  
13.8.1  Alliance DSMB  
This study will be monitored by the Alliance Data Safety Monitoring Board (DSMB), an 
NCI-approved functioning body. Reports containing efficacy, adverse event, consent 
withdrawal rates (as noted in Section 13.1), and administrative information will be 
provided to the DSMB every six months as per NCI guidelines. 
13.8.2 Data Mapping Utility (DMU) 
Data for this study will be submitted via the Data Mapping Utility (DMU) to the NCI. 
Cumulative protocol- and patient-specific data will be submitted weekly to CTEP 
electronically via the DMU. DMU Light reporting consists of Patient Demographics, 
On/Off Treatment Status, Abbreviated Treatment and Course information, and Adverse 
Events as applicable. Instructions for setting up and submitting data via DMU are available 
on the CTEP Website: ctep.cancer.gov/protocolDevelopment/dmu.htm.  

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14.0 BIOBANKING FOR FUTURE CORRELATIVE SCIENCE 
The optional tissue and blood collection for future studies must be offered to all patients enrolled on 
Alliance A092104 (although patients may opt to not participate). This collection does not require 
separate IRB approval. Testing of banked specimens will not occur until an amendment to this 
treatment protocol (or separate correlative science protocol) is reviewed and approved in accordance 
with National Clinical Trials Network (NCTN) policies. 
15.0 MONITORING PLAN 
Standard Alliance monitoring procedures will be used for this study. 
15.1 
IRB terminations 
Until institutions receive a formal notice from the Alliance regarding termination to patient 
follow-up, institutions must not close this trial with the IRB of record for the study. Please 
contact the Alliance Regulatory team at regulatory@alliancenctn.org with any questions. 
 
 
 
 
 

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Benson C, Ray-Coquard I, Sleijfer S, et al. Outcome of uterine sarcoma patients treated with 
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6. 
Chudasama P, Mughal SS, Sanders MA, et al. Integrative genomic and transcriptomic analysis of 
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7. 
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17.  Garcia del Muro X, Lopez-Pousa A, Martin J et. al. A phase II trial of temozolomide as a 6-week, 
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Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 2018; 23(1): 239-54 e6. 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
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van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma 
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27. 
Dueck AC, Scher HI, Bennett AV, Mazza GL, Thanarajasingam G, Schwab G, Weitzman AL, 
Rogak LJ, Basch E. Assessment of Adverse Events From the Patient Perspective in a Phase 3 
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28. 
Sztupinszki Z, Diossy M, Krzystanek M,et. al. Migrating the SNP array-based homologous 
recombination deficiency measures to next generation sequencing data of breast cancer. NPJ Breast 
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29. 
Knijnenburg TA, Wang L, Zimmerman MT, et. al. Genomic and Molecular Landscape of DNA 
Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep. 2018 23(1):239-254. 
30. 
Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A et. al. Efficacy and 
Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure 
of Conventional Chemotherapy: Results of a Phase III Randomized, Multicenter Clinical Trial. J 
Clin Oncol 2016 34(8) 786-793. 
31. 
Schmoll HJ, Lindner LH, Reichardt P et. al. Effiacy of Pazopanib With or Without Gemcitabine in 
Patients with Anthracycline- and/or Ifosfamide-Refractory Soft Tissue Sarcoma. JAMA Oncol 
2021;7(2):255-262. 
32. 
Grunwald V, Karch A, Schuler M, et. al. Randomized Comparison of Pazopanib and Doxorubicin 
as First-Line Treatment in Patients with Metastatic Soft Tissue Sarcoma Age 60 Years or Older: 
Results of a German Intergroup Study. J Clin Oncol 2020;38(30):3555-3564. 

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33. 
Seto T, Song MN, Trieu M et al. Real-World Experiences with Pazopanib in Patients with 
Advanced Soft Tissue and Bone Sarcoma in Northern California. Med. Sci. 2019;7(3). 
34. 
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J.  New 
response evaluation criteria in solid tumors:  revised RECIST guideline (version 1.1).  Eur J Cancer 
45(2):  228-247, 2009. 
 
 
 
 

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APPENDIX I:  CRADA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be 
maintained as such by the investigators. The protocol documents for studies utilizing Agents 
contain confidential information and should not be shared or distributed without the permission of 
the NCI. If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and use 
of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as “Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own Agent. 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and 
unless additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health Information 
set forth in 45 C.F.R. Part 164. 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-

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Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication. Collaborator(s) will have 30 days from the date of 
receipt for review. Collaborator shall have the right to request that publication be delayed for up 
to an additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in 
addition to Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must 
be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to presentation at 
the meeting or publication in the proceedings. Press releases and other media presentations must 
also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 

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APPENDIX III:  A092104 OLAPARIB MEDICATION DIARY 
Today’s date ______________________________ 
 
Patient Name___________________ (initials acceptable)  
Patient Study ID ____________ 
 
INSTRUCTIONS FOR THE PATIENT: 
1. 
Complete this form while you take olaparib. This form is a 21 day diary. You may need to complete 
more than one form between clinic visits. 
2. 
You will take your dose of olaparib twice a day for 7 consecutive days followed by 14 days off. One 
dose of olaparib should be taken together with temozolomide at approximately the same time (morning 
or night) of each day. 
3 
Your dose of olaparib is ____ mg twice daily which should be taken as ____ (# of tablets) ____ 
(strength of tablets in mg) twice daily.  
4 
Take the olaparib tablets with water and consistently take with or without food. This includes when 
taking olaparib with temozolomide. Temozolomide can be taken with or without food but it may be 
better tolerated if taken on an empty stomach. 
5. 
Record the date, the number of tablets you took, and when you took them. Record doses as soon as you 
take them; do not batch entries together at a later time. 
6. 
If vomiting occurs after the olaparib tablets are swallowed, the dose should only be replaced if all of the 
intact tablets can be seen and counted. If a scheduled dose of olaparib for any reason is missed, take the 
scheduled dose of olaparib up to a maximum of 2 hours after the scheduled dose time. If more than 2 
hours after the scheduled dose time, the missed dose of olaparib is not to be taken and take the next 
dose at the next scheduled time.. 
7. 
Swallow tablets whole, do not crush or chew. Do not dissolve tablets in water. 
8. 
You should not have grapefruit, grapefruit juice, or Seville oranges while on this study. 
9. 
If you have any comments or notice any side effects, please record them in the Comments column. If 
you make a mistake while you write, please cross it out with one line, put your initials next to it, and 
then write the corrected information next to your initials. Example: 10:30 am SB 9:30 am 
10. Please return this form to your doctor at your next appointment. You may need to return more than one 
form per clinic visit. You will also be asked to return your pill bottles at each visit. 
 
 

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APPENDIX IV:  A092104 TEMOZOLOMIDE MEDICATION DIARY 
Today’s date ______________________________ 
 
Patient Name___________________ (initials acceptable)  
Patient Study ID ____________ 
 
INSTRUCTIONS FOR THE PATIENT: 
1. 
Complete this form while you take temozolomide. This form is a 21 day diary. You may need to 
complete more than one form between clinic visits. 
2. 
You will take your dose of temozolomide once a day for 7 consecutive days followed by 14 days off. 
Temozolomide should be taken together with the morning dose or the evening dose of olaparib, at 
approximately the same time each day. 
3 
Your dose of temozolomide is ____ mg once daily.  
       To make up this dose, you will take temozolomide capsules together as follows: 
       ____ (# of capsules) ____ (strength of capsules in mg), plus 
       ____ (# of capsules) ____ (strength of capsules in mg), plus 
       ____ (# of capsules) ____ (strength of capsules in mg) 
4 
Take the temozolomide capsules with water at least one hour before a meal or at least two hours 
afterwards.  Temozolomide can be taken with or without food, but it may be better tolerated if taken on 
an empty stomach [(i.e. in the fasted state, either 1 hour before, or 2 hours after, a meal]). Take 
consistently with or without food. This includes when taking olaparib with temozolomide.  
For the first cycle of treatment, take ondansetron 8 mg approximately 30 minutes prior to taking the 
temozolomide to help prevent nausea. From cycle 2 onward, the use of ondansetron prior to 
temozolomide dosing is optional 
5. 
Record the date, the number of  capsules of each strength that you took, and when you took them. 
Record doses as soon as you take them; do not batch entries together at a later time. 
6. 
If a dose is missed for any reason (such as forgetting to take the capsules or vomiting), do not make up 
that dose; resume dosing with the next scheduled dose. 
7.     If capsules are accidently opened or damaged, avoid inhalation or contact with skin or mucous 
membranes. 
8. 
Swallow capsules whole, do not crush or chew. Do not dissolve capsules in water. 
9. 
If you have any comments or notice any side effects, please record them in the Comments column. If 
you make a mistake while you write, please cross it out with one line, put your initials next to it, and 
then write the corrected information next to your initials. Example: 10:30 am SB 9:30 am 
10. Please return this form to your doctor at your next appointment. You may need to return more than one 
form per clinic visit. 
 
 

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APPENDIX V:  A092104 PAZOPANIB MEDICATION DIARY 
Today’s date ______________________________ 
 
Patient Name___________________ (initials acceptable)  
Patient Study ID ____________ 
 
INSTRUCTIONS FOR THE PATIENT: 
1. 
Complete this form while you take pazopanib. This form is a 21 day diary. You may need to complete 
more than one form between clinic visits. 
2. 
Your dose of pazopanib is ____ mg once daily which should be taken as ____ (# 200 mg tablets) once 
daily. 
3 
Take the pazopanib tablets with water at least one hour before a meal or at least two hours afterwards. 
Take consistently with or without food. 
4. 
Record the date, the number of tablets you took, and when you took them. Record doses as soon as you 
take them; do not batch entries together at a later time. 
5. 
If a dose is missed, or if vomiting occurs after dose is administered do not make up that dose if it is less 
than 12 hours until the next dose; resume dosing with the next scheduled dose. 
6. 
Swallow tablets whole, do not crush or chew. Do not dissolve tablets in water. 
7. 
You should not have grapefruit, grapefruit juice, or Seville oranges while on this study. 
8.  In rare cases this medication can cause the following side effects:  
a) If you develop unusually severe, persistent or worsening pain in your abdomen. 
b) If you are unable to pass stools and gas, and your abdomen feels uncomfortably bloated. 
If these occur, stop taking the pazopanib tablets and call your doctor/health care provider. 
9. 
If concurrent use of a gastric acid-reducing agent cannot be avoided, consider short-acting antacids in 
place of proton pump inhibitors and H2-receptor antagonists; separate pazopanib administration from 
short-acting antacids by several hours. Consult your pharmacist. 
If these occur, stop taking the pazopanib tablets and call your doctor/health care provider. 
10. If you have any comments or notice any side effects, please record them in the Comments column. If 
you make a mistake while you write, please cross it out with one line, put your initials next to it, and 
then write the corrected information next to your initials. Example: 10:30 am SB 9:30 am. 
11. Please return this form to your doctor at your next appointment. You may need to return more than one 
form per clinic visit. You will also be asked to return your pill bottles at each visit. 
 
 
 

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Date 
Day 
Number of 
pazopanib 
tablets 
taken 
Time 
Taken 
Number of 
pazopanib 
tablets 
missed 
Comments 
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
Patient’s Signature: ___________________________________ Date: ____________________ 
Staff Signature: ___________________________________ Date: ____________________ 
 
(To be completed by Staff)  
Number of Pills Given:____________  
 
Pill Bottle(s) returned: Circle Yes or No  
Total Daily Dose:________________ mg once daily 
 
Number of Pills returned:_____________ 
 
 

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APPENDIX VII:  NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL CLASSIFICATION